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Evans CH, Ghivizzani SC, Robbins PD. The 2024 OREF Clinical Research Award: Progress Toward a Gene Therapy for Arthritis. J Am Acad Orthop Surg 2024; 32:1052-1060. [PMID: 39284030 DOI: 10.5435/jaaos-d-24-00831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Indexed: 10/20/2024] Open
Abstract
Osteoarthritis (OA) is a highly prevalent, disabling, incurable, and expensive disease that is difficult to treat nonsurgically. The pharmacokinetics of drug delivery to joints are such that it is not possible to target antiarthritic agents, especially biologics, to individual joints with OA at sustained, therapeutic concentrations. More than 30 years ago, we proposed that local, intra-articular gene transfer can overcome this barrier to therapy by engineering articular cells to synthesize antiarthritic gene products endogenously. This article summarizes the progress toward this goal. Initially, a retroviral vector was used to deliver cDNA encoding the interleukin-1 receptor antagonist (IL-1Ra) to the joints of experimental animals. Using an ex vivo strategy, cultures of autologous synovial fibroblasts were genetically modified in cell culture and introduced into joints by means of intra-articular injection. Successful development of this technology led to the first-in-human gene therapy trial for arthritis. This Phase I study targeted metacarpophalangeal joints with rheumatoid arthritis. Although successful, for various reasons, subsequent research targeted OA and used adeno-associated virus as a vector to deliver IL-1Ra by direct in vivo injection into the joint. A Phase I human clinical trial has just been completed successfully in subjects with mid-stage OA of the knee, leading to a Phase Ib study that is in progress.
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Affiliation(s)
- Christopher H Evans
- From the Departments of Physical Medicine & Rehabilitation, Orthopedic Surgery and Molecular Medicine, Mayo Clinic, Rochester, NY (Evans), the Department of Orthopedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL (Ghivizzani), and the Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota School of Medicine, Minneapolis, MN (Robbins)
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Budhiparama NC, Putramega D, Lumban-Gaol I. Orthobiologics in knee osteoarthritis, dream or reality? Arch Orthop Trauma Surg 2024; 144:3937-3946. [PMID: 38630251 PMCID: PMC11564396 DOI: 10.1007/s00402-024-05310-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 03/24/2024] [Indexed: 11/15/2024]
Abstract
Cartilage restoration or repair, also known as orthobiologic therapy, is indicated after the failure of conservative or supportive treatment. However, there is paucity in evidence supporting the efficacy of orthobiologic therapy. The blood-derived products, such as platelet-rich plasma (PRP), is one of the commonly used orthobiologic therapy for knee osteoarthritis. Several studies have shown that PRP is superior to other treatments, but the anatomic changes are scarce. Treatment with mesenchymal stem cells (MSCs) offers the greatest potential for curing degenerative disease due to their self-renewal ability, ability to migrate towards injured tissues (homing/trafficking), and ability to promote repair and regeneration of osteochondral defects. However, ethical concerns and high costs remain major challenges associated with MSC therapy. Gene therapy, another promising orthobiologic therapy, is currently in phase II clinical trial and has shown promising results. The key factors for successful orthobiologic therapy include patient selection, appropriate dosing, treatment of underlying mechanical problems, age, severity, and cost-effectiveness.
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Affiliation(s)
- Nicolaas Cyrillus Budhiparama
- Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
- Department of Orthopaedic and Traumatology, Faculty of Medicine, Universitas Airlangga, Jl. Mayjend. Prof. Dr. Moestopo 6-8, Surabaya, 60286, Indonesia.
- Nicolaas Institute of Constructive Orthopaedic Research & Education Foundation for Arthroplasty & Sports Medicine at Medistra Hospital, Jl. Jend. Gatot Subroto Kav. 59, Jakarta, 12950, Indonesia.
| | - Dananjaya Putramega
- Nicolaas Institute of Constructive Orthopaedic Research & Education Foundation for Arthroplasty & Sports Medicine at Medistra Hospital, Jl. Jend. Gatot Subroto Kav. 59, Jakarta, 12950, Indonesia
- Academic Hospital Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Imelda Lumban-Gaol
- Nicolaas Institute of Constructive Orthopaedic Research & Education Foundation for Arthroplasty & Sports Medicine at Medistra Hospital, Jl. Jend. Gatot Subroto Kav. 59, Jakarta, 12950, Indonesia
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Enayati M, Liu W, Madry H, Neisiany RE, Cucchiarini M. Functionalized hydrogels as smart gene delivery systems to treat musculoskeletal disorders. Adv Colloid Interface Sci 2024; 331:103232. [PMID: 38889626 DOI: 10.1016/j.cis.2024.103232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 05/10/2024] [Accepted: 06/10/2024] [Indexed: 06/20/2024]
Abstract
Despite critical advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy based on the delivery of therapeutic genetic sequences has strong value to offer effective, durable options to decisively manage such disorders. Furthermore, scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy, allowing for the spatiotemporal delivery of candidate genes to sites of injury. Among the many scaffolds for musculoskeletal research, hydrogels raised increasing attention in addition to other potent systems (solid, hybrid scaffolds) due to their versatility and competence as drug and cell carriers in tissue engineering and wound dressing. Attractive functionalities of hydrogels for musculoskeletal therapy include their injectability, stimuli-responsiveness, self-healing, and nanocomposition that may further allow to upgrade of them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. Such functionalized hydrogels may also be tuned to successfully transfer therapeutic genes in a minimally invasive manner in order to protect their cargos and allow for their long-term effects. In light of such features, this review focuses on functionalized hydrogels and demonstrates their competence for the treatment of musculoskeletal disorders using gene therapy procedures, from gene therapy principles to hydrogel functionalization methods and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are being discussed in the perspective of translation in patients. STATEMENT OF SIGNIFICANCE: Despite advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy has strong value in offering effective, durable options to decisively manage such disorders. Scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy. Among many scaffolds for musculoskeletal research, hydrogels raised increasing attention. Functionalities including injectability, stimuli-responsiveness, and self-healing, tune them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. This review introduces functionalized hydrogels for musculoskeletal disorder treatment using gene therapy procedures, from gene therapy principles to functionalized hydrogels and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are discussed from the perspective of translation in patients.
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Affiliation(s)
- Mohammadsaeid Enayati
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany
| | - Wei Liu
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany
| | - Rasoul Esmaeely Neisiany
- Biotechnology Centre, Silesian University of Technology, Krzywoustego 8, 44-100 Gliwice, Poland; Department of Polymer Engineering, Hakim Sabzevari University, Sabzevar 9617976487, Iran
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany.
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Walton BL, Shattuck-Brandt R, Hamann CA, Tung VW, Colazo JM, Brand DD, Hasty KA, Duvall CL, Brunger JM. A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.31.578281. [PMID: 38352576 PMCID: PMC10862827 DOI: 10.1101/2024.01.31.578281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Objective Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites characterized by cartilage degeneration. Methods An scFv specific for type II collagen (CII) was used to produce a synthetic Notch (synNotch) receptor that enables "CII-synNotch" mesenchymal stromal cells (MSCs) to recognize CII fibers exposed in damaged cartilage. Engineered cell activation by both CII-treated culture surfaces and on primary tissue samples was measured via inducible reporter transgene expression. TGFβ3-expressing cells were assessed for cartilage anabolic gene expression via qRT-PCR. In a co-culture with CII-synNotch MSCs engineered to express IL-1Ra, ATDC5 chondrocytes were stimulated with IL-1α, and inflammatory responses of ATDC5s were profiled via qRT-PCR and an NF-κB reporter assay. Results CII-synNotch MSCs are highly responsive to CII, displaying activation ranges over 40-fold in response to physiologic CII inputs. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated TGFβ3 expression resulted in upregulation of Acan and Col2a1 in MSCs, and inducible IL-1Ra expression by engineered CII-synNotch MSCs reduced pro-inflammatory gene expression in chondrocytes. Conclusion This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs.
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Affiliation(s)
- Bonnie L. Walton
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | | | - Catherine A. Hamann
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - Victoria W. Tung
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - Juan M. Colazo
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - David D. Brand
- Research Service, Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN 38105, USA
| | - Karen A. Hasty
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis VA Medical Center, Memphis, TN, USA
| | - Craig L. Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
- Center for Bone Biology, Vanderbilt University, Nashville, TN 37212, USA
| | - Jonathan M. Brunger
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
- Center for Bone Biology, Vanderbilt University, Nashville, TN 37212, USA
- Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, 37212, USA
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Watson-Levings RS, Palmer GD, Levings PP, Dacanay EA, Evans CH, Ghivizzani SC. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation. Front Bioeng Biotechnol 2022; 10:901317. [PMID: 35837555 PMCID: PMC9274665 DOI: 10.3389/fbioe.2022.901317] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
In orthopaedics, gene-based treatment approaches are being investigated for an array of common -yet medically challenging- pathologic conditions of the skeletal connective tissues and structures (bone, cartilage, ligament, tendon, joints, intervertebral discs etc.). As the skeletal system protects the vital organs and provides weight-bearing structural support, the various tissues are principally composed of dense extracellular matrix (ECM), often with minimal cellularity and vasculature. Due to their functional roles, composition, and distribution throughout the body the skeletal tissues are prone to traumatic injury, and/or structural failure from chronic inflammation and matrix degradation. Due to a mixture of environment and endogenous factors repair processes are often slow and fail to restore the native quality of the ECM and its function. In other cases, large-scale lesions from severe trauma or tumor surgery, exceed the body’s healing and regenerative capacity. Although a wide range of exogenous gene products (proteins and RNAs) have the potential to enhance tissue repair/regeneration and inhibit degenerative disease their clinical use is hindered by the absence of practical methods for safe, effective delivery. Cumulatively, a large body of evidence demonstrates the capacity to transfer coding sequences for biologic agents to cells in the skeletal tissues to achieve prolonged delivery at functional levels to augment local repair or inhibit pathologic processes. With an eye toward clinical translation, we discuss the research progress in the primary injury and disease targets in orthopaedic gene therapy. Technical considerations important to the exploration and pre-clinical development are presented, with an emphasis on vector technologies and delivery strategies whose capacity to generate and sustain functional transgene expression in vivo is well-established.
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Affiliation(s)
- Rachael S. Watson-Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Glyn D. Palmer
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Padraic P. Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - E. Anthony Dacanay
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christopher H. Evans
- Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MI, United States
| | - Steven C. Ghivizzani
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
- *Correspondence: Steven C. Ghivizzani,
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Khalid S, Ekram S, Salim A, Chaudhry GR, Khan I. Transcription regulators differentiate mesenchymal stem cells into chondroprogenitors, and their in vivo implantation regenerated the intervertebral disc degeneration. World J Stem Cells 2022; 14:163-182. [PMID: 35432734 PMCID: PMC8963382 DOI: 10.4252/wjsc.v14.i2.163] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain. Disc degeneration is characterized by reduced cellularity and decreased production of extracellular matrix (ECM). Mesenchymal stem cells (MSCs) have been envisioned as a promising treatment for degenerative illnesses. Cell-based therapy using ECM-producing chondrogenic derivatives of MSCs has the potential to restore the functionality of the intervertebral disc (IVD). AIM To investigate the potential of chondrogenic transcription factors to promote differentiation of human umbilical cord MSCs into chondrocytes, and to assess their therapeutic potential in IVD regeneration. METHODS MSCs were isolated and characterized morphologically and immunologically by the expression of specific markers. MSCs were then transfected with Sox-9 and Six-1 transcription factors to direct differentiation and were assessed for chondrogenic lineage based on the expression of specific markers. These differentiated MSCs were implanted in the rat model of IVDD. The regenerative potential of transplanted cells was investigated using histochemical and molecular analyses of IVDs. RESULTS Isolated cells showed fibroblast-like morphology and expressed CD105, CD90, CD73, CD29, and Vimentin but not CD45 antigens. Overexpression of Sox-9 and Six-1 greatly enhanced the gene expression of transforming growth factor beta-1 gene, BMP, Sox-9, Six-1, and Aggrecan, and protein expression of Sox-9 and Six-1. The implanted cells integrated, survived, and homed in the degenerated intervertebral disc. Histological grading showed that the transfected MSCs regenerated the IVD and restored normal architecture. CONCLUSION Genetically modified MSCs accelerate cartilage regeneration, providing a unique opportunity and impetus for stem cell-based therapeutic approach for degenerative disc diseases.
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Affiliation(s)
- Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, MI 48309, United States
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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Chen T, Weng W, Liu Y, Aspera-Werz RH, Nüssler AK, Xu J. Update on Novel Non-Operative Treatment for Osteoarthritis: Current Status and Future Trends. Front Pharmacol 2021; 12:755230. [PMID: 34603064 PMCID: PMC8481638 DOI: 10.3389/fphar.2021.755230] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 09/06/2021] [Indexed: 12/27/2022] Open
Abstract
Osteoarthritis (OA) is a leading cause of pain and disability which results in a reduced quality of life. Due to the avascular nature of cartilage, damaged cartilage has a finite capacity for healing or regeneration. To date, conservative management, including physical measures and pharmacological therapy are still the principal choices offered for OA patients. Joint arthroplasties or total replacement surgeries are served as the ultimate therapeutic option to rehabilitate the joint function of patients who withstand severe OA. However, these approaches are mainly to relieve the symptoms of OA, instead of decelerating or reversing the progress of cartilage damage. Disease-modifying osteoarthritis drugs (DMOADs) aiming to modify key structures within the OA joints are in development. Tissue engineering is a promising strategy for repairing cartilage, in which cells, genes, and biomaterials are encompassed. Here, we review the current status of preclinical investigations and clinical translations of tissue engineering in the non-operative treatment of OA. Furthermore, this review provides our perspective on the challenges and future directions of tissue engineering in cartilage regeneration.
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Affiliation(s)
- Tao Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Weidong Weng
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Yang Liu
- Department of Clinical Sciences, Orthopedics, Faculty of Medicine, Lund University, Lund, Sweden
| | - Romina H. Aspera-Werz
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas K Nüssler
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Jianzhong Xu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Abstract
» Orthopaedics pioneered the expansion of gene therapy beyond its traditional scope of diseases that are caused by rare single-gene defects. Orthopaedic applications of gene therapy are most developed in the areas of arthritis and regenerative medicine, but several additional possibilities exist. » Invossa, an ex vivo gene therapeutic for osteoarthritis, was approved in South Korea in 2017, but its approval was retracted in 2019 and remains under appeal; a Phase-III clinical trial of Invossa has restarted in the U.S. » There are several additional clinical trials for osteoarthritis and rheumatoid arthritis that could lead to approved gene therapeutics for arthritis. » Bone-healing and cartilage repair are additional areas that are attracting considerable research; intervertebral disc degeneration and the healing of ligaments, tendons, and menisci are other applications of interest. Orthopaedic tumors, genetic diseases, and aseptic loosening are additional potential targets. » If successful, these endeavors will expand the scope of gene therapy from providing expensive medicines for a few patients to providing affordable medicines for many.
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Calikoglu Koyuncu AC, Nayman AH, Telci D, Torun Kose G. Tissue transglutaminase_variant 2-transduced mesenchymal stem cells and their chondrogenic potential. Biotechnol Bioeng 2020; 117:1839-1852. [PMID: 32068240 DOI: 10.1002/bit.27311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 11/24/2019] [Accepted: 02/16/2020] [Indexed: 11/09/2022]
Abstract
As cartilage is incapable of self-healing upon severe degeneration because of the lack of blood vessels, cartilage tissue engineering is gaining importance in the treatment of cartilage defects. This study was designed to improve cartilage tissue regeneration by expressing tissue transglutaminase variant 2 (TGM2_v2) in mesenchymal stem cells (MSC) derived from bone marrow of rats. For this purpose, rat MSCs transduced with TGM2_v2 were grown and differentiated on three-dimensional polybutylene succinate (PBSu) and poly-l-lactide (PLLA) blend scaffolds. The transduced cells could not only successfully express the short form transglutaminase-2, but also deposited the protein onto the scaffolds. In addition, they could spontaneously produce cartilage-specific proteins without any chondrogenic induction, suggesting that TGM2_v2 expression provided the cells the ability of chondrogenic differentiation. PBSu:PLLA scaffolds loaded with TGM2_v2 expressing MSCs could be used in repair of articular cartilage defects.
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Affiliation(s)
| | - Ayse Hande Nayman
- Department of Genetics and Bioengineering/Faculty of Engineering, Yeditepe University, İstanbul, Turkey
| | - Dilek Telci
- Department of Genetics and Bioengineering/Faculty of Engineering, Yeditepe University, İstanbul, Turkey
| | - Gamze Torun Kose
- Department of Genetics and Bioengineering/Faculty of Engineering, Yeditepe University, İstanbul, Turkey
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Kesharwani D, Paliwal R, Satapathy T, Das Paul S. Rheumatiod Arthritis: An Updated Overview of Latest Therapy and Drug Delivery. J Pharmacopuncture 2019; 22:210-224. [PMID: 31970018 PMCID: PMC6970574 DOI: 10.3831/kpi.2019.22.029] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 06/11/2019] [Accepted: 11/25/2019] [Indexed: 12/26/2022] Open
Abstract
Rheumatoid arthritis is a severe autoimmune disorder, related to joints. It is associated with serious cartilage destruction. This causes disability and reduces the excellence of life. Numerous treatments are existed to combat this disease, however, they are not very efficient and possess severe side effects, higher doses, and frequent administration. Therefore, newer therapies are developed to overcome all these limitations. These include different monoclonal antibodies, immunoglobulins, small molecules used for immunotherapy and transgenes for gene therapy. One of the main goals of these new generation therapeutics is to address the underlying distressing biological processes by specifically targeting the causative agents with fewer systemic side effects and greater patient console. It is very fortuitous that loads of progressive investigations are going on in this field and many of them have entered into the successful clinical trial. But till date, a limited molecule has got FDA clearance and entered the market for treating this devastating disease. This review highlights the overview of conventional therapy and advancements in newer therapeutics including immunotherapy and gene therapy for rheumatoid arthritis. Further, different novel techniques for the delivery of these therapeutics of active and passive targeting are also described.
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Affiliation(s)
| | - Rishi Paliwal
- Assistant Professor, Faculty of Pharmacy, IGNTU, Amarkantak, Madhya Pradesh,
India
| | | | - Swarnali Das Paul
- Associate Professor, Faculty of Pharmaceutical Sciences, SSTC, SSGI, Bhilai, C.G,
India
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Armiento AR, Alini M, Stoddart MJ. Articular fibrocartilage - Why does hyaline cartilage fail to repair? Adv Drug Deliv Rev 2019; 146:289-305. [PMID: 30605736 DOI: 10.1016/j.addr.2018.12.015] [Citation(s) in RCA: 246] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/07/2018] [Accepted: 12/27/2018] [Indexed: 12/12/2022]
Abstract
Once damaged, articular cartilage has a limited potential to repair. Clinically, a repair tissue is formed, yet, it is often mechanically inferior fibrocartilage. The use of monolayer expanded versus naïve cells may explain one of the biggest discrepancies in mesenchymal stromal/stem cell (MSC) based cartilage regeneration. Namely, studies utilizing monolayer expanded MSCs, as indicated by numerous in vitro studies, report as a main limitation the induction of type X collagen and hypertrophy, a phenotype associated with endochondral bone formation. However, marrow stimulation and transfer studies report a mechanically inferior collagen I/II fibrocartilage as the main outcome. Therefore, this review will highlight the collagen species produced during the different therapeutic approaches. New developments in scaffold design and delivery of therapeutic molecules will be described. Potential future directions towards clinical translation will be discussed. New delivery mechanisms are being developed and they offer new hope in targeted therapeutic delivery.
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Affiliation(s)
| | - Mauro Alini
- AO Research Institute Davos, 7270 Davos Platz, Switzerland.
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Rey-Rico A, Cucchiarini M. Supramolecular Cyclodextrin-Based Hydrogels for Controlled Gene Delivery. Polymers (Basel) 2019; 11:polym11030514. [PMID: 30960498 PMCID: PMC6473339 DOI: 10.3390/polym11030514] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 03/15/2019] [Accepted: 03/17/2019] [Indexed: 12/27/2022] Open
Abstract
Controlled delivery of gene transfer vectors is a powerful strategy to enhance the temporal and spatial presentation of therapeutic agents in a defined target. Hydrogels are adapted biomaterials for gene delivery capable of acting as a localized depot of genes while maintaining the long term local availability of DNA vectors at a specific location. Supramolecular hydrogels based on cyclodextrins (CDs) have attracted considerable attention as potential biomaterials in a broad range of drug delivery applications. Their unique characteristics of thixotropicity and low cytotoxicity due to their production under mild conditions make them potential candidates to form injectable delivery systems. This work aims to provide an overview of the use of CD-based polypseudorotaxane hydrogels as controlled gene delivery systems for different applications in regenerative medicine.
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Affiliation(s)
- Ana Rey-Rico
- Cell Therapy and Regenerative Medicine Unit, Centro de Investigacións Científicas Avanzadas (CICA), Universidade da Coruña, Campus de A Coruña, 15071 A Coruña, Spain.
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, D-66421 Homburg/Saar, Germany.
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Graceffa V, Vinatier C, Guicheux J, Evans CH, Stoddart M, Alini M, Zeugolis DI. State of art and limitations in genetic engineering to induce stable chondrogenic phenotype. Biotechnol Adv 2018; 36:1855-1869. [PMID: 30012541 DOI: 10.1016/j.biotechadv.2018.07.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 05/16/2018] [Accepted: 07/12/2018] [Indexed: 12/18/2022]
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Ondrésik M, Azevedo Maia FR, da Silva Morais A, Gertrudes AC, Dias Bacelar AH, Correia C, Gonçalves C, Radhouani H, Amandi Sousa R, Oliveira JM, Reis RL. Management of knee osteoarthritis. Current status and future trends. Biotechnol Bioeng 2016; 114:717-739. [DOI: 10.1002/bit.26182] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 07/13/2016] [Accepted: 09/09/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Marta Ondrésik
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
| | - Fatima R. Azevedo Maia
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
| | - Alain da Silva Morais
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Ana C. Gertrudes
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Ana H. Dias Bacelar
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Cristina Correia
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Cristiana Gonçalves
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Hajer Radhouani
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Rui Amandi Sousa
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
- Stemmatters, Biotecnologia e Medicina Regenerativa SA; Guimaraes Portugal
| | - Joaquim M. Oliveira
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
| | - Rui L. Reis
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics; Universidade do Minho, Headquarters of the European Institute Regenerative Medicine; AvePark 4806-909, Caldas das Taipas Guimaraes Portugal
- ICVS/3B's-PT Government Associated Laboratory; Braga/Guimaraes Portugal
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Hydrogel-Based Controlled Delivery Systems for Articular Cartilage Repair. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1215263. [PMID: 27642587 PMCID: PMC5011507 DOI: 10.1155/2016/1215263] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 07/12/2016] [Indexed: 12/19/2022]
Abstract
Delivery of bioactive factors is a very valuable strategy for articular cartilage repair. Nevertheless, the direct supply of such biomolecules is limited by several factors including rapid degradation, the need for supraphysiological doses, the occurrence of immune and inflammatory responses, and the possibility of dissemination to nontarget sites that may impair their therapeutic action and raise undesired effects. The use of controlled delivery systems has the potential of overcoming these hurdles by promoting the temporal and spatial presentation of such factors in a defined target. Hydrogels are promising materials to develop delivery systems for cartilage repair as they can be easily loaded with bioactive molecules controlling their release only where required. This review exposes the most recent technologies on the design of hydrogels as controlled delivery platforms of bioactive molecules for cartilage repair.
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Tuszynski MH. Review : Gene Therapy: Applications to the Neurosciences and to Neurological Disease. Neuroscientist 2016. [DOI: 10.1177/107385849800400612] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Gene expression is involved in some way in every human disease. As our knowledge of gene structure and function has blossomed in the last 2 decades, so too has our potential genetically-based repertoire for combating disease. Gene therapy refers to the manipulation of gene expression, either by augmenting the expression of therapeutic genes or by diminishing the expression of deleterious genes. In some neurological diseases, such as trauma, ischemia, and neurodegenerative disorders, gene therapy might be used to express genes for such substances as growth factors or neurotransmitters to prevent neuronal degeneration or to compensate for lost function, respectively. In other cases, gene therapy could be used to block the expression of genes that cause disease such as β-amyloid precursor protein or the Huntingtin gene. In inherited diseases of the nervous system such as muscular dystrophy, normal gene copies could be placed into the nervous system to compensate for lost function resulting from abnormal gene expression. The tools for achieving well-targeted, sustained, and safe gene delivery in the nervous system are now becoming available, and this technology is likely to substantially alter the nature of neurological therapy in the future. NEUROSCIENTIST 4:398-407, 1998
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Affiliation(s)
- Mark H. Tuszynski
- Department of Neurosciences University of California-San
Diego La Jolla, California Veterans Affairs Medical Center San Diego, California
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17
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Madry H, Cucchiarini M. Gene therapy for human osteoarthritis: principles and clinical translation. Expert Opin Biol Ther 2015; 16:331-46. [PMID: 26593049 DOI: 10.1517/14712598.2016.1124084] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Osteoarthritis (OA) is the most prevalent chronic joint disease. Its key feature is a progressive articular cartilage loss. Gene therapy for OA aims at delivering gene-based therapeutic agents to the osteoarthritic cartilage, resulting in a controlled, site-specific, long-term presence to rebuild the damaged cartilage. AREAS COVERED An overview is provided of the principles of gene therapy for OA based on a PubMed literature search. Gene transfer to normal and osteoarthritic cartilage in vitro and in animal models in vivo is reviewed. Results from recent clinical gene therapy trials for OA are discussed and placed into perspective. EXPERT OPINION Recombinant adeno-associated viral (rAAV) vectors enable to directly transfer candidate sequences in human articular chondrocytes in situ, providing a potent tool to modulate the structure of osteoarthritic cartilage. However, few preclinical animal studies in OA models have been performed thus far. Noteworthy, several gene therapy clinical trials have been carried out in patients with end-stage knee OA based on the intraarticular injection of human juvenile allogeneic chondrocytes overexpressing a cDNA encoding transforming growth factor-beta-1 via retroviral vectors. In a recent placebo-controlled randomized trial, clinical scores were improved compared with placebo. These translational results provide sufficient reason to proceed with further clinical testing of gene transfer protocols for the treatment of OA.
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Affiliation(s)
- Henning Madry
- a Center of Experimental Orthopaedics , Saarland University , Homburg/Saar , Germany
| | - Magali Cucchiarini
- a Center of Experimental Orthopaedics , Saarland University , Homburg/Saar , Germany
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18
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Wang Q, Cheng H, Peng H, Zhou H, Li PY, Langer R. Non-genetic engineering of cells for drug delivery and cell-based therapy. Adv Drug Deliv Rev 2015; 91:125-40. [PMID: 25543006 DOI: 10.1016/j.addr.2014.12.003] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 12/04/2014] [Accepted: 12/18/2014] [Indexed: 12/13/2022]
Abstract
Cell-based therapy is a promising modality to address many unmet medical needs. In addition to genetic engineering, material-based, biochemical, and physical science-based approaches have emerged as novel approaches to modify cells. Non-genetic engineering of cells has been applied in delivering therapeutics to tissues, homing of cells to the bone marrow or inflammatory tissues, cancer imaging, immunotherapy, and remotely controlling cellular functions. This new strategy has unique advantages in disease therapy and is complementary to existing gene-based cell engineering approaches. A better understanding of cellular systems and different engineering methods will allow us to better exploit engineered cells in biomedicine. Here, we review non-genetic cell engineering techniques and applications of engineered cells, discuss the pros and cons of different methods, and provide our perspectives on future research directions.
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19
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Lee SY, Kim W, Lim C, Chung SG. Treatment of Lateral Epicondylosis by Using Allogeneic Adipose-Derived Mesenchymal Stem Cells: A Pilot Study. Stem Cells 2015. [PMID: 26202898 DOI: 10.1002/stem.2110] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cell therapy is a novel regenerative approach for treating tendinopathy. Here, we evaluated the safety and efficacy of allogeneic adipose-derived mesenchymal stem cells (allo-ASC) in treating lateral epicondylosis (LE). Under ultrasound guidance, allo-ASCs mixed with fibrin glue were injected into the hypoechoic common extensor tendon lesions of 12 participants with chronic LE; 6 subjects each were administered 10(6) or 10(7) cells in 1 ml. Safety was evaluated at day 3 and weeks 2, 6, 12, 26, and 52 post-injection. Efficacy was assessed by measuring patients' visual analog scale (VAS) score for elbow pain, modified Mayo clinic performance index for the elbow, and by evaluating longitudinal and transverse ultrasound images of tendon defect areas after 6, 12, 26, and 52 weeks. No significant adverse effects of allo-ASC injection were observed through 52 weeks of follow-up. From baseline through 52 weeks of periodic follow-up, VAS scores progressively decreased from 66.8 ± 14.5 mm to 14.8 ± 13.1 mm and elbow performance scores improved from 64.0 ± 13.5 to 90.6 ± 5.8. Tendon defects also significantly decreased through this period. Allo-ASC therapy was thus safe and effective in improving elbow pain, performance, and structural defects for 52 weeks. This clinical study is the first to reveal therapeutic value of mesenchymal stem cell injection for treating chronic tendinopathy.
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Affiliation(s)
- Sang Yoon Lee
- Department of Physical Medicine & Rehabilitation, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Won Kim
- Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chaiyoung Lim
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Sun G Chung
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Aging, Medical Research Center, Seoul National University, Seoul, South Korea.,Rheumatism Research Institute, Medical Research Center, Seoul National University, Seoul, South Korea
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20
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Guo P, Shi ZL, Liu A, Lin T, Bi F, Shi M, Yan SG. Effects of cartilage oligomeric matrix protein on bone morphogenetic protein-2-induced differentiation of mesenchymal stem cells. Orthop Surg 2015; 6:280-7. [PMID: 25430711 DOI: 10.1111/os.12135] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 05/27/2014] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE To investigate the effect of overexpression of cartilage oligomeric matrix protein (COMP) on bone morphogenetic protein-2 (BMP-2) induced osteogenic and chondrogenic differentiation of mesenchymal stem cells (MSCs). In this study, we used liposomes to transfect MSCs with plasmid encoding COMP and then induced the transfected MSCs to differentiate in osteogenic and chondrogenic differentiation media containing BMP-2. METHODS MSCs transfected with plasmid DNA encoding recombinant human COMP were induced to differentiate into osteocytes and chondrocytes by BMP-2. Real-time polymerase chain reaction (PCR) assays of osteogenesis-related markers (collagen type I alpha 1, runt-related transcription factor 2, osteopontin, bone gla protein) and chondrogenesis-related markers (collagen type II alpha 1, sry-related high-mobility group box 9, Aggrecan) was performed to evaluate the process of cell differentiation. Cell differentiation was evaluated by alkaline phosphatase (ALP) and Alizarin red S stains for osteogenic differentiation and alcian blue staining for chondrogenic differentiation. RESULTS Real-time PCR assay showed significantly greater COMP expression by MSCs when COMP gene had been transfected into the cells (P < 0.01). Overexpression of COMP down-regulated expression of osteogenesis-related markers and up-regulated expression of chondrogenesis-related markers. ALP staining and Alizarin red S staining were weakened, whereas alcian blue staining was enhanced. CONCLUSION Overexpression of COMP inhibits BMP-2-induced osteogenic differentiation and promotes BMP-2-induced chondrogenic differentiation. These findings may provide new insights for cartilage tissue engineering. The experiments in the present study were all in vitro, which has potential limitations. Further in vivo studies to investigate the effects of COMP in animal models are necessary, which will be the next step in our research.
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Affiliation(s)
- Peng Guo
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
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Stoddart MJ, Bara J, Alini M. Cells and secretome--towards endogenous cell re-activation for cartilage repair. Adv Drug Deliv Rev 2015; 84:135-45. [PMID: 25174306 DOI: 10.1016/j.addr.2014.08.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 06/26/2014] [Accepted: 08/20/2014] [Indexed: 01/01/2023]
Abstract
Regenerative medicine approaches to cartilage tissue repair have mainly been concerned with the implantation of a scaffold material containing monolayer expanded cells into the defect, with the aim to differentiate the cells into chondrocytes. While this may be a valid approach, the secretome of the implanted cells and its effects on the endogenous resident cells, is gaining in interest. This review aims to summarize the knowledge on the secretome of mesenchymal stem cells, including knowledge from other tissues, in order to indicate how these mechanisms may be of value in repairing articular cartilage defects. Potential therapies and their effects on the repair of articular cartilage defects will be discussed, with a focus on the transition from classical cell therapy to the implantation of cell free matrices releasing specific cytokines.
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22
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Nöth U, Rackwitz L, Steinert AF, Tuan RS. Principles of tissue engineering and cell- and gene-based therapy. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00021-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Kaur G, Long CR, Dufour JM. Genetically engineered immune privileged Sertoli cells: A new road to cell based gene therapy. SPERMATOGENESIS 2014; 2:23-31. [PMID: 22553487 PMCID: PMC3341243 DOI: 10.4161/spmg.19119] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Sertoli cells are immune privileged cells, important for controlling the immune response to male germ cells as well as maintaining the tolerogenic environment in the testis. Additionally, ectopic Sertoli cells have been shown to survive and protect co-grafted cells when transplanted across immunological barriers. The survival of ectopic Sertoli cells has led to the idea that they could be used in cell based gene therapy. In this review, we provide a brief overview of testis immune privilege and Sertoli cell transplantation, factors contributing to Sertoli cell immune privilege, the challenges faced by viral vector gene therapy, the use of immune privileged cells in cell based gene therapy and describe several recent studies on the use of genetically engineered Sertoli cells to provide continuous delivery of therapeutic proteins.
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Madry H, Cucchiarini M. Advances and challenges in gene-based approaches for osteoarthritis. J Gene Med 2014; 15:343-55. [PMID: 24006099 DOI: 10.1002/jgm.2741] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 08/06/2013] [Accepted: 08/30/2013] [Indexed: 12/11/2022] Open
Abstract
Osteoarthritis (OA), a paramount cause of physical disability for which there is no definitive cure, is mainly characterized by the gradual loss of the articular cartilage. Current nonsurgical and reconstructive surgical therapies have not met success in reversing the OA phenotype so far. Gene transfer approaches allow for a long-term and site-specific presence of a therapeutic agent to re-equilibrate the metabolic balance in OA cartilage and may consequently be suited to treat this slow and irreversible disorder. The distinct stages of OA need to be respected in individual gene therapy strategies. In this context, molecular therapy appears to be most effective for early OA. A critical step forward has been made by directly transferring candidate sequences into human articular chondrocytes embedded within their native extracellular matrix via recombinant adeno-associated viral vectors. Although extensive studies in vitro attest to a growing interest in this approach, data from animal models of OA are sparse. A phase I dose-escalating trial was recently performed in patients with advanced knee OA to examine the safety and activity of chondrocytes modified to produce the transforming growth factor β1 via intra-articular injection, showing a dose-dependent trend toward efficacy. Proof-of-concept studies in patients prior to undergoing total knee replacement may be privileged in the future to identify the best mode of translating this approach to clinical application, followed by randomized controlled trials.
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Affiliation(s)
- Henning Madry
- Center of Experimental Orthopaedics, Saarland University Medical Center, Saarland University, Homburg, Saar, Germany
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Roubille C, Pelletier JP, Martel-Pelletier J. New and emerging treatments for osteoarthritis management: will the dream come true with personalized medicine? Expert Opin Pharmacother 2014; 14:2059-77. [PMID: 24044485 DOI: 10.1517/14656566.2013.825606] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Osteoarthritis (OA) is a dynamic process involving the main tissues of the joint for which a global approach should be considered. No disease-modifying OA drug (DMOAD) has yet been approved. New therapeutic strategies are needed that would be cost effective by reducing the need for pharmacological interventions and surgical management while targeting specific pathways leading to OA. The treatment landscape of OA is about to change based on new agents having shown some structural effects and emerging therapies with DMOAD effects. AREAS COVERED In this review based on a Medline (via PubMed) search, promising new and emerging therapies with a potential structural effect (DMOAD) will be discussed including growth factors, platelet-rich plasma, autologous stem cells, bone remodeling modulators, cytokine inhibition, gene therapy, and RNA interference. EXPERT OPINION DMOAD development should focus on targeting some phenotypes of OA patients evidenced with sensitive techniques such as magnetic resonance imaging, as a single treatment will unlikely be appropriate for all OA patients. This will allow the development of DMOADs based on personalized medicine. An exciting new era in DMOAD development is within reach, provided future clinical trials are sufficiently powered, systematically designed, use the appropriate evaluation tools, and target the appropriate categories of OA patients.
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Affiliation(s)
- Camille Roubille
- University of Montreal Hospital Research Centre (CRCHUM), Osteoarthritis Research Unit , 1560 Sherbrooke Street East, Montreal, Quebec , Canada
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26
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Cartilage tissue engineering: molecular control of chondrocyte differentiation for proper cartilage matrix reconstruction. Biochim Biophys Acta Gen Subj 2014; 1840:2414-40. [PMID: 24608030 DOI: 10.1016/j.bbagen.2014.02.030] [Citation(s) in RCA: 177] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Revised: 02/06/2014] [Accepted: 02/26/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Articular cartilage defects are a veritable therapeutic problem because therapeutic options are very scarce. Due to the poor self-regeneration capacity of cartilage, minor cartilage defects often lead to osteoarthritis. Several surgical strategies have been developed to repair damaged cartilage. Autologous chondrocyte implantation (ACI) gives encouraging results, but this cell-based therapy involves a step of chondrocyte expansion in a monolayer, which results in the loss in the differentiated phenotype. Thus, despite improvement in the quality of life for patients, reconstructed cartilage is in fact fibrocartilage. Successful ACI, according to the particular physiology of chondrocytes in vitro, requires active and phenotypically stabilized chondrocytes. SCOPE OF REVIEW This review describes the unique physiology of cartilage, with the factors involved in its formation, stabilization and degradation. Then, we focus on some of the most recent advances in cell therapy and tissue engineering that open up interesting perspectives for maintaining or obtaining the chondrogenic character of cells in order to treat cartilage lesions. MAJOR CONCLUSIONS Current research involves the use of chondrocytes or progenitor stem cells, associated with "smart" biomaterials and growth factors. Other influential factors, such as cell sources, oxygen pressure and mechanical strain are considered, as are recent developments in gene therapy to control the chondrocyte differentiation/dedifferentiation process. GENERAL SIGNIFICANCE This review provides new information on the mechanisms regulating the state of differentiation of chondrocytes and the chondrogenesis of mesenchymal stem cells that will lead to the development of new restorative cell therapy approaches in humans. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
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Abstract
BACKGROUND In the past two decades, regenerative surgeons have focused increasing attention on the potential of gene therapy for treatment of local disorders and injuries. Gene transfer techniques may provide an effective local and short-term induction of growth factors without the limits of other topical therapies. In 2002, Tepper and Mehrara accurately reviewed the topic: given the substantial advancement of research on this issue, an updated review is provided. METHODS Literature indexed in the National Center for Biotechnology Information database (PubMed) has been reviewed using variable combinations of keywords ("gene therapy," "regenerative medicine," "tissue regeneration," and "gene medicine"). Articles investigating the association between gene therapies and local pathologic conditions have been considered. Attention has been focused on articles published after 2002. Further literature has been obtained by analysis of references listed in reviewed articles. RESULTS Gene therapy approaches have been successfully adopted in preclinical models for treatment of a large variety of local diseases affecting almost every type of tissue. Experiences in abnormalities involving skin (e.g., chronic wounds, burn injuries, pathologic scars), bone, cartilage, endothelia, and nerves have been reviewed. In addition, the supporting role of gene therapies to other tissue-engineering approaches has been discussed. Despite initial reports, clinical evidence has been provided only for treatment of diabetic ulcers, rheumatoid arthritis, and osteoarthritis. CONCLUSIONS Translation of gene therapy strategies into human clinical trials is still a lengthy, difficult, and expensive process. Even so, cutting-edge gene therapy-based strategies in reconstructive procedures could soon set valuable milestones for development of efficient treatments in a growing number of local diseases and injuries.
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Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy and its tortuous path into the clinic. Transl Res 2013; 161:205-16. [PMID: 23369825 PMCID: PMC3602127 DOI: 10.1016/j.trsl.2013.01.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 01/09/2013] [Accepted: 01/09/2013] [Indexed: 12/29/2022]
Abstract
Arthritis is a disease of joints. The biology of joints makes them very difficult targets for drug delivery in a manner that is specific and selective. This is especially true for proteinaceous drugs ("biologics"). Gene transfer is the only technology that can solve the delivery problem in a clinically reasonable fashion. There is an abundance of preclinical data confirming that genes can be efficiently transferred to tissues within joints by intra-articular injection using a variety of different vectors in conjunction with ex vivo and in vivo strategies. Using the appropriate gene transfer technologies, long-term, intra-articular expression of anti-arthritic transgenes at therapeutic concentrations can be achieved. Numerous studies confirm that gene therapy is effective in treating experimental models of rheumatoid arthritis (RA) and osteoarthritis (OA) in the laboratory. A limited number of clinical trials have been completed, which confirm safety and feasibility but only 3 protocols have reached phase II; as yet, there is no unambiguous evidence of efficacy in human disease. Only 2 clinical trials are presently underway, both phase II studies using allogeneic chondrocytes expressing transforming growth factor-β1 for the treatment of OA. Phase I studies using adeno-associated virus to deliver interleukin-1Ra in OA and interferon-β in RA are going through the regulatory process. It is to be hoped that the recent successes in treating rare, Mendelian diseases by gene therapy will lead to accelerated development of genetic treatments for common, non-Mendelian diseases, such as arthritis.
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Affiliation(s)
- Christopher H Evans
- Department of Orthopedic Surgery, Harvard Medical School, Boston, Mass., USA.
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Mashayekhi K, O’Brien M, Zugun-Eloae F, Labusca L. Novel approaches for treating musculoskeletal diseases: molecular orthopedics and systems medicine. Open Orthop J 2013; 7:144-51. [PMID: 23798982 PMCID: PMC3664448 DOI: 10.2174/1874325001307010144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Revised: 01/25/2013] [Accepted: 02/02/2012] [Indexed: 02/07/2023] Open
Abstract
Molecular medicine uses knowledge about cell structure and function for disease, diagnostics, stage characterisation and treatment. The advent of genomic technologies is considerably leading to developments in the field of molecular medicine. The accumulation of detailed information about gene expression, epigenetic variability, protein transcription and functional modulation is contributing to a new era in medicine. Rapid and early diagnostic procedures, molecular characterisation of degenerative and proliferative diseases and personalized therapies are predicted to lead to advancements in health prevention and treatment of disease. Diagnostic tools and therapies based on local and /or general modulation of cellular processes for traumatic or degenerative musculoskeletal conditions are becoming available. A logical consequence of the information derived from extensive data gathering, systems biology and systemic medicine has lead to significant improvements in understanding biological structure and function in a simultaneous bottom top and integrative, holistic manner. The description of disease mechanism at an intimate, subcellular level has a dual benefit. A thorough understanding of the crosstalk involved in molecular pathways both in the normal and the diseased state are expanding scientific knowledge and simultaneously are enabling design cell-targeted and individualized therapies. This paper presents a brief overview of current molecular based treatments available to the orthopedic surgeon and introduces the concept of systemic medicine from the perspective of musculoskeletal pathology.
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Affiliation(s)
- Kaveh Mashayekhi
- Systems Bioinformatics and Modelling GMBH,39 Basaltstrase D-62540, Tel+4915154924033 Frankfurt, Germany
- BioTalentum Ltd, Aulich Lajos str. 26.2100 Gödöllő, Hungary
- REMEDI National Centre for Biomedical Engineering Science (NCBES), Orbsen Building, NUI Galway, Ireland
| | - Margaret O’Brien
- National Centre for Biomedical Engineering Science (NCBES), Orbsen Building, NUI Galway, Ireland
| | - Florin Zugun-Eloae
- Molecular Genetics and Immunology Department, ”Gr. T. Popa” University of Medicine and Pharmacy, Iasi, Romania, Str. Universitatii nr.16 700115 Iasi, Romania
| | - Luminita Labusca
- Systems Bioinformatics and Modelling GMBH,39 Basaltstrase D-62540, Tel+4915154924033 Frankfurt, Germany
- University Hospital Saint Spiridon Iasi Romania 1st Independentei Boulevard Iasi, Romania
- Address correspondence to this author at the University Hospital Saint Spiridon Iasi Romania 1st Independentei Boulevard Iasi, Romania; Tel: +40749162219; E-mails: ,
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Ruan MZC, Guse K, Lee B. Prospects of Gene Therapy. GENETICS OF BONE BIOLOGY AND SKELETAL DISEASE 2013:133-150. [DOI: 10.1016/b978-0-12-387829-8.00010-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Wang Y, Grainger DW. RNA therapeutics targeting osteoclast-mediated excessive bone resorption. Adv Drug Deliv Rev 2012; 64:1341-57. [PMID: 21945356 DOI: 10.1016/j.addr.2011.09.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Accepted: 09/05/2011] [Indexed: 01/13/2023]
Abstract
RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing technique developed with dramatically increasing utility for both scientific and therapeutic purposes. Short interfering RNA (siRNA) is currently exploited to regulate protein expression relevant to many therapeutic applications, and commonly used as a tool for elucidating disease-associated genes. Osteoporosis and their associated osteoporotic fragility fractures in both men and women are rapidly becoming a global healthcare crisis as average life expectancy increases worldwide. New therapeutics are needed for this increasing patient population. This review describes the diversity of molecular targets suitable for RNAi-based gene knock down in osteoclasts to control osteoclast-mediated excessive bone resorption. We identify strategies for developing targeted siRNA delivery and efficient gene silencing, and describe opportunities and challenges of introducing siRNA as a therapeutic approach to hard and connective tissue disorders.
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Huang MJ, Wang L, Zheng XC, Zhang ZM, Yan B, Chen TY, Bai XC, Jin DD. Intra-articular lentivirus-mediated insertion of the fat-1 gene ameliorates osteoarthritis. Med Hypotheses 2012; 79:614-6. [PMID: 22939867 DOI: 10.1016/j.mehy.2012.07.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 07/30/2012] [Indexed: 10/27/2022]
Abstract
Osteoarthritis (OA) is a gradually progressive degenerative disease characterized by gradual inflammatory loss of articular cartilage caused by increased proteolytic catabolism, mediated by interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), matrix metalloproteinase (MMPs), aggrecanases and other proteinases, and reduced anabolism of cartilage components, contributed by interleukin-4 (IL-4), interleukin-10 (IL-10), insulin-like growth factor 1 (IGF-1), transforming growth factor β (TGF-β), and bone morphogenetic proteins (BMPs). Substantial studies showed n-3 polyunsaturated fatty acids (n-3 PUFAs) exhibit a powerful anti-inflammatory effects in and ex vivo through reducing the production of IL-1 and TNF-α and increasing the expression of IL-4, IL-10, TGF-β and IGF-1 in OA. Meanwhile, more convincing results are observed in the fat-1 transgenic mice, which are exogenously inserted in a fat-1 gene from Caenorhabditis elegans, which can endogenously convert n-6 polyunsaturated fatty acids (n-6 PUFAs) to n-3 PUFAs. Taken together, it has long been realized that dietary supplementation with fish oils that are plentiful of n-3 PUFAs can bring benefits in the treatment of osteoarthritis. Previously two phase I human studies based on in vitro transfer of the cDNA via lentivirus to arthritic joints have confirmed its feasibility and safety in human subjects. Consequently, we hypothesis that directly infect the chondrocytes and synoviocytes with lentivirus carrying the fat-1 gene could be a well therapeutic strategy for OA in humans.
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Affiliation(s)
- Min-jun Huang
- Department of Orthopaedic, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510665, Guangdong, PR China
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Stem cells and gene therapy for cartilage repair. Stem Cells Int 2012; 2012:168385. [PMID: 22481959 PMCID: PMC3306906 DOI: 10.1155/2012/168385] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2011] [Accepted: 12/06/2011] [Indexed: 01/06/2023] Open
Abstract
Cartilage defects represent a common problem in orthopaedic practice. Predisposing factors include traumas, inflammatory conditions, and biomechanics alterations. Conservative management of cartilage defects often fails, and patients with this lesions may need surgical intervention. Several treatment strategies have been proposed, although only surgery has been proved to be predictably effective. Usually, in focal cartilage defects without a stable fibrocartilaginous repair tissue formed, surgeons try to promote a natural fibrocartilaginous response by using marrow stimulating techniques, such as microfracture, abrasion arthroplasty, and Pridie drilling, with the aim of reducing swelling and pain and improving joint function of the patients. These procedures have demonstrated to be clinically useful and are usually considered as first-line treatment for focal cartilage defects. However, fibrocartilage presents inferior mechanical and biochemical properties compared to normal hyaline articular cartilage, characterized by poor organization, significant amounts of collagen type I, and an increased susceptibility to injury, which ultimately leads to premature osteoarthritis (OA). Therefore, the aim of future therapeutic strategies for articular cartilage regeneration is to obtain a hyaline-like cartilage repair tissue by transplantation of tissues or cells. Further studies are required to clarify the role of gene therapy and mesenchimal stem cells for management of cartilage lesions.
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Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy--lost in translation? J Cell Physiol 2012; 227:416-20. [PMID: 21948071 DOI: 10.1002/jcp.23031] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Orthopedic gene therapy has been the topic of considerable research for two decades. The preclinical data are impressive and many orthopedic conditions are well suited to genetic therapies. But there have been few clinical trials and no FDA-approved product exists. This paper examines why this is so. The reasons are multifactorial. Clinical translation is expensive and difficult to fund by traditional academic routes. Because gene therapy is viewed as unsafe and risky, it does not attract major funding from the pharmaceutical industry. Start-up companies are burdened by the complex intellectual property environment and difficulties in dealing with the technology transfer offices of major universities. Successful translation requires close interactions between scientists, clinicians and experts in regulatory and compliance issues. It is difficult to create such a favorable translational environment. Other promising fields of biological therapy have contemplated similar frustrations approximately 20 years after their founding, so there seem to be more general constraints on translation that are difficult to define. Gene therapy has noted some major clinical successes in recent years, and a sense of optimism is returning to the field. We hope that orthopedic applications will benefit collaterally from this upswing and move expeditiously into advanced clinical trials.
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Affiliation(s)
- C H Evans
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Madry H, Cucchiarini M. Clinical potential and challenges of using genetically modified cells for articular cartilage repair. Croat Med J 2012; 52:245-61. [PMID: 21674822 PMCID: PMC3131141 DOI: 10.3325/cmj.2011.52.245] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Articular cartilage defects do not regenerate. Transplantation of autologous articular chondrocytes, which is clinically being performed since several decades, laid the foundation for the transplantation of genetically modified cells, which may serve the dual role of providing a cell population capable of chondrogenesis and an additional stimulus for targeted articular cartilage repair. Experimental data generated so far have shown that genetically modified articular chondrocytes and mesenchymal stem cells (MSC) allow for sustained transgene expression when transplanted into articular cartilage defects in vivo. Overexpression of therapeutic factors enhances the structural features of the cartilaginous repair tissue. Combined overexpression of genes with complementary mechanisms of action is also feasible, holding promises for further enhancement of articular cartilage repair. Significant benefits have been also observed in preclinical animal models that are, in principle, more appropriate to the clinical situation. Finally, there is convincing proof of concept based on a phase I clinical gene therapy study in which transduced fibroblasts were injected into the metacarpophalangeal joints of patients without adverse events. To realize the full clinical potential of this approach, issues that need to be addressed include its safety, the choice of the ideal gene vector system allowing for a long-term transgene expression, the identification of the optimal therapeutic gene(s), the transplantation without or with supportive biomaterials, and the establishment of the optimal dose of modified cells. As safe techniques for generating genetically engineered articular chondrocytes and MSCs are available, they may eventually represent new avenues for improved cell-based therapies for articular cartilage repair. This, in turn, may provide an important step toward the unanswered question of articular cartilage regeneration.
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Affiliation(s)
- Henning Madry
- Experimental Orthopaedics and Osteoarthritis Research, Saarland University Medical Center, Homburg/Saar, Germany.
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36
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Qi Y, Feng G, Yan W. Mesenchymal stem cell-based treatment for cartilage defects in osteoarthritis. Mol Biol Rep 2011; 39:5683-9. [DOI: 10.1007/s11033-011-1376-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 12/13/2011] [Indexed: 12/20/2022]
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Abstract
The concept of using gene transfer strategies for cartilage repair originates from the idea of transferring genes encoding therapeutic factors into the repair tissue, resulting in a temporarily and spatially defined delivery of therapeutic molecules to sites of cartilage damage. This review focuses on the potential benefits of using gene therapy approaches for the repair of articular cartilage and meniscal fibrocartilage, including articular cartilage defects resulting from acute trauma, osteochondritis dissecans, osteonecrosis, and osteoarthritis. Possible applications for meniscal repair comprise meniscal lesions, meniscal sutures, and meniscal transplantation. Recent studies in both small and large animal models have demonstrated the applicability of gene-based approaches for cartilage repair. Chondrogenic pathways were stimulated in the repair tissue and in osteoarthritic cartilage using genes for polypeptide growth factors and transcription factors. Although encouraging data have been generated, a successful translation of gene therapy for cartilage repair will require an ongoing combined effort of orthopedic surgeons and of basic scientists.
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Affiliation(s)
- Henning Madry
- Saarland University, Homburg, Germany,Henning Madry, Saarland University, Kirrbergerstrasse 1, Homburg, 66424 Germany
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39
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Principles of tissue engineering and cell- and gene-based therapy. Rheumatology (Oxford) 2011. [DOI: 10.1016/b978-0-323-06551-1.00018-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Wehling P, Reinecke J, Baltzer AWA, Granrath M, Schulitz KP, Schultz C, Krauspe R, Whiteside TW, Elder E, Ghivizzani SC, Robbins PD, Evans CH. Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. Hum Gene Ther 2010; 20:97-101. [PMID: 18986219 DOI: 10.1089/hum.2008.075] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This paper provides the first evidence of a clinical response to gene therapy in human arthritis. Two subjects with rheumatoid arthritis received ex vivo, intraarticular delivery of human interleukin-1 receptor antagonist (IL-1Ra) cDNA. To achieve this, autologous synovial fibroblasts were transduced with a retrovirus, MFG-IRAP, carrying IL-1Ra as the transgene, or remained as untransduced controls. Symptomatic metacarpophalangeal (MCP) joints were injected with control or transduced cells. Joints were clinically evaluated on the basis of pain; the circumference of MCP joint 1 was also measured. After 4 weeks, joints underwent surgical synovectomy. There were no adverse events in either subject. The first subject responded dramatically to gene transfer, with a marked and rapid reduction in pain and swelling that lasted for the entire 4 weeks of the study. Remarkably, joints receiving IL-1Ra cDNA were protected from flares that occurred during the study period. Analysis of RNA recovered after synovectomy revealed enhanced expression of IL-1Ra and reduced expression of matrix metalloproteinase-3 and IL-1beta. The second subject also responded with reduced pain and swelling. Thus, gene transfer to human, rheumatoid joints can be accomplished safely to produce clinical benefit, at least in the short term. Using this ex vivo procedure, the transgene persisted within the joint for at least 1 month. Further clinical studies are warranted.
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Affiliation(s)
- Peter Wehling
- Department of Orthopedic Surgery, University of Düsseldorf School of Medicine, Germany
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41
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Therapeutic strategies for SLE involving cytokines: mechanism-oriented therapies especially IFN-gamma targeting gene therapy. J Biomed Biotechnol 2010; 2010. [PMID: 20827419 PMCID: PMC2933908 DOI: 10.1155/2010/461641] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 06/25/2010] [Indexed: 01/22/2023] Open
Abstract
Systemic lupus erythematosus (SLE: lupus) is a chronic complicated autoimmune disease and pathogenesis is still unclear. However, key cytokines have been recognized. Interferon (IFN)-γ and also IFNalpha/beta are of particular importance. Depending on the concept that lupus is a helper T(Th)1 disease and that dendritic cells (DCs) determine the direction of lupus, balance shift of Th1/Th2 and immunogenic/tolerogenic DCs is reviewed for therapy. (IFN)-gamma- and IFN-alpha/beta-targeted (gene) therapies are introduced. These consist of Th1/Th2 balance shift and elimination of IFN-gamma and IFN-gamma-related cytokines such as (interleukin)IL-12 and IL-18. Other approaches include suppression of immunocompetent cells, normalization of abnormal T-cell function, costimulation blockade, B lymphocyte stimulator (Blys) blockade, and suppression of nephritic kidney inflammation. Moreover, balance shift of IFN-alpha/beta and tumor necrosis factor (TNF)-alpha together with regulatory T(Treg) cells are briefly introduced. Clinical application will be discussed.
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Tang B, Cullins DL, Zhou J, Zawaski JA, Park H, Brand DD, Hasty KA, Gaber MW, Stuart JM, Kang AH, Myers LK. Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II. Arthritis Res Ther 2010; 12:R136. [PMID: 20615221 PMCID: PMC2945026 DOI: 10.1186/ar3074] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 04/12/2010] [Accepted: 07/08/2010] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a systemic disease manifested by chronic inflammation in multiple articular joints, including the knees and small joints of the hands and feet. We have developed a unique modification to a clinically accepted method for delivering therapies directly to the synovium. Our therapy is based on our previous discovery of an analog peptide (A9) with amino acid substitutions made at positions 260 (I to A), 261 (A to B), and 263 (F to N) that could profoundly suppress immunity to type II collagen (CII) and arthritis in the collagen-induced arthritis model (CIA). METHODS We engineered an adenoviral vector to contain the CB11 portion of recombinant type II collagen and used PCR to introduce point mutations at three sites within (CII124-402, 260A, 261B, 263D), (rCB11-A9) so that the resulting molecule contained the A9 sequence at the exact site of the wild-type sequence. RESULTS We used this construct to target intra-articular tissues of mice and utilized the collagen-induced arthritis model to show that this treatment strategy provided a sustained, local therapy for individual arthritic joints, effective whether given to prevent arthritis or as a treatment. We also developed a novel system for in vivo bioimaging, using the firefly luciferase reporter gene to allow serial bioluminescence imaging to show that luciferase can be detected as late as 18 days post injection into the joint. CONCLUSIONS Our therapy is unique in that we target synovial cells to ultimately shut down T cell-mediated inflammation. Its effectiveness is based on its ability to transform potential inflammatory T cells and/or bystander T cells into therapeutic (regulatory-like) T cells which secrete interleukin (IL)-4. We believe this approach has potential to effectively suppress RA with minimal side effects.
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Affiliation(s)
- Bo Tang
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
| | - David L Cullins
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
| | - Jing Zhou
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
| | - Janice A Zawaski
- Department of Biomedical Engineering, University of Tennessee Health Science Center, 920 Madison, Suite 407, Memphis, Tennessee 38163 USA
| | - Hyelee Park
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
- Department of Orthopedics, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 520, Memphis, Tennessee 38104 USA
| | - David D Brand
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
- Research Service, Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104 USA
| | - Karen A Hasty
- Department of Orthopedics, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 520, Memphis, Tennessee 38104 USA
| | - M Waleed Gaber
- Department of Biomedical Engineering, University of Tennessee Health Science Center, 920 Madison, Suite 407, Memphis, Tennessee 38163 USA
| | - John M Stuart
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
- Research Service, Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104 USA
| | - Andrew H Kang
- Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, Tennessee 38163, USA
- Research Service, Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis TN 38104 USA
| | - Linda K Myers
- Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Room 401, Memphis TN 38163 USA
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Haleem AM, Chu CR. Advances in Tissue Engineering Techniques for Articular Cartilage Repair. ACTA ACUST UNITED AC 2010; 20:76-89. [PMID: 29430164 DOI: 10.1053/j.oto.2009.10.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The limited repair potential of human articular cartilage contributes to development of debilitating osteoarthritis and remains a great clinical challenge. This has led to evolution of cartilage treatment strategies from palliative to either reconstructive or reparative methods in an attempt to delay or "bridge the gap" to joint replacement. Further development of tissue engineering-based cartilage repair methods have been pursued to provide a more functional biological tissue. Currently, tissue engineering of articular cartilage has three cornerstones; a cell population capable of proliferation and differentiation into mature chondrocytes, a scaffold that can host these cells, provide a suitable environment for cellular functioning and serve as a sustained-release delivery vehicle of chondrogenic growth factors and thirdly, signaling molecules and growth factors that stimulate the cellular response and the production of a hyaline extracellular matrix (ECM). The aim of this review is to summarize advances in each of these three fields of tissue engineering with specific relevance to surgical techniques and technical notes.
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Affiliation(s)
- A M Haleem
- Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - C R Chu
- Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Wang W, Li B, Li Y, Jiang Y, Ouyang H, Gao C. In vivo restoration of full-thickness cartilage defects by poly(lactide-co-glycolide) sponges filled with fibrin gel, bone marrow mesenchymal stem cells and DNA complexes. Biomaterials 2010; 31:5953-65. [PMID: 20488531 DOI: 10.1016/j.biomaterials.2010.04.029] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 04/14/2010] [Indexed: 10/19/2022]
Abstract
A composite construct comprising of bone marrow mesenchymal stem cells (BMSCs), plasmid DNA encoding transforming growth factor-beta1 (pDNA-TGF-beta1), fibrin gel and poly (lactide-co-glycolide) (PLGA) sponge was designed and employed to repair articular cartilage defects. To improve the gene transfection efficiency, a cationized chitosan derivative N,N,N-trimethyl chitosan chloride (TMC) was employed as the vector. The TMC/DNA complexes had a transfection efficiency of 9% to BMSCs and showed heterogeneous TGF-beta1 expression in a 10-day culture period in vitro. In vivo culture of the composite constructs was performed by implantation into full-thickness cartilage defects of New Zealand white rabbit joints, using the constructs absence of pDNA-TGF-beta1 or BMSCs as controls. Heterogeneous expression of TGF-beta1 in vivo was detected at 4 weeks, but its level was decreased in comparison with that of 2 weeks. After implantation for 12 weeks, the cartilage defects were successfully repaired by the composite constructs of the experimental group, and the neo-cartilage integrated well with its surrounding tissue and subchondral bone. Immunohistochemical and glycosaminoglycans (GAGs) staining confirmed the similar amount and distribution of collagen type II and GAGs in the regenerated cartilage as that of hyaline cartilage. The cartilage special genes expressed in the neo-tissue were closer to those of the normal cartilage. An overall score of 2.83 was obtained according to Wakitani's standard. By contrast, only part of the defects was repaired by the pDNA-TGF-beta1 absence constructs, and no cartilage repair but fibrous tissue was found for the BMSCs absence constructs. Therefore, combination of the PLGA sponge/fibrin gel scaffold with BMSCs and gene therapy is an effective method to restore cartilage defects and may have a great potential for practical applications in the near future.
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Affiliation(s)
- Wei Wang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
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Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E, Furst DE, Anklesaria P, Heald AE. Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann Rheum Dis 2009; 68:1247-54. [PMID: 18678578 DOI: 10.1136/ard.2008.089375] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis. METHODS In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated. RESULTS Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritus, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively. CONCLUSION A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.
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Affiliation(s)
- P J Mease
- Seattle Rheumatology Associates/Swedish Medical Center Research, Seattle, Washington, USA
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Kay JD, Gouze E, Oligino TJ, Gouze JN, Watson RS, Levings PP, Bush ML, Dacanay A, Nickerson DM, Robbins PD, Evans CH, Ghivizzani SC. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus. J Gene Med 2009; 11:605-14. [PMID: 19384892 PMCID: PMC2876984 DOI: 10.1002/jgm.1334] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND The adeno-associated virus (AAV) has many safety features that favor its use in the treatment of arthritic conditions; however, the conventional, single-stranded vector is inefficient for gene delivery to fibroblastic cells that primarily populate articular tissues. This has been attributed to the inability of these cells to convert the vector to a double-stranded form. To overcome this, we evaluated double-stranded self-complementary (sc) AAV as a vehicle for intra-articular gene delivery. METHODS Conventional and scAAV vectors were used to infect lapine articular fibroblasts in culture to determine transduction efficiency, transgene expression levels, and nuclear trafficking. scAAV containing the cDNA for interleukin (IL)-1 receptor antagonist (Ra) was delivered to the joints of naïve rabbits and those with IL-1beta-induced arthritis. From lavage of the joint space, levels of transgenic expression and persistence were measured by enzyme-linked immunosorbent assay. Infiltrating leukocytes were quantified using a hemocytometer. RESULTS Transgene expression from scAAV had an earlier onset and was approximately 25-fold greater than conventional AAV despite the presence of similar numbers of viral genomes in the nuclei of infected cells. Fibroblasts transduced with scAAV produced amounts of IL1-Ra comparable to those transduced with adenoviral and lentiviral vectors. IL1-Ra was present in lavage fluid of most animals for 2 weeks in sufficient quantities to inhibit inflammation of the IL-1beta-driven model. Once lost, neither subsequent inflammatory events, nor re-administration of the virus could re-establish transgene expression. CONCLUSIONS scAAV-mediated intra-articular gene transfer is robust and similarly efficient in both normal and inflamed joints; the resulting transgenic expression is sufficient to achieve biological relevance in joints of human proportion.
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Affiliation(s)
- Jesse D. Kay
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - Elvire Gouze
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - Thomas J. Oligino
- Departmeint of Statistics and Actuarial Sciences, University of Central Florida, Orlando, FL, USA
| | - Jean-Noel Gouze
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - Rachael S. Watson
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - Padraic P. Levings
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - Marsha L. Bush
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - Anthony Dacanay
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
| | - David M. Nickerson
- Departmeint of Statistics and Actuarial Sciences, University of Central Florida, Orlando, FL, USA
| | - Paul D. Robbins
- Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Christopher H. Evans
- Centre for Molecular Orthopedics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Steven C. Ghivizzani
- Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL, USA
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Abstract
Articular cartilage repair remains a challenge to surgeons and basic scientists. The field of tissue engineering allows the simultaneous use of material scaffolds, cells and signalling molecules to attempt to modulate the regenerative tissue. This review summarises the research that has been undertaken to date using this approach, with a particular emphasis on those techniques that have been introduced into clinical practice, via in vitro and preclinical studies.
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Affiliation(s)
- A. Getgood
- Orthopaedic Research Unit The University of Cambridge Orthopaedic Research Unit, Box 180, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
| | - R. Brooks
- Orthopaedic Research Unit The University of Cambridge Orthopaedic Research Unit, Box 180, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
| | - L. Fortier
- Cornell University College of Veterinary Medicine, Vet Box 32, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA
| | - N. Rushton
- Orthopaedic Research Unit The University of Cambridge Orthopaedic Research Unit, Box 180, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
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48
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Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy in 2008. Mol Ther 2009; 17:231-44. [PMID: 19066598 PMCID: PMC2835052 DOI: 10.1038/mt.2008.265] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Accepted: 10/26/2008] [Indexed: 02/07/2023] Open
Abstract
Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic joints, and the development of bone-healing applications is at an advanced, preclinical stage. Other potential uses include the treatment of Mendelian diseases and orthopedic tumors, as well as the repair and regeneration of cartilage, ligaments, and tendons. Many of these goals should be achievable with existing technologies. The main barriers to clinical application are funding and regulatory issues, which in turn reflect major safety concerns and the opinion, in some quarters, that gene therapy should not be applied to nonlethal, nongenetic diseases. For some indications, advances in nongenetic treatments have also diminished enthusiasm. Nevertheless, the preclinical and early clinical data are impressive and provide considerable optimism that gene therapy will provide straightforward, effective solutions to the clinical management of several common debilitating disorders that are otherwise difficult and expensive to treat.
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Affiliation(s)
- Christopher H Evans
- Center for Molecular Orthopaedics, Harvard Medical School, Boston, Massachusetts, USA.
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Evans CH, Ghivizzani SC, Robbins PD. Gene therapy of the rheumatic diseases: 1998 to 2008. Arthritis Res Ther 2009; 11:209. [PMID: 19232068 PMCID: PMC2688220 DOI: 10.1186/ar2563] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
During the decade since the launch of Arthritis Research, the application of gene therapy to the rheumatic diseases has experienced the same vicissitudes as the field of gene therapy as a whole. There have been conceptual and technological advances and an increase in the number of clinical trials. However, funding has been unreliable and a small number of high-profile deaths in human trials, including one in an arthritis gene therapy trial, have provided ammunition to skeptics. Nevertheless, steady progress has been made in a number of applications, including rheumatoid arthritis and osteoarthritis, Sjögren syndrome, and lupus. Clinical trials in rheumatoid arthritis have progressed to phase II and have provided the first glimpses of possible efficacy. Two phase I protocols for osteoarthritis are under way. Proof of principle has been demonstrated in animal models of Sjögren syndrome and lupus. For certain indications, the major technological barriers to the development of genetic therapies seem to have been largely overcome. The translational research necessary to turn these advances into effective genetic medicines requires sustained funding and continuity of effort.
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Affiliation(s)
- Christopher H Evans
- Center for Advanced Orthopaedic Studies, Harvard Medical School, BIDMC-RN115, 330 Brookline Avenue, Boston, MA 02215, USA.
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Abstract
Gene therapy offers great possibilities for treating rheumatoid arthritis (RA). Traditional surgical and pharmaceutical methods of treating RA have met with limited therapeutic success and have failed to produce a cure, but the past several years have seen extensive progress toward development of a gene therapy for arthritis. Numerous vectors and therapeutic genes have been investigated in animal models of arthritis, and the potential of gene therapy to treat or manage RA has been demonstrated in several clinical studies. Gene therapy offers the possibility of overcoming many of the limitations of current biologic therapies by providing long-term, high-level localized expression of therapeutic genes, potentially in as little as a single dose. In this review, we explore the advances in gene therapy for RA and summarize the recent preclinical and clinical data. In addition, we provide an overview of vectors and targets for RA gene therapy.
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