Gene Therapy for Arthritis, Musculoskeletal and Skin (AMS) Diseases


Gene therapy offers advantages over other therapeutic approaches. For diseases caused by mutations in single genes, gene therapy has the possibility of replacing or correcting the defective gene, thus addressing the root cause of the disorder. For more common diseases caused by multiple gene and environmental interactions, gene therapy approaches can up- or down-regulate pathways involved in pathology or natural repair. The therapeutic products of gene therapy can be synthesized, processed, and delivered specifically to the site of disease, potentially at constant dosage levels. This could provide great improvements for the treatment of tissue location-specific diseases, such as those affecting the joints or skin. In order to realize the benefits of gene therapy, investigators must overcome the obstacles inherent with the types of vectors being used, the transgenes, routes of delivery, and the response of the host to these potentially foreign antigens.

Session Goals/Relevance to NIAMS Mission

This retreat session focused on gaps and opportunities in NIAMS support of the research fields of gene therapy for diseases and disorders affecting the musculoskeletal and skin systems. Types of gene therapy discussed in this session and contained within the current NIAMS portfolios include in vivo gene delivery by recombinant viral or other vectors, and ex vivo delivery of genes into cells that are subsequently employed in transplantation or tissue engineering. Targeting delivery to stem cells may be important for gene therapy applications for several tissues. Within our mission area, multiple gene therapy approaches are being explored for the treatment of single gene disorders such as muscular dystrophies, epidermolysis bullosa, and osteogenesis imperfecta. Both in vivo and ex vivo approaches are also being studied to promote the repair and regeneration of tissues as treatments for joint diseases, fracture non-unions, and cutaneous wounds. An analysis of the current NIAMS gene therapy research grants and contracts revealed that the majority are basic or preclinical exploratory projects focused on testing the efficacy of viral vector-mediated delivery of therapeutic genes in animal models. NIAMS currently supports three phase I, dose escalation, gene therapy clinical trials; one delivering platelet-derived growth factor b (PDGFb) to the site of the lesion to promote wound healing, a second delivering interleukin (IL) 1 receptor antagonist to the synovium of osteoarthritis (OA)-affected knee joints, and the third involving intramuscular delivery of the alpha-sarcoglycan gene in limb-girdle muscular dystrophy patients with mutations in this gene. Several other clinical trials for diseases in our mission area are being conducted with support from industry and other private sources. NIAMS has also supported training and career development awards and conference grants focused on gene therapy topics.

Current scientific and non-scientific needs for accelerating progress toward effective gene therapy treatments for these diseases were discussed during the retreat session. Based on communications with investigators, we have identified critical needs for basic knowledge, infrastructure, communication and training. Several investigators have expressed concern that the rush to develop and test therapies, without a sufficient knowledge base of the underlying biology - ""vectorology," immune response, route of delivery, regulation of transgene expression, etc.-has led to unsuccessful clinical trials and increased risk to the participants. The costs of vector production and preclinical testing in mice and large animal models are prohibitive for all but a very few investigators. The NIH-supported National Gene Vector Laboratories are no longer accepting requests for these services. We examined the impact of this on investigators within our mission area, and what steps could be taken to facilitate access to needed resources. Clinical studies of gene therapies require a unique set of regulatory approval steps. The impact of these requirements and approaches to help investigators fulfill them were also discussed. Finally, participants in this session addressed the safety concerns that arise in peer review discussions of gene therapy studies, and whether there are data to support these concerns.

Key Questions

  • What are the high priority basic research questions that, when answered, are likely to lead to significant advances in gene therapy approaches?
  • How useful are current animal models in testing for the safety and efficacy of gene therapies, and what strategies should be used to deal with the limitations?
  • Can the obstacles of large-scale vector production or cell culture/tissue engineering be overcome with support for infrastructure, or are new technologies needed in order to facilitate clinical trials and, eventually, treatments?
  • What would be effective ways to promote productive collaborations among gene therapy investigators in different disease fields, or among basic and clinical researchers, to stimulate advances?
  • Can the burden of regulatory approval for gene therapy clinical studies be decreased through more effective communication and data sharing among investigators and among regulatory organizations?
  • Are there special review considerations for gene therapy proposals, such as the need for appropriate reviewer expertise for non-hypothesis driven, translational studies?
  • What are the safety concerns that enter into peer review discussions about gene therapy trials, and are there data to support them?

Relevant Review Articles

Carofino BC, Lieberman JR. Gene therapy applications for fracture-healing. J Bone Joint Surg Am. 2008.

Evans CH, Ghivizzani SC, Robbins PD. Gene therapy for arthritis: what next? Arthritis Rheum. 2006.

Jensen TG. Cutaneous gene therapy. Ann Med. 2007.

Rodino-Klapac LR, Chicoine LG, Kaspar BK, Mendell JR. Gene therapy for duchenne muscular dystrophy: expectations and challenges. Arch Neurol. 2007.

Last Reviewed: 04/14/2008