BOSTON, Mass. – TNF inhibitors and other biologicals may command more attention, and stem cells may be more controversial, but arthritis gene therapy continues to move quietly ahead, said Christopher Evans, PhD, DSc, director of the Center for Molecular Orthopaedics at Harvard Medical School in Boston, Massachusetts. Dr. Evans reviewed new developments and future prospects of gene therapy for arthritis in the June issue of Arthritis & Rheumatism.¹

"The advantages of gene therapy are that it is potentially longer lasting, safer, cheaper, and more effective than other arthritis treatments," Dr. Evans said.

Looking back over the past year or so, he points to encouraging developments:

• Publication of the first clinical trial of arthritis gene therapy²
• Demonstration (in preliminary, unpublished data in two patients) of the first evidence of efficacy in human arthritis
• Identification of a population of accessible cells within the joint that do not turn over and which are therefore able to maintain long-term, intraarticular transgene expression
• Funding by National Institutes of Health of the first human trial in OA (pending regulatory review and approval)

Dr. Evans also sees the major barriers to progress for gene therapy in RA, including:

• The perception that TNF inhibitors and other biologics have removed the need for additional new therapies
• The perception that gene therapy is somehow bad or dangerous
• Funding, especially for clinical trials

• The lack of a truly effective and affordable gene transfer vector

"Development of gene therapy for OA is further hampered by lack of sufficient understanding of the pathophysiology of the disease to know exactly what the targets are," Dr. Evans said. "Another major barrier is that new bandwagons have supplanted gene therapy among those who follow fashion. The new focus is on stem cells and small interfering RNA (siRNA), although, at a stretch, we might claim siRNA within the realm of gene therapy."

The basic approach to arthritis gene therapy is to transfer a complementary DNA (cDNA) coding for a useful anti-arthritis compound into the body in an effort to produce sustained endogenous synthesis of compounds such as interleukin-1 receptor antagonist (IL-1Ra). Dr. Evans and colleagues demonstrated the feasibility of intra-articular gene delivery by transferring synovial fibroblasts transduced with a retrovirus carrying IL-1Ra cDNA into metacarpophalangeal (MCP) joints in the hands of nine women with RA and demonstrating clusters of cells expressing high levels of IL-1Ra on the synovia of the transduced joints.²

The downside of local delivery includes the need to inject large numbers of joints in patients with widespread disease and the lack of effect on extraarticular symptoms. Dr. Evans suggests that intramuscular or intravenous delivery might be more durably effective than the frequent injections or infusions required with current biologics. However, one of the advantages of conventional methods, namely the ability to withhold treatment in the face of an adverse event, is lost unless expression of the transgene is subject to tight, deliberate regulation," he writes.

Preclinical studies have already changed understanding of arthritis pathogenesis by demonstrating "an unexpected contralateral response: the introduction of an antiarthritis cDNA into one knee joint produced a therapeutic effect in both," Dr. Evans writes. Small numbers of genetically modified cells were found in the contralateral joint and in draining lymph nodes but not in the peripheral blood mononuclear leukocyte fraction, spleen, or other organs.

"The most likely explanations are based on the ability of joints to communicate via the nervous system, and the ability of cells (particularly antigen-presenting cells and dendritic cells) to traffick between joints," Dr. Evans said. "My colleague Paul Robbins has intriguing data to suggest that small vesicles, known as exosomes [which are] derived from APCs, play a major role in all this. There is reasonable experimental support of the cell/exosome trafficking hypothesis, but the role of the nervous system remains to be investigated."

Dr. Evans contends that intraarticular gene therapy has been successful enough in animal models of RA and OA to justify clinical trials in humans but that these must be done with extremely careful choice of delivery system and transgene. "These choices are important, because acceptance of a gene therapy approach for nongenetic, nonlethal diseases such as arthritis is marginal, and a serious adverse event could destroy the entire enterprise."

The cost of developing and producing the large amounts of recombinant, clinical-grade viral vector needed for clinical trials would be high. Dr. Evans suggests that, given the existence of competing new therapies, gene therapy for RA is likely to be a nonstarter but that "OA presents an enormous market opportunity."

Dr. Evans recently collaborated with veterinary surgeon Alan J. Nixon, director of the Comparative Orthopaedics Laboratory at Cornell University's College of Veterinary Medicine in Ithaca, New York, to show that adenoviral mediated transduction of insulin-like growth factor-I (IGF-I) genes into the MCP synovial tissues of horses can significantly raise IGF-I levels in synovial fluid without adverse effects.³ The investigators hope that this will promote cartilage healing, since IGF-I is important in cartilage repair but is notoriously short-lived and difficult to maintain at therapeutic levels in the joint. That study was published early online in the May 18 issue of Gene Therapy.

References

1. Evans CH, Ghivizzani SC, Robbins PD. Gene therapy for arthritis. What next? Arthritis Rheum. 2006;54:1714-1729.
2. Evans CH, Robbins PD, Ghivizzani SC, et al. Gene transfer to human joints: Progress toward a gene therapy of arthritis. Proc Natl Acad Sci USA. 2005;102:8698-8703.
3. Goodrich LR, Brower-Toland BD, Warnick L, et al. Direct adenovirus-mediated IGF-I gene transduction of synovium induces persisting synovial fluid IGF-I ligand elevations. Gene Ther. 2006 May 18; [Epub ahead of print]