The 2024 OREF Clinical Research Award: Progress Toward a Gene Therapy for Arthritis

Area of Science:

• Biotechnology
• Molecular Medicine
• Rheumatology

Background:

• Osteoarthritis (OA) is a widespread, debilitating condition with limited non-surgical treatment options.
• Current drug delivery methods struggle to achieve sustained therapeutic concentrations of antiarthritic agents in affected joints.
• Intra-articular gene transfer was proposed over 30 years ago to engineer cells for endogenous production of therapeutic proteins.

Purpose of the Study:

• To summarize the progress of intra-articular gene transfer as a therapeutic strategy for osteoarthritis.
• To highlight the development and application of gene therapy for delivering anti-inflammatory agents to the joint.
• To report on the clinical translation of gene therapy for osteoarthritis treatment.

Main Methods:

• Early research utilized retroviral vectors for ex vivo gene transfer of interleukin-1 receptor antagonist (IL-1Ra) in animal models.
• Subsequent studies employed adeno-associated virus (AAV) vectors for direct in vivo intra-articular injection of IL-1Ra.
• Clinical trials were conducted in humans, initially for rheumatoid arthritis and subsequently for osteoarthritis.

Main Results:

• The ex vivo gene therapy approach led to the first human clinical trial for arthritis.
• Direct in vivo AAV-mediated gene transfer of IL-1Ra has been successfully applied to osteoarthritis.
• A completed Phase I clinical trial in knee OA subjects demonstrated successful outcomes, progressing to a Phase Ib study.

Conclusions:

• Intra-articular gene transfer is a viable strategy to overcome drug delivery challenges in treating osteoarthritis.
• Gene therapy engineering articular cells to produce IL-1Ra offers a promising localized treatment for OA.
• Ongoing clinical trials indicate the potential of gene therapy for managing osteoarthritis effectively.