An adenovirus gene therapy developed at Baylor College of Medicine for osteoarthritis is demonstrating encouraging outcomes in Phase 1 clinical trials, marking a significant advancement in the potential treatment of this prevalent joint condition. The therapy, known as PCRX-201, has shown sustained improvements in knee pain, stiffness, and function up to 104 weeks following local administration.
Adenovirus-Based Gene Therapy
The foundation of this therapeutic approach lies in the use of a high-capacity adenovirus to deliver DNA into cells. Early versions of adenovirus vectors were associated with immunogenicity and systemic inflammation. However, advancements led to the development of helper-dependent adenoviruses, engineered to remove the viral genome and minimize the immune response. Experiments at Baylor demonstrated that these high-capacity adenoviruses could express genetically modified DNA for extended periods without triggering severe immune reactions.
Targeting Inflammation in Osteoarthritis
Researchers at Baylor combined their work on gene therapy with their research on skeletal disorders, focusing on osteoarthritis. The Centers for Disease Control and Prevention estimates that 33 million adults in the U.S. have osteoarthritis, highlighting the significant need for effective treatments. The advantage of using high-capacity adenovirus gene therapy in the knee joint is that the joint is a closed system. Injections to the knee joint do not enter the bloodstream and, therefore, are protected from the body’s immune system.
The gene therapy developed in Dr. Brendan Lee's lab uses interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory protein, delivered via a high-capacity adenovirus vector with an NFkB responsive promoter. This design ensures that IL-1Ra expression is activated only when inflammation is present in the joint, offering a targeted approach to managing inflammation.
Clinical Trial and Future Directions
Following preclinical testing in mice and horse models, the therapy was licensed and eventually acquired by Pacira BioSciences, Inc. PCRX-201 received Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA, which supports accelerated drug development and approval.
Pacira presented two-year safety and efficacy data from the Phase 1 trial, demonstrating sustained improvements in knee pain, stiffness, and function up to 104 weeks after administration. Pacira is planning a Phase 2, double-blind, active-controlled study next year. According to Dr. Kilian Guse, CEO and co-founder of GQ Bio Therapeutics, the Phase 1 clinical trial with 72 knee osteoarthritis patients has been the largest clinical trial with a high-capacity adenovirus and in the field of osteoarthritis gene therapy in general.
Dr. Lee notes that this therapy has the potential to be the first disease-modifying therapy for osteoarthritis, addressing a significant unmet need. The promising clinical trial results represent a major step forward in the development of this therapy, which began in the lab at Baylor.
