Feb. 12, 2020

Treatment of arthritis is limited by the pharmacokinetics of joints, which impede the sustained, intra-articular delivery of therapeutic agents. Gene transfer provides a strategy for overcoming this limitation. It is based upon the hypothesis that the delivery of genes, or their complementary DNAs (cDNAs), to cells within the joint will lead to the sustained, local, endogenous synthesis of the transgene products.

According to Christopher H. Evans, Ph.D., director of Mayo Clinic's Rehabilitation Medicine Research Center, development of a safe, effective treatment for osteoarthritis (OA) will have significant impact. "OA carries a massive burden of disease for patients and society," explains Dr. Evans. "It is incurable, largely untreatable and the major cause of disability among the elderly."

Approximately 27 million Americans have OA, a number that is increasing due to demographic changes, and health care costs have been estimated at $185 billion a year.

A history marked by challenges

Researchers began exploring the use of gene therapy for orthopedic conditions during the late 1980s. Among the challenges at that time was the development of technologies permitting the efficient delivery of genes in a way that ensured their sustained delivery. However, the overriding issue was safety, especially because viruses were used as the delivery vehicles and arthritis is not life-threatening.

Dr. Evans and his colleagues worked through these issues, and in a 2005 article published in the Proceedings of the National Academy of Sciences, they described the world's first gene transfer to a human joint. A cDNA encoding the interleukin-1 receptor antagonist (IL-1Ra) was delivered to the metacarpophalangeal joints in nine patients with rheumatoid arthritis.

"This study showed that it is possible to transfer a potentially therapeutic gene safely to human arthritic joints and to obtain intra-articular expression of a biologically active transgene product," explains Dr. Evans. "IL-1 plays a key role as an intra-articular mediator of inflammation, pain and loss of cartilage, making its natural inhibitor, IL-1Ra, a promising therapeutic."

In a 2018 article published in Human Gene Therapy, and in a 2019 editorial published in Bone & Joint Research, Dr. Evans chronicles the turbulent history of gene therapy as a whole and orthopedic gene therapy in particular. Impediments to progress have included technological constraints, serious adverse events in clinical trials and difficulties in manufacturing clinical-grade viral vectors. The last of these remains a major bottleneck for the entire field of gene therapy.

New progress

Dr. Evans notes that after overcoming many of the barriers to progress and with the first gene medicines recently getting FDA approval, the field of gene therapy is undergoing explosive new growth. A particular advance has been the development of vectors based upon adeno-associated virus (AAV) that are safe, effective, relatively stable and able to transfer genes to cells in situ.

In 2019 Dr. Evans and a team of PM&R clinicians, researchers and allied health professionals began a clinical trial to confirm the safety of using AAV to deliver IL-1Ra cDNAs to the knee joints of patients with OA. This vector was effective in preclinical testing, and its safety was confirmed in a large audited toxicology study under good laboratory practice conditions.

Preclinical testing confirmed that the vector efficiently delivered genes to cells in the synovium and cartilage of the injected joints, with minimal escape to extra-articular tissues. In horses, expression of the gene occurs for at least 18 months, with no sign of decline, providing the basis for a sustained therapeutic effect.

"Our goal is to assess the local and systemic safety of three different doses of our vector delivered under ultrasound guidance into one knee joint of nine individuals with moderate OA of the knee," explains Dr. Evans. The team will follow patients in the trial for one year to assess safety, dosing and, in a preliminary manner, efficacy.

Looking ahead

According to Dr. Evans, the field of gene therapy is developing a great deal of momentum. "We expect that the involvement of large pharmaceutical companies will mobilize experience and resources," he says. "These will accelerate the pace of this type of research and promote the development of clinical applications in gene therapeutics for musculoskeletal conditions."

For more information

Rehabilitation Medicine Research Center. Mayo Clinic.

Evans CH, et al. Gene transfer to human joints: Progress toward a gene therapy of arthritis. Proceedings of the National Academy of Sciences of the United States of America. 2005; 24:8698.

Evans CH, et al. Gene delivery to joints by intra-articular injection. Human Gene Therapy. 2018;29:2.

Evans CH, et al. The vicissitudes of gene therapy. Bone & Joint Research. 2019;10:469.

Mayo Clinic. Safety of Intra-Articular Sc-rAAV2.5IL-1Ra in Subjects With Moderate Knee OA (AAVIL-1Ra). ClinicalTrials.gov.