Here Comes Genetically Engineered OA Therapy

The 2024 Orthopaedic Research and Education Foundation (OREF) Clinical Research Award has been presented to Christopher H. Evans, Ph.D. (Mayo Clinic), Steven C. Ghivizzani, Ph.D. (University of Florida), and Paul D. Robbins, Ph.D. (University of Minnesota), for their groundbreaking research on local gene therapy for osteoarthritis (OA).

For more than 30 years, this team has spearheaded and shepherded groundbreaking OA genetic research and patiently, persistently, moved the science from laboratory concept to human clinical trials.

The OREF Award recognizes outstanding clinical research related to musculoskeletal disease or injury.

“Gene therapy was focused on curing genetic diseases when we entered the field,” said Dr. Evans, John and Posy Krehbiel Professor of Orthopedics, Mayo Clinic, and Professor of Molecular Medicine, Mayo Clinic Alix School of Medicine in Rochester, Minnesota.

“At the time, studying gene therapy for arthritis was radically different because, instead of treating a genetic disease, we were looking at treating a non-genetic one, albeit one of the most common diseases on the planet. This was not a genetic fix, but we wanted to explore a sophisticated way of delivering anti-arthritic gene products to those who need therapy as there were not many treatment advances for OA.”

From Concept to Clinical Trials

Initially targeting rheumatoid arthritis (RA), the researchers achieved the first-in-human transfer of a gene to a joint. With the rise of non-genetic RA treatments, however, the team shifted its focus to OA.

In terms of the details of the gene transfer process, Dr. Evans explained, “The gene transfer process involves genetically modifying a harmless virus (Adeno-associated virus; AAV) so that it carries DNA (‘gene’) that encodes the therapeutic protein product of interest, in our case the interleukin-1 receptor antagonist (IL-1Ra).”

“The modified virus is then injected into the joint with osteoarthritis where the virus delivers its genetic payload to cells within the joint, including synovial cells and chondrocytes. As a consequence, these cells then produce IL-1Ra which accumulates locally within the joint at therapeutic concentrations in a sustained fashion.”

“The most challenging part concerns the gene transfer technology, especially which vector to use to transfer the gene into cells within the joint. During the extended pre-clinical development of this project, we tried many different types of vectors, both viral and non-viral. And after the best vector was identified, manufacturing clinical grade material was another huge challenge.”

The researchers filed an Investigational New Drug application with the FDA in 2015. In a Phase I clinical trial, nine patients (three cohorts) were injected with scAAV.IL-1Ra in escalating doses of 10 (low dose), 10 (medium dose), or 10 (high dose) by an intra-articular injection into one knee joint with OA. Eligible patients had mid-stage disease, symptomatic OA and failed at least two conservative treatments prior to the study.

Partial outcomes included:

• No serious adverse events were reported.
• Patients reported improved symptoms based on VAS and WOMAC. Patients who received the lowest dose reported mild and temporary improvement. Patients who received the medium and high doses saw sustained symptomatic improvement during the entire 12-month follow-up timeframe.
• Expression of IL-1Ra, a natural anti-inflammatory protein, was higher in the high-dose and medium-dose groups. This elevated expression in these groups was sustained through the 12 months of follow up, suggesting that the 10 dose could be the most cost-effective dose, but further investigation is needed.

“This was the first study that used localized gene therapy, meaning we could deliver the therapeutic target directly to the joint, which has enormous implications for safety and significantly reduces the cost associated with this procedure/therapy,” said Dr. Evans.

“By focusing on the joint, you don’t have to treat the whole body as many of the previous vectors delivered systemically go straight to the liver, causing liver damage. The amount of vector we delivered to the knee is significantly less than what is used in systemic diseases, which cuts down on the cost dramatically.”

Going forward, asked OTW, what are your thoughts on how the level and persistence of IL-1Ra expression in the joint may be affected by immune suppression?

“Although we have fiddled around with the DNA sequence of the gene,” said Dr. Evans, “the IL-1Ra protein we express is identical to the IL-1Ra protein produced naturally by the body. For this reason, it should not be recognized as foreign by the immune system and therefore not affected by immunosuppression.”

“This was the first suggested use of gene therapy to treat a disease that is not a genetic disease or cancer!”