Osteoarthritis Gene Therapy Research Honored With OREF Award

The 2024 Orthopaedic Research and Education Foundation (OREF) Clinical Research Award has been bestowed upon 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 research on local gene therapy for osteoarthritis (OA). Together, the team spearheaded the research from a laboratory concept to human clinical trials over the course of 30 years. The OREF Award recognizes outstanding clinical research related to musculoskeletal disease or injury.
 
According to the Centers for Disease Control and Prevention, OA is the most common form of arthritis, affecting 32.5 million Americans and inflicting a significant economic burden on patients and the economy.ⁱ OA, which is caused by the breakdown of joint cartilage between bones, can cause pain, stiffness and swelling, potentially leading to reduced function or even disability.ⁱ There is no cure for OA and treatment options are limited; many patients eventually receive a total joint replacement. When the researchers began to study the use of gene therapy—which modifies a person’s genes to treat or cure diseaseⁱⁱ—for arthritis and other non-lethal diseases, gene therapy clinical trials were in the early stages and had only involved cancer and rare genetic diseases.
 
“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, Minn. “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.”
 
Evolution from Concept to Clinical Trials
Dr. Evans and his colleagues targeted rheumatoid arthritis (RA) when they began their research 30 years ago at the University of Pittsburgh as, unlike with OA, there was significant information about the biology of the rheumatoid joint. The team accomplished a major milestone, the first-in-human transfer of a gene to a joint, made possible by several articular (joint) gene transfer technologies developed by Drs. Evans, Ghivizzani, and Robbins. However, when numerous successful non-genetic RA treatments were introduced, it reduced the need for gene therapy for RA. The technologies and key learnings from the RA research were redirected to a new disease indication: OA.
 
To transfer genes, vectors are used, which are essentially vehicles that deliver therapeutic genetic materials directly into a cell.ⁱⁱⁱ The research team explored using self-complementary adeno-associated virus (scAAV), a small virus that can be engineered to deliver DNA to target cells,^iv as it caused no known human disease and allowed for delivery directly to the joints. Dr. Evans and his colleagues developed the scAAV.IL-1Ra vector as a therapeutic agent for OA.
 
Following animal studies that showed the efficacy of scAAV.IL-1Ra in joints with OA, a successful Investigational New Drug application was filed with the U.S. Food and Drug Administration (FDA) in 2015. In a Phase I clinical trial, nine patients (three cohorts of three patients) were injected with scAAV.IL-1Ra in escalating doses of 1011 (low dose), 1012 (medium dose), or 1013 (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. Patients reported pain (visual analog scale, VAS) and function (Western Ontario MacMaster University Osteoarthritis Index, WOMAC) and were followed for one year. Outcomes included:
 

• No reported serious adverse events.
• 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 1012 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.”
 
Future Studies
The team is currently enrolling for a Phase Ib trial with 50 patients who have mid-stage OA. The study will include a placebo group and examine how the level and persistence of IL-1Ra expression in the joint is affected by immune suppression. It will also determine the appropriate vector dose – 1012 or 1013. If the 1012 dose is found to be the most effective, it could mean a ten-fold lower cost and less risk of adverse events for patients.

Due to the expense of gene therapy trials, Drs. Evans, Ghivizzani and Robbins co-founded an arthritis gene therapy startup company, Genascence Corporation, which will help fund future clinical trials.
 
The OREF Clinical Research Award was established in 1995 to recognize outstanding clinical research related directly to musculoskeletal disease or injury. All submitted manuscripts are reviewed, graded and selected by the AAOS Research Development Committee. The award provides $20,000 to recipients. 
 
The Orthopaedic Research and Education Foundation (OREF) is an independent, 501(c)3 non-profit organization that raises funds to support research on diseases and injuries of bones, nerves and muscles and to enhance clinical care leading to improved health, increased activity and a better quality of life for patients. To further its mission, OREF is committed to exploring ways to partner with others to move the field of musculoskeletal research forward. 
 
References 
ⁱ Centers for Disease Control and Prevention. Osteoarthritis (OA). https://www.cdc.gov/arthritis/basics/osteoarthritis.htm. Reviewed 7/27/2020. Accessed 12/20/2023.
ⁱⁱ U.S. Food and Drug Administration. What is Gene Therapy? https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy. Published 7/25/2018. Accessed. 12/20/2023.
ⁱⁱⁱ American Society of Gene +Cell Therapy. Vectors 101. https://patienteducation.asgct.org/gene-therapy-101/vectors-101. Updated 11/05/2021. Accessed 12/21/2023.
^iv Naso MF, Tomkowicz B, Perry WL 3rd, Strohl WR. Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. BioDrugs. 2017 Aug;31(4):317-334.