2024 OREF Clinical Research Award Celebrates Study of Local Gene Therapy to Treat Osteoarthritis

The Orthopaedic Research and Education Foundation (OREF) Clinical Research Award recognizes outstanding clinical research related to musculoskeletal disease or injury. The 2024 OREF Award was presented to Christopher H. Evans, PhD, from the Mayo Clinic; Steven C. Ghivizzani, PhD, from the University of Florida; and Paul D. Robbins, PhD, from the 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.

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. 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. At present, 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 disease) 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, the John and Posy Krehbiel Professor of Orthopedics at Mayo Clinic and professor of molecular medicine at 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.”

Dr. Evans and his colleagues targeted rheumatoid arthritis (RA) when they began their research 30 years ago at the University of Pittsburgh because, 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 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.

Vectors, which are essentially vehicles that deliver therapeutic genetic materials directly into a cell, are used to transfer genes. The research team explored using self-complementary adeno-associated virus (scAAV), a small virus that can be engineered to deliver DNA to target cells, 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 demonstrated the efficacy of scAAV.IL-1Ra in joints with OA, a successful Investigational New Drug Application was filed with the FDA in 2015. In a phase I clinical trial, nine patients (three cohorts of three patients) with mid-stage disease, symptomatic OA, and failure with at least two conservative treatments prior to the study 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. Patients reported pain (visual analog scale) and function (Western Ontario McMaster University Osteoarthritis Index [WOMAC]) and were followed for 1 year. Outcomes included:

• No serious adverse events were reported.
• Patients reported improved symptoms based on the visual analog scale and WOMAC. Patients who received the lowest dose reported mild and temporary improvement. Patients who received the medium and high doses experienced 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. The elevated expression 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.”

Drs. Evans, Ghivizzani, and Robbins, will be honored at the Your Academy event Wednesday morning.

1. Centers for Disease Control and Prevention: Osteoarthritis. Available at https://www.cdc.gov/arthritis/basics/osteoarthritis.htm.
2. U.S. Food and Drug Administration: What Is Gene Therapy? Available at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy.
3. American Society of Gene + Cell Therapy: Vectors 101. Available at https://patienteducation.asgct.org/gene-therapy-101/vectors-101.
4. Naso MF, Tomkowicz B, Perry WL, et al: Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 2017;31(4):317-34.