Osteoarthritis gene therapy: Expanding the scope of genetic therapies

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Gene therapy has traditionally targeted rare Mendelian disorders and cancer. Indeed, of the 25 gene therapies that have gained US Food and Drug Administration (FDA) approval by May 15^th, 2025, 14 address the former category and 11 the latter (https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products). However, gene transfer may also be harnessed to treat common, complex diseases, delivering therapeutic cDNAs into patients who are genetically unremarkable. In such cases, gene therapy does not compensate for a genetic defect or boost immune responses to malignant cells. Instead, it serves as a sophisticated drug delivery system for the encoded therapeutic gene product, enabling the target tissue to synthesize its own medicine endogenously. The potential for extended periods of transgene expression makes this approach particularly attractive for chronic diseases such as osteoarthritis (OA).

Over 30 million individuals in the US and approximately 600 million worldwide suffer from OA,¹ which is debilitating, incurable, and very difficult to treat. Present therapeutic approaches do not slow the progression of the disease, which is why over 850,000 knee joint replacement and 450,000 hip joint replacement surgeries are performed every year in the US.² These make major contributions to the annual $185 billion cost of OA to the US healthcare system.³

The lack of effective, non-surgical treatments for OA is partly a reflection of its earlier dismissal as an inevitable result of wear and tear, resistant to pharmacological intervention. We now know that OA has a complex, multifaceted, biological etiopathophysiology, the study of which has identified several promising therapeutic targets. Of these, interleukin-1 (IL-1) is of particular interest because it is a highly pleiotropic cytokine whose properties identify it as an important mediator of pathologies within joints with OA.

The IL-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 and therefore a potential therapeutic product for treating OA. However, like all proteins, IL-1Ra is difficult to deliver to joints by systemic delivery and rapidly exits joints following intra-articular delivery.⁴ The recombinant form of IL-1Ra, available as the drug anakinra, has been injected into knee joints with OA as part of a clinical trial that demonstrated a small therapeutic effect lasting only a few hours because of rapid clearance.⁵ Unlike traditional delivery systems, local gene transfer has the potential to achieve sustained, therapeutic concentrations of IL-1Ra in joints.⁶

We have developed a novel, self-complementary adeno-associated virus (AAV) vector serotype 2.5 that encodes IL-1Ra (sc-rAAV2.5IL-1Ra) for intra-articular injection. Pre-clinical data show safe and efficient gene transfer to both the synovial lining cells of the joint and chondrocytes throughout the full thickness of the cartilage, with intra-articular IL-1Ra expression persisting for at least a year in equine joints. Therapeutic efficacy was demonstrated in an equine model of OA.^7,8 Following a successful investigational new drug (IND) application, we initiated a phase I clinical trial in which sc-rAAV2.5IL-1Ra was injected into human knee joints with mid-stage OA (ClinicalTrials.gov, identifier NCT02790723). The results were published recently in Science Translational Medicine.⁹

This trial enrolled 3 cohorts of 3 patients with mid-stage OA of the knee who received 1 × 10¹¹ (low dose), 1 × 10¹² (mid-dose), or 1 × 10¹³ (high dose) viral genomes (vg) sc-rAAV2.5IL-1Ra by intra-articular injection. Patients were followed for 1 year. The primary outcome measures were safety and tolerability. Secondary outcome measures included transgene expression, as determined by IL-1Ra concentrations in synovial fluid, humoral and cell-mediated responses to AAV2.5, and patient-reported outcome measures of pain and function. Radiologic assessment of the index knee joints used X-ray and MRI.

Safety issues are of particular importance when targeting a highly prevalent, non-lethal condition like OA. There were no drug-related serious adverse events during the course of this trial. Two patients experienced joint effusions after injection of sc-rAAV2.5IL-1Ra, but these resolved with conservative treatment. There were no important changes in vital signs, physical examination, or clinical laboratory measures. Although neutropenia is a known side effect of IL-1 blockade, neutropenia did not occur in patients receiving sc-rAAV2.5IL-1Ra. Small amounts of vector DNA were detected in peripheral blood 24 h after injection of the vector, but these represented no more than 1% of the administered dose and were cleared within a week. High titers of neutralizing antibodies against AAV2.5 developed in the synovial fluids and sera of patients who received the mid- and high doses of sc-rAAV2.5IL-1Ra, but no cell-mediated responses were detected.

Synovial fluid concentrations of IL-1Ra rose in all patients after injection of the vector. The increase was greater in the two highest vector doses, but patient-to-patient variability obscured any potential difference in expression between the mid- and high-dose cohorts. IL-1Ra expression remained elevated throughout the study period, but in three patients IL-1Ra concentrations fell from peak values. Two of these individuals had experienced effusions after injection of vector, which may be related to the subsequent decline in IL-1Ra expression. Patient-reported outcomes confirmed improvements in pain and function to varying degrees, but in the absence of a placebo group and with small group sizes, these results remain anecdotal. Radiologic assessment showed only minor changes, as expected for a follow-up period of only 1 year.

Overall, the study confirmed the safety and tolerability of sc-rAAV2.5IL-1Ra administered intra-articularly at doses up to 1 × 10¹³ vg while achieving long-term intra-articular expression of the transgene with preliminary evidence of efficacy.

The encouraging data provided by this trial prompted a subsequent, phase 1b study (ClinicalTrials.gov: NCT05835895) involving a greater number of patients and including a placebo group. Among its aims are identifying the optimum dose of sc-rAAV2.5IL-1Ra, evaluating the merit of immune conditioning, and determining potential biomarkers. The last patient recently exited this study, and the data are being analyzed.

As well as expanding the scope of gene therapy into novel therapeutic areas, the example of OA illustrates how local gene therapy can address some of the issues that confound traditional applications of this technology. For example, local gene therapy greatly reduces the amount of vector needed for treating the patient. Our data suggest that 1 × 10¹²–1 × 10¹³ vg will be optimal for treating a human knee. The amounts needed for smaller joints, such as those of the hand, will be much less. This compares favorably with the ≥10¹³ vg/kg dose used for systemic treatment of a Mendelian disorder. The lower viral dose not only lowers considerably the manufacturing costs and thus cost of goods (COGS) but also reduces safety concerns, especially as the joint is a somewhat isolated body cavity; pre-clinical data and results from our clinical trial confirm that there is very little escape of the vector from the joint and no lasting transduction of extra-articular tissues. Intra-articular injection of the vector also simplifies cell targeting. Once injected into the joint, there are few places for the vector to go except to synovium and cartilage, the two primary target tissues.

Given the central role of inflammation in many diseases, sc-rAAV2.5IL-1Ra is likely to be of therapeutic benefit in multiple settings. Moreover, success in treating joint diseases will encourage the further expansion of gene therapies into additional common, non-genetic conditions and related applications, such as regenerative medicine.¹⁰

Declaration of interests

The authors are co-founders of the arthritis gene therapy company Genascence Corp. C.H.E. is a consultant for L&J Bioscience, Cellastra, Inc., and Orthogen AG. P.D.R. is a consultant for L&J Bioscience, Innate Biologics, Glo-Pharma, Infinity Research Labs, and Itasca Therapeutics. T.W.C. has held board or consulting positions with Ethris GmbH, Cardiac Risk Inhibitors, Inc., Exhaura, Ltd., and Catena Biosciences.