The idea behind intra-articular gene therapy for treating osteoarthritis (OA) is to deliver the gene-altering vector or cells directly to the precise site of the disease with a single injection — so to speak. That is, it delivers the therapy directly into the affected joint in a single shot, eliminating the need for ongoing treatments.

The knee has drawn much attention from gene therapy researchers because clinicians treating OA have so much experience injecting corticosteroids directly into the joint. ClinicalTrials.gov shows five investigative intra-articular gene therapy platforms for knee OA in human trials at sites in the US.

However, the multifaceted nature of OA means that more than one pathway is likely causing the condition, suggesting that a gene therapy targeting one pathway may need to be combined with others.

“Many people have had a shot of cortisone in their knee, except we’re not injecting the steroid,” said Christopher Evans, PhD, Mayo Clinic researcher whose laboratory has developed a gene therapy for OA. “We’re injecting a virus that carries a therapeutic gene or a gene that will promote and direct the synthesis of a therapeutic protein.”

Once that protein gets into the joint, “it does what its biology has endowed it to do,” he said — that is, it deliver its DNA to the cell nuclei so that the cells can start making the therapeutic protein in large amounts for months or years.

Riding the Gene Therapy Wave

This is all part of a resurgence in gene therapy that has occurred over the past two decades, since the FDA in 2003 suspended human gene therapy trials. That decision came after two children in a gene therapy trial in France developed a leukemia-like disease, and a teen volunteer in a gene therapy study at the University of Pennsylvania in Philadelphia died. “That kind of shut down the industry quite a bit,” said Daniel Grande, PhD, biomedical researcher at Feinstein Institutes for Medical Research at Northwell Health in Manhasset, New York. “Trying to raise money for gene therapy was nonexistent for many years.”

Those mishaps were attributed to the use of adenoviral vectors, which promoted inflammation, he said. Since then, safer recombinant adeno-associated virus (rAAV) vectors have ushered in a resurgence in gene therapy, he said. “I’m quite excited about it,” Grande said.

All the OA gene therapies in the pipeline align with the pathophysiologic properties of OA, said Nancy Lane, MD, rheumatologist and researcher at the University of California Davis School of Medicine in Sacramento, California. “The issue is that with the introduction of these molecules — some with a virus, others with molecules in which there could be an immunologic immunologic reaction — there is a requirement for some of them to give steroids/glucocorticoids with the medication to reduce the potential for an immune response,” she said.

Ultimately, OA is a joint disease, she said. “If we can get something into the joint that continuously reduces inflammation, resulting in less pain and slower deterioration of the joint, that would be a major step forward.”

The ultimate goal, Evans said, is to have a therapy that reduces joint pain and restores or improves flexibility with a single injection. All but one of the five investigational gene-based disease-modifying OA drugs have been evaluated as single-injection treatments.

PCRX-201 (Formerly Called FX201)

PCRX-201 (enekinragene inzadenovec) has been described in a clinical trial for low back pain as a high-capacity, helper virus-dependent adenovirus serotype 5 vector that expresses interleukin (IL)-1 receptor antagonist (IL-1Ra). A phase 2 clinical trial evaluating the treatment in knee OA is currently recruiting (n = 135).

Results of a phase 1 trial of 72 patients with knee OA showed that those who received an intra-articular corticosteroid injection before getting the PCRX-201 injection had greater improvement in pain scores than those who did not, so pretreatment corticosteroid injections are mandated in the phase 2 trial. In the phase 1 trial, a single intra-articular injection of PCRX-201 with corticosteroid pretreatment demonstrated an acceptable safety profile and sustained pain relief for up to 156 weeks.

PCRX-201 requires a pretreatment corticosteroid because “the adenovirus is very inflammatory,” Evans said. The phase 1 results “seem reasonably encouraging in terms of symptomatic relief.”

GNSC-001

Like PCRX-201, GNSC-001 delivers IL-1Ra via a serotype 2.5 rAAV. Results of a phase 1 trial of 67 patients demonstrated an acceptable safety profile and sustained expression of IL-1Ra in the synovial fluid of the knee. Like the PCRX-201 trial, patients who had pretreatment with a corticosteroid injection had increased IL-1Ra expression.

“The extra steroid actually increases the viral replication in the joint, which then usually means that more gene is inserted into the DNA and potentially more activity,” Lane said. 

Evans, who has overseen research of GNSC-001 at his Mayo Clinic laboratory, said a phase 2/3 study is pending. The FDA in 2024 granted it Fast Track designation.

XT-150

What makes XT-150 different from the IL-1Ra-expressing viral vectors is that it is a nonviral, plasmid gene therapy designed to express a proprietary variant of IL-10, Howard Rutman, MD, MBA, chief medical officer of Xalud Therapeutics, New York City, reported at the Osteoarthritis Research Society International (OARSI) World Congress on Osteoarthritis 2024.

A phase 2 clinical trial of 289 patients had been completed with results reported last year. The results showed that patients who received two injections of one of two doses of XT-150 — either a low dose of 0.15 mg/mL or a high dose of 0.45 mg/mL — had lower response rates and higher nonresponse rates than the placebo group. The primary outcome was a 30% improvement from baseline in the Western Ontario and McMasters Universities Arthritis Index pain score.

XT-150 developer Xalud Therapeutics has not reported any update on the program since 2023 and did not respond to a request for updated information.

The plasmid is designed to target the nerve endings, Evans said. “They’re trying to shut down nociception,” he said. Grande said because XT-150 is an anti-inflammatory cytokine, “That seems to me to be a very interesting approach.”

TissueGene-C (TG-C)

This cellular gene therapy uses a unique delivery system consisting of allogeneic human chondrocytes expressing transforming growth factor (TGF)-beta 1. It has been evaluated in nine separate clinical trials over the past decade or so, with two phase 3 trials (NCT03291470 and NCT03203330) in 1066 patients with mild or moderate osteoarthritis ongoing but not recruiting.

A readout of 33 patients in the phase 2 trial and 110 from the phase 3 trial who completed 2 years of follow-up showed that the proportion of treated patients who needed total knee arthroplasty was less than half the rate of patients who were not treated with TG-C (7% at 5.7 years after OA diagnosis vs 15.5% at 5.1 years after diagnosis). The data were reported last year at OARSI 2025. At the 2026 J.P. Morgan Healthcare Conference in January, Jeon Seung-ho, CEO of Kolon TissueGene, said the company would announce top-line phase 3 data in July.

“The concept is to return the joint, as an organ system, to homeostasis,” Grande said. Through this mechanism, macrophages convert from M1 type to M2, “to directly target M2s where you can have amelioration of symptoms and a return to joint homeostasis,” he added. “I think that’s a more profitable way to go for treating the disease itself.”

The phase 3 results “are going to be really pivotal,” Evans said. “If it’s successful,” he said, “it will legitimize the whole field” of cellular-based gene therapy.

ICM-203

ICM-203 is an rAAV vector designed to express a truncated form of the transcription factor Nkx3.2, which plays a key role in the activity of chondrocytes, the cells found only in the articular cartilage, and synoviocytes, which are cells found in the synovial membrane. 

A phase 1/2 study is planned but not yet recruiting, while another phase 1/2 trial in Australia is in final data analysis. A readout of the latter, presented last year at the American Society of Gene and Cell Therapy annual meeting, demonstrated that ICM-203 was safe and well-tolerated in patients and seemed superior to placebo in those with negative serum neutralizing antibody titers at enrollment.

After a year of treatment in eight patients, the study found no significant changes in articular cartilage and osteophytes. ICM-203 developer ICM Biotech Australia has not reported any update on the program since last year and did not respond to a request for updated information.

Which Is Most Promising?

TG-C may be the most promising at this point, Grande said, and not just because it’s the only one in a phase 3 study. “They explore more of the concept of returning the joint to homeostasis,” he said.

TG-C seems to be the furthest along, Evans said. He expects the sponsoring company, Kolon TissueGene, to submit a biologics license application to the FDA in the near future. 

A successful gene therapy strategy for knee OA may need to target multiple pathways, Grande said. “My prediction is that it may require not just one signaling pathway, but multiple ones,” Grande said. One example would be combining a therapy that reduces hypertrophic chondrocytes, such as ICM-203, with the TGF-beta1-expressing properties of TG-C, or with one of the candidates that express IL-1Ra, he said.

A more global approach to OA involves M1-to-M2 macrophage transition, as with the TG-C cell-based treatment, he said. Grande has a paper in press that confirms previously published research that the M1-M2 transition plays a key role in OA progression and severity.

“Remember, osteoarthritis isn’t just the cartilage. It’s the synovium, it’s the subchondral bone, it’s the fat pad, it’s the synovial fluid — it’s a multiplex disease,” he said. “So, when you try to block IL-1, you will get some improvements,” but there is redundancy in the pathobiology of OA, “such that targeting one thing is not going to necessarily” improve all aspects of the health of the joint.

Evans is the co-founder of Genascence, and Lane reported being on its advisory board. Grande reported having no relevant financial relationships. 

Richard Mark Kirkner is a medical journalist based in Philadelphia.