Could Gene Therapy for RA Soon Be Ready to ‘Take Off’?

The search for gene therapies to treat rheumatoid arthritis (RA) has moved in fits and starts over the past two decades, with trials starting and stopping, and their focus shifting to osteoarthritis (OA). One gene therapy trial in OA is under way and another in RA is close to reaching human study, but that’s a year or more away. The road for gene therapies in RA is complicated, costly and fraught with obstacles, as researchers explain it.

But it is also promising, with active research into a host of gene-editing strategies to modulate the immune response and reduce inflammation in RA. Several approaches involve using CRISPR-Cas9 technology to change pathogenic gene alleles into healthy ones or to engineer cells that secrete therapeutic cytokines in response to inflammatory signals. Another approach involves placing gene vectors directly into the affected joints.

“It’s very promising,” is how Christopher Evans, PhD, a researcher at Mayo Clinic in Rochester, Minnesota, summarized the outlook for gene therapy to treat RA and OA. “The basic concept is entering the mainstream, and the volume of preclinical research has picked up considerably.”

He cited a small number of clinical trials and a few startup companies that are developing gene therapies for OA and RA. “Large pharmaceutical companies are watching this area carefully, without committing,” Evans said. “Once clinical trials start to show clear evidence of safety and efficacy, the field will take off.”

A key to some of the gene therapy approaches for potentially treating RA lies in CRISPR-Cas gene editing. CRISPR-associated protein enzymes (Cas) use RNA guide strands to locate specific DNA sequences where they employ a predetermined enzymatic pathway to cut the DNA and introduce new DNA sequences in a cell’s genome, including those of bone marrow stem cells that go on to become T and B lymphocytes, which play a pivotal role in the pathogenesis of RA.

CRISPR Therapy Ready for Human Study

In the United States, RG0401, a CRISPR-Cas9 gene therapy, is ready to move into phase 1 human trials next year, Brian Freed, PhD, cofounder and chief scientific officer of RheumaGen, Aurora, Colorado, company developing the treatment, told Medscape Medical News.

The therapy, which grew out of Freed’s work as a professor of medicine and immunology at the University of Colorado Anschutz Medical Campus in Aurora, Colorado, is designed for patients with RA who have failed existing therapies. Freed explained that RG0401 targets an amino acid within a certain allele of the HLA-DRB1 gene that confers high risk for severe RA. RG0401 edits the allele to remove this high risk–conferring amino acid and instead expresses an amino acid that makes the resulting protein bind much less strongly to self-peptides such as collagen. RG0401 would be delivered through an autologous transplant in which the patient’s stem cells are collected from the bone marrow, their high-risk HLA-DRB1 allele is edited, and then the edited stem cells are reinfused. Antigen-presenting cells such as macrophages, monocytes, and dendritic cells that have this edited HLA-DRB1 allele then go on to replace prior cells of their type without the DNA marker change, without causing the global immunosuppression found with current therapeutic drugs.

Freed’s research team is also looking to test RG0401 in editing another DNA marker in HLA-DRB1 to further reduce the resulting protein’s ability to bind to most other peptides, including collagen. “So what we’re doing right now is quantitating how much change in peptide repertoire do we get with those two different ways of doing it, and, therefore which one is better?” He said long-term results of the phase 1 trial should answer that question.

Other CRISPR Treatment Approaches

In his laboratory at the University of Washington in St. Louis, Farshid Guilak, PhD, has studied using CRISPR-Cas9 genome editing technology to engineer cells that secrete therapeutic agents in response to inflammatory signals in OA. But similarities exist between OA and RA, Guilak told Medscape Medical News.

“It’s been shown that osteoarthritis has an inflammatory component, not unlike rheumatoid arthritis,” he said. “It’s a multifaceted, complex disease, but a lot of the same cytokines that are used as treatment targets in rheumatoid arthritis are present and functioning in osteoarthritis.” Risk factors for OA, such as joint injury or obesity, cause increases in the same cytokines complicit in RA — namely, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) — he said.

Guilak and his research team reported in a 2021 study that their editing approach targets induced pluripotent stem cells to reprogram gene circuits so they can sense changing levels of inflammatory cytokines and trigger a therapeutic response.

“When these cells see inflammation, instead of making more proinflammatory mediators that cause degradation and pain, we divert that pathway so they make the right drug,” he said. “So for example, when a cell sees TNF, it now makes the natural gene that inhibits TNF, such as soluble TNF receptor 1. So this is basically making a drug factory in your cells, and it responds to the inflammation.”

The platform uses a small cartilage implant with cells seeded onto woven scaffolds, which is then placed under the skin of mice. “So instead of just gushing out drug continuously, like a normal gene therapy would, it only makes drugs when you have high levels of controlled levels of TNF or IL-1 or IL-6. So this way, it’s a feedback-controlled system.”

So far their work has been in animal models, but the approach has shown sustainability. “We’ve tracked them out 6, 8 months in an animal model, and there are still signs the cells are chugging away,” Guilak said.

Guilak has reported on another gene therapy approach that uses a different pathway, editing of the fat-1 gene, to prevent obesity and OA. “We created a gene therapy that delivers an enzyme that converts the bad fats into good fats inside your body,” he said. “Basically, it’s a desaturase that converts omega-6 fatty acids into omega-3 fatty acids. What we like to say is, it converts your French fry oil into fish oil.” The research is still preclinical.

An Adeno-Associated Virus (AAV) Vector Placed in the Knee

OA is also the focus of Evans’s research at Mayo Clinic. It has resulted in a gene therapy called GNSC-001, a recombinant AAVvector that encodes an IL-1 receptor antagonist (IL-1Ra) to inhibit IL-1 expression. Evans cofounded a company called Genascence that is conducting an ongoing phase 1b clinical trial of an intra-articular injection of GNSC-001 in 67 patients with knee OA. Six-month data from the trial that were announced last month showed acceptable safety and tolerability and a signal of biological activity. The investigational agent received Fast Track Designation from the US Food and Drug Administration (FDA) in November 2024.

“Data from preclinical studies in horses, and now preliminary data from humans, suggest that expression of IL-1Ra can last for at least a year,” Evans told Medscape Medical News. “The gene therapy strategy was developed because recombinant IL-1Ra protein, other small molecules, and biologics don’t penetrate the cartilage efficiently and are rapidly removed from the joint via the lymphatics.”

The research has potential application in RA, Evans said. “Strangely enough, when we started this work we were targeting rheumatoid arthritis and actually completed a phase 1 clinical trial with different technology that we no longer use,” he said, noting that results of the study were published in 2005. A small study in Germany was shut down after two patients were enrolled “because of serious adverse events in an unrelated clinical trial … that used the same retroviral vector backbone,” according to the authors. “There was anecdotal evidence of symptomatic improvement,” Evans added.

“I would be very interested in returning to RA and applying our vector in this setting” he said.

Challenges for Gene Therapy in RA

The development of gene therapy in RA and other autoimmune diseases faces a number of hurdles. “These are complex, multifactorial diseases,” Guilak said. “So inhibiting just one pathway, especially in osteoarthritis, may not be enough.”

One challenge is to “multiplex” drug delivery in a way that will get cells that produce cytokines to neutralize all the major disease pathways, he said. “A lot of the challenges for us will be on the regulatory side, of getting FDA approval to use a cell-based therapy that’s genetically modified for what’s often considered a nonlethal disease,” Guilak said.

Another challenge with gene therapy for rheumatologic disease is a lack of familiarity with delivering vectors. “In the field of rheumatology, this is beyond the norm; they’re not used to doing bone marrow transplants,” he said. “Conceptually, this seems much more dangerous than current therapies.” However, he pointed out that existing therapies, such as methotrexate and TNF-alpha inhibitors, are “very immunosuppressive.”

The costs of doing the bone marrow transplants can be another hurdle, Freed said. Access to that expertise, as Freed’s research team has with the bone marrow team at the University of Colorado medical campus, can reduce the cost of moving gene therapy into trials by about 90%, he said.

Evans is cofounder of Genascence Corp. Freed is cofounder of RheumaGen. Guilak is founder and chairman of Cytex Therapeutics.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.