Osteoarthritis is a debilitating and painful wearing down of joint cartilage tissues. Every year, more than three million people in the U.S. (and millions more worldwide) are diagnosed with the disease. Current therapies consist mainly of either steroids or non-steroidal anti-inflammatory drugs (NSAIDs), both of which are largely ineffective, especially as the disease progresses. Biologics have not been effective thus far, as local biological therapies quickly leave the knee tissues, and systemic biological therapies can cause severe side effects.
An Unexpected Model
When planning preclinical studies for a new biologic, researchers usually evaluate safety and efficacy using smaller animals like mice or rats. Horses are rarely part of the preclinical picture, due in part to their size and maintenance costs. However, for one gene therapy startup company exploring new treatments for osteoarthritis, the horse was a perfect model. Horses’ knee joints were large enough to provide data that correlate with human knees, and horses do not limp unless they feel pain, making them “honest” subjects.
That’s why when Palo Alto, CA-based Genascence wanted to test its arthritis gene therapy candidate (now called GNSC-001), the company’s scientists used 50 horses as models, injecting the gene therapy directly into the animals’ knees and then looking for any pain reduction and structural changes in the joint.
The data were promising enough for Genascence to enter GNSC-001 into clinical trials, according to an article in Endpoints News.
A Joint Effort
Interleukin-1 (IL-1) is a major contributor to the development of osteoarthritis. The drug candidate is a gene that codes the sequence of the IL-1 receptor antagonist and is delivered into the knee by an adeno-associated virus (AAV). Following a successful preclinical phase in horses, Genascence moved to Phase 1 trial with nine patients who had mild osteoarthritis. The Phase 1 study, which tested three dose-escalated cohorts, was a safety study that did not evaluate the effectiveness of GNSC-001. The study results showed no severe adverse events and no signs of neutropenia, abnormally low neutrophils often seen with systemic delivery of IL-1 inhibitors. The company announced its preliminary findings at the annual meeting of the American Society of Gene & Cell Therapy.
The hope is that, by introducing an IL-1 antagonist gene into the affected joint, the therapy will produce copies of the receptor antagonist, reducing the biological damage that IL-1 can wreak on joint tissues. In addition, injecting the AAV-delivered therapy directly into the knee should avoid problems seen in systemic applications of gene therapy.
Overcoming a Rough Start
Systemic gene therapy delivered by AAVs has resulted in promising treatments for a number of disorders such as cancer, blindness, immune and neuronal disorders, and blood disorders including sickle-cell anemia, hemophilias, Gaucher disease, hemochromatosis, and porphyria. However, human host immune responses to the wild-type virus from which the AAV vector is engineered, or to the gene product being delivered, can interfere with the intended therapy and have been known to cause severe adverse events, even death.
In 2007, the U.S. Food and Drug Administration placed a clinical hold on a study being conducted by a firm called Targeted Genetics after one patient died and other patients experienced severe side effects in the Phase 1 study. Post-hoc data was not conclusive and introduced doubt that the drug was adequately injected in the intra-articular space of the knee and whether a second dose of the therapy spurred a severe immune response. Ultimately the trial was allowed to continue, but intra-joint gene therapy was largely avoided from that point forward as the perceived benefits did not outweigh the potential safety risk.
Despite the setbacks experienced by Targeted Genetics, the founders of Genascence started their work in taking gene therapies away from their typical application—single-gene rare diseases—and into broader areas like immunology. The success of GNSC-001 so far is an improvement over previous attempts at gene therapies for arthritis and may overcome the patient safety issues of the past. According to Genascence CEO Thomas Chalberg, “Using a localized gene therapy enclosed in the knee joint, meanwhile, offers the opportunity to use minuscule amounts of the AAV vector used to transport the therapy and prevent any ‘systemic leakage’ into other tissues.”
As for GNSC-001’s future, Genascence is moving toward Phase 2 trials, which will study efficacy as well as safety. In addition, it is looking at applying the drug to other indications of osteoarthritis (in hips, hands, and spines), as well as possibly developing other localized immunology therapies.
Meanwhile, horses are proving themselves to be a clinically relevant model in areas beyond degenerative joint disease. They also suffer from tendinopathy with similar pathophysiology to humans in terms of etiology and risk factors such as over-exercise and age. Perhaps more surprisingly, Severe Equine Asthma shares many features with human asthma and could also prove to be a helpful model for clinical trials. What remains to be seen is if the potential of clinical relevance will overcome the barrier of cost, not to mention public perception, compared to more traditional, smaller animal models.
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