MDA 2025: INS1202 gene therapy shows promise in SOD1-ALS mice
A single dose of investigational treatment boosted motor function, survival
A single dose of Insmed’s investigational gene therapy INS1202 preserved motor function and prolonged survival in a mouse model of amyotrophic lateral sclerosis (ALS) associated with SOD1 gene mutations.
The therapy was also found to protect against nerve cell loss and had other beneficial effects on disease-related biomarkers.
“These preclinical data show very high efficacy that translates not only in improvement in survival and motor performance, but also in all of the biomarkers that we have measured,” Laura Ferraiuolo, PhD, an executive director in research and development at Insmed, said in a presentation at this week’s Muscular Dystrophy Association’s (MDA) Clinical & Scientific Conference in Dallas. The talk was titled, “CSF Delivery of INS1202 AAV9-SOD1-shRNA rescues muscle function and hallmarks of neurodegeneration in a disease model of ALS.”
In ALS, the loss of motor neurons, the specialized nerve cells involved in muscle control, leads to progressive muscle weakness and related symptoms. Up to 20% of familial ALS and around 2% of sporadic ALS cases are tied to mutations in the SOD1 gene that result in a toxic version of the SOD1 protein being produced that clumps up and damages motor neurons.
INS1202 is designed to reduce SOD1 production, including the toxic version that drives ALS neurodegeneration, the expectation being that this will slow disease progression.
When the information in a gene is used to make a protein, it’s first converted into an intermediate molecule called messenger RNA (mRNA) that can travel to the cell’s protein-making machinery and serve as a template for protein production. INS1202 contains a lab-made molecule called a short hairpin RNA that binds to SOD1 mRNA and causes it to be degraded. This prevents SOD1 from being produced.
The treatment is packaged up into a common viral carrier, called adeno-associated virus 9 (AAV9), that helps it be taken up by both neurons and non-neuronal cells, according to Ferraiuolo. In people, it’s eventually intended to be delivered via a one-time infusion into the spinal canal.
Testing INS1202 in mice with SOD1-associated ALS
The scientists tested INS1202’s effects in a mouse model of SOD1-associated ALS. At a day old — before any ALS symptoms were evident — some mice received a one-time injection of INS1202 directly into the fluid-filled spaces of the brain and others underwent the same procedure, but didn’t receive any active treatment.
Results showed INS1202 extended survival in the ALS model by up to 70%. While untreated mice lived, on average for 129 days, or around four months, some mice given INS1202 survived up to 300 days, nearly 10 months, according to Ferraiuolo.
INS1202 also led to dose-dependent gains in a test of motor coordination and endurance, with the highest dose significantly improving motor function by 90% relative to the untreated group. The treatment also boosted muscle force in the ALS mouse model, which may be a more clinically-relevant measure of the functional effects of INS1202, Ferraiuolo said.
While mice that didn’t receive INS1202 showed an up to 70% loss of motor neurons in the spinal cord by the time they were around 4 months old, these cells were significantly preserved at levels similar to healthy mice in those that received the treatment.
Effect on ALS biomarkers
Consistently, blood levels of neurofilament light chain (NfL), a biomarker of nerve damage that’s elevated in ALS, were significantly lower in treated mice, with levels being similar to healthy animals.
NfL levels in INS1202-treated mice collected at later timepoints — when their untreated counterparts were already severely affected by the disease — were still substantially lower than levels in untreated mice at early, presymptomatic stages.
“So we really have a very profound efficacy here,” Ferraiuolo said.
INS1202 also appeared to prevent the activation of glia, a class of nerve support cells including astrocytes and microglia that contribute to neuroinflammation in ALS.
While motor neurons are “the star of the show,” according to Ferraiuolo, these other cell types are also important contributors to disease progression, so INS1202’s ability to target them is notable. While AAV9 is not really effective at targeting microglia, there might be a “positive crosstalk between astrocytes and microglia,” leading to a reduced activation of these cells in the process.
The beneficial efficacy data stemmed from the treatment’s ability to significantly reduce levels of the mutant SOD1 protein, by about 50%, in the brain and spinal cord. In nonhuman primates and human cell models, this reduction appears to be even higher, by up to 80%.
Ferraiuolo sai the ultimate goal of treatment in people would be similar to the mouse studies — to treat patients with SOD1 mutations early, preventing disease progression while they’re presymptomatic. She noted, however, that in other experiments, data suggest the treatment may slow disease progression even when administered after symptom onset, which could be the focus of initial clinical trials.
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