Roche puts its back into fighting SMA

Oral treatment for spinal muscular atrophy appears effective in mice

Zack Anchors
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BASEL, Switzerland—The results of a preclinical study published in early August in Science suggests that an oral treatment for spinal muscular atrophy (SMA) was effective at preventing some of the most debilitating consequences of the disease in mice.
Scientists demonstrated that continuous treatment of mice with SMA increased lifespan, normalized body weight and prevented both disease-related motor dysfunction and neuromuscular deficits. The mice began to be treated with RNA splicing modifiers of the SMN2 gene shortly after birth.
“We know that the gene defect is caused by a mutation in the SMN1 gene, but we currently don’t have a gene replacement therapy available to correct this,” Anirvan Ghosh, head of neuroscience discovery at Roche, a partner in the research, tells DDNews. “So the next best approach in our mind was to figure out a way of restoring SMN protein levels by an alternate method, which is what this paper demonstrates.”
SMA is a genetic disease caused by mutation or deletion of the survival of motor neuron (SMN1) gene. It affects one in approximately 10,000 live births, and in the most severe forms is associated with a high rate of childhood mortality. The disease leads to a progressive loss of motor neurons, muscle weakness and atrophy. The disease mainly affects mainly proximal muscles, including intercostal muscles, and patients often die due to respiratory complications.
“Right now there is no standard treatment that is effective,” says Ghosh. “But there is lots of interest across the industry in trying to develop indication, and we hope this study represents progress in that direction.” Early clinical trials using the oral compounds in healthy volunteers are already underway to determine the safety and tolerability of the approach used in the study.
The findings presented in Science were the result of a research collaboration between Roche Pharma Research and Early Development, PTC Therapeutics, the Spinal Muscular Atrophy Foundation, the University of Southern California and Harvard University.
PTC Therapeutics is a New Jersey-based company focused on the discovery and development of orally administered small-molecule drugs that target post-transcriptional control processes. The SMA Foundation, which helped fund the research, is a nonprofit organization that provides targeted funding of clinical research and novel drug development with the goal of accelerating progress toward a treatment for SMA.
“The findings of this preclinical study contribute significantly to our understanding of SMA and provide further evidence suggesting that our strategy to upregulate SMN with small molecules could be effective,” said Loren Eng, president of the SMA Foundation. “We are proud to have seeded this important work, and we believe it could have a meaningful impact on the lives of patients who suffer from SMA.”
Scientists leading the study identified orally available small molecules that selectively alter the splicing of the SMN2 pre-mRNA to produce stable full-length SMN protein. The SMN2 splicing modifiers that were used penetrated into all mouse tissues tested, including brain, spinal cord and muscle tissues. This resulted in improved SMN2 RNA splicing, which increased SMN protein production in these disease-relevant tissues. The increase in SMN protein prevented the progression of SMA in the mice. These compounds also corrected SMN2 RNA splicing and increased SMN protein levels in cell cultures obtained from SMA patients.
“One of the most exciting outcomes of the study was the very significant improvements across the board in this mice model,” says Ghosh. “When you look at the data, the increase of the survival of the animals is really quite striking, and that increases our confidence that it might hold similar benefits for humans with SMA as well.”
Ghosh says that the study’s outcome also holds significance beyond its potential to lead to an effective treatment for SMA. “This offers an indication that we might be able to develop a new class of small-molecule therapeutics to treat a wide range of genetic disorders,” he says. “Historically, those kinds of disorders have been very hard to treat, and so the ability to have a small-molecule approach like the one used in this study could be of widespread value.”

Zack Anchors

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