Research Yields Oral Compounds That Are Able to Prevent SMA Progression in Mice

A collaborative international study published in the renowned journal Science revealed that specific small-molecule compounds are effective in preventing spinal muscular atrophy (SMA) progression in mouse models. The study is entitled “SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.”

SMA is the leading genetic cause of death in infants worldwide, affecting approximately 1 in 10,000 live births. It is a rare, devastating motor neuron disease, characterized by the degeneration of nerves controlling muscles and voluntary movement, resulting in muscle weakness, atrophy, paralysis and eventually death. Patients often succumb due to respiratory failure, as the disease affects muscles in the chest. SMA is the result of a mutation or deletion in a gene called survival of motor neuron 1 (SMN1), which causes insufficient production of the SMN protein. SMA has no approved treatment.

Besides SMN1, humans also have an SMN2 variant of the protein, although it is mainly produced as an unstable and shortened version due to a single nucleotide difference in the gene, and therefore cannot compensate for SMN1 loss. Researchers have been studying the possibility of modifying SMN2 to be expressed mainly as a full-length protein, and consequently increase the protein levels of functional SMN as a therapeutic strategy for SMA.

Researchers from the biopharmaceutical company PTC Therapeutics, Inc., as well as from University of Southern California in Los Angeles, Harvard University, the SMA Foundation and from Roche Pharmaceutical Research and Early Development were involved in a preclinical study to identify RNA splicing modifiers of SMN2 gene to promote expression of the gene as a stable full-length protein.

The research team found that continuous oral treatment of SMA mouse models with these specific compounds, starting early after birth, resulted in an increase of SMN protein levels that led to an increased life span, normalized body weight and most importantly, prevented both motor dysfunction and neuromuscular disabilities. In addition, these compounds were also found to be effective in assays based on cell cultures derived from SMA patients.

“Although still preclinical, these results demonstrate how SMN2 splicing modifiers could correct the molecular deficit that causes SMA,” said Dr. Luca Santarelli, one of the study’s authors and Head of Neuroscience, Ophthalmology and Rare Diseases at Roche, in a news release. “This study represents an important step towards developing a potential therapeutic option for this devastating and currently untreatable condition. Early clinical trials are currently underway to determine the safety and tolerability of this approach.”

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“The investigational compounds used in this study represent the first orally available SMN2 splicing modifiers for SMA,” noted Dr. Stuart Peltz, CEO of PTC Therapeutics, Inc. “Using the experience and expertise in RNA biology we have gained at PTC over the last 16 years, we used our alternative splicing technology to identify and subsequently optimize investigational compounds that target the SMN2 splicing to produce the SMN protein. Our unique partnership with Roche and the SMA Foundation has allowed this project to rapidly move into clinical development.”

“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,” concluded the President of the SMA Foundation, Dr. Loren Eng. “We are proud to have seeded this important work — we believe it could have a meaningful impact on the lives of patients who suffer from SMA.”