Researchers at Mizzou — the University of Missouri — have started a new company, Shift Pharmaceuticals, to test the clinical effectiveness of a molecule that may help improve the outcomes of people with spinal muscular atrophy (SMA).
SMA develops due to mutations in the survival motor neuron-1 (SMN1) gene. As a result, a key protein called SMN is produced at lower levels, impairing the survival of motor nerve cells.
A second gene called SMN2, a nearly identical copy of SMN1, codes for a functional SMN protein. But due to a small change in the gene, the amount of SMN protein produced is much lower than that required for normal nerve cell function.
In 2016, University of Missouri College of Veterinary Medicine researchers, led by Christian L. Lorson, developed a molecule — an antisense oligonucleotide (ASO) — that targets the SMN2 gene and stimulates an increased production of the SMN protein.
“More than a decade of research has guided our fine-tuning of a potential therapeutic for SMA and what it does,” Chris Lorson said in a press release.
“We identified a genetic ‘switch’ that turns bits and pieces of the genetic code on and off. Using this information, we then developed a molecule called an antisense oligonucleotide, or ASO, that essentially is a synthetic string of nucleic acid that binds to a specific sequence in the SMN2 gene,” he added.
The compound was found to be highly effective in animal models of SMA, where it was administered via an intracerebroventricular injection — directly into a specific region of the brain — increased the animals’ lifespan. The treatment showed a strong dose-response and high specificity for SMN2.
“Our current treatment helps the body induce a backup mechanism to combat the disease and extends survival in mice with SMA giving them more mobility,” Lorson said. “This compound helps produce the right form of SMN, the one that was only produced at very low levels before. The mice are able to move around and live fairly normal lives.”
Researchers at Shift Pharmaceuticals will now perform additional studies that, if successful, may help take their lead molecule into clinical trials. The company has recently received a Technology and Therapeutic Development Grant from the U.S. Department of Defense, through the congressionally directed medical research program, a valuable aid in moving the compound closer to the clinic.