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Hope for Spinal Muscular Atrophy Patients

There have been scientific studies with more scintillating, attention-grabbing titles, but “A screen for regulators of survival of motor neuron protein levels,” contains encouraging news for the parents of children suffering from spinal muscular atrophy (SMA), as well as for Harvard Stem Cell Institue (HSCI) Therapeutic Screening Center.

SMA is a devastating genetic motor neuron disease, functionally very similar to amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig’s disease. SMA affects newborns and young children and claims the lives of 70 percent its victims before their third birthday. At this time there is no effective treatment or cure for SMA, which strikes about 1 in every 10,000 children born in the US.

At this point, two important things are known about the course of SMA — it occurs when levels of a ubiquitous protein called survival of motor neuron (SMN) drop to levels of 25 percent or less of normal, leading inexorably to the death of the patient; and, drugs that elevate SMN may be effective in treating the disease.

Led by Lee Rubin, PhD, Director of HSCI’s Therapeutic Screening Center and a professor in Harvard’s Department of Stem Cell and Regenerative Biology, HSCI researchers are using motor neurons derived from stem cells to screen for drugs that may treat the disease.

“We’ve been looking for small molecules, drug-like molecules, that could be used to treat this in kids by elevating the levels of the survival of motor neuron protein,” Rubin said.

“We did a very sophisticated and difficult screen” in HSCI’s Therapeutic Screening Center, a facility more often found in a pharmaceutical company research center than in an academic institute, “which involved growing motor neurons derived from stem cells in culture, and imaging them using an automated high-throughput screening microscope. We were looking for any molecule that would raise the level of SMN,” Rubin said.

The experiments resulted in the identification of approximately 150 molecules which raised the levels of SMN, and the team is now focused on subsets that are the most drug-like.

“In the paper in Nature Chemical Biology we described one of these drug-like substances that acts as a kinase inhibitor. It not only causes the level of SMN to stabilize but it increases it over time,” Rubin said. “And when that happens, it does just what we were hoping for — it keeps alive motor neurons that would otherwise die.”

“The next steps in this project are to start testing this compound and others in mouse models of spinal muscular atrophy, and then we would be very excited to start moving some of these substances into clinical trials,” Rubin said.