Methods and compounds for the treatments of spinal muscular atrophy and ALS

Scientists in the Rubin laboratory have carried out an image-based screen of pharmacologically active small molecules to find compounds that increase SMN in patient fibroblasts. They have discovered more than 150 active compounds that fell into several classes that were able to increase cellular SMN. Among the most important was the RTK–PI3K–AKT–GSK-3 signaling cascade. Glycogen synthase kinase 3 (GSK-3) is a particularly key druggable intracellular target, and inhibitors of GSK-3 not only increase SMN but rescue motor neuron death. We believe that this is the first time that an SMA screen has produced compounds that have such a striking effect on a major component of the disease. Future work will be directed at testing GSK-3 inhibitors and other modulators of intracellular signaling in mouse models of SMA.


Spinal Muscular Atrophy (SMA) is the leading genetic cause of death in infants. This neurodegenerative disease results from diminished levels of the protein Survival of Motor Neuron (SMN) in motor neurons and other cell types, such as muscle. Data derived from SMA patients and from SMA mouse models suggest that therapeutics that elevate Survival of Motor Neuron (SMN) levels will be effective in treating this disease. Current treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. No high-throughput screen has been performed to identify drug compounds that modulate SMN levels in cells. Therefore, there is an unmet need in compounds and methods for direct treatments of SMA and other neurodegenerative disorders that are affected by SMN levels.

Intellectual Property Status: Patent(s) Pending