Targeted stabilization of Munc18-1 function via pharmacological chaperones.

Heterozygous de novo mutations in the neuronal protein Munc18-1 cause syndromic neurological symptoms, including severe epilepsy, intellectual disability, developmental delay, ataxia, and tremor. No disease-modifying therapy exists to treat these disorders, and while chemical chaperones have been shown to alleviate neuronal dysfunction caused by missense mutations in Munc18-1, their required high concentrations and potential toxicity necessitate a Munc18-1-targeted therapy. Munc18-1 is essential for neurotransmitter release, and mutations in Munc18-1 have been shown to cause neuronal dysfunction via aggregation and co-aggregation of the wild-type protein, reducing functional Munc18-1 levels well below hemizygous levels. Here, we identify two pharmacological chaperones via structure-based drug design, that bind to wild-type and mutant Munc18-1, and revert Munc18-1 aggregation and neuronal dysfunction in vitro and in vivo, providing the first targeted treatment strategy for these severe pediatric encephalopathies.