Readthrough of premature termination codons for treatment of Rett Syndrome

Allan Jacobson, PhD / Jonathan Watts, PhD | UMASS

$323,000 AWARDED

This project lays the foundation for developing a therapeutic specific to mutations that cause a premature stop, otherwise known as nonsense mutations. These are mutations that end in X, for example, R168X, R270X, R255X, which tell the cell to stop reading the DNA instructions for MeCP2 too early.

What if there was a way for the cell to ignore that premature stop and just continue through it to the correct stopping point? Imagine a railroad track with a sign signaling that part of the track is out. We know that even a small piece of missing track would derail the train. Imagine that this same sign on the track also sends out a message that all incomplete tracks should be completely destroyed. Now imagine a drug that provides a quick fix to the problem by laying down a temporary piece of track to prevent track destruction and allow the train to reach its destination.

The applicants propose to develop a combination treatment that allows the cell to ignore and continue through the premature stop, thus allowing more trains to get to their normal stop destination and create full length functional MECP2.

A key advantage to this approach is that the path to drug development could be fast-tracked. One part of the treatment, called Ataluren, is already approved in 45 countries for Duchenne Muscular Dystrophy. The other molecule resembles a treatment FDA has recently approved, Spinraza. Together the combination treatment may provide a clearer path to FDA approval based on existing precedent.

We are providing 1 year of funding to generate proof of concept data that this approach in fact can generate full length functional MeCP2 in cultured cells. If the preliminary data are convincing the applicants will submit a follow up proposal to begin in vivo mouse work.

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