RNA-editing as a gene therapy approach for Rett Syndrome

Guoping Feng, PhD /Feng Zhang, PhD /Robert Desimone, PhD MIT/Broad/Harvard

$2,332,000 AWARDED

Guoping Feng is a distinguished neuroscientist who has significantly advanced the field of neurodevelopmental and psychiatric disorders through his work in deciphering how neurons communicate with each other. Now, he and his esteemed colleagues are focused on Rett.

This project is being led by a world-class group of investigators that includes Feng Zhang, one of the discoverers of CRISPR. The goal is to develop therapeutics using the CRISPR/Cas13 platform that can edit RNA and fix MECP2 mutations via a one-time injection.

The investigators are starting with G > A mutations within MECP2 because the enzyme that can restore the A base to a G base is known. G > A mutations represent an A in the sequence when it should be a G.  G>A editing will be accomplished using a two-component protein. One component recognizes the specific RNA sequence where the mutation lurks. The second component is the editing enzyme that can convert the mutated nucleotide base, in this case A back to the correct base, G.

The vast majority of Rett-causing mutations however are C > T mutations. The enzyme that can revert a T base back to the base that should have been there originally, a C, is still unknown. The investigators will take on the bold challenge of discovering this enzyme and then develop the necessary two-component proteins to address these mutations.

Importantly Dr. Feng recently received a sizable NIH grant from the Somatic Cell Genome Editing Program. RSRT funding will leverage this investment and facilitate applying the learnings specifically to Rett Syndrome.

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