ARTICLE | Discovery & Translation

Excision of CGG repeats in fragile X; plus VLP’s saRNA COVID vaccine and more

BioCentury’s roundup of translational news

May 26, 2023 10:16 PM UTC

A Harvard Medical School team led by Fulcrum Therapeutics Inc. (NASDAQ:FULC) co-founder Jeannie Lee revealed in Cell that MEK and BRAF inhibitors together elicited CGG repeat contraction and full FMR1 reactivation in an induced pluripotent stem cell (iPSC) line from a male fragile X syndrome patient with a full mutation, defined as greater than 200 copies of the CGG repeat.

The mechanism by which the kinase inhibitors led to CGG repeat reduction involved triggering DNA damage repair pathways. The process started with the kinase inhibitors upregulating TET1 and TET2, which demethylated the FMR1 promoter. Demethylation induced de novo transcription from FMR1 and led to the formation of RNA polymerase II-mediated R-loops that became aberrantly stabilized over the long CGG repeats. The aberrant R-loops in turn triggered DNA damage signals, which were then resolved by repair pathways. Resolution of the R-loops reduced the tract of CGG repeats to a premutation status, meaning less than 200 but greater than 50 repeats. The treatment led to FMR1 reactivation and restoration of FMRP expression. ...