Researchers at Massachusetts General Hospital (MGH) have discovered that stimulating cells’ DNA repair mechanisms may correct the inherited genetic mutation that defines fragile X syndrome, a leading cause of autism spectrum disorders.

The findings are published in Cell in an article titled, “Site-specific R-loops induce CGG repeat contraction and fragile X gene reactivation.”

“Here, we describe an approach to correct the genetic defect in fragile X syndrome (FXS) via recruitment of endogenous repair mechanisms,” wrote the researchers. “A leading cause of autism spectrum disorders, FXS results from epigenetic silencing of FMR1 due to a congenital trinucleotide (CGG) repeat expansion. By investigating conditions favorable to FMR1 reactivation, we find MEK and BRAF inhibitors that induce a strong repeat contraction and full FMR1 reactivation in cellular models.”

“We wondered if we could treat FXS by contracting the trinucleotide repeat in FMR1 and restoring FMRP expression,” explained senior author Jeannie T. Lee, MD, PhD, a molecular biologist at MGH and a professor of genetics at Harvard Medical School. “While the industry is trying to restore expression by gene therapy and gene editing, our approach was to contract the CGG repeat and restore protein expression by stimulating the body’s own DNA repair mechanisms.”

Lee and postdoctoral fellow and first author, Hun-Goo Lee, PhD, generated models derived from the cells of patients with FXS and exposed the models to different laboratory conditions. They discovered conditions that induce a strong repeat contraction and full FMR1 reactivation. The conditions required the presence of inhibitors of two kinases called MEK and BRAF. Inhibiting these enzymes led to enhanced production of special nucleic acid structures called “R-loops” formed between DNA and RNA, which cells see as DNA damage and therefore trigger repair mechanisms to fix the problem. The cells’ repair mechanisms then excise the expanded CGG repeats to achieve more normal CGG levels, enabling cells to re-express the crucial FMR1 gene.

“Because the disease is caused by the expanded CGG repeat, contracting the repeat through R-loop formation is potentially a one-and-done treatment,” said Lee. “We are now extending the technology to patient neurons and to the brain in animal models.”

Their findings may lead to a potential method of treating FXS in the future.

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