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New research by Massachusetts General Hospital (MGH) has identified a potential method for treating Fragile X syndrome, a leading cause of autism spectrum disorders that is characterized by an inherited repeat of certain nucleotides within the DNA sequence of the FMR1 gene. The researchers found that stimulating cells’ DNA repair mechanisms may correct the inherited genetic defect that defines fragile X syndrome.

Their research is published in Cell.

“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.

The researchers are now extending the technology to patient neurons and to the brain in animal models.

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