A Novel DNA Repair Stimulant Treats ASD

New research has revealed a viable treatment strategy for fragile X syndrome, a leading cause of autism spectrum disorders (ASD) characterized by a hereditary repeat of specific nucleotides within the FMR1 gene’s DNA sequence. The study, undertaken by researchers at Massachusetts General Hospital (MGH), has been published in the journal Cell.

The growth of the trinucleotide repeat CGG within FMR1, which stands for Fragile X Messenger Ribonucleoprotein 1, causes FXS. FMR1 produces a protein called FMRP that is required for brain development; however, the CGG expansion in people born with FXS causes reduced production of this protein, resulting in developmental delays, learning difficulties, and social and behavioral issues. ASD is a developmental disability caused by differences in the brain. One in every 3,000 boys and one in every 6,000 girls suffer from the disease.

“We wondered if we could treat FXS by contracting the trinucleotide repeat in FMR1 and restoring FMRP expression,” explains senior author Jeannie T. Lee, MD, Ph.D., 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, Ph.D. established settings that produce a strong repetitive contraction and full FMR1 reactivation by developing models derived from the cells of FXS patients and exposing the models to varied laboratory conditions. The presence of inhibitors of two kinases known as MEK and BRAF was essential.

Inhibiting these enzymes increased the development of unique nucleic acid structures termed “R-loops” created between DNA and RNA, which cells recognize as DNA damage and so activate repair mechanisms to correct the problem. The repair mechanisms of the cells then remove the enlarged CGG repeats to restore normal CGG levels, allowing cells to re-express the critical 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,” says Lee. “We are now extending the technology to patient neurons and to the brain in animal models.”

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