Researchers identify a potential method for treating fragile X syndrome

A recent study published in the journal Cell has revealed a potential therapeutic approach for fragile X syndrome (FXS), a prominent cause of autism spectrum disorders. The research, conducted by scientists from Massachusetts General Hospital (MGH), highlights the impact of an inherited repetition of specific nucleotides within the DNA sequence of the FMR1 gene.

Fragile X syndrome arises from an expansion of the trinucleotide repeat CGG in the FMR1 gene, where FMR1 represents Fragile X Messenger Ribonucleoprotein 1. FMR1 plays a vital role in brain development by producing a protein called FMRP. However, individuals born with FXS experience reduced expression of this protein due to the CGG expansion, resulting in developmental delays, learning disabilities, and difficulties with social and behavioral patterns. The disorder affects approximately 1 in 3,000 boys and 1 in 6,000 girls.

''We wondered if we could treat FXS by contracting the trinucleotide repeat in FMR1 and restoring FMRP expression. 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."

Through the generation of models derived from FXS patients' cells and subjecting them to various laboratory conditions, Dr. Hun-Goo Lee, in collaboration with Lee and other researchers, made a significant discovery. They identified specific conditions that can induce a substantial contraction of repeated sequences and reactivate the FMR1 gene in its entirety. These conditions required the presence of inhibitors targeting two kinases known as MEK and BRAF.

Inhibiting these enzymes resulted in an increased formation of "R-loops," unique structures formed between DNA and RNA. These R-loops were perceived by cells as DNA damage, prompting the activation of repair mechanisms to resolve the issue. As part of the repair process, the expanded CGG repeats were excised, leading to a restoration of more normal CGG levels and enabling the crucial FMR1 gene to be expressed once again.

Dr. Lee explains, "Since the disease is caused by the expanded CGG repeat, contracting the repeat through R-loop formation has the potential to serve as a one-time treatment." The researchers now plan to expand their investigation to patient neurons and animal models to further explore the technology.

The study involved the contributions of additional authors, including Sachiko Imaichi, Elizabeth Kraeutler, Rodrigo Aguilar, Yong-Woo Lee, and Steven D. Sheridan. Funding for this research was provided by grants from the FRAXA Research Foundation, the National Institutes of Health, and MGH Sundry Funds.