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Gene Therapy for Fragile X Syndrome, Challenges, and Promises

Milen Velinov

Published 2025 in Journal of Gene Medicine

ABSTRACT

Fragile X syndrome (FXS) is the most common single gene cause of inherited intellectual disability and autism spectrum disorder (ASD). FMR1, the gene associated with FXS, is located on chromosome X. Accordingly, males with loss‐of‐function (full) mutations are more severely affected than females. Strategies for therapeutic intervention for this disorder have included behavioral and medication therapy. To date, no management strategies have been shown to be curative. Gene therapy that aims to supply the functional protein product of the gene FMR1 to the brain is an attractive concept for curative treatment. Experiments aimed at activating the mutant FMR1, modifying its abnormal RNA product, or supplying functional FMR1 copies to the CNS have been conducted. The delivery of the FMR1 gene and its product to animal models of FXS have been primarily conducted with intrathecal applications because of the low efficiency of the gene therapy vectors to cross the blood–brain barrier (BBB). This delivery approach is associated with a higher risk of complications and appears to distribute the gene product unevenly across different brain regions. We have explored the efficiency of a recently developed adeno‐associated virus (AAV) vector with increased BBB crossing in certain strains of mice to deliver FMR1 with peripheral IV administration. Our experiments demonstrated very high delivery efficiency and also highlighted the risk of oversupplying the brain with FMRP, the protein product of the FMR1 gene. Other AAV vectors with enhanced crossing of the BBB in primates have been developed, providing an attractive option for further experiments involving peripheral administration. Providing the gene product to specific brain cells remains a difficult challenge for future experiments. It may also be important or even necessary to regulate the gene expression to mimic physiological expression patterns since the levels of FMRP change dramatically during development, with maximum levels early in the postnatal period and a decline across early life. In addition, there are 12 identified mouse isoforms of FMRP due to alternative RNA splicing, and an even higher number of isoforms is found in humans. It may thus be a challenge to determine what FMR1 isoform or set of isoforms would have the optimum efficiency in correcting the phenotype. Despite these challenges, the recent developments establish the basis for future research to develop efficient and minimally invasive gene therapy protocols for FXS.

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