Unravelling fragile minds: the promise of CRISPR and RNA therapy in Fragile X Syndrome

Background: Fragile X Syndrome (FXS) is caused by the deficiency or absence of the fragile X mental retardation protein (FMRP) due to CGG trinucleotide repeat expansions in the FMR1 gene. This results in cognitive impairments, and behavioural abnormalities, and is a leading monogenic cause of autism spectrum disorder. Despite extensive research, effective treatments remain limited, prompting exploration into advanced genetic therapies such as CRISPR/Cas9 gene editing and RNA-based therapies. Methods: A systematic search was conducted using the PICO framework to identify studies involving individuals with FXS investigating CRISPR/Cas9 gene editing and RNA-based therapies. Inclusion criteria encompassed clinical trials, cohort studies, case-control studies, and systematic reviews/meta-analyses published in English. Excluded were studies not involving FXS, those not focusing on CRISPR/Cas9 or RNA-based therapies, and articles not reporting on long-term efficacy and safety. Data were extracted and synthesised based on SANRA guidelines. Objectives: This narrative review aims to evaluate the neurobiological mechanisms underlying FXS, and compare the long-term efficacy and safety of CRISPR/Cas9 gene editing with RNA-based therapies. It seeks to provide a comprehensive understanding of these advanced genetic technologies in the management of FXS, highlight current research, identify knowledge gaps, and discuss clinical, healthcare, societal, and research implications. Discussion: CRISPR/Cas9 offers precise genetic correction by targeting the FMR1 gene, with preclinical models showing promising results in symptom reduction. However, challenges such as off-target effects and delivery methods persist. RNA-based therapies like antisense oligonucleotides (ASOs) and RNA interference (RNAi) show potential in restoring FMRP levels but face clinical translation challenges. This review emphasizes the need for further research to address these challenges and validate the efficacy and safety of these therapies in clinical settings.