Challenges in Gene-Directed Therapies for Rare Neurodevelopmental Disorders Using HNRNPU as an Exemplar.

Abstract

Next-generation sequencing has radically transformed the diagnostic capability of rare neurodevelopmental disorders (RNDDs), yet translating these molecular insights into viable therapeutics remains a hurdle. While gene-directed modalities, specifically viral-mediated supplementation, antisense oligonucleotides (ASOs), and CRISPR-based activation or precision editing, offer a means to rescue loss-of-function phenotypes, successful clinical implementation requires moving past the reductive framework of merely increasing the expression of the target gene towards approaches that account for spatial, developmental, and therapeutic windows. This review uses HNRNPU-related rare neurodevelopmental disorder (HNRNPU-RNDD), a condition marked with global developmental delay and refractory epilepsy, as an exemplar to discuss these translational hurdles. We discuss the homeostatic boundaries of this scaffold attachment factor, where unregulated overexpression risks localised cytotoxicity, and altered chromatin dynamics compromise editing safety. Furthermore, we assess how cell-type sensitivity and narrow developmental windows may dictate clinical efficacy. By using HNRNPU-RNDD to critically analyse the challenges of using each therapeutic platform, we hope to inform the creation of gene-directed therapies that aim to treat disorders resulting from structural pleiotropic dosage-sensitive proteins.