Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.
Keywords: AAV; ALDH5A1; Dravet syndrome; GABA; KCC2; SLC6A1; autosomal dominant; autosomal recessive; delivery route; disease modeling; epilepsy; gene expression; genetic inheritance; haploinsufficiency; neurodevelopment; promoters; protein interaction; viral vector.
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