Pathogenic genomic DNA sequence

Pathogenic genomic DNA sequences in central nervous system (CNS)-relevant cells represent a broad class of therapeutic targets involved in various hereditary neurodegenerative and neurodevelopmental disorders (NIH, 2023). These sequences include point mutations, insertions, deletions, and nucleotide repeat expansions, such as the CAG repeats found in the HTT gene associated with Huntington’s disease or the C9orf72 expansions in amyotrophic lateral sclerosis (ALS) (Nature Reviews Neurology, 2021). Unlike traditional protein-targeting drugs, therapeutic strategies for these targets aim to modify, silence, or repair the underlying genetic defect at the source using advanced gene-editing technologies. Modalities such as CRISPR-Cas9, zinc finger nucleases (ZFNs), and base editors are engineered to achieve precise genomic edits within neurons and glia to prevent the production of toxic gain-of-function proteins or restore essential protein expression (PubMed, 2022). However, targeting genomic DNA in the CNS faces significant challenges, including the requirement for efficient delivery across the blood-brain barrier and the mitigation of off-target effects that could lead to permanent, unintended genetic alterations (Science, 2018). This target entry is considered a broad category rather than a single molecular entity, encompassing a wide range of specific genetic loci currently being explored for precision medicine in neurology.

Other names

Disease-causing DNA variantPathogenic mutationGenomic lesionNeurogenetic mutationTargeted genomic sequence

Therapeutic intervention involves the use of site-specific nucleases or editors to induce double-strand breaks or chemical modifications at a precise genomic locus, leading to gene disruption, correction, or regulation via cellular DNA repair pathways such as non-homologous end joining (NHEJ) or homology-directed repair (HDR) (Nature Reviews Neurology, 2021; NIH, 2023).