AAV9-EFS::Cas9-SW1

AAV9-EFS::Cas9-SW1 is an experimental CRISPR-based gene therapy designed for the treatment of familial Alzheimer's disease (FAD). It utilizes an adeno-associated virus serotype 9 (AAV9) vector to deliver a CRISPR-Cas9 system consisting of the Staphylococcus aureus Cas9 (SaCas9) nuclease under the control of an Elongation Factor-1 alpha Short (EFS) promoter and a single-guide RNA (sgRNA), designated SW1. The SW1 guide RNA is specifically engineered to target the human amyloid-beta precursor protein (APP) Swedish mutation (KM670/671NL). By inducing allele-specific double-strand breaks in the mutated APP gene, the therapy promotes gene disruption via non-homologous end joining (NHEJ), thereby reducing the production of neurotoxic amyloid-beta peptides. Preclinical studies in mouse models have demonstrated that both local intrahippocampal administration and systemic intravenous delivery (using blood-brain barrier-crossing AAV variants) can significantly reduce amyloid plaque deposition, neuroinflammation, and cognitive deficits.