GENE REPLACEMENT OF MUTANT PRESENILIN1 NORMALIZES GAMMA‐SECRETASE FUNCTION IN MODELS OF AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE

Paros Bio is developing an AAV gene therapy for the treatment of Autosomal Dominant Alzheimer’s Disease (ADAD), an early onset form of AD (onset at <65 years of age). ADAD is mainly caused by mutations in the presenilin 1 (PSEN1) gene, which encodes the catalytic subunit of γ‐secretase complex and is responsible for the cleavage of amyloid precursor protein (APP). This cleavage produces Aβ of varying lengths, with longer peptides like Aβ42 being more prone to aggregation than shorter peptides such as Aβ40. Of the >150 distinct, 100% penetrant PSEN1 mutations associated with ADAD, most lead to a partial or nearly complete loss of g‐secretase function, resulting in decreased production of Aβ40 and an increase in the ratio of Aβ42:Aβ40. Aggregation of Aβ peptides into amyloid plaques in the brain is a hallmark of ADAD.