APOE2 (gene therapy)

Class

AAV-delivered APOE2 gene therapy

APOE (apolipoprotein E) is a lipid-transport protein made mainly by astrocytes and other glial cells in the brain. It packages cholesterol and phospholipids into particles that neurons take up through cell-surface receptors, supporting membrane maintenance, synaptic repair, and clearance of amyloid-beta, a peptide implicated in Alzheimer's disease. The APOE gene exists in three common versions—APOE2, APOE3, and APOE4—that differ by only one or two amino acids but produce proteins with markedly different behavior. APOE4 is the strongest known genetic risk factor for late-onset Alzheimer's disease, associated with less efficient amyloid clearance and greater neuroinflammation, while APOE2 is comparatively protective and linked to lower disease risk. Gene therapy approaches in this space use an adeno-associated virus (AAV) vector to deliver an additional copy of the APOE2 gene directly into the central nervous system, with the goal of increasing local production of the protective isoform, particularly in people who carry one or two copies of APOE4. The underlying rationale is that shifting the balance of ApoE isoforms present in the brain toward APOE2 could improve lipid handling and amyloid clearance and slow the neurodegenerative processes associated with the APOE4 genotype. This mechanism is being studied mainly in Alzheimer's disease and related conditions where APOE genotype is a major driver of risk.