Gene Therapy for APOE4 Homozygous Alzheimer's Disease

. Variants of APOE are the major genetic risk factors for Alzheimer’s disease (AD). APOE has 3 common variants; APOE3 average risk, APOE4 high risk and APOE2 protective. This data, and in E2E4 heterozygotes, E2 cancels out deleterious effects of E4, led to the concept that gene therapy of a protec- tive APOE in the CNS would reduce the risk for AD in APOE4 homozygotes. Should the CNS gene ther- apy to treat APOE4 homozygotes be with APOE2 (the naturally occurring “protective” allele), or can we modify the CNS of APOE4 homozygotes with a more potent protective APOE? We focused on APOE Christchurch (Ch, R136S), a gain-of-function allele that protects against development of Tau pa- thology and clinical AD in the PSEN1/E280 Colombian family with early onset dominant AD. Using the AAVrh.10 neurotropic adeno-associated virus (AAV) capsid, we tested the hypothesis that AAVrh.10- mediated CNS delivery of the APOE2 allele with the Ch mutation (“E2Ch”), will provide superior protection against APOE4-associated AD amyloid and tau pathology compared to unmodified APOE2 (“E2”). The vectors were assessed in 2 mouse strains with humanized APOE4: APP.PSEN1/TRE4 “amyloid mice” and P301S/TRE4, “tau mice”. The novel E2Ch variant was more effec- tive than E2 alone to treat both the amyloid and tau pathology of murine AD in APOE4 background. Based on this and extensive safety data, we are ready to initiate a Phase I clinical trial of administration of AAVrh.10hAPOE2Ch to the CNS of APOE4 homozygotes with early onset AD. Aim 1 (UG3). Carry out a Phase 1A safety/dose-ranging clinical trial of CSF administration of AAVrh.10hAPOE2Ch to APOE4 homozygotes with early AD to determine the highest tolerable dose. Gain regulatory approval [FDA (IND), IRB, Biosafety, DSMB] to initiate the clinical trial. Manufacture clinical grade AAVrh.10hAPOE2Ch for Phase 1A. Vector administration to CSF via C1-C2, doses 5.7x1012 to 5.7x1014 total genome copies in 5, ½ log increments, n=3 participants each dose. Primary endpoint – safety parameters to determine the highest tolerable dose. Secondary endpoint – preliminary assessment of efficacy biomarkers and CSF levels of APOE2Ch. Aim 2 (UH3). Carry out a Phase 1B study at the highest tolerable dose from Phase 1A focused on exploratory assessment of efficacy parameters. Manufacture clinical grade AAVrh.10hAPOE2Ch for Phase 1B, CSF administration of the highest tolerable dose to n=10 early AD APOE4 homozygotes. Primary endpoint. Pre- and post-therapy evaluation of: target engagement (quan- tification of binding of CSF vector derived APOE to heparin); amyloid and tau PET scans; CSF levels of APOE4 and APOE2Ch, amyloid (Aβ42, Aβ40), tau (total tau, p-tau) GFAP, NfL, biomarkers; MRI CNS vol- umes and cognitive testing. Secondary endpoint – safety parameters. Project Number: 1UG3AG098024-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: RONALD CRYSTAL | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $3,252,734 | Activity Code: UG3 | Study Section: Special Emphasis Panel[ZRG1 NV-F (51)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291103