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Hum Gene Ther Clin Dev. 2018 Mar;29(1):24-47. doi: 10.1089/humc.2017.231. Epub 2018 Mar 13.

AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease.

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1 Department of Genetic Medicine, Weill Cornell Medical College , New York, New York.
2 Department of Neurosurgery, Weill Cornell Medical College , New York, New York.
3 Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College , New York, New York.
Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University , Weill Cornell Medical College, New York, New York.
6 Department of Radiology, Weill Cornell Medical College , New York, New York.
7 Voyager Therapeutics, Inc. , Cambridge, Massachusetts.


Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.


AAV; APOE2; Alzheimer's disease; CNS; gene therapy

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