TY - JOUR
T1 - AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
AU - Rosenberg, Jonathan B.
AU - Kaplitt, Michael G.
AU - De, Bishnu P.
AU - Chen, Alvin
AU - Flagiello, Thomas
AU - Salami, Christiana
AU - Pey, Eduard
AU - Zhao, Lingzhi
AU - Ricart Arbona, Rodolfo J.
AU - Monette, Sebastien
AU - Dyke, Jonathan P.
AU - Ballon, Douglas J.
AU - Kaminsky, Stephen M.
AU - Sondhi, Dolan
AU - Petsko, Gregory A.
AU - Paul, Steven M.
AU - Crystal, Ronald G.
N1 - Funding Information:
We thank Jojo Borja and Simon Morim for help with the CNS imaging studies, Veronica Mitchell for NHP behavior observations, and N. Mohamed for help with the manuscript. These studies were supported in part by the Alzheimer’s Drug Discovery Foundation, # 20141209. The Center for Comparative Medicine and Pathology and the La- boratory of Comparative Pathology are supported in part by NCI Cancer Center Support Grant P30 CA008748. M.G.K was supported, in part, by the JPB Foundation.
Publisher Copyright:
© Copyright 2018, Mary Ann Liebert, Inc.
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
KW - AAV
KW - APOE2
KW - Alzheimer's disease
KW - CNS
KW - gene therapy
UR - http://www.scopus.com/inward/record.url?scp=85045402640&partnerID=8YFLogxK
U2 - 10.1089/humc.2017.231
DO - 10.1089/humc.2017.231
M3 - Article
C2 - 29409358
AN - SCOPUS:85045402640
SN - 2324-8637
VL - 29
SP - 24
EP - 47
JO - Human Gene Therapy Clinical Development
JF - Human Gene Therapy Clinical Development
IS - 1
ER -