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

Jonathan B. Rosenberg, Michael G. Kaplitt, Bishnu P. De, Alvin Chen, Thomas Flagiello, Christiana Salami, Eduard Pey, Lingzhi Zhao, Rodolfo J. Ricart Arbona, Sebastien Monette, Jonathan P. Dyke, Douglas J. Ballon, Stephen M. Kaminsky, Dolan Sondhi, Gregory A. Petsko, Steven M. Paul, Ronald Crystal

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish
Pages24-47
Number of pages24
JournalHuman Gene Therapy Clinical Development
Volume29
Issue number1
DOIs
Publication statusPublished - 1 Mar 2018

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Genetic Therapy
Alzheimer Disease
Central Nervous System
Apolipoprotein E2
Homozygote
Safety
Apolipoproteins E
Nervous System Diseases
Toxicology
Primates
Nervous System
Animal Models
Complementary DNA
Alleles
Messenger RNA
DNA
Population
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease. / Rosenberg, Jonathan B.; Kaplitt, Michael G.; De, Bishnu P.; Chen, Alvin; Flagiello, Thomas; Salami, Christiana; Pey, Eduard; Zhao, Lingzhi; Ricart Arbona, Rodolfo J.; Monette, Sebastien; Dyke, Jonathan P.; Ballon, Douglas J.; Kaminsky, Stephen M.; Sondhi, Dolan; Petsko, Gregory A.; Paul, Steven M.; Crystal, Ronald.

In: Human Gene Therapy Clinical Development, Vol. 29, No. 1, 01.03.2018, p. 24-47.

Research output: Contribution to journalArticle

Rosenberg, JB, Kaplitt, MG, De, BP, Chen, A, Flagiello, T, Salami, C, Pey, E, Zhao, L, Ricart Arbona, RJ, Monette, S, Dyke, JP, Ballon, DJ, Kaminsky, SM, Sondhi, D, Petsko, GA, Paul, SM & Crystal, R 2018, 'AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease' Human Gene Therapy Clinical Development, vol. 29, no. 1, pp. 24-47. https://doi.org/10.1089/humc.2017.231
Rosenberg, Jonathan B. ; Kaplitt, Michael G. ; De, Bishnu P. ; Chen, Alvin ; Flagiello, Thomas ; Salami, Christiana ; Pey, Eduard ; Zhao, Lingzhi ; Ricart Arbona, Rodolfo J. ; Monette, Sebastien ; Dyke, Jonathan P. ; Ballon, Douglas J. ; Kaminsky, Stephen M. ; Sondhi, Dolan ; Petsko, Gregory A. ; Paul, Steven M. ; Crystal, Ronald. / AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease. In: Human Gene Therapy Clinical Development. 2018 ; Vol. 29, No. 1. pp. 24-47.
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