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Apolipoprotein E is a critical carrier of lipids in the brain. The APOE gene has three common variants E2, E3, and E4 that influence the risk for developing Alzheimer’s disease (AD). While APOE4 homozygotes have a 15-fold greater risk than the common E3/E3 genotype, E4/E2 heterozygotes only have 1.8-fold elevated risk. This gives rise to the hypothesis that gene therapy delivery of the APOE2 variant would protect E4/E4 homozygotes from developing AD. This chapter describes a series of studies using mouse models which have established that viral gene transfer vectors can deliver APOE2 to the brain and relieve the morphological, biochemical, and behavioral manifestations of AD. These studies show that APOE protein expressed from gene transfer vectors administered to the cerebral spinal fluid readily diffuses through the brain. Based on previous clinical experience of AAV-mediated gene transfer to human brain, clinical trials are in progress to determine safety and evaluate the efficacy of CSF administration of AAVrh.10 expressing APOE2.

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CNS Gene Therapy for APOE4 Homozygote-Associated Alzheimer’s Disease

  • 章节

  • 发表日期：

    2025年

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  • Neil R. Hackett,
  • Caner Günaydin,
  • Dolan Sondhi,
  • Stephen M. Kaminsky,
  • Ronald G. Crystal

摘要

Apolipoprotein E is a critical carrier of lipids in the brain. The APOE gene has three common variants E2, E3, and E4 that influence the risk for developing Alzheimer’s disease (AD). While APOE4 homozygotes have a 15-fold greater risk than the common E3/E3 genotype, E4/E2 heterozygotes only have 1.8-fold elevated risk. This gives rise to the hypothesis that gene therapy delivery of the APOE2 variant would protect E4/E4 homozygotes from developing AD. This chapter describes a series of studies using mouse models which have established that viral gene transfer vectors can deliver APOE2 to the brain and relieve the morphological, biochemical, and behavioral manifestations of AD. These studies show that APOE protein expressed from gene transfer vectors administered to the cerebral spinal fluid readily diffuses through the brain. Based on previous clinical experience of AAV-mediated gene transfer to human brain, clinical trials are in progress to determine safety and evaluate the efficacy of CSF administration of AAVrh.10 expressing APOE2.