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Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer's Disease Identifies a Need for Improved Vector Delivery.
- Source :
-
Human gene therapy [Hum Gene Ther] 2020 Apr; Vol. 31 (7-8), pp. 415-422. Date of Electronic Publication: 2020 Mar 30. - Publication Year :
- 2020
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Abstract
- Nerve growth factor (NGF) gene therapy rescues and stimulates cholinergic neurons, which degenerate in Alzheimer's disease (AD). In a recent clinical trial for AD, intraparenchymal adeno-associated virus serotype 2 (AAV2)-NGF delivery was safe but did not improve cognition. Before concluding that NGF gene therapy is ineffective, it must be shown that AAV2-NGF successfully engaged the target cholinergic neurons of the basal forebrain. In this study, patients with clinically diagnosed early- to middle-stage AD received a total dose of 2 × 10 <superscript>11</superscript> vector genomes of AAV2-NGF by stereotactic injection of the nucleus basalis of Meynert. After a mean survival of 4.0 years, AAV2-NGF targeting, spread, and expression were assessed by immunolabeling of NGF and the low-affinity NGF receptor p75 at 15 delivery sites in 3 autopsied patients. NGF gene expression persisted for at least 7 years at sites of AAV2-NGF injection. However, the mean distance of AAV2-NGF spread was only 0.96 ± 0.34 mm. NGF did not directly reach cholinergic neurons at any of the 15 injection sites due to limited spread and inaccurate stereotactic targeting. Because AAV2-NGF did not directly engage the target cholinergic neurons, we cannot conclude that growth factor gene therapy is ineffective for AD. Upcoming clinical trials for AD will utilize real-time magnetic resonance imaging guidance and convection-enhanced delivery to improve the targeting and spread of growth factor gene delivery.
- Subjects :
- Aged
Alzheimer Disease pathology
Amyloid beta-Peptides metabolism
Autopsy
Basal Forebrain pathology
Cholinergic Neurons metabolism
Female
Humans
Male
Middle Aged
Neuropsychological Tests
Alzheimer Disease genetics
Alzheimer Disease therapy
Dependovirus
Gene Transfer Techniques
Genetic Therapy
Genetic Vectors
Nerve Growth Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-7422
- Volume :
- 31
- Issue :
- 7-8
- Database :
- MEDLINE
- Journal :
- Human gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 32126838
- Full Text :
- https://doi.org/10.1089/hum.2019.367