Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer's Disease Identifies a Need for Improved Vector Delivery.
Hum Gene Ther
; 31(7-8): 415-422, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-32126838
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 × 1011 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
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Técnicas de Transferência de Genes
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Dependovirus
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Fator de Crescimento Neural
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Doença de Alzheimer
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Vetores Genéticos
Tipo de estudo:
Clinical_trials
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Guideline
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Prognostic_studies
Limite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article