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Original Investigation
July 2018

Adeno-Associated Viral Vector (Serotype 2)–Nerve Growth Factor for Patients With Alzheimer DiseaseA Randomized Clinical Trial

Author Affiliations
  • 1Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego
  • 2Department of Neuroscience, University of California in San Diego, San Diego
  • 3Department of Neurosurgery, University of California in San Diego, San Diego
  • 4Veterans Affairs Medical Center, San Diego, California
  • 5Nestle Health Science, Florham Park, New Jersey
JAMA Neurol. 2018;75(7):834-841. doi:10.1001/jamaneurol.2018.0233
Key Points

Question  Can stereotactically guided gene transfer of nerve growth factor using adeno-associated viral vector (serotype 2) (AAV2-NGF) provide long-standing neurotrophic support to cholinergic neurons in patients with mild to moderate Alzheimer disease and prevent decline on cognitive measures as well as standard Alzheimer disease biomarkers?

Findings  In this multicenter randomized clinical trial, AAV2-NGF was safe and well-tolerated through 2 years. Magnetic resonance imaging and fludeoxyglucose F18-labeled positron emission tomography imaging and neuropsychological testing showed no evidence of efficacy.

Meaning  This trial further demonstrates the feasibility of sham-surgery–controlled stereotactic gene delivery studies in patients with Alzheimer disease; it remains to be determined, through future pathological examination of brains, whether AAV2-NGF was accurately targeted to the nucleus basalis of Meynert and whether nerve growth factor protein spread sufficiently from sites of administration to influence its cholinergic cellular targets.

Abstract

Importance  Nerve growth factor (NGF) is an endogenous neurotrophic factor that prevents the death and augments the functional state of cholinergic neurons of the basal forebrain, a cell population that undergoes extensive degeneration in Alzheimer disease (AD).

Objective  To determine whether stereotactically guided intracerebral injections of adeno-associated viral vector (serotype 2)–nerve growth factor (AAV2-NGF) are well tolerated and exhibit preliminary evidence of impact on cognitive decline in mild to moderate AD-associated dementia.

Design, Setting, and Participants  In a multicenter phase 2 trial, 49 participants with mild to moderate AD were randomly assigned in a 1:1 ratio to receive stereotactically guided intracerebral injections of AAV2-NGF or sham surgery. Participants were enrolled between November 2009 and December 2012. Analyses began in February 2015. The study was conducted at 10 US academic medical centers. Eligibility required a diagnosis of mild to moderate dementia due to AD and individuals aged 55 to 80 years. A total of 39 participants did not pass screening; the most common reason was Mini-Mental State Examination scores below cutoff. Analyses were intention-to-treat.

Interventions  Stereotactically guided intracerebral injections of AAV2-NGF into the nucleus basalis of Meynert of each hemisphere or sham surgery.

Main Outcomes and Measures  Change from baseline on the Alzheimer’s Disease Assessment Scale–cognitive subscale at month 24.

Results  Among 49 participants, 21 (43%) were women, 42 (86%) self-identified as white, and the mean (SD) age was 68 (6.4) years. AAV2-NGF was safe and well-tolerated through 24 months. No significant difference was noted between the treatment group and placebo on the primary outcome measure, the Alzheimer’s Disease Assessment Scale–cognitive subscale (mean [SD] score, 14.52 [4.66] vs 9.11 [4.65], P = .17).

Conclusions and Relevance  This multicenter randomized clinical trial demonstrated the feasibility of sham-surgery–controlled stereotactic gene delivery studies in patients with AD. AAV2-NGF delivery was well-tolerated but did not affect clinical outcomes or selected AD biomarkers. Pathological confirmation of accurate gene targeting is needed.

Trial Registration  clinicaltrials.gov Identifier NCT00876863

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