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JAMA Neurol. 2018 Jul 1;75(7):834-841. doi: 10.1001/jamaneurol.2018.0233.

Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial.

Author information

1
Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego.
2
Department of Neuroscience, University of California in San Diego, San Diego.
3
Department of Neurosurgery, University of California in San Diego, San Diego.
4
Veterans Affairs Medical Center, San Diego, California.
5
Nestle Health Science, Florham Park, New Jersey.

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, 14.52ā€‰[4.66] vs 9.11ā€‰[4.65], Pā€‰=ā€‰.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.

PMID:
29582053
PMCID:
PMC5885277
DOI:
10.1001/jamaneurol.2018.0233

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