Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with Alzheimer disease a randomized clinical trial
© 2018 American Medical Association. All rights reserved. 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 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 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.
Rafii, MS; Tuszynski, MH; Thomas, RG; Barba, D; Brewer, JB; Rissman, RA; Siffert, J; Aisen, PS; Mintzer, J; Lerner, A; Levey, A; Burke, J; Sano, M; Turner, S; Zamrini, E; Grill, J; Marson, D
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