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?
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.
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.
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).
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.
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.
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.
clinicaltrials.gov Identifier NCT00876863
Rafii MS, Tuszynski MH, Thomas RG, et al. Adeno-Associated Viral Vector (Serotype 2)–Nerve Growth Factor for Patients With Alzheimer DiseaseA Randomized Clinical Trial. JAMA Neurol. 2018;75(7):834–841. doi:10.1001/jamaneurol.2018.0233
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