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

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.

Figure 1.. Patient Flow Diagram

Figure 2.. Primary and Secondary End Points

A, Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog 11). There was no benefit from adeno-associated viral vector (serotype 2)–nerve growth factor on ADAS-Cog 11 at 24 months. The mean change was 14.52 (95% CI, 9.86-19.18) vs placebo 9.11 (95% CI, 4.46-13.76); P = .17. B, Clinical Dementia Rating–sum of boxes (CDR-SOB) change score. The treatment group increased by 4.75 (95% CI, 3.20-6.30) points, while the placebo group increased by 2.81 (95% CI, 1.34-4.28) points (P = .09). C, The treatment group’s modified Clinical Global Impression of Change (mCGIC) score increased by mean of 5.59 (95% CI, 5.26-5.92) points, while placebo increased by 5.33 (95% CI, 5.06-5.60) points (P = .21). D, The treatment group’s Mini-Mental State Examination (MMSE) scores declined 6.18 (95% CI, 4.00-8.36) points vs 4.17 (95% CI, 1.50-6.84) points in the placebo group (P = .16). E, The treatment group’s Neuropsychiatric Inventory score increased by 6.61 (95% CI, 1.85-11.37) points vs 9.18 (95% CI, −0.71 to 19.07) in the placebo group (P = .95). F, The treatment group’s Alzheimer Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score change declined 17.65 (95% CI, 10.81-24.49) points vs 12.94 (95% CI, 3.75-22.13) in the placebo group (P = .61). With the exception of Neuropsychiatric Inventory, the treatment group tended to perform worse on all other clinical outcome measures. The error bands (shading) are the 95% confidence intervals.

Figure 3.. Bilateral Posterior Cingulate Change in Regional Cerebral Blood Glucose Metabolism

Change in bilateral posterior cingulated gyri decreased by 0.152 (95% CI, 0.128-0.176) standardized update value ratio (SUVR). In the placebo group it decreased by 0.142 (95% CI, 0.124-0.302) SUVR.

Figure 4.. Magnetic Resonance Imaging Volumetric Measures

A, Hippocampal volume declined 0.41 (95% CI, 0.39-0.49) cm³ in the treatment group, while in the placebo group, it declined by 0.43 (95% CI, 0.36-0.50) cm³ at month 24. B, In the treatment group, ventricular volume increased by 52.16 (95% CI, 47.15-57.17) change units, while it increased by 44.84 (95% CI, 34.91-54.78) change units in the placebo group.