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

Publication ,  Journal Article
Rafii, MS; Tuszynski, MH; Thomas, RG; Barba, D; Brewer, JB; Rissman, RA; Siffert, J; Aisen, PS; AAV2-NGF Study Team,
Published in: JAMA Neurol
July 1, 2018

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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Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

July 1, 2018

Volume

75

Issue

7

Start / End Page

834 / 841

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Stereotaxic Techniques
  • Severity of Illness Index
  • Positron-Emission Tomography
  • Parvovirinae
  • Nerve Growth Factor
  • Middle Aged
  • Male
  • Magnetic Resonance Imaging
  • Injections
 

Citation

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Rafii, M. S., Tuszynski, M. H., Thomas, R. G., Barba, D., Brewer, J. B., Rissman, R. A., … AAV2-NGF Study Team, . (2018). Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol, 75(7), 834–841. https://doi.org/10.1001/jamaneurol.2018.0233
Rafii, Michael S., Mark H. Tuszynski, Ronald G. Thomas, David Barba, James B. Brewer, Robert A. Rissman, Joao Siffert, Paul S. Aisen, and Paul S. AAV2-NGF Study Team. “Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial.JAMA Neurol 75, no. 7 (July 1, 2018): 834–41. https://doi.org/10.1001/jamaneurol.2018.0233.
Rafii MS, Tuszynski MH, Thomas RG, Barba D, Brewer JB, Rissman RA, et al. Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2018 Jul 1;75(7):834–41.
Rafii, Michael S., et al. “Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial.JAMA Neurol, vol. 75, no. 7, July 2018, pp. 834–41. Pubmed, doi:10.1001/jamaneurol.2018.0233.
Rafii MS, Tuszynski MH, Thomas RG, Barba D, Brewer JB, Rissman RA, Siffert J, Aisen PS, AAV2-NGF Study Team. Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2018 Jul 1;75(7):834–841.

Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

July 1, 2018

Volume

75

Issue

7

Start / End Page

834 / 841

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Stereotaxic Techniques
  • Severity of Illness Index
  • Positron-Emission Tomography
  • Parvovirinae
  • Nerve Growth Factor
  • Middle Aged
  • Male
  • Magnetic Resonance Imaging
  • Injections