Two years ago, investigators announced mixed results of a small, Phase 2 trial of a gene therapy aimed at nurturing the survival of at-risk cholinergic neurons in people with AD. While brain injections of CERE-110, an adeno-associated virus carrying nerve growth factor (AAV-NGF), caused no discernable harm, they did not seem to help, either.

  • Intracerebral injections of AAV-NGF appeared safe.
  • Treatment did not slow cognitive decline two years after surgery.
  • Study shows feasibility of blinded, sham-surgery placebo control.

The full results of the trial, led by Michael Rafii of the Alzheimer’s Therapeutic Research Institute at the University of Southern California and Mark Tuszynski of the University of California, San Diego, were published March 26 in JAMA Neurology. Alzforum previously covered Rafii’s presentation of the data at the Clinical Trials on Alzheimer’s Disease conference in 2015 (Nov 2015 conference news). 

Because the trial was small, the investigators could not draw conclusions about efficacy. Nonetheless, it demonstrated it is possible to recruit people to undergo invasive experimental procedures, even when they know they might receive placebo. While Rafii knows of no active gene therapy efforts for AD, the strategy is being tested for other neurodegenerative diseases, including Parkinson’s and spinal muscular atrophy, and he expects others may follow (Mar 2018 news; Dec 2015 conference news). “There is interest in gene therapy for neurodegenerative diseases. Hopefully, our work will be used to inform the design of future studies,” he told Alzforum. He does not anticipate any further trials of AAV-NGF.

In the trial, 26 participants with mild to moderate AD received bilateral, stereotactically guided injections of AAV-NGF. Another 23 underwent a sham procedure where surgeons drilled only partway through the skull, and skipped the needle insertion. The neurosurgical team knew which patients had sham surgery or viral injection; the neurologists and participants remained blinded throughout the study.

People tolerated the surgery and AAV-NGF well. Two years later, however, both treatment and placebo showed a similar decline in cognitive function on the primary measure, the ADAS-Cog, and a battery of secondary outcomes. If anything, the treatment group declined slightly more than placebo, but the difference was not statistically significant. The same held for imaging biomarkers of hippocampal size or ventricular volume.

It’s not known if the treatment boosted NGF as hoped. However, examination of postmortem brain tissue from previous trial participants found AAV-NGF expression persisting for years after surgery and at levels sufficient to coax new cholinergic afferents from neurons (Oct 2015 news). Is that enough? In a JAMA Neurology editorial, Lawrence Honig of Columbia University in New York speculated that even full restoration of cholinergic neurons would give only a modest benefit, similar to that seen with cholinesterase inhibitors, because neurodegeneration in AD spreads far beyond the cholinergic system.

The drug’s maker, Sangamo, ended development of CERE-110 in 2015.—Pat McCaffrey


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Therapeutics Citations

  1. CERE-110

News Citations

  1. Truly New to Déjà Vu: For Five Hopefuls, Lights Go Out After Phase 2
  2. So Far, So Good for Parkinson’s Gene Therapy
  3. Gene and Stem Cell Therapies Make Strong Showing at ALS/MND Meeting
  4. Reinforcement, or Replacement? Stem Cell Strategies Divide to Conquer

External Citations

  1. Phase 2

Further Reading


  1. . A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease. Alzheimers Dement. 2014 Jan 7; PubMed.

Primary Papers

  1. . 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. PubMed.
  2. . Gene Therapy in Alzheimer Disease-It May Be Feasible, but Will It Be Beneficial?. JAMA Neurol. 2018 Jul 1;75(7):791-793. PubMed.