The later stages of Alzheimer’s disease are characterized by massive loss of neurons, and researchers are looking at ways to boost molecular support systems in the hope of preserving some of those cells. At the Sixth Clinical Trials Conference on Alzheimer’s Disease (CTAD) held November 14–16 in San Diego, Raymond Bartus, who runs his own biotech consulting firm, RTBioconsultants, described his earlier work for San Diego-based biotechnology company Ceregene to develop nerve growth factor (NGF) as a therapy. Ceregene was acquired by Sangamo BioSciences Inc., Richmond, California, in August 2013. Bartus and colleagues had engineered an adenovirus to deliver NGF to vulnerable cholinergic neurons. At CTAD, he presented formal results of the Phase 1 trial of the gene therapy CERE-110. The treatment appeared safe and showed some hints of stabilizing brain metabolism. A Phase 2 study started in 2009 and is still ongoing.

Meanwhile, other groups are taking a different approach to modulate trophic signaling. Frank Longo and colleagues at Stanford University, Palo Alto, California, are developing small molecules that activate expression of specific growth factor receptors. These ligands have more targeted effects than native growth factors do, Longo told Alzforum. In the November 27 Journal of Neuroscience, Longo and colleagues report that one such molecule shows promise in mice that model Huntington’s disease. Another is currently in Phase 1 for Alzheimer’s disease, but not listed in

Bartus and colleagues focused on cholinergic neurons because they are known to play a key role in learning and memory, degenerate in AD, and are the target of cholinesterase-inhibitor drugs approved for AD. The researchers injected CERE-110 into the nucleus basalis of Meynert, the deep-brain structure where cholinergic neurons reside (see Jan 2013 news story). Neurons then take up the DNA and begin to produce and secrete the protein. In the Phase 1, dose-ranging study, 10 AD patients each received a single injection of CERE-110, which is meant to last for the lifetime of the patient, Bartus told Alzforum. The researchers have followed the participants for nearly three years. During this time there were no adverse events that were believed to be due to the drug. Three of the patients died from unrelated causes and donated their brains for autopsy. In these samples, the researchers confirmed that the added gene was producing active protein. One indication of this was that cholinergic neurons in the vicinity of the injection sites plumped up by about 20 percent, which is a classic measure of NGF bioactivity.

There were signs the treatment preserved neuronal health, Bartus said. In AD patients, brain glucose metabolism as measured by fluorodeoxyglucose PET progressively decreases. In the Phase 1 cohort, it stayed stable over the course of the study but because of the small sample size, the researchers cannot be certain this finding is significant. Cognitive test scores declined over the two years in the treated patients, and the trial was not powered to show slowing in the rate of that decline. Bartus hopes that the ongoing placebo-controlled Phase 2 study, which is run through the Alzheimer’s Disease Cooperative Study, will answer these questions. This study enrolled 49 mild to moderate AD patients, about half of whom received CERE-110, the other half sham surgery. The trial will conclude in 2015.

One advantage of gene therapy is that it can be delivered to a targeted area of the brain, which may lessen side effects, Longo told Alzforum. On the downside, it involves surgery, and there is no practical way to modulate the dose should it become necessary later. Like conventional drugs, Longo’s small molecules can be taken orally and stopped at any time. These compounds activate only one receptor and have distinct effects from the native protein ligands. They are being developed through the biotech company PharmatrophiX, Raleigh, North Carolina, which Longo founded (see Feb 2010 news story; Apr 2010 news story).

One compound, LM11A-31, activates the p75 neurotrophin receptor. This receptor modulates binding of NGF and other neurotrophins to tyrosine kinase receptors on neurons and can also signal independently. LM11A-31 is currently in Phase 1 safety and dosage testing in young and old healthy adults. In animal models, the molecule shows potential to treat spinal cord and traumatic brain injury as well, Longo said. The Journal of Neuroscience paper describes another molecule, LM22A-4, which binds to the TrkB receptor that is normally activated by brain-derived neurotrophic factor (BDNF). First author Danielle Simmons found that in HD model mice, this agent preserved synapses in the striatum and improved some motor abilities. LM22A-4 also benefits mice that model other disorders, promoting recovery of movement after stroke, for example (see Han et al., 2012). The researchers are now developing chemical derivatives of this compound that better enter the brain, and hope to take one of these into the clinic, Longo said.—Madolyn Bowman Rogers


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News Citations

  1. Cut to the Chase: Therapies Go Directly to Central Nervous System
  2. Copper Mountain: Death and Trophin Receptors—New Insight, New Drugs?
  3. Research Brief: BDNF Data Speak Volumes, Offer Therapeutic Target

Paper Citations

  1. . Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke. 2012 Jul;43(7):1918-24. PubMed.

External Citations

  1. Phase 1 trial
  2. Phase 2 study

Further Reading

Primary Papers

  1. . A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease. J Neurosci. 2013 Nov 27;33(48):18712-27. PubMed.