Gene therapy treatment shows benefits to Alzheimer’s patients

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Gene therapy treatment shows benefits to Alzheimer’s patients

Gene therapy treatment developed at the CNPRC shows benefits to brain cells for Alzheimer’s patients

Reporting on the first-of-its-kind human clinical trials designed to test the potential benefits of nerve growth factor gene therapy for Alzheimer’s patients, Mark Tuszynski, MD, PhD, CNPRC affiliate scientist, has found that an experimental gene therapy he developed at the California National Primate Research Center (CNPRC) at UC Davis reduces the rate at which nerve cells in the brains of Alzheimer’s patients degenerate and die (Tuszynski, M. H., et al. (2015). Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurology, published online August 24, 2015).

Novel gene therapies, first developed at the CNPRC in the early 2000s, showed great promise in patients with mild Alzheimer’s disease.  Further research at the CNPRC with gene transfer therapy using Nerve Growth Factor (NGF) demonstrated in nonhuman primate studies that reversal of damage and restoration of brain function was possible.

This program is determining the potential of NGF to prevent or reduce cell degeneration in important cortical regions of the brain.

Targeted injection of the Nerve Growth Factor gene into the patients’ brains rescued dying cells around the injection site, enhancing their growth and inducing them to sprout new fibers. In some cases, these beneficial effects persisted for 10 years after the therapy was first delivered.

Alzheimer’s is the world’s leading form of dementia, affecting an estimated 47 million people worldwide. This figure is predicted to almost double every 20 years, with much of this increase is likely to be in the developing world. And despite the huge amounts of time, effort, and money devoted to developing an effective cure, the vast majority of new drugs have failed in clinical trials.

In 2001, Dr. Tuszynski and his colleagues at the University of California, San Diego School of Medicine launched a clinical trial based on his research at UC San Diego and the CNPRC, designed to assess whether NGF gene therapy might slow or prevent the neuronal degeneration and cell death characteristic of Alzheimer’s Disease.

“The rationale for doing the study is certainly supported by the fact that there is a wealth of information from primate studies that shows that this is an effective approach in preventing aging in monkeys and cell death in monkey brains” says Dr. Tuszynski.

In phase I of this trial, eight patients with mild Alzheimer’s Disease received ex vivo therapy to deliver the NGF gene directly into the brain. This involved first taking a skin biopsy from the patients’ backs, isolating connective tissue cells called fibroblasts, genetically modifying them to express the NGF genes, and then implanting the cells into the patients’ basal forebrain. They used this strategy because NGF is too large to cross the blood-brain barrier, and can stimulate other nerve cells, leading to unwanted side-effects such as pain and weight loss.

The latest results come from post-mortem examination of these patients’ brains, all of whom had also been recruited in a safety trial between March 2001 and October 2012, plus those of two others, who had received in vivo therapy, involving injection of a modified virus carrying the NGF gene into the basal forebrain, in a subsequent phase I trial.

Some of the participants died about one year after undergoing therapy, and others survived for 10 years after the treatment. But the autopsies revealed that all of them had responded to the treatment – all the brain tissue samples taken from around the implantation sites contained diseased neurons, as expected, but the cells were overgrown, and had sprouted axonal fibers that had grown towards the region into which NGF had been delivered. By contrast, cells in samples taken from the untreated side of the brain exhibited no such response.

This trial was conducted to test the safety of the treatment and, confirming the earlier findings, it showed that none of the patients experienced long-term adverse effects from the treatment, even after long periods of time.

The results also suggest that NGF is successfully taken up by nerve cells following targeted delivery; that the cells synthesize NGF protein so that its concentration dramatically increases in and around the delivery site; and that the cells’ responses to NGF can persist for many years after the gene has been delivered into the brain.

Now, the big outstanding question is, does the observed cellular response to NGF alleviate disease symptoms? Although phase II trials testing the efficacy of the treatment are on-going, preliminary findings from the initial study suggest that the therapy did indeed slow the rate at which mental function declined in one of the patients involved. These new results indicate that gene therapy is a viable strategy for treating Alzheimer’s and other neurodegenerative diseases, and warrants further research and development.

Research on the Aging Brain at the CNPRC

Researchers from across the nation come to the CNPRC, one of just seven federally funded centers nationwide developed to breed, house, care for and study monkeys for medical and behavioral research.

“They’re absolutely world experts in geriatric primatology,” said Carol Barnes, PhD, CNPRC affiliate scientist and a leading neurological researcher and regents professor at the University of Arizona.

“There are other centers that have aging primates, but they have a particularly large colony of aged animals and have amassed a particularly spectacular group of veterinarians who know about aging,” said Barnes, who is doing memory research at the CNPRC. “People come to train at Davis to learn about aged monkeys.”

Unlike rats or mice, rhesus monkeys go through menopause much like humans. Their brain structures resemble those of humans. What that means, says incoming CNPRC director John Morrison, PhD, is that results of monkey testing can help scientists design better human trials, so that only the most promising approaches are tried on people.

Dr. Morrison recently published an extensive review that highlights a new understanding of how estrogen affects higher cognitive functions and synaptic health, with studies in nonhuman primates, mice and humans (Read more here). Among the many functions estrogen has on the brain, estrogen also improves cerebral metabolic rate and blood flow, and exerts many antioxidant effects. The antioxidant effects of estrogen are noteworthy in light of strong evidence that mitochondrial dysfunction and damage accrued from oxidative stress precede, and may be causative for, neurodegenerative disorders such as Alzheimer’s disease.