An experimental gene therapy reduces the rate at which nerve cells in the brains of Alzheimer’s patients degenerate and die, according to new results from a small clinical trial, published in the current issue of the journal JAMA Neurology.

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 fibres. 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.

The new results are preliminary findings from the very first human trials designed to test the potential benefits of nerve growth factor (NGF) gene therapy for Alzheimer’s patients.

NGF was discovered in the 1940s by Rita Levi-Montalcini, who convincingly demonstrated that the small protein promotes the survival of certain sub-types of sensory neurons during development of the nervous system. Since then, others have shown that it also promotes the survival of acetylcholine-producing cells in the basal forebrain, which die off in Alzheimer’s.

In 2001, Mark Tuszynski and his colleagues at the University of California, San Diego School of Medicine launched a clinical trial based on these findings. The first of its kind, it was designed to assess whether NGF gene therapy might slow or prevent the neuronal degeneration and cell death characteristic of Alzheimer’s Disease.

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.

One of these patients died just 5 weeks after receiving the therapy. Tuszynski’s team got permission to perform an autopsy; in 2005 they reported that the treatment led to robust growth responses, and did not cause any adverse effects.

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 fibres 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.

References

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. DOI: 10.1001/jamaneurol.2015.1807. [Full text]

Tuszynski, M. H., et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11: 551 – 555. [Full text]