An experimental gene therapy was able to produce positive
results in substantial reduction of 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 (NGF) 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 originally
delivered.
The new results are still considered as preliminary
findings as they represent 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 ongoing, 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.
One of the upsides to gene therapy treatment is that it
is targeted and can be restricted to specific, affected areas of the brain
without damaging healthy cells nearby. But Tuszynski is also excited about the
one-and-done aspect of the treatment.
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