Gene therapy can be performed safely in
the human salivary gland, according to scientists at the National
Institute of Dental and Craniofacial Research (NIDCR), part of the
National Institutes of Health.
This finding comes from the first-ever
safety, or Phase I, clinical study of gene therapy in a human
salivary gland. Its results, published this week in the Proceedings
of the National Academy of Sciences, also show that the transferred
gene, Aquaporin-1, has great potential to help head and neck cancer
survivors who battle with chronic dry mouth. Aquaporin-1 encodes a
protein that naturally forms pore-like water channels in the
membranes of cells to help move fluid, such as occurs when salivary
gland cells secrete saliva into the mouth.
These initial results clear the way for
additional gene therapy studies in the salivary glands. Although
sometimes overlooked, salivary glands present an ideal target for
gene therapy. They are easily accessible and, once a gene is
introduced, it has no obvious escape route into the bloodstream,
where it can have unintended consequences.
“You cannot imagine how fulfilling it is
to jot down an idea on a napkin in 1991 and then see it enter a
clinical trial and help people.,” said Bruce Baum, D.M.D., Ph.D.,
lead author on the study and recently retired NIDCR scientist who
spent the last 21 years moving gene therapy in the salivary glands
from the research bench to the clinic. “Can a scientist ask for
anything better?”
Baum's interest in helping head and neck
cancer survivors dates to the early 1980s. While attending to
patients in the NIDCR's Dry Mouth Clinic, Baum encountered numerous
people with head and neck cancer who had received radiation therapy
to shrink their tumors. The radiation, while effective in treating
cancer, had inadvertently damaged nearby salivary glands,
compromising their ability to secrete saliva into the mouth.
Baum said he was thoroughly frustrated
at the time because he had no effective moisture-restoring
treatments to offer most patients. They had beaten cancer, but the
radiation had left them with a permanent parched sensation in their
mouths that diminished their quality of life and often led to
chronic oral problems, such as difficulty swallowing, inflammation,
infection, bad breath, and pain.
In the early 1990s, as the first
gene-therapy studies entered research clinics, Baum saw an
opportunity to make a difference. An initial napkin sketch of the
procedure and 15 years of research later, Baum and his colleagues
had assembled a compelling scientific case in animal studies that
the transferred Aquaporin-1 gene, once expressed, will create new
water channels in the impermeable salivary gland cells and allow
water to flow through them. After rigorous reviews by NIH and the U.
S. Food and Drug Administration, the Phase I protocol was launched
and the first patients treated in 2008.
The scientists gave 11 head and neck
cancer survivors a single-dose injection of the Aquaporin-1 gene
directly into one of their two parotid salivary glands, the largest
of the major salivary glands. The gene was packaged in a disabled,
non-replicating adenovirus, the cause of the common cold when intact
but incapable of causing a cold in this case. As is standard in gene
therapy studies, the virus served as the vector, or Trojan horse, to
deliver the gene into the cells lining the salivary gland.
The scientists found that five
participants had increased levels of saliva secretion, as well as a
renewed sense of moisture and lubrication in their mouths, within
the study's first 42 days, the period covered in this report. Of the
six who didn't benefit from gene therapy, none had serious side
effects. The most common side effect was a transient and relatively
minor immune response against the disabled adenovirus.
“It is time to evaluate a different
vector to deliver the Aquaporin-1 gene, one that will cause only a
minimal immune response,” said Baum. “But these data will serve as
stepping stones for other scientists to improve on this first
attempt in the years ahead. The future for applications of gene
therapy in the salivary gland is bright.”
See also
Intensity-Modulated Radiotheraphy Protects Saliva Function and
Improves Quality of Life for Head and Neck Cancer Patients Compared
with Conventional Radiotherapy (25/01/2011)
http://www.mybestlife.com/health/News_2011/January/25012011_IMRT_head_
neck_cancer.htm
For more information about NIDCR
http://www.nidcr.nih.gov
(MDN) |