Gene Therapy Shows Promise in Treating Sjogren’s Syndrome in an Animal Model|
Interleukin-10 gene transfer inhibits salivary gland inflammation, preserves saliva flow
Researchers have reported the first successful use of gene therapy to limit
salivary gland inflammation and preserve saliva flow in a mouse model of Sjogren’s
syndrome, an autoimmune disorder that can render people unable to produce saliva
The scientists found that transferring the gene for human interleukin-10 (IL-10)
via an adeno-associated virus into the animals’ salivary glands reduced
salivary gland inflammation and preserved saliva flow. The treatment worked
whether it was started before or after the onset of salivary dysfunction. The
scientists describe their findings in the November 20 issue of Human Gene
Therapy. The journal has pre-published the paper online at http://www.liebertpub.com/specialpaper.pdf.
“We were certainly happy to find that the animals that received the experimental
treatment had dramatically higher salivary function than control animals,”
said Dr. Bruce Baum, the study’s senior author and chief of the Gene Therapy
and Therapeutics Branch, National Institute of Dental and Craniofacial Research
(NIDCR). “And although we have more research to do, this brings us one
step closer to the possibility of salivary gland gene therapy in humans with
Sjogren’s (SHOW-grins) syndrome affects approximately 1-2 million people,
mostly females, in the U.S. It is an autoimmune disorder in which immune system
cells mistakenly attack the body’s moisture-producing glands, causing
them to become inflamed. The disorder usually affects the salivary glands and
the glands that produce tears, but can also injure other tissues and organs.
It can occur by itself or with other, common autoimmune diseases like rheumatoid
arthritis and lupus. There is no cure for Sjogren’s syndrome at present.
Treatment for the lack of saliva consists mostly of palliative measures such
as sipping water, chewing sugarless gum, and using artificial saliva. There
are prescription drugs that can stimulate salivary flow in patients who have
some salivary gland function, but these drugs do not slow or stop disease progression.
Without enough saliva, people with Sjogren’s syndrome can endure considerable
discomfort, and may develop rampant tooth decay, oral fungal infections, and
difficulty eating and speaking.
In their study, Dr. Baum and his colleagues used the female non-obese diabetic
mouse, a standard animal model of type I diabetes as well as Sjogren’s
syndrome. These animals typically develop salivary gland dysfunction between
8 and 12 weeks of age.
The scientists created a gene ‘package’ made up of the human IL-10
gene and an adeno-associated virus vector that acted as the gene’s carrier
into salivary gland cells. “We chose the IL-10 gene because of its well
known anti-inflammatory properties and because of its reputation for inhibiting
the progress of other, similar autoimmune diseases in animal models,”
Dr. Baum said. IL-10 is an immunomodulatory protein, or cytokine, a type of
molecule made by immune system cells. Cytokines help these cells communicate
with one another, thereby fine-tuning the immune response.
The researchers introduced the gene package either into the animals’
salivary glands through a tiny tube in their mouth, or by injection into their
thigh muscle. Two groups of mice received the gene directly in their salivary
glands one group at 8 weeks of age (before the onset of salivary dysfunction)
and one group at 16 weeks of age (after the onset of salivary dysfunction).
Two other groups received the gene by injection into their thigh muscles at
the same time intervals. There were also animals that served as controls; they
were given a gene that was not biologically active.
“We found that the long-term (20 week) salivary function was about three
times higher in animals that were given the gene directly in their glands when
we compared them to control animals,” Dr. Baum said. “And the improvement
was seen whether the treatment was administered before or after the onset of
salivary dysfunction.” There was also some improvement of salivary flow
in the mice that received the gene via intramuscular injection at the late treatment
time, Dr. Baum said.
The scientists also examined the animals’ salivary glands for inflammation,
which at 20 weeks is typically moderate to severe in untreated animals. They
found much less salivary gland inflammation in the animals that received the
gene directly in their glands compared to control animals, suggesting that local
delivery of the gene inhibited the inflammatory process. The animals that received
the gene via intramuscular injection did not show any reduction of inflammation.
“These study results are important because they show us that an immunomodulatory
gene delivered locally to the salivary glands can be quite effective in limiting
the functional damage that occurs in this mouse model of Sjogren’s syndrome,”
Dr. Baum said.
Future studies will seek to understand the molecular changes that resulted
in preserved salivary function. “One unexpected finding in the treated
glands was increased levels of certain molecules that cause inflammation, the
opposite of what we had expected,” said Dr. Baum. “We don’t
know yet what mechanism lessened inflammation and preserved saliva flow and
we need to do more research to determine that before clinical trials are considered.”
He also cautioned that safety and toxicology tests are necessary prior to clinical
Collaborating with Dr. Baum were Drs. Marc Kok, Seichii Yamano, Beatrijs Lodde,
Jianghua Wang, Antony Voutetakis, Michael Schmidt, Sandra Afione, Stanley Pillemer,
Marjorie Tsutsui and John Chiorini from NIDCR; Ross Couwenhoven from the University
of Maryland Dental School; Derek Leroith and Shoshana Yakar from the National
Institute of Diabetes and Digestive and Kidney Disorders; and Paul-Peter Tak
from the University of Amsterdam.