Research Updates
JDRF Research E-Newsletter #13
November 20, 2001
The Juvenile Diabetes Research Foundation’s Research E-Newsletter is
published twice a month to provide all those interested with the
latest information about research on Type 1 diabetes and its
complications.
Subcribe to the JDRF Research E-newsletter!
In This issue:
Restoring Normal Blood Sugar Levels and Complications: Two JDRF
Centers Launched at U. of Pennsylvania
Restoring Normal Blood Sugar Levels: Helping Beta Cells Survive
Complications: JDRF-Funded Scientists Report at Neuroscience Meeting
Update: NIH Posts Stem Cell Registry
1. Restoring Normal Blood Sugar Levels And Complications: Two JDRF
Centers Launched at U. of Pennsylvania
At a ceremony in Philadelphia on November 13, 2001, JDRF awarded
$15.5 million to fund diabetes research at the JDRF-W.W. Smith
Charitable Trust Center for Islet Transplantation at the University
of Pennsylvania School of Medicine and the JDRF Center for Gene
Therapy at the University of Pennsylvania School of Medicine.
Islet Transplant Progress
The transplantation-focused Center, under the director of Ali Naji,
MD, PhD, integrates three projects focused on:
the use of non-invasive positron emission topography (PET) technology
to observe transplanted islets after transplantation and understand
their fate;
preclinical animal studies to further affirm the promising strategy
of transplanting islets in the thymus, where as demonstrated by the
Penn researchers in earlier small animal experiments they have a
greater chance of survival;
a Human Islet Transplantation Clinical Program testing the Edmonton
Protocol for islet transplantation, using a combination of three
steroid-free drugs to prevent rejection of the donor islets (the
first trials recently began, although published data is not expected
until next spring).
Gene Therapy Approaches to Complications
At the second newly-launched center, the JDRF Center for Gene
Therapy, with James Wilson, MD, PhD, as director, scientists are
making progress in these complications focus areas:
Wound healing and foot ulcers: With a human clinical trial under way,
researchers are delivering growth factor genes directly to wounded
tissue in an attempt to promote healing where it is needed.
Researchers are assessing whether transferring vascular endothelial
growth factor (VEGF) genes to veins and arteries could promote blood
vessel growth.
Diabetic retinopathy: Researchers have had success restoring sight to
an animal model of a childhood blindness disorder and are now working
on applying this advance to human diabetic retinopathy. They are also
using a new technology magnetic resonance angiography to learn
how blood vessels are formed. Finally, they are developing new
vectors to deliver genes to the eye that will cause cells to produce
proteins in the vitreous fluid. Abnormal blood vessel growth would be
slowed down or stopped.
A “Biological Insulin Pump”
In another project, Dr. Wilson is exploring an important challenge in
gene therapy: the ability to control gene expression when
transferring genes responsible for insulin production. There needs to
be control because unchecked expression can lead to life-threatening
hypoglycemia. Dr. Wilson is developing a way to turn the action of a
particular gene on and off through a “biological insulin pump.” His
team is using a virus vector to deliver the insulin gene into the
body. The patient would activate this transferred gene and switch on
the “pump” by taking an oral drug. When the patient stops the drug,
the insulin would switch off. The goal is the control of blood sugar
levels in a simple, patient-directed manner.
2. Restoring Normal Blood Sugar Levels: Helping Beta Cells Survive
Dr. Naji also has been involved in research that may lead to ways of
helping beta cells survive. Dr. Naji and colleagues investigated the
mechanism of action and function for the protein Akt, also called
protein kinase B (PKB), which has been implicated in recent years as
an important mediator of insulin action. Akt appears to be a strong
suppressor of apoptosis the type of cell death triggered in
pancreatic beta cells that cause Type 1 diabetes.
A research team at the University of Pennsylvania School of Medicine
that included Dr. Naji and was led by Howard Hughes Medical Institute
investigator Morris Birnbaum, MD, PhD, found that boosting the
expression of Akt in the beta cells of mice could cause an increase
in the size of the beta cells as much as tenfold and the size of
the islets they make up. This increase improved the animals’ ability
to regulate glucose levels and even allowed them to resist
artificially induced diabetes. The finding, reported in the October
issue of the journal Nature Medicine, suggests that boosting Akt
expression in human beta cells could enlarge the pool of beta cells
available for transplant to diabetic patients.
3. Complications: JDRF-Funded Scientists Report at Neuroscience
Meeting
The Society for Neuroscience (the world’s largest organization of
scientists and physicians dedicated to understanding the brain,
spinal cord, and peripheral nervous system) recently held its 31st
Annual Meeting in San Diego, CA. With 28,000 attendees, including
representatives from the JDRF Research department, the six-day
program included presentations and poster presentations by a number
of JDRF-funded researchers, covering research about the effects of
diabetes on the brain and research in understanding and treating
diabetic neuropathy, the complication that causes infection and
debilitating pain, and can lead to life-threatening conditions
including heart failure Among the JDRF-funded presenters:
Lawrence Reagan, PhD, of Rockefeller University’s Laboratory of
Metabolic Diseases, and a JDRF Advanced Postdoctoral Fellow, reported
on his team’s experiments examining how stressful stimuli increase
neuronal damage in diabetic subjects. Using sophisticated new
technology, Dr. Reagan confirmed that the combined effects of
diabetes and corticosterone (a steroid released in response to
stressful stimuli) produces neuron damage and death in a particular
region of the brain known as the hippocampus, a region critical to
the development, retention and retrieval of learning and memory. Dr.
Reagan identified two proteins, HNE and MDA, that cause oxidative
stress and, because of increased levels in the hippocampus, may lead
to irreversible neuronal damage. He is investigating the use of a
recently-identified glucose transporter, GLUTx1 (a member of the
family of proteins that facilitate the entry of glucose from the
blood into cells), and drug treatments to reverse or eliminate these
neuronal complications.
David M. Stern, MD, director, Anne Marie Schmidt, MD, co-director of
the JDRF Center for Diabetes Complications at Columbia University,
and colleagues, presented progress reports on their cutting edge
research into the key molecules on the surface of cells called
Receptors for Advance Glycation Endproducts (RAGE). RAGE expression
(caused by oxidation and other processes) has long been implicated in
an ascending spiral of cell inflammation and degeneration that drive
the diabetes complications process forward. The researchers presented
evidence that an artificial form of RAGE, called soluble RAGE (sRAGE)
is proving successful in blockading RAGE and halting or preventing
complications in preclinical tests. The researchers also reported
that RAGE provides an important therapeutic target for treatment of
Alzheimer’s disease.
David Fink, MD, a member of the team at the JDRF Center for Gene
Therapy Approaches to Type 1 Diabetes at Children’s Hospital of
Pittsburgh and the University of Pittsburgh, and colleagues presented
new evidence in their JDRF-funded study of progressive nerve damage
in diabetes. In preclinical tests using models of diabetic
neuropathy, the researchers reported that the nerve growth factor
neurotrophin-3 (NT-3) delivered through gene transfer “is the first
demonstration of a protective effects [in preventing nerve
degeneration] achieved by gene transfer to neurons” in a particular
nerve cluster called DRG (dorsal root ganglia) of the spinal order.
4. NIH Posts Stem Cell Registry
On November 7, the National Institutes of Health (NIH) posted on its
Web site its list of human embryonic stem cell lines that meet the
eligibility criteria set by President Bush on August 9. The Human
Embryonic Stem Cell Registry lists a total of 72 lines that may be
used for federally-funded research.
In addition to the registry, NIH has published the President’s
criteria for stem cell lines that may be used in federally-funded
research, extended the deadline for stem cell research applications
for the October cycle until November 27.
However, it remains unclear how many stem cell lines are actually
ready for researchers to use immediately. The Web site notes that the
stem cell lines are at “varying stages of development.” It also
appears that researchers must still negotiate access to the listed
stem cell lines with those entities that control them.
JDRF Research E-newsletter
The Juvenile Diabetes Research Foundation’s Research E-Newsletter is
published twice a month to provide all those interested with the
latest information about research on Type 1 diabetes and its
complications. Subcribe to the JDRF Research E-newsletter!