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 Investigators:
Harry Nick, Anupam
Agarwal
Insulin dependent diabetes mellitus (IDDM) is a common
disorder affecting about 1 million individuals in the US population.
This disease results primarily from abnormal glucose metabolism
due to lack of the hormone, insulin, which is produced exclusively
by beta cells in the Islets of Langerhans of the pancreas. Multiple
organs including the kidney, eye, nerves and blood vessels can be
affected with significant patient suffering. Current treatments
include insulin replacement therapy, and pancreas/islet transplantation,
the latter being complicated by the process of rejection. Unfortunately,
insulin replacement does not cure diabetes and more importantly
does not completely prevent the onset of complications.
The onset of the disease is caused by the progressive
loss or death of the beta cells through an attack of the patient's
own immune system. A prominently accepted explanation for beta cell
death is the immune-dependent production of toxic oxygen molecules,
referred to as reactive oxygen species, inside and outside the beta
cell. These reactive oxygen species can cause considerable damage
to cell membranes, DNA and proteins leading to cell death. Normal
oxygen metabolism also generates reactive oxygen species which are
rendered non-toxic by so called antioxidant enzymes in our cells.
Unfortunately, the beta cell has a reduced capacity to produce these
protective enzymes, thus making the beta cell more vulnerable to
injury through the action of these immune- activated reactive oxygen
species. Increasing the level of these protective enzymes has been
shown to be beneficial in beta cell survival. Islet transplantation,
or the delivery of insulin-producing islet cells into people with
diabetes offers the ability to restore normal levels of blood sugar,
ending the dependency on insulin injections and provides the potential
to reverse or prevent further complications. A difficulty of this
promising strategy is the patient's own activated immune system
and the problem of transplant rejection of the foreign islet cells.
We, therefore, propose to isolate islets from normal animals and
genetically engineer them to overexpress two of the most potent
protective, antioxidant enzymes, heme oxygenase-l and manganese
superoxide dismutase. This will be followed by transplantation of
the genetically engineered islets into diabetic animals. The genetic
manipulation or gene therapy will be performed using an innocuous
virus called adeno-associated virus (AAV) to deliver the genes for
these protective enzymes to islet cells before transplantation.
This gene delivery system shows great promise since it does not
evoke an immune response similar to other viruses (e.g. adenovirus)
that have been employed for gene therapy. We expect that overexpression
of these antioxidant enzymes will protect islet cells from the patient's
immune system as well as from transplant rejection. This would greatly
enhance islet cell survival and function, leading to normal insulin
production and blood glucose levels, thereby providing a sustainable
treatment option for patients with IDDM.
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