|
Because of their unique immune modulating
and anti-inflammatory properties, Lisofylline (LSF) and our related
oral compounds target type 1, type 2 diabetes, and some
diabetes-related complications.
Adjunct to islet cell transplant
therapy. Islet cell transplant therapy is an emerging treatment
for type 1 diabetes. Preclinically, LSF demonstrated enhancement
and protection of human beta-cell function and viability during the
isolation procedure; a 30% reduction in islet
number was sufficient to control diabetes using the LSF treated
islets as compared to controls. Importantly, LSF administration as a
post-transplant infusion significantly prolonged islet graft
survival in these models.
An upcoming phase 2 clinical trial
sponsored by the National Institute of Allergy and Infectious
Diseases (NIAID) and National Institute of Diabetes & Digestive &
Kidney Diseases (NIDDK) will test LSF. The trial will focus on
treating islets pre-transplant, and recipients (during and
post-transplant). LSF was one of few agents selected because it has
a unique spectrum of anti-inflammatory, anti-apoptotic and beta-cell
enhancing properties that improves β cell function and viability.
This should allow for maximum pre-transplant functional islet mass,
islet engraftment and long-term function in patients with type 1
diabetes.
Reverse or arrest of the progression
of type 1 diabetes, without using toxic immunosuppressant
drugs. Each year in the U.S. alone 30,000, new cases type 1 diabetes
are diagnosed. Once diagnosed, destruction of beta cells continues
and essentially all type 1 diabetic patients become dependent on
insulin within one to two years of onset.
 In
a study of non-obese diabetic (NOD) mice, a well-established model
of type 1 diabetes, the animals were treated for 28 days with a
combination of LSF/Extendin-4. The treatment completely reversed
diabetes as evidenced by restored glucose homeostasis.
Additionally, there was evidence of new cell growth in the area of
the islet cells in the mice given the combined therapy. Although
NOD mice treated similarly with saline or Extendin-4 alone
experienced no improvement in the diabetic condition, animals
treated with LSF alone showed some improvement. As part of the same
study, isolated mouse pancreatic islets exposed to inflammatory
cytokines and treated with the
LSF/Extendin-4 combination
experienced a 2.5 fold increase in metabolism and a 40% decrease in
apoptosis (cell death) than controls.
Treatment of insulin-requiring type 2 diabetics.
About 30% of the type 2 diabetic population uses insulin. The goal
of the therapy would be to preserve the viability and function of
the patient’s remaining
 islet cells. New research shows that type 2
diabetes is associated with progressive loss of insulin producing
cells over time as a result of inflammatory damage to the
beta-cells.
In a rat model of type 2 diabetes, LSF was shown to improve insulin
secretion and glycemic control. This improved function of the
remaining insulin producing cells supports the rationale for
development of
oral agents related to LSF for treatment of insulin
requiring type 2 diabetics.
Latent Autoimmune Diabetes in Adults
(LADA) is a newly recognized subset of type 1 diabetes and is
thought to account for up to 10%-20% of all cases of diabetes.
Although it has characteristics similar to adult onset type 1
diabetes, the beta-cell destruction is less aggressive. LADA offers
a unique opportunity to develop immune modulation as potential
therapy in the field of diabetes.
Two lead candidate compounds (DT 22669
and DT 23552) have demonstrated oral bioavailability in primates and
are currently in pre-clinical development to target prevention and
treatment LADA.
Diabetic nephropathy, or kidney
disease, is one of the most frequent complications of diabetes.
Up to 21% of all patients with diabetes have nephropathy.
Nephropathy often ends in kidney failure or end-stage renal disease
(ESRD). Approximately 43% of new cases of ESRD are a result of
diabetes progression. Although certain high blood pressure
medications have been found to be helpful in slowing the progression
of kidney disease in people with diabetes, there is no cure.
DT 22669 has demonstrated oral bioavailability in primates
and is currently in pre-clinical development to target prevention
and treatment of diabetic nephropathy. In addition, preclinical
efficacy data in human kidney cells adds to the scientific rationale
for further development in this indication.
Diabetic retinopathy, leads to
proliferation of blood vessels in the retina of the eye and is
another frequent complication of diabetes. It represents the major
cause of blindness in adults. It is estimated that between 12,000
and 24,000 people lose their sight in the U. S. each year to
diabetes, making it the leading cause of new cases of blindness in
adults. There is no cure for diabetic retinopathy.
DT 23552 has demonstrated oral
bioavailability in primates and is currently in pre-clinical
development to target prevention and treatment of
diabetic retinopathy. In addition, preclinical efficacy data in
blood vessel cells adds to the scientific rationale for further
development in this indication.
|
