Why Mitochondria? MitoKor scientists have made two fundamental observations linking mitochondrial function to the most common form of diabetes, namely type 2, or non-insulin dependent diabetes mellitus (NIDDM). First, they have demonstrated that glucose stimulated insulin secretion (GSIS), which normally occurs after a meal to regulate blood sugar levels, is very tightly controlled by mitochondrial ATP production, and not by ATP from other cellular sources. Second, they have shown that metabolic defects observed in many patients can be traced to declines in mitochondrial function. The Company is now focusing on elucidating how mitochondrial dysfunction contributes to the pathogenesis of the disease, while also developing novel strategies for therapeutic intervention and diagnostics based on mitochondrial targets.
Current standard-of-care treatments for diabetes rectify only a subset of symptoms of the disease and, as a result, have been ineffective in controlling disease progression and the resulting complications. MitoKor believes that by treating mitochondria, it should be possible to preempt many of the biochemical defects associated with diabetes before such complications arise. MitoKor is the first and only company to focus on mitochondrial medicine and has developed a proprietary position that exploits the functional involvement of the mitochondria in type 2 diabetes.
Why Type 2 Diabetes? Diabetes, widely recognized as one of the leading causes of death and disability, affects an estimated 16 million people in the United States alone. It is associated with serious long-term complications including blindness, heart disease, stroke, kidney failure, amputation and nerve damage and usually leads to premature death. It is estimated to cost the health care system over $100 billion per year. Type 2 diabetes (NIDDM) is the most common form of diabetes and accounts for nearly 90 percent of all diabetes mellitus cases worldwide. Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) usually occurs early in life and accounts for less than 10 percent of cases. Other rare forms of diabetes, accounting for 1 to 2 percent of all cases, have also been identified and have been linked with mutations in mitochondrial DNA.
There is considerable evidence to show that mitochondrial dysfunction plays a role in the etiology of a majority of patients with diabetes. For example, diabetes mellitus is a common component of the approximately 50 syndromes caused by mutations or deletions in mitochondrial DNA. These mutations disrupt electron transfer complex (ETC) activity, reducing the generation of energy (in the form of ATP), while increasing production of reactive oxygen species (ROS). Further evidence for mitochondrial dysfunction in the more common forms of diabetes includes excessive free radical levels in the plasma, increased reactive oxygen species, decreased ATP synthase activity in engineered cell lines (cybrids) containing mitochondria from diabetic patients, and by the observed maternal inheritance patterns of the disease. Moreover, the presumed role of apoptotic processes in the death of pancreatic b-cells and the major involvement of mitochondria in essentially all forms of cell death strengthen the mitochondrial connection in common diabetes.
Why MitoKor? The data linking mitochondrial ATP production and glucose-stimulated insulin secretion, has led to a novel approach for improving early insulin secretion in type 2 diabetes. MitoKor has identified specific mitochondrial molecular targets that participate in the regulation of oxidative ATP production in the pancreatic b-cell. Using small molecules and/or peptides that interact with the selected mitochondrial targets, we have developed novel methods to enhance GSIS.
MitoKor’s first approach exploits the physiological role of mitochondrial calcium fluxes in the regulation of GSIS. A prototype compound, MITO-2915, has been employed to demonstrate that modulation of intramitochondrial calcium levels during physiological glucose stimulation markedly enhances the insulin secretory response in rat islets. Moreover, the secretagogue effect of MITO-2915 is synergistic with the effects of sulfonylureas and a-ketoisocaproic acid, suggesting that MitoKor’s novel approach may be appropriate not only for monotherapy, but for combination therapy with other secretagogues as well. Novel small molecules such as MITO-4837 have emerged from screens and are being evaluated in animal models.
The second approach under development at MitoKor exploits physiological regulation of the oxidative phosphorylation pathway. MITO-3384, a test molecule that interacts with the selected mitochondrial target, enhances GSIS by altering the activity of the target protein. Like the first approach, this type of intervention harnesses normal physiological mechanisms that respond to hyperglycemia, thereby minimizing the risks of hypoglycemia and chronic hyperinsulinemia.
MitoKor’s Assets MitoKor has developed technology for rapid discovery of novel molecular targets and has created over 50 assays for measuring mitochondrial function and cell death for use in high throughput drug screening. MitoKor’s drug discovery pipeline for diabetes is supported by exploratory projects dealing with mitochondrial biogenesis and b-cell apoptosis, as well as by an extensive effort to define mitochondrial SNPs associated with type 2 diabetes. In addition, our proteomics and genomics programs will contribute to future target discovery in the diabetes program.