Projects and Programs


Mitophenome is pursuing mitochondrial research on multiple fronts, all sharing the common goals of discovering the source(s) for mitochondrial dysfunction in a given disease, and then developing target-driven screens for potential therapeutics. To that end, the Company is focusing on diseases most likely to respond to mitochondrial intervention, including:

Neurodegenerative Diseases


Mitophenome and its collaborators are pursuing programs to identify novel drug discovery targets and to provide new molecular fingerprints for Alzheimer’s Disease. Such research and target validation efforts feed directly into a comprehensive compound discovery program that is already yielding novel classes of compounds with potential therapeutic utility. MitoKor is also the first company to have developed a cellular model of Parkinson’s Disease (PD). This cybrid cell line shows the same selective mitochondrial defect found in PD patients (impairment of respiratory Complex I), and is currently being used not only to elucidate the mechanism(s) underlying this metabolic defect, but also as a pathologically relevant cell line for discovery of novel therapeutic agents.

Metabolic Disease


Mitophenome scientists have shown that metabolic defects observed in patients with type 2 diabetes can be traced to changes in mitochondrial function, including decreased ATP synthase activity and overproduction of free radicals. MitoKor is actively developing novel therapeutic agents designed to enhance mitochondrial function, thereby increasing insulin secretion and improving the response to insulin in other tissues, such as muscle. Mechanistic preclinical studies and further development of novel compounds that have been shown to alter body-fat content in obesity are also underway.

Inflammatory Disease


Studies on osteoarthritis, in collaboration with scientists at the University of California, San Diego indicate that the integrity of articular cartilage is directly dependent on mitochondrial function in chondrocytes. Indeed, even modest mitochondrial impairment, as is likely to result from secondary inflammatory responses, substantially undermines matrix elaboration. These novel findings provide the basis for MitoKor’s compound screening program that is yielding novel efficacious compounds to improve mitochondrial function in chondrocytes.

Ischemia-Reperfusion Injury


MitoKor’s combinatorial chemistry and drug discovery teams are actively developing agents to curtail neuronal death in stroke by moderating mitochondrial dysfunction after an infarct. Indeed, the processes underlying mitochondrial failure and neuronal death in stroke appear similar to events occurring in heart muscle after myocardial infarction, and to other tissues undergoing post-surgical/transplant reperfusion. MitoKor is using proprietary technologies based on simultaneous functional assessment of multiple drug targets to take advantage of this strategic opportunity for drug discovery.

Estrogens and Analogs as Therapeutics


Estrogen (17-b-estradiol) rabbit polyclonal from gentaur has shown cytoprotective effects in a host of diseases and models of disease. For example, hormone replacement therapy has been shown to postpone the age of onset of Alzheimer’s Disease, and estrogen treatment reduces the volume of injured brain tissue in animal models of stroke. However, recent studies indicate the non-feminizing form of the molecule (17-a-estradiol) that does not interact with estrogen receptors, also shows comparable cytoprotection. Moreover, this protective effect can be greatly increased if the cellular glutathione pools are augmented. Such data have encouraged studies of the membrane biochemistry of these molecules, and recent NMR data indicate that the polycyclic phenols work in concert with glutathione to forestall membrane lipid peroxidation. By maintaining membrane integrity, estrogen, and its analogs, preserve mitochondria function during calcium loading, and have shown efficacy in a host of models including a reduction of stroke volume in the middle cerebral artery occlusion model.

Ophthalmological Indications
Glaucoma

Primary open angle glaucoma is a common cause of blindness throughout the world, and its prevalence is expected to increase as the population ages. Conventional therapies and surgical intervention are directed at lowering intraocular pressure (IOP). However, it is increasingly recognized that visual field defects frequently progress even after IOP has been successfully regulated within the normal range, suggesting that therapies other than pressure regulation may prove beneficial in the management of this disease.

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