1. Development of experimental drugs that modify mitochondrial function for treatment of cancer, obesity, type 2 diabetes, non-alcoholic steatohepatitis (NASH)
Overview: Mitochondria are at the center of the most important medical challenges of our time: obesity, type 2 diabetes, NASH, cancer, and neurodegenerative diseases (see inserted figure). Mitochondria not only provide the majority of energy (ATP) for cellular activity but also are central in producing metabolic intermediates for macromolecule biosynthesis supporting cell proliferation. Moreover, the byproducts of mitochondrial oxidation, reactive oxygen species (ROS), are the main intrinsic causal factor of aging and aging related diseases including neurodegenerative diseases. My laboratory is interested in developing experimental therapeutics that modify mitochondrial activity and function for the treatment of obesity, type 2 diabetes, cancer, and neurodegenerative diseases.
Metabolic diseases: One focus is the development of safe mitochondrial uncouplers as investigational drug leads. Mitochondrial uncoupling is a process by which protons enter mitochondrial matrix in a way that bypasses the ATP synthase. As a result, mitochondrial uncoupling leads to an increase in lipid oxidation and a reduction in lipid synthesis, an excellent therapeutic strategy for obesity and type 2 diabetes. Our recent discovery of using a safe mitochondrial uncoupler, which is a modified formulation of an FDA approved drug, for treating type 2 diabetes (Nature Medicine 20, 1263-1269 (2014)) provided proof-of-principle for this approach. Current projects in this direction include developing new mitochondrial uncouplers for other metabolic diseases including obesity, NASH and alcoholic fatty liver disease. We collaborate with the laboratory of David Augeri, the lead inventor of the Bristol-Myers Squibb type 2 diabetes drug saxagliptin, on the drug discovery program.
Cancer: Almost all cancer cells exhibit aerobic glycolysis (the Warburg effect), which prevents complete oxidation of glucose or glutamine in mitochondria. As a result, glucose is shunt to pathways for producing metabolic intermediates for biosynthesis of RNA, DNA, and proteins, which are essential for cancer cell proliferation. Mitochondrial uncoupling greatly increase glucose oxidation in cancer cells and deplete the glucose metabolites essential for macromolecule synthesis. This effectively inhibits cancer cell proliferation and represents a novel anti-cancer therapeutic strategy (Amer Alasadi et al, Cell Death and Disease, 2017, accepted). We are developing new chemical leads for treating a variety of cancers including colon cancer, pancreatic cancer, and leukemia.
Aging and neurodegeneration: Mitochondrial ROS production is very sensitive to the mitochondrial membrane potential (MMP). A slight increase in MMP dramatically increase ROS production while slight reduction in MMP would reduce the resistance of mitochondrial electron transport chain, thereby reduces ROS production. Mild mitochondrial uncoupling could be a potential strategy for treating neurodegenerative diseases caused by aberrant mitochondrial ROS production. We are exploring this strategy of intervention.
Mitophagy: Finally, my laboratory has extensive experience and expertise in study of mitophagy. Mitophagy is the physiological process of removing damaged mitochondria through targeted autophagic degradation. Mitophagy is critical for the maintenance of a healthy population of mitochondria in cells. It is expected that enhancement in mitophagy would promote mitochondrial health and might be the ultimate solution to many diseases of mitochondria origin. My laboratory is engaging basic research in this area, using a powerful system identified in my laboratory, the adipocyte differentiation system. White adipocytes have a unique cellular structure, in which over 99% of the cell volume is occupied by a gigantic lipid droplet, while the rest of cell structure, including nucleus, occupies little space. The mature white adipocytes are developed from pre-adipocytes, which are fibroblast-like and contain abundant cytoplasmic components such as mitochondria. Drastic cytoplasmic reorganization and cytoplasm elimination occur during adipocyte differentiation. Tremendous mitochondrial biogenesis occurs in the early phase of adipogenesis, which is required for lipogenesis. We found that massive induction of mitophagy is triggered in later stages of adipogenesis, which is responsible for eliminating mitochondria and other cytosolic components, making room for lipid droplet (PNAS, 106 (47): 19860-5, 2009, and Autophagy, 5(8):1118-30, 2009). This well-characterized model system provides an excellent opportunity to identify the molecular components in mitophagy and the regulatory pathways.
2. Applying proprietary precision gene editing technology for developing therapeutics for treating genetic diseases caused by a point mutation.
Over 6,000 human genetic diseases are caused by a point mutation. Recent development in CRISPR technology generates hope of cure for those diseases. Current CRISPR- based gene-editing approaches rely on generating double strand DNA breaks (DSB) which facilitate homologous recombination (HR) near the breaking site for gene correction. Unfortunately, these approaches have two main limitations: somatic cells do not have HR activity or have very low HR activity, and DNA double strand breaks are highly oncogenic. As a result, the CRISPR-HR- based technology has limited therapeutic potential at its current form.
We designed a new CRISPR gene editing platform that does not generate DSB and does not use HR for gene correction (Jin, Shengkan; Collantes, Juan. Nuclease-independent targeted gene editing platform and uses thereof. PCT/US16/42413, patent pending). Instead, the new platform uses a nuclease deficient Cas9 for sequence recognition and a RNA based recruitment of cytidine deaminase or adenosine deaminase for C to T or A to G base correction. The technology overcomes the main limitations of the HR- based gene editing technologies and has excellent potential for development of therapeutics which aim to correct point mutations in somatic tissues in patients. We are working on proof-of-concept therapeutics in treating a number of important genetic diseases in cellular and animal models.
