Evaluating the efficacy of MSI-1436 in slowing the progression and in reversing diabetic nephropathy in the BTBR ob/ob mouse
Viravuth Yin   (Bar Harbor, ME)
Abstract Diabetic nephropathy (DN) is a major cause of morbidity and mortality in type 1 diabetics and is becoming an increasingly serious problem in type 2 diabetics. DN is characterized by progressive loss of glomerular function due to fibrosis, capillary damage and loss of podocytes and is the primary cause of chronic and end-stage renal disease in the world. Therapies aimed at inducing the regeneration of lost tissues and cells have been proposed as therapeutic strategies for slowing and reversing diabetic glomerular damage. MSI-1436 is a readily synthesized aminosterol isolated from dogfish sharks. We have demonstrated that MSI-1436 induces a 2-3-fold stimulation in regeneration of amputated zebrafish cardiac, nerve, bone, skin, connective and vascular tissues without malformation. In adult mice, MSI-1436 stimulates injured skeletal muscle stem cell activation over 2-fold, and increases survival, improves heart function ~2-fold, stimulates regenerative cardiomyocyte proliferation ~4-fold and reduces infarct size by ~55% 4 weeks after cardiac ischemic injury induced by permanent cardiac artery ligation. MSI-1436 has been studied extensively. The molecule inhibits the tyrosine phosphatase PTP1B and was tested by Genaera Corp. in 2007 in Phase 1 and 1b clinical trials for treatment of obesity and type 2 diabetes. Metabolic changes consistent with inhibition of PTP1B were reported and patients showed no adverse reactions to the drug. Importantly, the stimulatory effects on tissue repair and regeneration we observe in zebrafish and mice occur at doses 5- and 50-times lower than the maximum dose shown previously to be safe in humans. Given the effect of MSI-1436 on animals as diverse as zebrafish and mice and its ability to stimulate repair and regeneration of highly diverse tissues, we postulate that the molecule will stimulate the regeneration of diverse cell types in the diabetic kidney. The overall Aim of this pilot project application is to carry out a proof-of-concept study to test the efficacy of MSI-1436 in slowing and reversing glomerular damage in the BTBR ob/ob mouse. Demonstrated efficacy will provide an essential foundation for more in-depth preclinical studies in order to establish whether MSI-1436 is a candidate for clinical evaluation. The demonstrated safety of MSI-1436 and extensive knowledge of its target and mode of action greatly reduce the time and costs associated with developing this molecule as a regenerative medicine therapy.
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