Neurotrophic Drug Development for Alzheimer's Disease

Drug development for the cognitive deficits in Alzheimer’s Disease has proven to be challenging. Although major progress has been made in understanding disease pathophysiology and removal of pathogenic agents, it has not resulted in substantial cognitive improvement. Failures of clinical trials and strong side effects of approved drugs has made it necessary to explore alternate approaches. We propose a neurotrophic therapeutic approach to address the debilitating cognitive dysfunction in AD. Erythropoietin (EPO), which is widely prescribed for the treatment of anemia, has been shown to exhibit robust neurotrophic activity in the brain. It is understood that these neurotrophic effects are centrally involved in its ability to improve cognitive function. Multiple clinical trials in psychiatric disorders have reported significant improvement in cognitive function after EPO treatment. However, EPO has potent erythropoietic activity that can result in adverse hematological consequences with chronic administration. To overcome this key limitation, we have produced a triple substitution, recombinant neurotrophic molecule that is non-erythropoietic but retains the neurotrophic and cognitive effects of EPO. The goal of this proposal is to perform Phase I feasibility studies to advance our invention. The aims are designed to test bioreactor scaleup of protein production, determine toxicity and demonstrate functional efficacy in AD model mice. The results of the Phase I studies can provide a new direction towards commercial development of a neurotrophic action based therapeutic molecule.