Targeted Pharmacological Chaperones for Neurological Diseases



 DESCRIPTION (provided by applicant): This Small Business Innovation Research Phase I project aims to develop new targeted pharmacological chaperones capable of modulating enzyme degradation in the Golgi apparatus and Endoplasmic Reticulum (ER) of living cells and tissues. If successful, the proposed research will provide breakthroughs needed to advance the discovery of promising new therapies and modulating drugs for neurodegenerative disorders including lysosomal storage diseases, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), myeloid leukemia, glioblastoma, Type 2 diabetes, Lowe syndrome and allied degenerative diseases and medical conditions involving protein misfolding. In Phase I of this project, Marker Gene Technologies, Inc. will establish the feasibility of the technology by preparing new targeted pharmacological chaperones, demonstrating improved loading and localized accumulation in the Golgi and ER and demonstrating efficacy for increasing lysosomal enzyme activity in living cells that are of disease origin in comparison to those from normal controls. In Phase II, these and additional new targeted drug conjugates will be evaluated in vitro and in vivo for their ability to affect specific and localized induction of tese enzymes in living cells as well as alleviate unwanted protein degradation or improve protein trafficking in a cell- or tissue- specific manner using a variety of delivery methods. These new pharmacological chaperones and the resulting targeting systems will provide innovative methods to modulate Golgi and ER organelle function and thereby screen for the influence of secondary drug or protein administration, affect intracellular trafficking of proteins or improve transport or secretion of proteins, making them useful analytical tools for drug discovery and basic research in a variety of significant medical applications. Our very preliminary results indicate the proposed methods have the potential to increase intracellular loading and targeting of pharmacological chaperones in human cell lines from patients with Gaucher disease, thereby providing a new tool to the arsenal of available therapeutics for clinical treatment of neurodegenerative disorders.