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.
The success of this project opens up enormous commercial possibilities in the fields of medical intervention in a variety of neurodegenerative diseases such 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 medical conditions, as well as in the screening of new proteins and drugs in cell-culture systems for efficacy in modulating intracellular enzyme activity in these diseases. The development of new, general and organelle specific targeting strategies will find use in potential treatment of organelle specific viral and bacterial diseases such as Cholera, Chlamydia or malarial infection. The developed products will also be useful in non-mammalian cells systems that exhibit defective protein folding and ER/Golgi accumulation or degradation including plant, yeast and bacterial species and will lead to commercial and licensable products in these areas.
