The goal of this SBIR proposal is to develop an effective enzyme replacement therapy (ERT) for patients suffering from GM1 Gangliosidosis by applying a novel ERT enzyme-lectin fusion delivery strategy developed at BioStrategies LC and by exploiting safety, supply, and cost advantages of a plant-based ERT protein bio-manufacturing system. GM1 Gangliosidosis is a rare lysosomal disease affecting less than 200,000 people in the U.S. It is caused by a defect in the gene encoding the enzyme ?-galactosidase and is characterized by progressive degeneration of normal childhood development especially in brain function leading to death at an early age. Current treatment options are limited to management of disease symptoms and development of an effective ERT drug has been hindered by challenges of delivering these drugs across the blood brain barrier to the brain and central nervous system. This research project is a collaboration between BioStrategies LC, a company focused on doing innovative research in lysosomal disease ERT development, and St. Jude Children?s Research Hospital, an international center for GM1 Gangliosidosis research. This SBIR Phase II is designed to lead to an effective ERT treatment for GM1 Gangliosidosis patients, a patient population with desperate need for new therapeutic options. In Phase I we met project goals by showing that a plant-produced ERT consisting of a fusion between human ?-gal and the plant RTB lectin could be delivered into lysosomes of human disease cells where it reduced the pathogenic levels of GM1 substrate to normal. Follow up animal studies in the GM1 disease mouse model showed that this ERT complex was effective in delivering active enzyme to tissues of both visceral organs and the CNS producing a significant reduction in the high levels of GM1 enzyme substrate associated with the GM1 disease phenotype. These results raise the hope that this novel plant lectin-ERT fusion cell delivery technology could lead to a general paradigm shift for ERT-based treatment approaches in which ERTs could be used to effectively treat diseases that significantly affect the central nervous system. Based on our successful Phase I outcomes, Phase II will focus on detailed analyses confirming disease correction within the CNS and visceral organs of GM1 gangliosidosis mice, product scale-up and characterization to support further preclinical assessments and follow-on long-term animal studies on pharmacodynamics, dosing/administration parameters, and amelioration of disease manifestations with larger cohort sizes and gender representation consistent with Rigor and Reproducibility guidance. These studies will support our goal of gaining sufficient data to support a successful application to FDA for IND approval.
The family of human genetic diseases represented by GM1 gangliosidosis and other lysosomal disorders (LDs) include some of the most devastating human afflictions known and the most costly to patients, their families, and the public health system. The currently approved enzyme replacement therapeutics (ERTs) available to treat several of these diseases, although effective for many patients, still suffer from problems of safety, high cost, availability of adequate product supplies to patient populations, and product effectiveness in treating all organs of body. The new therapeutics technologies for GM1 developed in this SBIR Phase II R&D project would address all of these issues by employing new drug delivery technology that more effectively targets affected cell types, cellular compartments, and organs. The need for delivering new treatment options such as that described in this proposal to the central nervous system (CNS) and brain is particularly critical as current drug options for LDs are generally not effective in the brain. The innovative drug delivery technology developed in this project including our use of cheaper plant-based manufacturing would further the national goal of reducing the suffering and costs for patients afflicted with these devastating genetic diseases.
