Enzyme Replacement Therapy for GM1 Gangliosidosis Lysosomal Rare Disease

Cramer, Carole; D'Azzo, Alessandra; Radin, David

Abstract

The goal of this proposal is to develop an effective enzyme replacement therapy (ERT) for patients suffering from GM1 Gangliosidosis by integrating a novel protein fusion ERT cell delivery strategy under development at BioStrategies LC and by exploiting safety, supply, and cost advantages of new plant-based enzyme therapeutics bio-manufacturing systems. GM1 Gangliosidosis is a rare genetic lysosomal storage disorder 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 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 is designed to lead to an effective ERT-based treatment for GM1 Gangliosidosis patients, a patient population with desperate need for new therapeutic options. Our novel plant lectin-ERT fusion tissue delivery technology could also lead to a paradigm shift for ERT-based treatment approaches in general by developing alternative cell targeting mechanisms aimed at trans-blood-brain-barrier drug delivery. The FDA approval in 2012 of the first plant-made ERT, Elelyso (glucoceribrocidase), to treat Gaucher lysosomal disease and the continued growth of interest in rare diseases will support the competitive potential of innovative technologies incorporating new ERT delivery options and plant-based bio-production. This Phase I project addresses the following specific questions: 1) Are plants capable of producing bioactive human ? -galactosidase (? -gal)? 2) Can ?-gal-plant lectin fusions be produced that retain both ? -gal enzyme activity and novel carbohydrate-binding/cell targeting selectivity?, and 3) Are these plant-made fusion proteins delivered to GM1 diseased brain cells and corrective for disease phenotype in cellular and animal GM1 disease models? Success in these aims will demonstrate the feasibility of plant-based bioproduction of bioactive lysosomal ? -galactosidase and BioStrategies LC proposed lectin-fusion ERT protein delivery technology. Future follow-up research in a subsequent Phase II SBIR project will complete product characterization and scaled-up production to support preclinical studies for testing safety and efficacy of this new GM1 ERT drug candidate, prerequisites for an IND, investigational new drug, application to FDA.

Public Health Relevance

The family of human genetic diseases belonging to the group of lysosomal storage disorders (LSDs) including GM1 Gangliosidosis represents some of the most devastating disease afflictions known and the most costly to patients, their families and the public health care system. Currently available enzyme replacement therapeutics (ERTs) for several of these diseases, although effective for many patients, suffer from problems of safety, high cost, product effectiveness, and availability of adequate product supplies to patient populations. The new therapeutics innovations developed in this SBIR Phase I R&D project would address many of these issues by developing ERTs that are more effectively targeted to diseased cell types and tissues (e.g. the brain) and that are safer and cheaper to supply to patient populations by virtue of employing newer plant-based production technologies. The innovative drug delivery technology developed in this project would further the goal of reducing the cost and suffering of patients afflicted with these devastating genetic diseases.