DESCRIPTION (provided by applicant): The long-term goal of this project is to develop an improved enzyme replacement therapeutic (ERT) for MPS I that integrates safety and cost advantages of plant-based bioproduction with innovations that enhance ERT delivery and disease correction. MPS I (encompassing Hurler, Hurler/Scheie, Scheie syndromes), the most common MPS disease, is caused by genetic deficiencies in the lysosomal enzyme ¿-L-iduronidase (IDUA). Current IDUA-based ERTs for MPS I patients effectively treat most somatic symptoms, but do not correct significant debilitating manifestations of this disease, especially those affecting the central nervous system (CNS). To expand the delivery of corrective IDUA enzyme to critical cells and tissues exhibiting MPS I pathology, we have produced fusion proteins that combine IDUA with a galactose/galactosamine-selective plant lectin. This lectin has high affinity for glycoproteins and glycolipids common on mammalian cell surfaces and mediates efficient cellular uptake, transcytosis, and lysosomal delivery of IDUA. In vitro analyses of MPS I patient fibroblasts treated with our IDUA-Lectin fusions (termed IDUAL) demonstrate rapid and efficient correction of cellular disease phenotypes. They also indicate that IDUAL utilizes different cell binding and uptake mechanisms compared to current ERT drugs for lysosomal diseases. We hypothesize that IDUAL will provide ERT access to a broader array of cell types, including cells of the central nervous system, that are not treated by current
MPS I drugs. The goal of this SBIR Phase I feasibility study is to assess the in vivo efficacy of the IDUAL fusion as an ERT in the MPS I mouse model. Specific aims for Phase I are 1) to produce IDUAL fusion protein at a scale to support in vivo trials using a transient plant-based expression platform suitable for commercial production, and 2) to demonstrate biodistribution and initial in vivo efficacy of IDUAL in the MPS I mouse model. The in vivo studies will include analyses of cognitive behavior and brain histopathology to assess ERT delivery to the brain and potential for ameliorating CNS pathologies. While our IDUAL fusion protein has shown significant in vitro efficacy in MPS I fibroblasts this SBIR represents the first test of in vivo animal efficacy and will provide a critical proof-of-concept for the lectin carrier and the IDUAL fusion drug candidate. Based on successfully meeting the Phase I milestones, follow-on Phase II research will address key preclinical studies required for filing an IND for this product. In anticipation of this long term goal, BioStrategies LC has initiated clinical and manufacturing partnerships for the Phase II SBIR to support cGMP-like bioproduction scale-up with Kentucky BioProcessing LLC and extended in vivo preclinical research with the University of Minnesota Medical School necessary to support IND filing with FDA and follow- on clinical trials directed toward delivering this technology to affected MPS I patients.