Enzyme Replacement Therapy for Sanfilippo A Lysosomal Rare Disease

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DESCRIPTION (provided by applicant): The goal of this proposal is to develop an effective enzyme replacement therapy (ERT) for Sanfilippo A patients by exploiting safety, supply, and cost advantages of plant-based enzyme bioproduction while integrating novel ERT delivery strategies being development at BioStrategies LC. Sanfilippo A (MPS-IIIA) 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 heparin N-sulfatase (SGSH) and is characterized by progressive degeneration in normal childhood development especially in brain function leading to death at an early age. Current treatment options are limited to symptom management and development of an effective ERT drug has been hindered by challenges of delivering these drugs to the brain and central nervous system (CNS). The promise of plant-made bioproduction has recently been recognized with the FDA approval of Elelyso (taliglucerase), Protalix/Pfizer's plant-made glucocerebrosidase ERT for Gaucher Disease. If successful, this SBIR will lead to an effective ERT-based treatment for Sanfilippo A patients, a patient population with desperate need and limited options. Utilizing BioStrategies' new plant lectin-ERT fusion and delivery technology to be further developed during this project, this research will lead to a fundamental paradigm shift for ERT-based treatment approaches based on innovative alternate cell targeting mechanisms, mucosal delivery, and trans-blood-brain-barrier (BBB) activity. The potential for a marketable product is very high. With the recent FDA approval of plant-made Elelyso and industry showing elevated interest in rare disease targets and lowering drug development and production cost/timelines, these new technologies for plant-based bioproduction are highly competitive. Independent of the lectin delivery aspects, plant-derived SGSH will bring cost and safety advantages over mammalian cell-derived SGSH ERT. If the promise of lectin- mediated ERT delivery is met, lectin:SGSH fusions would be a treatment of choice for MSP-IIIA and this drug delivery technology could be broadly developed to target other diseases with strong CNS involvement or indications for transmucosal delivery. This Phase I project will address the following specific questions: a) Are plants capable of producing bioactive human heparin sulfatase (SGSH)?, b) Can SGSH - plant lectin fusions be produced that retain both SGSH enzyme activity and carbohydrate binding selectivity?, and c) Are these plant-made proteins delivered to and corrective in in vitro Sanfilippo A cell models. Success in Phase I will demonstrate the feasibility of plant-based bioproduction of bioactive SHSG and the lectin-fusion ERT with SGSH and will support subsequent Phase II studies to further product characterization, scaled-up production to support animal trials, in vivo disease correction and ERT efficacy studies in MSP-IIIA mouse models, and assessment of BBB transcytosis and CNS disease substrate clearance.