Mucopolysaccharidosis Type IVA (MPS-IVA; also called Morquio A Syndrome) is a rare genetic childhood disorder characterized by multi-systemic pathologies affecting the respiratory, cardiovascular, musculoskeletal, and central nervous systems leading to devastating quality-of-life and early death. The disease is due to deficiencies in N-acetylgalactosamine-6-sulfate sulfatase (GALNS) causing progressive and pathological accumulation of the glucosaminoglycans (GAGs) keratan sulfate and chondroitin sulfate in multiple organs and tissues. The impact of keratan/chondroitin sulfate accumulation on bone, cartilage, and connective tissues is particularly striking, leading to debilitating cardiac, respiratory, and skeletal pathologies. An enzyme replacement therapy (ERT) comprising recombinant human GALNS is currently available but shows no improvement of these pathologies. Immunogenicity involving the development of neutralizing anti-drug antibodies is also an issue with this ERT. BioStrategies LC has developed an enzyme delivery technology based on the plant lectin RTB which greatly enhances delivery of fused enzymes to hard-to-treat cells and tissues including musculoskeletal, cardiac, respiratory and central nervous systems – sites that have been particularly recalcitrant to effective delivery of corrective doses of replacement enzymes. Previous studies using murine MPS I as a model system demonstrated that weekly treatment with enzyme-RTB fusions showed normalization of key bone structural parameters, CNS substrate accumulation, and behavioral benchmarks of the disease. Additionally, the RTB carrier successfully mitigated any issues associated with anti-drug immunogenicity. Thus, RTB-mediated delivery may address the key limitation of current Morquio ERTs to treat the debilitating multisystemic pathologies of this disease. Our goal in this SBIR is to develop a ”delivery-enhanced” gene therapy drug comprising an RTB:GALNS fusion and to perform key preclinical studies. The specific aims of this Phase I SBIR are to 1) Develop and optimize an RTB:GALNS construct for optimal expression and secretion that retain enzymatic activity and lectin binding capacity; 2) Determine long-term transgene expression and serum stability by assessing different promoters; and 3) Evaluate biodistribution of the enzyme and substrate reduction in difficult-to-treat tissues in the Morquio A mouse model. Our objective is to translate these breakthroughs to produce a “delivery-enhanced” MPS IVA therapy that will effectively treat disease manifestations that remain a significant unmet medical need for these patients. The proof of concept generated in these studies will provide the basis to design IND enabling studies in a Phase II that include GMP manufacture plans, tox studies, and regulatory IND submissions.

NARRATIVE – PUBLIC HEALTH RELEVANCE: The family of human genetic diseases represented by Mucopolysaccharidosis IVA (MPS IVA; Morquio A Syndrome) and other rare lysosomal disorders include some of the most devastating human afflictions known and the most costly to patients, their families, and the public health system. For MPS IVA patients, the several manifestations are particularly severe and recalcitrant to treatment--current ERTs are ineffective in treating skeletal, cardiac, respiratory and CNS pathologies and immune sensitivity based on anti-drug antibodies further reduces ERT effectiveness over time. This project addresses the need for delivering the missing or defective enzyme in patients by a new mechanism that significantly increases targeting and efficacy to bone, lung, heart and CNS while reducing the immune sensitivity roadblock seen in current ERT drugs.