Morquio A therapy integrating gene transfer with lectin-enhanced enzyme delivery to treat multisystemic clinical impairments of rare metabolic childhood diseases

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.

Grant Number: 1R43HD114328-01
NIH Institute/Center: NIH
Principal Investigator: Walter Acosta