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

Award Number: R43HD114328
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	BIOSTRATEGIES LC	504 UNIVERSITY LOOP W	JONESBORO	AR	72401	CRAIGHEAD	USA	Child Health and Human Development Extramural Research	000	1	9/23/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $295,923 )
2023	2023	BIOSTRATAGIES LC	504 UNIVERSITY LOOP E	JONESBORO	AR	72401	CRAIGHEAD	USA	Child Health and Human Development Extramural Research	000	1	9/20/2023	NEW	$295,923
2023	2023	BIOSTRATAGIES LC	504 UNIVERSITY LOOP E	JONESBORO	AR	72401	CRAIGHEAD	USA	Child Health and Human Development Extramural Research	001	1	9/29/2023	NEW	$0
														Subtotal = $295,923

Grand Total All Awards = $295,923

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

Award Number: R43HD114328

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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