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Development of novel genetic medicine approaches to treat orphan diseases

Award Number: R44AR083801
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Development of novel genetic medicine approaches to treat orphan diseases - SUMMARY: Adeno-associated viral (AAV) vectors hold great promise for treating genetic disorders. AAVs efficiently transduce tissues, including skeletal and cardiac muscles, which is attractive for treating multisystemic muscular diseases. The primary shortcoming of using AAV vectors is their limited cargo capacity (~5 kb), which excludes many disorders, such as dystro- or dysferlinopathies, from using these vectors as gene transporters. Due to the large coding sequences of the defective genes, respectively DMD or DYSF, these muscular dystrophies have not fully taken advantage of this promising therapeutic modality. To circumvent this limitation, miniaturized forms (i.e, micro-dystrophin or mini-dysferlin) can be delivered by a single AAV vector. However, therapeutic minigenes have failed to provide complete rescue in animal models, pointing to the need to express full-length proteins for maximal benefit. We and others produced full-length dysferlin or larger dystrophins using simultaneous delivery of two independent AAV vectors, each one carrying the 5’ or 3’ part of the cDNA flanked by a short region of homology. This dual vector strategy allows recombination of AAV genomes into an open-reading frame, leading to the expression of large and highly functional proteins when administrated locally. However, low protein levels occur after systemic delivery of high AAV doses. To address this fundamental challenge in delivering large genetic cargo in AAVs, we propose to test a novel method, SIMPLI-GT (Split Intein-Mediated Protein Ligation for Gene Therapy). This strategy expresses large stable proteins with high efficiency by use of split inteins to mediate peptide trans-splicing extending the use of AAV gene transfer to genes exceeding the maximum cargo capacity. In a first in vivo proof-of-concept study, we showed the feasibility of dual or triple AAV approaches to express mini- or full-length dystrophin. Moreover, using AAV-Myo, we found that low dose (2x1013 vg/kg) generates large dystrophins in striated muscles with nearly complete physiological rescue. Further, we used this method to efficiently reconstitute full-length dysferlin in vitro. Therefore, we propose to apply SIMPLI-GT for the treatment of dysferlinopathies: Phase 1: Aim1: Demonstrate the feasibility of dual-AAV delivery of split dysferlin by IM injections. Phase 1, Aim 2: Study the functionality of intein-generated dysferlin in murine and human-derived myoblast. Phase 2: Aim 1: Evaluate and optimize systemic delivery regimen of AAV-Myo intein/dysferlin in mice. Phase 2, Aim 2: Validate the effectiveness of full-length intein-generated dysferlin in human iPSC-derived 3D- engineered muscle tissues. Phase 2, Aim3: Refine the optimal stoichiometry of dual vector in a dose-finding study in mice. Phase 2, Aim 4: Evaluate the biodistribution of AAV-Myo split intein/dysferlin following intravenous delivery in large animal.


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: 2026 ( Subtotal = $0 )
2026	2024	KINEA BIO INC	12600 HUMMINGBIRD ST	MUKILTEO	WA	98275	SNOHOMISH	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	11/19/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,214,305 )
2025	2025	KINEA BIO INC	12600 HUMMINGBIRD ST	MUKILTEO	WA	98275	SNOHOMISH	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/9/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,159,305
2025	2025	KINEA BIO INC	12600 HUMMINGBIRD ST	MUKILTEO	WA	98275	SNOHOMISH	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	6/11/2025	SUPPLEMENT FOR EXPANSION	$55,000
2025	2024	KINEA BIO INC	12600 HUMMINGBIRD ST	MUKILTEO	WA	98275	SNOHOMISH	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/17/2025	NEW	$0
														Subtotal = $1,214,305

Issue Date FY: 2024 ( Subtotal = $303,065 )
2024	2024	KINEA BIO INC	3000 WESTERN AVE	SEATTLE	WA	98121	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/20/2024	NEW	$303,065
														Subtotal = $303,065

Grand Total All Awards = $1,517,370

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Development of novel genetic medicine approaches to treat orphan diseases

Award Number: R44AR083801

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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