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Laminin protein therapy for the treatment of Laminin-alpha2 deficient congenital muscular dystrophy

Award Number: R01NS136281
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Laminin protein therapy for the treatment of Laminin-alpha2 deficient congenital muscular dystrophy - Project Summary Laminin-α2-related Congenital Muscular Dystrophy (LAMA2-CMD), also known as Merosin Deficient Congenital Muscular Dystrophy type 1A (MDC1A), is a devastating neuromuscular disease characterized by progressive muscle weakness from birth. LAMA2-CMD is caused by mutations in the LAMA2 gene, which results in the loss of the Laminin-α2 protein. Laminin-α2 is critical for the formation of laminin-211 and laminin-221 heterotrimers, which are major components of the muscle basal lamina that support muscle structure and function. LAMA2-CMD patients exhibit muscle weakness from birth, loose ambulation, require ventilator support, feeding tube insertion and die prematurely. There is currently no cure or effective treatment for LAMA2- CMD and patients die as young as the first decade of life. Laminin-111 is functionally similar to Laminin-211 and found abundantly the basement membrane of kidneys. Laminin-111 is therefore unlikely to trigger and immune response in the adult compared to Laminin-211 replacement in LAMA2-CMD. We have shown that treatment with EH&S derived mouse Laminin-111, a form of laminin found in embryonic muscle, reduces muscle pathology, maintains muscle strength and dramatically increases life expectancy in a mouse model of LAMA2- CMD. We have shown that mouse Laminin-111 treatment can functionally substitute for Laminin-211 to slow muscle disease progression after disease onset in the dyW-/- mouse model of LAMA2-CMD. Finally, we have demonstrated mouse Laminin-111 protein therapy is scalable and promotes muscle regeneration in the GRMD dog model of Duchenne muscular dystrophy. Together these data support the idea that Laminin-111 could serve as an effective protein substitution therapy for LAMA2-CMD. Recently, large quantities of recombinant human Laminin-111 (rhLAM-111) have been produced in using a propriety cell line and purification strategy. Our studies have shown rhLAM-111 treatment improved the activity of dyW-/- mice, reduced kyphosis and increased the strength of Laminin-2 deficient muscle. These studies have also raised important questions concerning the biological role that Laminin isoforms play in myomatrix remodeling, muscle cell signaling, myogenesis, motor neuron myelination and nerve conduction. The central hypothesis of this proposal is that recombinant human laminin can restore the myomatrix, promote muscle regeneration and improve neuromuscular function in a mouse model of LAMA2-CMD. This hypothesis will be tested in three specific aims: First, we will examine and quantify changes to the muscle myomatrix and muscle signaling pathways with rhLAM-111 or rhLAM-211 treatment using CosMx digital spatial profiling and super-resolution microscopy. Second, we will investigate if rhLAM-111 or rhLAM-211 protein therapy restores myogenic repair program by assaying myogenic renewal and muscle repair in a mouse model of LAMA2-CMD. Finally, we will determine if rhLAM-111 or rhLAM- 211 protein therapy restores motor neuron myelination and nerve conduction in a mouse model of LAMA2-CMD. Together, this study will contribute to our understanding of how laminin treatment can remodel the extracellular matrix, the role laminin plays in muscle regeneration, and if laminin treatment can improve nerve conduction and restore neuromuscular function.


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 = $413,661 )
2026	2026	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/31/2026	NON-COMPETING CONTINUATION	$413,661
														Subtotal = $413,661

Issue Date FY: 2025 ( Subtotal = $403,872 )
2025	2025	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/7/2025	NON-COMPETING CONTINUATION	$363,484
2025	2025	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/21/2025	NON-COMPETING CONTINUATION	$40,388
														Subtotal = $403,872

Issue Date FY: 2024 ( Subtotal = $374,832 )
2024	2024	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/1/2024	NEW	$374,832
														Subtotal = $374,832

Grand Total All Awards = $1,192,365

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Laminin protein therapy for the treatment of Laminin-alpha2 deficient congenital muscular dystrophy

Award Number: R01NS136281

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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