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Drug repurposing for ALD: can gene families share therapies?

Award Number: R21NS148703
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: 06/16/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Drug repurposing for ALD: can gene families share therapies? - PROJECT SUMMARY X-linked adrenoleukodystrophy (ALD) is a devastating neurological disorder with very few therapeutic options. Mutations in ABCD1, which codes for a peroxisomal membrane transporter (ALDP), prevents the import of very long chain fatty acids (VLCFA) into the peroxisome for degradation by β-oxidation. VLCFA accumulate and incorporate into cell membranes, leading to disrupted mitochondrial function, cell stress, and a pro- inflammatory state. Roughly 40% of ALD males suffer a rapidly progressive and fatal neuroinflammatory phenotype resulting in demyelination of the cerebral white matter during school-age, referred to as childhood cerebral ALD (ccALD) and the remainder of hemizygous males, and half of all adult heterozygote females, develop the chronic slowly progressing adult-onset adrenomyeloneuropathy (AMN), a long tract axonopathy, presenting with spastic paraparesis, sensory ataxia, paresthesias, neuropathic pain, as well as sexual and bladder dysfunction. ABCD1 is a member of the ABC transporter superfamily, one of the oldest and largest gene families. Recent work in the field of cystic fibrosis (CF) led to the development and FDA approval of cystic fibrosis transmembrane conductance regulator (CFTR) modifiers, which stabilize and improve channel gating. CFTR is encoded by ABCC7, a relative of ABCD1 that shares sequence homology throughout the nucleotide- binding domain (NBD) – a hotspot for ALD disease causing variants. Based on homologous sequences, CF and ALD pathogenic variants at homologous residue positions, and our preliminary data, we hypothesize that ALD patient cells harboring missense variants will be responsive to CFTR corrective drugs. The overall goal of this proposal is to explore a novel therapeutic strategy, borrowed from CF to directly restore ALDP function in ALD patients. We will first test the ability of CFTR modulators to reduce accumulation of VCLFA within primary patient cells and to then use brain organoids to determine if this therapeutic strategy can alter complex cell function enough to mitigate ALD disease burden. These studies are designed to systematically test CFTR responsive potentiators, correctors, activators, and stabilizers (PCAS) in ALD patient cells to critically explore CFTR channel regulators as a viable therapeutic strategy in ALD. Drug repurposing is an appealing route, especially for a severe neurodegenerative disease that has seen very few successes in the clinic. We hope this novel idea for a proven strategy in cystic fibrosis paves the way for continued studies focusing on efficacy and pharmacokinetics of drug activity.


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 = $445,500 )
2026	2026	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/18/2026	NEW	$445,500
														Subtotal = $445,500

Grand Total All Awards = $445,500

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Drug repurposing for ALD: can gene families share therapies?

Award Number: R21NS148703

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: 06/16/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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