Drug repurposing for ALD: can gene families share therapies?

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. Project Number: 1R21NS148703-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Christina Nemeth Mertz | Institution: HUGO W. MOSER RES INST KENNEDY KRIEGER, BALTIMORE, MD | Award Amount: $445,500 | Activity Code: R21 | Study Section: Therapeutic Approaches to Genetic Diseases Study Section[TAG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11349416