2026-02-12 | Discovery of N-Acetyltransferase 8-Like (NAT8L) inhibitors based on a N-Acylated (Piperidin-3-ylmethyl)-1,2,4-Oxadiazole Scaffold.
Canavan disease (CD) is an autosomal recessive genetic disorder caused by mutations in the ASPA gene, which encodes the enzyme aspartoacylase. These mutations lead to a deficient enzymatic activity and increased concentrations of its substrate, N-acetylaspartate (NAA), in the brain and other tissues. Aspartate N-acetyltransferase, encoded by the N-acetyltransferase 8-like (NAT8L) gene, catalyzes the biosynthesis of NAA from aspartate and acetyl-CoA. Therefore, inhibition of NAT8L has been implicated as a promising therapeutic strategy for CD by normalizing NAA levels in the brain. Our high throughput screening campaign followed by a rigorous hit validation process identified 2-(2-fluorophenoxy)-1-(3-((3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-1-yl)ethan-1-one (4a) as a low micromolar, noncarboxylic acid inhibitor of NAT8L. Subsequent structural optimization led to the discovery of two submicromolar NAT8L inhibitors. Although these inhibitors displayed high clearance in liver microsomes, the new scaffold, devoid of a carboxylic acid moiety, could potentially lead to potent and brain-penetrant NAT8L inhibitors through further molecular refinement.
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2026-01-24 | Human iPSC-derived neural progenitor cells rescue motor function and brain pathology in symptomatic Canavan disease mice.
Canavan disease (CD) is a severe neurodegenerative disorder caused by aspartoacylase (ASPA) deficiency, leading to N-acetyl-L-aspartic acid (NAA) accumulation and spongy degeneration. While several therapeutic candidates improve outcomes in CD mouse models when delivered before symptom onset, there remains a need for treatments targeting established disease pathology. Here, we demonstrate that transplantation with human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) expressing a functional ASPA gene (ASPA iNPCs) can rescue disease manifestations in symptomatic CD (Nur7) mice. When administered at postnatal day 21 (P21), ASPA iNPCs successfully engrafted, differentiated into neural lineage cells, and restored ASPA activity as revealed by reduced NAA level. Transplanted mice showed a significant reduction in brain and cerebrospinal fluid (CSF) NAA levels, decreased vacuolation across multiple brain regions, improved myelination, and enhanced motor function 6-month post-transplantation. Our findings demonstrate that ASPA iNPC transplantation can effectively reverse established CD pathology, suggesting therapeutic potential for treating symptomatic patients.
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2025-10-29 | A Rare Leukodystrophy Revealed in a Moroccan Infant: A Case Report of Canavan Disease
Introduction: Canavan disease is a rare autosomal-recessive leukodystrophy characterized by spongiform degeneration of the cerebral white matter secondary to aspartoacylase (ASPA) deficiency. It presents early with axial hypotonia, global psychomotor delay, and progressive macrocephaly. Objective: This work aims to illustrate the clinical, biological, and radiological particularities of this disorder through a Moroccan case. Case Report: We report the case of a 10-month-old female infant, born to first-degree consanguineous parents, presenting with severe axial hypotonia, absence of head control, generalized seizures, and macrocephaly. Brain MRI showed diffuse, symmetrical T2-weighted hyperintensities of the white matter, typical of spongiform leukodystrophy. Urinary assay revealed marked elevation of N-acetyl-aspartic acid (NAA), and molecular analysis confirmed homozygosity for the c.924del ASPA mutation. Management was symptomatic, including motor rehabilitation and nutritional assistance. Discussion: This observation illustrates the severe infantile form of Canavan disease. The combination of macrocephaly, developmental delay, and diffuse white-matter abnormalities should alert the clinician. Although differential diagnoses include other leukodystrophies, increased NAA and molecular confirmation are specific. Familial consanguinity and the presence of an affected sibling highlight the need for family screening and genetic counseling. Conclusion: Although no curative treatment exists, early identification of this rare disease allows appropriate management and opens perspectives for innovative therapeutic strategies, particularly gene therapy.
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