Postnatal gene restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD) reveals phenotype reversibility
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Le résumé fourni par la source
ABSTRACT Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive metabolic disorder due to loss-of-function ALDH5A1 mutations impairing the catabolism of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. In SSADHD, pathologic accumulation of GABA and its metabolic by-product γ-hydroxybutyrate (GHB) corresponds to a clinical syndrome dominated by developmental delay and epilepsy in half of patients with risk of sudden death in adolescence and adulthood. Brain-wide ALDH5A1 gene replacement for SSADHD is unavailable, and whether such treatment will reverse the SSADHD phenotype is unknown. We developed an inducible mouse SSADHD model, Aldh5a1 lox-STOP , enabling Cre-dependent Aldh5a1 restoration to evaluate gene therapy feasibility. In the absence of SSADH, Aldh5a1 lox-STOP mice exhibit hyperactivity and excessive serum GHB levels, culminating in death by ∼postnatal day 22, recapitulating the severe SSADHD condition. Systemic delivery of a blood-brain barrier (BBB)-penetrating adeno-associated virus (AAV) carrying a Cre gene to Aldh5a1 lox-STOP mice leads to brain-wide SSADH restoration, serum GHB level reduction, normalization of hyperactivity, and substantial increase in survival. As a step toward clinical translation, we further assessed an AAV encompassing a functional native promoter (FLnP) of ALDH5A1 tethered to its human coding sequence, namely AAV-FLnP-hALDH5A1. Aldh5a1 lox-STOP mice were effectively rescued when treated with AAV-FLnP-hALDH5A1 packaged in the blood-brain barrier (BBB)-penetrating capsid PHP.eB. These findings provide preclinical proof that SSADH gene replacement therapy is feasible and potentially effective.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Postnatal gene restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD) reveals phenotype reversibility
- Date Crossref
- 26/03/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Boston Children's Hospital Department of Neurology pays non établi dans la noticeÉtablissement de santé
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University of Veterinary Medicine Hannover Department of Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Baylor Medical Center at Garland pays non établi dans la noticeÉtablissement de santé
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Baylor Scott & White Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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Institute of Metabolic Disease pays non établi dans la noticeStructure de recherche
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Epilepsy & Clinical Neurophysiology pays non établi dans la noticeÉtablissement de santé
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Horae Gene Therapy Center pays non établi dans la noticeInstitution
Department of Neurology — Boston Children's Hospital, Department of Pharmacology — University of Veterinary Medicine Hannover et Baylor Medical Center at Garland, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.