PuSH - Publikationsserver des Helmholtz Zentrums München

Segur-Bailach, E.* ; Mateu-Bosch, A.* ; Bofill-De Ros, X.* ; Parés, M.* ; da Silva Buttkus, P. ; Rathkolb, B. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Moeini, P.* ; Gonzalez-Aseguinolaza, G.* ; Tort, F.* ; Ribes, A.* ; van Karnebeek, C.D.M.* ; García-Villoria, J.* ; Fillat, C.*

Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice.

Mol. Ther. 33, 4820-4833 (2025)
Postprint DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-CoA dehydrogenase in the lysine degradation pathway, characterized by the accumulation of toxic metabolites in the central nervous system. We reasoned that substrate reduction therapy targeting the alpha-Aminoadipic Semialdehyde Synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored to reduce the expression of AASS by an artificial microRNA with AASS target sequences embedded in a miR-16 backbone (miR_AASS). We analyzed several delivery routes and AAV serotypes and evaluated the therapeutic efficacy of a systemic neonatal delivery of AAV9_miR_AASS in the Gcdh-/- mouse model of GA1. We detected dose-dependent miR-AASS expression and AASS inhibition in liver and striatum, the main tissues affected in GA1. Treatment with AAV9_miR_AASS in lysine overload challenged mice reduced the accumulation of neurotoxic metabolites, up to six months post-treatment in the striatum, prevented the neuropathological alterations and improved mouse survival. Our results show that AAV9_miR_AASS supports AASS-lowering as a potential gene therapy strategy for GA1.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Aass ; Aav ; Adeno-associated Virus ; Artificial Mirnas ; Gene Therapy ; Glutaric Aciduria; Mouse Model; Design; Brain; Shrna
ISSN (print) / ISBN 1525-0016
e-ISSN 1525-0024
Zeitschrift Molecular Therapy
Quellenangaben Band: 33, Heft: 10, Seiten: 4820-4833 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Förderungen Generalitat de Catalunya, Spain
ERA-Net for Research on Rare Diseases
Spanish Ministerio de Ciencia e Innovacin
CIBERER is an initiative of the ISCIII
La Caixa" Foundation
CERCA Program/Generalitat de Catalunya
Instituto de Salud Carlos III (ISCIII)