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

Eulàlia Segur-Bailach; Anna Mateu-Bosch; Xavier Bofill-De Ros; Marta Parés; Patricia da Silva Buttkus; Birgit Rathkolb; Valérie Gailus-Durner; Martin Hrabě de Angelis; Pedram Moeini; Gloria Gonzalez-Aseguinolaza; Frederic Tort; Antonia Ribes; Clara D.M. van Karnebeek; Judit García-Villoria; Cristina Fillat

doi:10.1016/j.ymthe.2025.07.022

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

Eulàlia Segur-Bailach
, Anna Mateu-Bosch
, Xavier Bofill-De Ros
, Marta Parés
, Patricia da Silva Buttkus
, Birgit Rathkolb
, Valérie Gailus-Durner
, Martin Hrabě de Angelis
, Pedram Moeini
, Gloria Gonzalez-Aseguinolaza
, Frederic Tort
, Antonia Ribes
, Clara D.M. van Karnebeek
, Judit García-Villoria
, Cristina Fillat^*

^*Corresponding author for this work

Department of Molecular Biology and Genetics - RNA Biology and Innovation

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

2 Citations (Scopus)

Abstract

Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-coenzyme A 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 α-aminoadipic semialdehyde synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored reducing 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 6 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.

Original language	English
Journal	Molecular Therapy
Volume	33
Issue	10
Pages (from-to)	4820-4833
Number of pages	14
ISSN	1525-0016
DOIs	https://doi.org/10.1016/j.ymthe.2025.07.022
Publication status	Published - 1 Oct 2025

Keywords

AASS
AAV
adeno-associated virus
artificial miRNAs
gene therapy
glutaric aciduria

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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. (2025). Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice. Molecular Therapy, 33(10), 4820-4833. https://doi.org/10.1016/j.ymthe.2025.07.022

@article{2348298720ed480f942d35c2bd4b877c,

title = "Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice",

abstract = "Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-coenzyme A 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 α-aminoadipic semialdehyde synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored reducing 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 6 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.",

keywords = "AASS, AAV, adeno-associated virus, artificial miRNAs, gene therapy, glutaric aciduria",

author = "Eul{\`a}lia Segur-Bailach and Anna Mateu-Bosch and \{Bofill-De Ros\}, Xavier and Marta Par{\'e}s and \{da Silva Buttkus\}, Patricia and Birgit Rathkolb and Val{\'e}rie Gailus-Durner and \{Hrab{\v e} de Angelis\}, Martin and Pedram Moeini and Gloria Gonzalez-Aseguinolaza and Frederic Tort and Antonia Ribes and \{van Karnebeek\}, \{Clara D.M.\} and Judit Garc{\'i}a-Villoria and Cristina Fillat",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = oct,

day = "1",

doi = "10.1016/j.ymthe.2025.07.022",

language = "English",

volume = "33",

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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, CDM, García-Villoria, J & Fillat, C 2025, 'Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice', Molecular Therapy, vol. 33, no. 10, pp. 4820-4833. https://doi.org/10.1016/j.ymthe.2025.07.022

Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice. / Segur-Bailach, Eulàlia; Mateu-Bosch, Anna; Bofill-De Ros, Xavier et al.
In: Molecular Therapy, Vol. 33, No. 10, 01.10.2025, p. 4820-4833.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice

AU - Segur-Bailach, Eulàlia

AU - Mateu-Bosch, Anna

AU - Bofill-De Ros, Xavier

AU - Parés, Marta

AU - da Silva Buttkus, Patricia

AU - Rathkolb, Birgit

AU - Gailus-Durner, Valérie

AU - Hrabě de Angelis, Martin

AU - Moeini, Pedram

AU - Gonzalez-Aseguinolaza, Gloria

AU - Tort, Frederic

AU - Ribes, Antonia

AU - van Karnebeek, Clara D.M.

AU - García-Villoria, Judit

AU - Fillat, Cristina

PY - 2025/10/1

Y1 - 2025/10/1

N2 - Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-coenzyme A 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 α-aminoadipic semialdehyde synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored reducing 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 6 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.

AB - Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-coenzyme A 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 α-aminoadipic semialdehyde synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored reducing 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 6 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.

KW - AASS

KW - AAV

KW - adeno-associated virus

KW - artificial miRNAs

KW - gene therapy

KW - glutaric aciduria

UR - https://www.scopus.com/pages/publications/105012040638

U2 - 10.1016/j.ymthe.2025.07.022

DO - 10.1016/j.ymthe.2025.07.022

M3 - Journal article

C2 - 40682274

AN - SCOPUS:105012040638

SN - 1525-0016

VL - 33

SP - 4820

EP - 4833

JO - Molecular Therapy

JF - Molecular Therapy

IS - 10

ER -

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

Abstract

Keywords

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