Optimizing gene therapy for infant mice with citrullinemia type 1

Citrullinemia type 1 (CTLN1) is a rare genetic disorder that is inherited in an autosomal recessive manner. It is caused by mutations in the gene that encodes argininosuccinate synthetase 1 (ASS1), which catalyzes the formation of argininosuccinate from citrulline and the aspartic acid in the urea c...

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Autor: Bazo-Ochoa, A. (Andrea)|||/items/a2d3d7c6-1393-4429-8093-eccdb72a959c
Tipo de recurso: tesis doctoral
Fecha de publicación:2023
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/67875
Acceso en línea:https://hdl.handle.net/10171/67875
Access Level:acceso abierto
Palabra clave:Materias Investigacion::Ciencias de la Salud::Genética
Citrullinemia type 1
Urea cycle disorders
Gene therapy
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spelling Optimizing gene therapy for infant mice with citrullinemia type 1Bazo-Ochoa, A. (Andrea)|||/items/a2d3d7c6-1393-4429-8093-eccdb72a959cMaterias Investigacion::Ciencias de la Salud::GenéticaCitrullinemia type 1Urea cycle disordersGene therapyCitrullinemia type 1 (CTLN1) is a rare genetic disorder that is inherited in an autosomal recessive manner. It is caused by mutations in the gene that encodes argininosuccinate synthetase 1 (ASS1), which catalyzes the formation of argininosuccinate from citrulline and the aspartic acid in the urea cycle. This disorder leads to a reduced ability to eliminate nitrogen from the body, which results in increased levels of circulating ammonia and other toxic byproducts of the urea cycle. These can cause severe neurological symptoms, such as metabolic encephalopathy, irreversible brain damage, or even death. The current standard of care (SoC) for CTLN1 involves reduced protein intake and daily administration of nitrogen-scavenging agents being liver transplantation the best therapeutic option. However, these treatments do not always produce satisfactory results and often cannot avoid neurological sequelae. While they may prevent further brain damage, patients remain at risk of life-threatening complications. We evaluated the potential therapeutic efficacy of a recombinant adeno-associated viral vector (rAAV) encoding for the ASS1 gene under the control of a liver-specific promoter (VTX-804), alone or in combination with SoC to three-week-old Ass1fold mice, which serve as a CTLN1 mouse model. All the animals that received VTX-804 in combination with SoC exhibited normal weight gain, normalized ammonia levels and experienced a reduction in citrulline levels in their bloodstream. Furthermore, these mice displayed 100% survival over a period of 7 months. Similar to the clinical manifestations observed in CTLN1 patients, the CTLN1 mice showed several behavioral abnormalities including anxiety, reduced welfare and impaired innate behavior. Importantly, treatment with VTX-804 alone significantly ameliorated all of these parameters. In conclusion, the results obtained from this study strongly indicate that VTX-804 gene therapy holds great promise as a potential treatment for CTLN1 patients in the future. These findings open up new possibilities for the development of effective interventions to improve the clinical outcomes and overall quality of life for individuals affected by CTLN1.Universidad de NavarraAldabe, R. (Rafael)Lantero-García, A. (Aquilino)Dadun. Depósito Académico Digital Universidad de Navarra20232023-11-1620232023-11-1620232023-11-1620232023-06-30doctoral thesishttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisapplication/pdfhttps://hdl.handle.net/10171/67875reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/678752026-06-21T12:47:57Z
dc.title.none.fl_str_mv Optimizing gene therapy for infant mice with citrullinemia type 1
title Optimizing gene therapy for infant mice with citrullinemia type 1
spellingShingle Optimizing gene therapy for infant mice with citrullinemia type 1
Bazo-Ochoa, A. (Andrea)|||/items/a2d3d7c6-1393-4429-8093-eccdb72a959c
Materias Investigacion::Ciencias de la Salud::Genética
Citrullinemia type 1
Urea cycle disorders
Gene therapy
title_short Optimizing gene therapy for infant mice with citrullinemia type 1
title_full Optimizing gene therapy for infant mice with citrullinemia type 1
title_fullStr Optimizing gene therapy for infant mice with citrullinemia type 1
title_full_unstemmed Optimizing gene therapy for infant mice with citrullinemia type 1
title_sort Optimizing gene therapy for infant mice with citrullinemia type 1
dc.creator.none.fl_str_mv Bazo-Ochoa, A. (Andrea)|||/items/a2d3d7c6-1393-4429-8093-eccdb72a959c
author Bazo-Ochoa, A. (Andrea)|||/items/a2d3d7c6-1393-4429-8093-eccdb72a959c
author_facet Bazo-Ochoa, A. (Andrea)|||/items/a2d3d7c6-1393-4429-8093-eccdb72a959c
author_role author
dc.contributor.none.fl_str_mv Aldabe, R. (Rafael)
Lantero-García, A. (Aquilino)
Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Materias Investigacion::Ciencias de la Salud::Genética
Citrullinemia type 1
Urea cycle disorders
Gene therapy
topic Materias Investigacion::Ciencias de la Salud::Genética
Citrullinemia type 1
Urea cycle disorders
Gene therapy
description Citrullinemia type 1 (CTLN1) is a rare genetic disorder that is inherited in an autosomal recessive manner. It is caused by mutations in the gene that encodes argininosuccinate synthetase 1 (ASS1), which catalyzes the formation of argininosuccinate from citrulline and the aspartic acid in the urea cycle. This disorder leads to a reduced ability to eliminate nitrogen from the body, which results in increased levels of circulating ammonia and other toxic byproducts of the urea cycle. These can cause severe neurological symptoms, such as metabolic encephalopathy, irreversible brain damage, or even death. The current standard of care (SoC) for CTLN1 involves reduced protein intake and daily administration of nitrogen-scavenging agents being liver transplantation the best therapeutic option. However, these treatments do not always produce satisfactory results and often cannot avoid neurological sequelae. While they may prevent further brain damage, patients remain at risk of life-threatening complications. We evaluated the potential therapeutic efficacy of a recombinant adeno-associated viral vector (rAAV) encoding for the ASS1 gene under the control of a liver-specific promoter (VTX-804), alone or in combination with SoC to three-week-old Ass1fold mice, which serve as a CTLN1 mouse model. All the animals that received VTX-804 in combination with SoC exhibited normal weight gain, normalized ammonia levels and experienced a reduction in citrulline levels in their bloodstream. Furthermore, these mice displayed 100% survival over a period of 7 months. Similar to the clinical manifestations observed in CTLN1 patients, the CTLN1 mice showed several behavioral abnormalities including anxiety, reduced welfare and impaired innate behavior. Importantly, treatment with VTX-804 alone significantly ameliorated all of these parameters. In conclusion, the results obtained from this study strongly indicate that VTX-804 gene therapy holds great promise as a potential treatment for CTLN1 patients in the future. These findings open up new possibilities for the development of effective interventions to improve the clinical outcomes and overall quality of life for individuals affected by CTLN1.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-11-16
2023
2023-11-16
2023
2023-11-16
2023
2023-06-30
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/67875
url https://hdl.handle.net/10171/67875
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidad de Navarra
publisher.none.fl_str_mv Universidad de Navarra
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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