Optimizing gene therapy for infant mice with citrullinemia type 1

  1. Bazo-Ochoa, Andrea
Supervised by:
  1. Rafael Aldabe Director
  2. Aquilino Lantero García Director

Defence university: Universidad de Navarra

Fecha de defensa: 30 June 2023

  1. (FM) Medicina Interna

Type: Thesis


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.