Touramanidou, Loukia;
(2023)
Lentiviral Gene Therapy for Argininosuccinic Aciduria.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Thesis L. Touramanidou.pdf - Accepted Version Download (4MB) | Preview |
Abstract
The urea cycle facilitates the disposal of nitrogen waste and the elimination of harmful ammonia. Argininosuccinic aciduria (ASA), a urea cycle defect caused by a deficiency in argininosuccinate lyase (ASL), is the second most frequent urea cycle defect. Individuals with this condition may experience hyperammonaemia, leading to coma and death if not treated, along with an increased likelihood of severe cognitive impairment and epilepsy. Liver transplantation can be a curative option, but this requires perpetual immunosuppression. Lentiviral vector gene therapy has shown effective results in ex vivo gene replacement treatment in various inherited metabolic disorders. Furthermore, in vivo studies have shown remarkable safety in self-inactivating lentiviral vectors gene therapy. This study aimed to develop a safe in vivo liver-directed gene therapy strategy for ASA using a lentiviral vector carrying the wild-type hASL transgene. This neonatal in vivo lentiviral gene therapy with codon-optimisation of the transgene was tested in an ASL-deficient AslNeo/Neo mouse model. A single intravenous administration of gene therapy showed a normalisation of the growth, fur coat pattern, and urea cycle biomarkers, a significant increase of liver ASL activity and expression comparable to physiological levels at 3 months. Safety study was conducted to assess the presence of genotoxic events driven by the lentiviral vector in vivo. The results showed no significant difference in survival, liver/body ratio, and pathology analysis revealed no signs of tumours. Prior to administering lentiviral and AAV injections in wild-type animals, we evaluated liver transduction subsequent to systemic administration of clodronate, a macrophage inhibitor. Results showed a significant liver transduction increase following clodronate liposomes with lentiviral but not with AAV vector. This research showed the feasibility of lentiviral gene therapy for ASA in vivo, and a substantial enhancement in hepatocyte transduction using macrophage inhibitors.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Lentiviral Gene Therapy for Argininosuccinic Aciduria |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10178763 |
Archive Staff Only
 |
View Item |
