- Author
-
S.J. Aronson
- Title
- Gene therapy for inherited jaundice
- Supervisors
-
U.H.W. Beuers
R.P.J. Oude Elferink - Co-supervisors
-
P.J. Bosma
- Award date
- 26 February 2021
- Number of pages
- 230
- ISBN
- 9789493197459
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
This thesis describes experimental and clinical studies that bring adeno-associated virus (AAV)-mediated gene therapy for inherited jaundice a step closer toward clinical application. This may prevent the need of life-long phototherapy in patients suffering from Crigler-Najjar syndrome, caused by an enzyme deficiency impairing bilirubin metabolism. In addition, this technology may relieve symptoms and prevent the need of liver transplantation in patients suffering from progressive familial intrahepatic cholestasis, which results from a transport defect involved in bile formation.
We show a high disease burden of Crigler-Najjar syndrome (CN) and regional differences in treatment outcome in the largest, worldwide patient cohort for this disease to date. In preparation of the clinical gene therapy trial for CN, the optimal production strategy of adeno-associated virus (AAV) vectors was validated and the subsequent toxicology and bio-distribution studies show to be safe and effective in the relevant animal models. Additionally, a quantitative in vitro assay to determine the potency of adeno-associated virus vectors was developed to assess vector quality, reducing assay time, costs and animal experiments.
We found that the seroprevalence of anti-AAV neutralizing antibodies in CN patients is comparable with that in other populations and show that the negative effect of low antibody titers on liver transduction can be overcome by a favorable full-to-empty capsid ratio.
Furthermore, liver-directed gene therapy results in long-term correction of progressive familial intrahepatic cholestasis type 3 (PFIC3) in a mouse model, encouraging translational studies for application in patients with PFIC3. - Persistent Identifier
- https://hdl.handle.net/11245.1/21c167f6-4915-4c12-9bf5-247093ea0bbd
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: Disease burden and management of Crigler-Najjar syndrome: Report of a world registry
Chapter 2: Disruption of HNF1α binding site causes inherited severe unconjugated hyperbilirubinemia
Chapter 3: Biliverdin reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
Chapter 4: Preclinical development of an AAV8-hUGT1A1 vector for the treatment of Crigler-Najjar syndrome
Chapter 5: A quantitative in vitro potency assay for adeno-associated virus vectors encoding for the UGT1A1 transgene
Chapter 6: Prevalence and relevance of pre-existing anti-AAV immunity in the context of gene therapy for Crigler-Najjar syndrome
Chapter 7: Liver-directed gene therapy results in long term correction of progressive familial intrahepatic cholestasis type 3 in mice
Chapter 8: Summary, discussion and future perspective
Nederlandse samenvatting; Contributing authors; List of publications; PhD portfolio; Dankwoord; About the author
- Supplementary materials
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library, or send a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.