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A Gene Therapy Approach for Argininosuccinic Aciduria

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A GENE THERAPY APPROACH FOR ARGININOSUCCINIC ACIDURIA Dr Julien Colomban Baruteau A thesis submitted for the degree of Doctor of Philosophy University College London June 2017 DECLARATION I, Julien Baruteau, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Where experimental work has been completed by others, this has been stated in the relevant section of this thesis. However, the instances are also listed below: - Paraffin-embedding and cutting of peripheral organ samples of mice were performed by the Histopathology Department, Institute of Neurology, University College London, UK (Section 2.7.6). - Periodic acid-Schiff, Oil red O and Masson trichrome staining of murine liver samples were performed by the Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK (Section 2.7.9-12). - Processing of liver samples for electron microscopy was performed by Dr Kerrie Verner, Electron Microscopy Department, Institute of Neurology, University College London, UK (Section 2.8). Part of the work of this thesis has been published in the following articles for which copyright clearance has been obtained (see Appendices 10.5): - Baruteau J, et al. Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects. J Inherit Metab Dis. In Press. - Baruteau J, et al. Delivering efficient liver-directed AAV-mediated gene therapy. Gene Ther. 2017 May;24(5):263-264. - Baruteau J, et al. Expanding the phenotype in argininosuccinic aciduria: need for new therapies. J Inherit Metab Dis. 2017 May;40(3):357-368. I confirm that these publications were written by me and may therefore partly overlap with my thesis. Julien Baruteau 1 ACKNOWLEDGEMENTS It has been a privilege to meet and work under the supervision of talented scientists Dr Simon Waddington, Prof Paul Gissen, Dr Philippa Mills and Dr Suzy Buckley. I would like to express my deep gratitude to my primary supervisor Simon, who has guided me through this work and has been an excellent academic lead. Extremely patient and available, he has paid lots of attention to the project with endless support, kindness and encouragement. I am very grateful to Paul for having believed in this project in its first days, having provided fruitful advices and encouragement for getting it funded and having largely contributed to these achievements. It is a pleasure for me to carry on working with him in developing translational projects of gene therapy for paediatric metabolic patients. I would like to thank Philippa who has demonstrated treasures of patience and kindness throughout these years for teaching me mass spectrometry, gene sequencing, and correcting manuscripts. A big thank you to Suzy and Dr Steve Howe for their teaching and support in this work. A huge thank you to my colleagues in the Gene Transfer Technology Group at the Institute for Women’s Health especially Dany Perocheau for his precious skills and lab tips, in the Translational Omics Group at the Institute of Child Health, to Dr Ahad Rahim and his group at the School of Pharmacy, to Paul Gissen’s group at the MRC Laboratory for Molecular Cell Biology for their friendship and willingness to help. I am confident they all have made good progress with their French skills. I am indebted to the patients and the metabolic physicians who have taken part in this research. I am sincerely grateful to Action Medical Research for having entrusted me in funding this project and providing me this unique opportunity. Many thanks to Kelly for her everlasting loving support and to our lovely bright stars, Beatriz Emmanuelle and Constance Louise, who were born during this PhD and have grown up in parallel with this work making it more challenging but so much more inspiring. I am extremely grateful to my parents Remi and Véronique, my brother and sisters and their in-laws Alban & Gabrielle, Florence & Albin, Marie and Alix, my extended French and Brazilian families and all my friends for their very kind and relentless support along these years. 2 ABSTRACT Argininosuccinate lyase (ASL) is central to two metabolic pathways: i) the liver-based urea cycle, which detoxifies ammonia, ii) the citrulline-nitric oxide cycle, which synthesises nitric oxide from L-arginine. Patients deficient in argininosuccinate lyase present with argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with a severe neurological phenotype. Compared to other urea cycle disorders, argininosuccinic aciduria presents a low frequency of hyperammonaemic crises but a high frequency of cognitive impairment. This paradox questions the causative role of hyperammonaemia in the neuropathology. An observational UK-wide study was designed to study the natural history. Data about clinical status, neuroimaging and hASL genotyping were collected from 56 patients. Six had molecular analysis performed in this work. A homogeneous neurological phenotype was observed in most patients. hASL sequencing was available in 19 patients and 20 mutations were found. A genotype-phenotype correlation showed that the prognosis was more likely related to genotype rather than severity of hyperammonaemia. The hypomorph mouse model AslNeo/Neo mimicking the human disease was used to study the neuropathology in argininosuccinic aciduria and showed a neuronal disease with oxidative/nitrosative stress. To define the role of hyperammonaemia in this finding, a gene therapy approach using an adeno-associated viral vector (AAV) encoding the murine Asl gene was delivered in AslNeo/Neo mice. The long-term correction of both pathways was observed: i) the urea cycle after a single systemic injection in adult mice; ii) the citrulline-nitric oxide cycle in the brain after a single systemic injection at birth. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This demonstrated the key-role of a neuronal disease independent from hyperammonaemia in argininosuccinic aciduria. This work provides new insight in the neuropathology of argininosuccinic aciduria and a proof of concept of successful AAV-mediated gene therapy. 3 TABLE OF CONTENTS DECLARATION .......................................................................................................... 1 ACKNOWLEDGEMENTS ........................................................................................... 2 ABSTRACT ................................................................................................................. 3 TABLE OF CONTENTS .............................................................................................. 4 LIST OF TABLES ..................................................................................................... 15 LIST OF FIGURES .................................................................................................... 17 ABBREVIATIONS ..................................................................................................... 25 1. BACKGROUND .................................................................................................... 27 1.1 Urea cycle and related inherited human diseases ...................................... 27 1.1.1 The urea cycle ........................................................................................... 27 1.1.2 Urea cycle defects ..................................................................................... 28 1.2 Argininosuccinic aciduria ............................................................................. 31 1.2.1 Argininosuccinate lyase ............................................................................. 31 1.2.2 Pathophysiology ........................................................................................ 35 1.2.3 Clinical phenotype ..................................................................................... 39 1.2.4 Diagnosis ................................................................................................... 45 1.2.5 Therapeutics .............................................................................................. 46 1.2.6 Long-term outcome .................................................................................... 51 1.2.7 Phenotype-genotype correlation ................................................................ 52 1.2.8 Newborn screening .................................................................................... 53 1.2.9 Animal models ........................................................................................... 55 1.3 Gene therapy for monogenic disorders ....................................................... 56 4 1.3.1 Overview of gene therapy development .................................................... 56 1.3.2 Strategies for gene transfer ....................................................................... 60 1.3.3 Liver-directed gene therapy: clinical applications ...................................... 64 1.3.4 Adeno-associated virus ............................................................................. 68 1.3.5 Recombinant adeno-associated viral vectors ............................................ 73 1.3.6 Main challenges of AAV-mediated gene therapy for liver diseases ........... 80 1.3.7 Urea cycle defects and gene therapy ........................................................ 85 1.4 Hypothesis and aims
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