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Open Research Online Oro.Open.Ac.Uk Open Research Online The Open University’s repository of research publications and other research outputs Development of a Liver Gene Therapy Strategy for Haemophilia B With Lentiviral Vectors Thesis How to cite: Cantore, Alessio (2013). Development of a Liver Gene Therapy Strategy for Haemophilia B With Lentiviral Vectors. PhD thesis The Open University. For guidance on citations see FAQs. c 2013 The Author https://creativecommons.org/licenses/by-nc-nd/4.0/ Version: Version of Record Link(s) to article on publisher’s website: http://dx.doi.org/doi:10.21954/ou.ro.0000f0bd Copyright and Moral Rights for the articles on this site are retained by the individual authors and/or other copyright owners. For more information on Open Research Online’s data policy on reuse of materials please consult the policies page. oro.open.ac.uk (v£s-nS\ creD Alessio Cantore, M.Sc. Development of a Liver Gene Therapy Strategy for Haemophilia B with Lentiviral Vectors PhD thesis in fulfilment o f the requirements o f the Open University for the degree ofDoctor o f Philosophy in Molecular and Cellular Biology 17th December 2012 Director of Studies External Supervisor Prof. Luiai Naldini Prof. Thierry VandenDriessche Additional Supervisor Prof. Maria Grazia Roncarolo Vita-Salute San Raffaele University Telethon Institute for Gene Therapy (TIGET) DIBIT, San Raffaele Scientific Institute, Milan, Italy The Open University, UK Dtfvce _s,o m\ ss vdA Z IR CL £ o 12 ProQuest Number: 13835931 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13835931 Published by ProQuest LLC(2019). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 CONSULTAZIONE TESIDIDOTTORATO DI RICERCA/PH.D. THESIS CONSULTATION II sottoscritto Name Alessio Surname Cantore n° matr. / Id number 0003011 - A4230209 nato a / Place of Birth Bologna (BO), Italy, il (Date o f Birth) 19th August 1982 autore della tesi di Dottorato di Ricerca dal titolo / author o f the PhD thesis entitled : Development of a liver gene therapy strategy for haemophilia B with lentiviral vectors AUTORIZZA / AUTHORIZES la consultazione della tesi stessa / the consultation o f the thesis E’ fatto divieto di riprodurre, in tutto o in parte, quanto in essa contenuto / It is not allowed to copy, in whole or in part, the data and the contents o f the thesis La Consultabilita della tesi non e autorizzata per 12 mesi a partire dalla data di conseguimento del titolo e precisamente dal 17/12/2012 al 17/12/2013 Poiche: The Consultation o f the thesis is not allowed for 12 months from the PhD thesis date, specifically from 17/12/2012 to 17/12/2013 because: ci sono parti di tesi che sono gia state sottoposte a un editore o sono in attesa di pubblicazione / Parts o f the thesis have already been submitted to a publisher or are in press Data Firma “Eppur si muove” - “Yet it moves” (G. Galilei) DECLARATION This thesis has been composed by myself and has not been used in any previous application for a degree. Throughout the text I use both T and ‘We’ interchangeably. All the results presented here were obtained by myself, except for: 1) Large-scale vector manufacturing and some of the quality controls, which were performed in collaboration with MolMed s.p.a. (Milan, Italy) or Genethon (Evry, France) 2) Haemophilia B dogs maintenance, portal vein infusion and coagulation assays on canine samples, which were performed by Timothy Nichols and his team (University of North Carolina, Chapel Hill, USA) 3) Activated partial thromboplastin time and Bethesda assay on mouse samples, which were performed in collaboration with Patrizia Della Valle and Armando D’Angelo (San Raffaele, Scientific Institute, Milan, Italy) 4) Histopathology analysis, which was performed by Francesca Sanvito and Claudio Doglioni (San Raffaele Scientific Institute, Milan, Italy) 5) Fractionation and sorting of liver cell populations, T- and B-cell assays, which were performed in collaboration with Andrea Annoni and Maria Grazia Roncarolo (Telethon Institute for Gene Therapy, Milan, Italy) 6) Coagulation Factor IX delivery by integrase-defective lentiviral vectors, which was performed in the laboratory of Thierry VandenDriessche and Marinee Chuah (Free University of Brussels, Brussels, Belgium) 7) Integration site analysis, which was performed in collaboration with Cynthia Bartholomae and Manfred Schmidt (National Center for Tumour Diseases, Heidelberg, Germany) Genotoxicity studies in mouse models sensitised to develop hepatocellular carcinoma were performed in collaboration with Marco Ranzani and Eugenio Montini (Telethon Institute for Gene Therapy, Milan, Italy). Since my contribution was minor in these studies, data are not shown in the “results” chapter, but are mentioned in the discussion, as they are relevant for the overall understanding of the described liver gene therapy strategy. All sources of information are acknowledged by means of reference. ______________ ABSTRACT Lentiviral vectors (LVs) are attractive tools for liver gene therapy, by virtue of their ability to stably integrate in the genome of target cells and the absence of pre-existing humoral and cellular immunity against vector components in most humans. We have previously reported long-term phenotypic correction of haemophilia B and transgene- specific immune tolerance induction after a single intravenous administration of LVs in mice, provided that transgene expression is stringently targeted to hepatocytes. This is achieved by a combination of transcriptional control, mediated by a synthetic hepatocyte-specific promoter and post-transcriptional control obtained by including in the transgene sequences complementary to the haematopoietic-specific microRNA 142, which binds and targets for degradation any residual transgene mRNA expressed in antigen presenting cells of liver and spleen. We have now evaluated this gene therapy strategy in a large animal model. Our results show long-term canine Factor IX (FIX) expression up to 0.5-1% of normal levels and clinical improvement (almost complete prevention of spontaneous bleedings) in two haemophilia B dogs (>3.5 years cumulative follow up), with mild acute toxicity and without long-term adverse effects nor anti-transgene immune responses. The use of codon-optimised and hyper-functional FIX transgenes increased the potency of LVs (in the pharmacological meaning of efficacy per dose) >15-fold, allowing correction of the disease phenotype at low vector doses in mice, thus improving the therapeutic index of the gene therapy and prompting us to test this improvement in the next treated dog. We have investigated additional improvements in the potency of LVs for liver gene therapy, such as the use of the baculovirus envelope protein gp64, which improves hepatocyte targeting and LV particles resistance to complement-mediated inactivation. We performed a quantitative analysis of LV biodistribution within the liver cell populations and show that Kupffer cells uptake most vector genomes, despite being a small fraction of the total cells, and limit hepatocyte transduction at low administered LV doses. However, pre-treatment with a single dose of a clinically used proteasome inhibitor prior to LV administration reduces this trapping effect and increases hepatocyte transduction and therapeutic efficacy up to 3-fold in haemophilia B mice. We provide evidence that liver gene therapy can establish long-term FIX expression and immune tolerance in mice even in the presence of pre-existing anti-FIX antibody immunity. Since insertional mutagenesis is a concern for integrating vectors, we set out to explore the potential advantages of integrase-defective LVs (IDLVs) to express transgenes in the adult liver, in which hepatocytes turnover is slow. We show that, while not optimal for stable gene replacement therapy in their current design, IDLVs may represent a valuable strategy to induce stable antigen-specific tolerance by transient gene transfer and offer a treatment for immune-mediated diseases. On the other hand, since LV integration is preferable for efficient stable liver gene transfer, we stringently assessed the risk of oncogenesis associated to LV integration in ad hoc mouse models that are sensitised to develop hepatocellular carcinoma and found no detectable increase in carcinogenesis upon liver gene therapy with LVs. Overall our results position LVs as a promising platform for liver gene therapy that may well complement other available vectors to address the different challenges posed by the presentation of haemophilia and its complications in different patients and clinical conditions and may conceivably offer a therapeutic option for lysosomal and metabolic diseases. TABLE OF CONTENTS ACRONYMS AND ABBREVIATIONS 5 LIST OF FIGURES AND TABLES 8 INTRODUCTION 9 1.1 Gene Therapy 9 1.1.1 A brief history of gene therapy 10 1.1.2 Gene therapy strategies 14 1.1.3 Gene transfer vectors 15 1.1.4 Transgene expression control 16 1.1.5 Immune response 17 1.1.6 Insertional mutagenesis 18 1.1.7 Site-specific integration 19 1.1.8 Liver gene therapy 20 1.1.8.1 Immune
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