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Can We Treat Congenital Blood Disorders by Transplantation Of Can we Treat Congenital Blood Disorders by Transplantation of Stem Cells, Gene Therapy to the Fetus? Panicos Shangaris University College London 2019 A thesis submitted for the degree of Doctor of Philosophy 1 Declaration I, Panicos Shangaris 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. 2 Abstract Congenital diseases such as blood disorders are responsible for over a third of all pediatric hospital admissions. In utero transplantation (IUT) could cure affected fetuses but so far in humans, successful IUT has been limited to fetuses with severe immunologic defects, due to the maternal immune system and a functionally developed fetal immune system. I hypothesised that using autologous fetal cells could overcome the barriers to engraftment. Previous studies show that autologous haematopoietic progenitors can be easily derived from amniotic fluid (AF), and they can engraft long term into fetal sheep. In normal mice, I demonstrated that IUT of mouse AFSC results in successful haematopoietic engraftment in immune-competent mice. Congenic AFSCs appear to have a significant advantage over allogenic AFSCs. This was seen both by their end haematopoietic potential and the immune response of the host. Expansion of haematopoietic stem cells (HSC) has been a complicated and demanding process. To achieve adequate numbers for autologous stem cells for IUT, HSCs need to be expanded efficiently. I expanded and compared AFSCs, fetal liver stem cells and bone marrow stem cells. Culturing and expanding fetal and adult stem cells in embryonic stem cell conditions maintained their haematopoietic potential. Using a humanised mouse model of thalassaemia, in which heterozygous animals are affected by anaemia, splenomegaly and extramedullary haematopoiesis, I explored whether in utero gene therapy (IUGT) to the fetal HSC compartment using a vector carrying the corrected beta-globin gene might cure the disease before birth. IUGT resulted in phenotypic normalisation with increased levels of beta-globin and associated downregulation of gamma globin, consistent with a switch from fetal to adult human haemoglobin, confirming successful prenatal correction of the genetic defect. 3 Impact Statement Cell-free fetal DNA is detectable in the mother’s circulation from the fifth week of pregnancy, which makes it possible in the future, to detect any gene disorder, such as thalassaemia, much earlier than currently feasible (Byrou et al., 2018; Hudecova and Chiu, 2017; Saba et al., 2017). Earlier detection would give parents more time to consider their options and clinicians to consider early interventions. Currently, the two main alternatives are 1) termination of pregnancy or 2) careful monitoring and delivery followed by postnatal treatment where appropriate. This thesis addresses a potential third option; in-utero treatment of the genetic disorder by delivering the corrected version of a cell or protein. In the last two decades, studies in animal models have shown promising results, where gene therapy or stem cell delivery to the fetus in utero corrected hereditary disorders (Hartman et al., 2018; Loukogeorgakis et al., 2019; Loukogeorgakis and De Coppi, 2016; Shangaris et al., 2017, 2018, 2019; Shaw et al., 2015; Witt et al., 2018). The results from this thesis demonstrate that amniotic fluid stem cells have haematopoietic potential and can be used in an in-utero therapy setting. The culture of amniotic fluid stem cells was optimised, and the cells maintained their hematopoietic potential in vitro for up to 7 days (Loukogeorgakis et al., 2019). The developing fetus can mount an immune response to non-self (allogenic) stem cells but not to self (congenic) amniotic fluid stem cells. This is a fundamentally important principle for the development of clinical trials of in utero therapies for severe congenital disease such as haemoglobinopathies, and skeletal dysplasias. This important element in the pathway towards prenatal therapy for blood disorders has been disseminated to the scientific community with two publications in Stem Cells and Stem Cells and Development (Loukogeorgakis et al., 2019; Shangaris et al., 2018). The results were also presented to many nationals and international conferences, such as the Society of Reproductive investigation, European Society of Gene and Cell Therapy, Gynaecological Visiting Society and Blair Bell Academic Meeting and International Society of Stem Cell 4 Research. The second study in this thesis demonstrates the successful application of in utero gene therapy to the treatment of heterozygous beta-thalassemia, using a unique humanised mouse model in which the developmental haemoglobin switch occurs just as in humans, due to insertion of a “switching cassette”. Injection of a GLOBE lentivector intra-hepatically into fetal mice, resulted in long-term clinical improvement, as evidenced by a reduction in anaemia, extramedullary haematopoiesis, hepatosplenomegaly, and improvement in cardiac function. Furthermore, the results also demonstrate the utility of non-invasive MRI as a tool to assess clinical status of individuals with beta-thalassemia with respect to cardiac function and organ damage/organomegaly. The results of the study were presented in international conferences, and it received more than five awards. The final results were disseminated to the scientific community via a publication in Scientific Reports Journal(Shangaris et al., 2019). A presentation to lay, members of the UK Thalassemia society, resulted in securing further funding to test a new superior and more efficient lentivector. This treatment would have a huge impact, especially in those countries such as the Middle East and the Far East where termination of pregnancy may not be available, blood transfusions are prohibitively expensive, and where thalassaemia is most prevalent. 5 Table of Contents DECLARATION ............................................................................................................................ 2 ABSTRACT ................................................................................................................................... 3 IMPACT STATEMENT ................................................................................................................. 4 TABLE OF CONTENTS ................................................................................................................ 6 TABLE OF FIGURES ................................................................................................................. 14 TABLE OF TABLES ................................................................................................................... 26 ACKNOWLEDGEMENTS ........................................................................................................... 28 PRIZES & AWARDS ................................................................................................................... 31 FUNDING ................................................................................................................................... 33 PUBLICATIONS ......................................................................................................................... 33 CONFERENCE PRESENTATIONS (ORAL & POSTER) ........................................................... 35 ABBREVIATIONS (SELECTIVE) ............................................................................................... 37 INTRODUCTION .............................................................................................. 39 1.1 INTRODUCTION ...................................................................................................................... 39 1.2 THE CONCEPT OF PERINATAL THERAPY .................................................................................. 40 1.3 STEM CELLS ......................................................................................................................... 41 1.4 STEM CELL HIERARCHY ......................................................................................................... 41 1.5 SELECTING THE RIGHT CELLS FOR THERAPY ........................................................................... 42 1.6 HAEMATOPOIETIC STEM CELLS ............................................................................................... 43 1.7 FETAL LIVER STEM CELLS ...................................................................................................... 44 1.8 AMNIOTIC FLUID STEM CELLS ................................................................................................. 45 1.9 BONE MARROW STEM CELLS .................................................................................................. 46 1.10 RATIONALE FOR IN UTERO STEM CELL TRANSPLANTATION ........................................................ 47 1.11 SELECTING THE RIGHT DISEASE FOR PERINATAL THERAPY ........................................................ 48 1.12 SELECTING THE RIGHT VECTOR FOR PERINATAL GENE THERAPY ............................................... 51 1.13 NON-VIRAL VECTORS ............................................................................................................. 52 1.14 ADENOVIRUS ......................................................................................................................... 53 6 1.15 ADENO-ASSOCIATED VIRUS VECTORS (AAV) ..........................................................................
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