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Gene therapy and therapeutic gene editing: what are the predictors of success? Bobby Gaspar Professor of Paediatrics and Immunology Centre for Immunodeficiency.

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Presentation on theme: "Gene therapy and therapeutic gene editing: what are the predictors of success? Bobby Gaspar Professor of Paediatrics and Immunology Centre for Immunodeficiency."— Presentation transcript:

1 Gene therapy and therapeutic gene editing: what are the predictors of success? Bobby Gaspar Professor of Paediatrics and Immunology Centre for Immunodeficiency UCL Institute of Child Health/Great Ormond Street NHS Trust

2 Gene therapy and paediatric conditions Cystic fibrosis Duchennes MD Inborn errors OCT, Hurlers X-ALD Retinal abnormalities Haemophilia Severe immunodeficiencies Skin conditions EB Fanconis anaemia Haemoglobinopathies Acute leukaemias

3 Primary Immunodeficiency red blood cell platelets white blood cells neutrophils /monocytes white blood cells / Immune cells stem cells

4 Virus Bacteria Fungi Pneumonia, diarrhoea, repeated infections Severe combined immunodeficiency (SCID)

5 TB NK HSC-multi SCID/CID c, IL7Ra, JAK3, ZAP-70 RAG1/2, artemis, ligase IV, Cernunnos ADA, PNP MHC I/II, CD3 / /, CD45, ORAI1 Molecular defects in SCID

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7 How do we get genes into cells? Disabled viruses Adenovirus Adeno-associated virus Non-viral vectors Retrovirus

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9 X Stem cells lymphocytes B Blood Bone marrow T NK Thymus X In X-SCID growth of lymphocytes is blocked Pathology of SCID-X1

10 MoLV U5 Y R SD SA R Q IL2RG LTR-driven gammaretroviral vector: MFG C MoLV Criteria for entry: No matched sibling donor Molecularly confirmed diagnosis Common gamma chain vector: PG 13 producer cells (GALV envelope) titre approximately 1x10e6 transducing units per ml SCID-X1 gene therapy protocol

11 Lymphocyte recovery CD3 P1 P2 P3 P4 P5 P6 P7 P8 P10 T Lymphocytes/µl Weeks P9

12 Patient details Age at therapy (months) Maternal graft MutationGamma chain expression Total cells infused (x10e6) P1 10++R289X A+W P S238N -180 A+W P34 -Y125C +/-78 A+W P43y -R289X A+W P510 -R222C A+W P610 -PolyA -200 A+W P76 -M1i-84 A+W P813 -C182Y+207 A+W P97 -S108P+160 A+W P1012 -del-60 A+W Current status

13 Biochemical defect in ADA deficiency DNA d-adenosine d-inosine d-adenosine d-ATP increase is toxic to lymphocyte function dCydK ADA

14 T cell recovery post ADA gene therapy

15 Metabolic correction post gene therapy

16 Summary of ADA-Deficient SCID Patients Retroviral Vectors, Myeloreductive Conditioning –Milan/London/CHLA-NHGRI, NIH-UCLA Center # PtsF/U (yrs) 1 Off EnzymeSurvivalDFS 2 Milan – /18100%83.3% London 80.5 – 7.54/8100%50% CHLA-NHGRI UCLA-NHGRI – /6 7/8 100% 50% 87.5% TOTAL400.1 – /40100%72.5% 1 As of April DFS Alive without BMT or PEG-ADA re- start Data: Courtesy HB Gaspar (London) and Alessandro Aiuti (Milan)

17 Patient details Age at therapy (months) Maternal graft MutationGamma chain expression Total cells infused (x10e6) P1 10++R289X A+W P S238N -180 A+W P34 -Y125C +/-78 A+W P43y -R289X A+W P510 -R222C A+W P610 -PolyA -200 A+W P76 -M1i-84 A+W P813 -C182Y+207 A+W P97 -S108P+160 A+W P1012 -del-60 A+W Current status

18 LMO2CAPRIN1NAT10CD59FBXO3 Forward Strand Chromosome 11p Mb33.85Mb34.05Mb ABTB2C11orf41 X VIRUS INTEGRATION Fold Difference Relative to: Leukaemia panel DP1 T cells DP2 T cells Activation of LMO2

19 MoLV U5 Y R SD SA R Q IL2RG LTR-driven gammaretroviral vector: MFG gC MoLV U5 Y R R Q MP Δ SD PRE Prom. IL2RG EF1 (S) SF RSV New gammaretroviral SIN vectors: Sin11 / SRS11 Development of a new vector for SCID-X1

20 SFEFSSF.HS P < detection limit 23/24 mice long term survival Reduced mutagenesis with SIN configuration

21 Gene transfer for SCID-X1 using a self-inactivating (SIN) gammaretroviral vector A multi-institutional phase I/II trial evaluating the treatment of SCID-X1 patients with retrovirus- mediated gene transfer Sites: Great Ormond Street Hospital, UK (1) Hôpital Necker Enfants Malades, France (4) Childrens Hospital Boston, US (2) Cincinnati Childrens Hospital Medical Center, US Mattel Childrens Hospital, Los Angeles, US (1)

22 Lentiviral vector gene therapy for ADA-SCID

23 Phase I/II, non-controlled, open-label, nonrandomised, trial to assess the safety and efficacy of EF1αS-ADA lentiviral vector mediated gene modification of autologous CD34+ cells from ADA-deficient individuals Sites: Great Ormond Street Hospital, UK (2) Mattel Childrens Hospital, Los Angeles, US Vector production: Indiana University Vector Production Facility

24 Testing of efficacy and safety Phase I/II study of 10 patients Development of vector January 2007July 2009 December 2012 January 2018 MRC Research Grant MRC DPFS MRC DCS Lentiviral vector mediated Gene Therapy for ADA SCID Collaborations: UCLA Indiana University Vector Production Facility 1 st patient treated Feb patients treated in total

25 LV Phase I/II trial for Wiskott-Aldrich syndrome

26 Lentiviral Vector for CGD

27 Therapeutic gene editing

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29 Gene therapy and paediatric conditions Cystic fibrosis Duchennes MD Inborn errors OCT, Hurlers X-ALD Retinal abnormalities Haemophilia Severe immunodeficiencies Skin conditions EB Fanconis anaemia Haemoglobinopathies Acute leukaemias

30 Cures now available for specific SCID conditions First ever cures with Gene Therapy Morbidity and mortality still low compared to other treatments and prev innovations Need new safer vectors Each disease should be considered individually (gene regulation, expression, tissue specificity) Gene therapy in PID

31 Great Ormond Street Hospital Paul Veys Persis Amrolia Kanchan Rao Graham Davies Alison Jones Cathy Cale Lesley Henderson Jane Gaspar Jin Hua Xu-Bayford Lucie Brown Nursing and support staff Jude Cope Jodi New Institute of Child Health Emma Bjorkeren Kate Parsley Kimberly Gilmour Sam Cooray Elena de Falco Jo Sinclair Doug King Steve Howe Stuart Adams Suzy Thornhill Michelle Quaye Daleen Lopez-Begg Sue Swift Fang Zhang Lin Zhang Claudia Montiel Equiha Maria Alonso-Ferrero Marlene Carmo Christine Rivat Claire Booth Karen Buckland Sue Swift Nourredine Himoudi Anne-Marie McNicol Purine Res Lab, Guys Hospital Lynette Fairbanks Manchester Brian Bigger Fiona Wilkinson Collaborators Chris Baum Axel Schambach Christof von Kalle Manfred Schmidt Mik Antoniou Marina Cavazzana-Calvo Alain Fischer David Williams Manuel Grez Vicky Bordon Theoni Petropolou Many thanks to Adrian Thrasher Bobby Gaspar

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