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Bobby Gaspar Professor of Paediatrics and Immunology

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Presentation on theme: "Bobby Gaspar Professor of Paediatrics and Immunology"— 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
Retinal abnormalities Skin conditions EB Cystic fibrosis Inborn errors OCT, Hurlers X-ALD Haemophilia Severe immunodeficiencies Duchenne’s MD Fanconi’s anaemia Haemoglobinopathies Acute leukaemias

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

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

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

6

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

8

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

10 SCID-X1 gene therapy protocol
MoLV U5 Y R SD SA Q IL2RG LTR-driven gammaretroviral vector: MFG gC 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

11 Lymphocyte recovery CD3
T Lymphocytes/µl Weeks P9

12 Patient details P1 10 ++ R289X ++ 180 A+W P2 10 ++ S238N - 180 A+W
Patient details Age at therapy (months) Maternal graft Mutation Gamma chain expression Total cells infused (x10e6) Current status P R289X A+W P S238N A+W P Y125C +/ A+W P4 3y - R289X A+W P R222C A+W P PolyA A+W P M1i A+W P C182Y A+W P S108P A+W P del A+W

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

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 # Pts F/U (yrs)1 Off Enzyme Survival DFS2 Milan 18 0.8 – 11.5 15/18 100% 83.3% London 8 0.5 – 7.5 4/8 50% CHLA-NHGRI UCLA-NHGRI 6 2– 5 0.1-2 3/6 7/8 87.5% TOTAL 40 0.1 – 11.5 29/40 72.5% 1 As of April 2012 2DFS ≡ Alive without BMT or PEG-ADA re-start Data: Courtesy HB Gaspar (London) and Alessandro Aiuti (Milan) 16

17 Patient details P1 10 ++ R289X ++ 180 A+W P2 10 ++ S238N - 180 A+W
Patient details Age at therapy (months) Maternal graft Mutation Gamma chain expression Total cells infused (x10e6) Current status P R289X A+W P S238N A+W P Y125C +/ A+W P4 3y - R289X A+W P R222C A+W P PolyA A+W P M1i A+W P C182Y A+W P S108P A+W P del A+W

18 Activation of LMO2 Chromosome 11p13 X Forward Strand 33.65Mb 33.85Mb
C11orf41 CD59 FBXO3 LMO2 CAPRIN1 NAT10 ABTB2 VIRUS INTEGRATION Fold Difference X Relative to: Leukaemia panel DP1 T cells DP2 T cells

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

20 Reduced mutagenesis with SIN configuration
SF EFS SF.HS P < 0.001 detection limit 23/24 mice long term survival 20

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) Children’s Hospital Boston, US (2) Cincinnati Children’s Hospital Medical Center, US Mattel Children’s Hospital, Los Angeles, US (1)

22 Lentiviral vector gene therapy for ADA-SCID

23 safety and efficacy of EF1αS-ADA lentiviral
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 Children’s Hospital, Los Angeles, US Vector production: Indiana University Vector Production Facility

24 Testing of efficacy and safety Phase I/II study of 10 patients
Lentiviral vector mediated Gene Therapy for ADA SCID MRC Research Grant MRC DPFS MRC DCS Development of vector Testing of efficacy and safety Phase I/II study of 10 patients January 2007 July 2009 December 2012 January 2018 Collaborations: UCLA Indiana University Vector Production Facility 1st patient treated Feb 2012 3 patients treated in total

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

26 Lentiviral Vector for CGD

27 Therapeutic gene editing

28

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

30 Gene therapy in PID 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)

31 Many thanks to Adrian Thrasher Bobby Gaspar Manchester
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 Nourredine Himoudi Anne-Marie McNicol 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 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 Purine Res Lab, Guys Hospital Lynette Fairbanks Manchester Brian Bigger Fiona Wilkinson Adrian Thrasher Bobby Gaspar

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