Development of an enhanced lentiviral vector for gene therapy of ADA-SCID

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

Adenosine deaminase deficiency is a condition in which affected children lack a functional immune system and die from infection in the first year of life. The nature of the gene defect is such that severe defects are also found in other systems of the body. Due to the limitations of other treatment options, gene therapy has recently been used with some success in correcting the immune defects. In this study we hope to build on this and test better gene therapy delivery vectors that may correct both the immune system and non-immune system problems. We will also use vectors that have improved safety profiles compared to presently used constructs. We will test our new vectors in cellular systems and also aim to correct a murine model of the disease.

Technical Summary

Somatic gene therapy has long been held as a major goal for correction of monogenic diseases. The promise of over two decades of basic and pre-clinical research has now been realised with the demonstration of significant therapeutic effect in clinical studies on a number of severe congenital immunodeficiencies including SCID-X1 (X-linked severe combined immunodeficiency), ADA-SCID (adenosine deaminase deficient SCID) and X-CGD (X-linked chronic granulomatous disease). To date, successful gene transfer has been mediated by conventional gammaretroviral vectors which show efficient and stable integration into haematopoietic stem cells (HSC) but have also demonstrated the potential for significant side effects through inadvertent gene activation. For ADA-SCID, where the ADA gene is expressed in all somatic tissues and where clinically defects exist outside of the immune system, systemic gene delivery may have added therapeutic benefit. In this application, we aim to build on our highly promising phase I/II gene therapy trials for ADA-SCID and to develop and test vectors with improved safety profiles and enhanced ADA gene delivery. We plan to develop lentiviral vectors in which the ADA gene is transcribed from a non-viral promoter which is also under the influence of the beta-globin locus control region (LCR). Using this construct, we hope to achieve high level expression in lymphocytes to allow T and B cell development, but also beta-globin LCR driven expression in erythrocytes which may allow for greater systemic ADA expression and provide better metabolite detoxification. The use of a lentiviral construct with deleted long terminal repeat sequences and an internal promoter will also provide an improved safety profile.

Publications

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Debnath S (2017) Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia. in Molecular therapy : the journal of the American Society of Gene Therapy

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Ghosh S (2017) Gene Therapy Approaches to Immunodeficiency. in Hematology/oncology clinics of North America

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Ghosh S (2015) Gene therapy for monogenic disorders of the bone marrow. in British journal of haematology

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Rivat C (2012) Gene therapy for primary immunodeficiencies. in Human gene therapy

 
Description Development of a gene therapy vector for the treatment of Mucopolysaccharidosis type I-Hurler
Amount £247,565 (GBP)
Funding ID W1084 
Organisation Great Ormond Street Hospital Children's Charity (GOSHCC) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Development of a lentiviral vector for gene therapy of ADA deficiency
Amount £613,850 (GBP)
Funding ID G0802483 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2009 
End 06/2012
 
Description Great Ormond Street Hospital Biomedical Research Centre Call for Project grants
Amount £100,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start  
 
Description UCL/MRC Confidence in Concept scheme
Amount £90,099 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 08/2015
 
Title ENHANCED LENTIVIRAL VECTOR 
Description WE HAVE DESIGNED AND TESTED A NOVEL LENTIVIRAL VECTOR CONSTRUCT THAT IS CAPABLE OF UPREGULATED ADA EXPRESSION IN ERYTHROCYTE LINEAGES 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact NONE AS YET BUT FURTHER TESTING IS ONGOING AND WE EXPECT A PUBLICATION IN 2010 
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation Albert Ludwig University of Freiburg
Department Center for Chronic Immunodeficiency (CCI)
Country Germany 
Sector Academic/University 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation Genethon
Country France 
Sector Public 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation Genewerks
Country Australia 
Sector Private 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation Hannover Medical School
Department Institute of Experimental Hematology
Country Germany 
Sector Academic/University 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation Leiden University
Country Netherlands 
Sector Academic/University 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation Necker-Enfants Malades Hospital
Country France 
Sector Hospitals 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description EU consortium for collaborations with clinical partners for trials for gene therapy for SCID 
Organisation San Raffaele Hospital
Country Italy 
Sector Hospitals 
PI Contribution Leading clinical trials for ADA SCID and X-linked SCID
Collaborator Contribution contributing to taking forward gene therapy for SCID in the context of a European partnership
Impact Award of a H2020 EU grant
Start Year 2015
 
Description H2020 project - RECOMB 
Organisation Leiden University Medical Center
Department Immunology (LUMC-I)
Country Netherlands 
Sector Hospitals 
PI Contribution Know how in ex vivo gene therapy
Collaborator Contribution Details on transduction of haematopoietic stem cells
Impact None so far
Start Year 2018
 
Company Name Orchard Therapeutics 
Description Ex vivo bone marrow gene therapy company 
Year Established 2016 
Impact none so far but intention to take gene therapy developments to licensed medicines
Website http://orchard-tx.com/
 
Description Royal Society Christmas lecture 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Invitation to Royal Society Lecture to talk about gene therapy
Year(s) Of Engagement Activity 2018