Development of a lentiviral vector for gene therapy of ADA deficiency

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

ADA deficiency is a severe form of immunodeficiency which leaves affected children very vulnerable to infections from all types of bacteria and viruses. Bone marrow transplant can correct the disease but carries with it major difficulties especially if a fuly matched donor is not available. For this reason, attempts to cure the disease by gene therapy have been developed. In initial trials, this has been very promising but the current methods by which the ADA gene is introduced into the child s cells may have potential problems for the future. We are now trying to develop safer ways of carrying genes into cells and in this project we aim to test whether these new methods are both effective and safe.

Technical Summary

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency resulting in recurrent infections and death in the first year of life without definitive treatment. Gene therapy using gammaretroviral vector mediated correction of autologous haematopoietic stem cells (HSCs) has shown significant efficacy in correcting the immunological defects associated with ADA deficiency. However, the use of gammaretroviral vectors is complicated by their potential for insertional mutagenesis which has led to the development of leukaemia in patients treated by gene therapy for other immunodeficiencies. There is a pressing need to move to safer but equally efficacious vector strategies. Lentiviral vectors are able to transduce HSCs effectively but exhibit a significantly reduced potential for insertional mutagenesis. We have generated lentiviral vectors with the ADA gene under the transcriptional control of an internal mammalian promoter. We aim to demonstrate the efficacy and safety of this lentiviral vector in promoting immune and metabolic correction in cellular and animal models of ADA deficiency. These studies are critical before such vectors can be used in clinical studies.

Publications

10 25 50

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

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Whitmore KV (2016) Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency. in Frontiers in immunology

 
Description EC FP7 funding
Amount £84,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start  
 
Description EU H2020
Amount € 6,926,317 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2016 
End 12/2019
 
Description Phase I/II trial of lentiviral vector mediated gene therapy for Adenosine Deaminase deficiency
Amount £1,472,122 (GBP)
Funding ID MR/K015427/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 12/2017
 
Description RECOMB
Amount € 4,500,000 (EUR)
Funding ID 755170 
Organisation European Commission 
Department Horizon 2020
Sector Public
Country European Union (EU)
Start 01/2018 
End 12/2022
 
Description Clinical trial 
Organisation University of California, Los Angeles (UCLA)
Country United States 
Sector Academic/University 
PI Contribution Partnership in a clinical trial development and a clinical trial
Collaborator Contribution Partnership in a clinical trial development and a clinical trial
Impact manuscripts
Start Year 2011
 
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
 
Title A lentiviral vector for the treatment of ADA SCID 
Description A lentiviral vector for the treatment of ADA SCID 
IP Reference KEMP.P0052US.P1 
Protection Patent application published
Year Protection Granted
Licensed Yes
Impact Successful treatment of ADA SCID
 
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 Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Lecturing at a patient awareness day

n/a
Year(s) Of Engagement Activity 2009
 
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