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.
Organisations
- University College London, United Kingdom (Lead Research Organisation)
- Genewerks (Collaboration)
- Albert Ludwig University of Freiburg (Collaboration)
- Hannover Medical School, Germany (Collaboration)
- Necker-Enfants Malades Hospital (Collaboration)
- Genethon (Collaboration)
- University of Leiden, Netherlands (Collaboration)
- San Raffaele Hospital (Collaboration)
- Leiden University Medical Center (Collaboration)
Publications

Carbonaro DA
(2014)
Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency.
in Molecular therapy : the journal of the American Society of Gene Therapy

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

Gaspar HB
(2012)
Gene therapy for ADA-SCID: defining the factors for successful outcome.
in Blood

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

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

Kohn DB
(2017)
How We Manage Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA SCID).
in Journal of clinical immunology

Kohn DB
(2019)
Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency.
in The Journal of allergy and clinical immunology

Montiel-Equihua CA
(2012)
The ß-globin locus control region in combination with the EF1a short promoter allows enhanced lentiviral vector-mediated erythroid gene expression with conserved multilineage activity.
in Molecular therapy : the journal of the American Society of Gene Therapy

Montiel-Equihua CA
(2012)
Gene therapy for severe combined immunodeficiency due to adenosine deaminase deficiency.
in Current gene therapy

Montiel-Equihua CA
(2009)
Development of gene therapy: potential in severe combined immunodeficiency due to adenosine deaminase deficiency.
in Stem cells and cloning : advances and applications
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 | 09/2013 |
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 | Public |
Country | United Kingdom |
Start | 05/2009 |
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 | Academic/University |
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 | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2014 |
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 | Charity/Non Profit |
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 |