Clinical trial of self-inactivating vectors for gene therapy of X-linked Severe Combined Immunodeficiency (SCID-X1)

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

Abstract

Gene therapy has the potential to treat a wide range of inherited diseases. Recently, several trials have shown that children with defects of their immune system (often called bubble babies because they are kept in germ free rooms) can be successfully treated in this way by putting new genes into the blood-making factory called bone marrow. However, the way in which the new genes are transplanted into the bone marrow, using modified viruses or vectors, has also been shown in a few children to have unfortunate side-effects. We now know that these arise because the vectors inadvertantly activate other genes that keep the cells in our body healthy. In the worst case, this can cause cancer. However, we also now believe that the risk of this occuring can be substantially limited by improved design of the vectors themselves. Following on from highly encouraging experiments in the laboratory, we would now like to test this strategy in patients for whom coventional bone marrow transplantation is difficult. This will not only provide a new treatment for patients with immune defects, but will provide a platform on which gene therapy can be safely developed for many other diseases.

Technical Summary

Somatic gene therapy has been proposed as an exciting new therapeutic strategy for treatment of human genetic disease. Four recent studies have demonstrated highly effective gene therapy for the X-linked form of severe combined immunodeficiency (SCID-X1) and ADA-deficiency, using mammalian retroviruses to deliver the therapeutic genes into haematopoietic stem cells ex vivo. SCID-X1, caused by mutations in the common cytokine receptor gamma chain (gamma-c), is invariably fatal in the absence of therapeutic bone marrow transplantation. In the presence of HLA-matched family donors, the majority of patients can expect to be cured. For other donor sources, particularly parental, success rates are reduced, and full restoration of immunity is often not achieved. We have recently successfully treated seven children with molecularly defined SCID-X1 by gene transfer to bone marrow CD34+ cells using a gibbon ape leukaemia virus (GALV)-pseudotyped gammaretroviral vector. However, the development of leukaemia in patients enrolled in a similar trial has highlighted the risk of inadvertent gene activation through insertional mutagenesis. We have therefore explored strategies to minimise this risk by development of gammaretroviral vectors that are deleted for powerful endogenous viral enhancer sequences (SIN). We are currently in the final phases of testing these vectors, but have shown that they retain the capacity for correction of the SCID-X1 disease phenotype in animal models, and have a significantly reduced mutagenic potential in vitro. Here we propose a clinical trial for testing these novel vectors in human patients. This will be the first clinical study using SIN gammaretroviral technology, and will hopefully establish a solid platform for the development of safe and efficacious gene therapy in many other disease types.

Publications

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Hacein-Bey-Abina S (2014) A modified ?-retrovirus vector for X-linked severe combined immunodeficiency. in The New England journal of medicine

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Huston MW (2011) Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. in Molecular therapy : the journal of the American Society of Gene Therapy

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

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Thornhill SI (2008) Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. in Molecular therapy : the journal of the American Society of Gene Therapy

 
Description BRC (ADA)
Amount £97,217 (GBP)
Organisation Great Ormond Street Hospital (GOSH) 
Department NIHR Great Ormond Street Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 03/2011 
End 12/2014
 
Description MRC Developmental Pathway Clinical Studies Grant (ADA)
Amount £1,226,390 (GBP)
Funding ID MR/K015427/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2013 
End 03/2018
 
Title SIN gammaretroviral vector 
Description therapeutic retrovirus for gene therapy of SCID 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact First in man trial open 
 
Description Overseas clinical trials 
Organisation Boston University
Country United States 
Sector Academic/University 
PI Contribution pre clinical data vector development and proof of principle
Collaborator Contribution preclinical data
Impact Clinical trials submitted to regulatory authorities in Europe and US. Permissions granted and recruiting in progress.
Start Year 2007
 
Description Overseas clinical trials 
Organisation Necker-Enfants Malades Hospital
Country France 
Sector Hospitals 
PI Contribution pre clinical data vector development and proof of principle
Collaborator Contribution preclinical data
Impact Clinical trials submitted to regulatory authorities in Europe and US. Permissions granted and recruiting in progress.
Start Year 2007
 
Title Gene therapy for X-linked SCID 
Description stem cell gene therapy currently part of international multicentre study, MRC funded. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Improved survival compared with conventional therapies 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=4601
 
Title retroviral vector 
Description retroviral vector for gene therapy 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier CRN7313
Impact results awaited from clinical trial 
 
Description BSGT/BSGCT 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact British Society for Gene Therapy, Warwick, March 2007
Successful bone marrow gene therapy for inherited immunodeficiency

British Society for Gene Therapy, Edinburgh, April 2008
Severe combined immunodeficiency: clinical update and development of safer protocols

Joint BSGT/ESGCT meeting, Brighton 27th-31st October 2011
"Gene therapy for immunodeficiency"


Much interest
Year(s) Of Engagement Activity 2007,2008,2011
 
Description Children's Hospital of Chongqing Medical University, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Children's Hospital of Chongqing Medical University, China, October 2010
"Gene therapy for immunodeficiency"


Very positive feedback.
Year(s) Of Engagement Activity 2010
 
Description Cologne Summer School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact University of Cologne Summer School: Gene Therapy and Regenerative Medicine, 3rd-5th September 2012
"Learning from Gene Therapies for Immunodeficiencies"


Generated much interest
Year(s) Of Engagement Activity 2010,2012
 
Description German Society for Gene Therapy Summer School, Cologne 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Vector Development and Gene Therapy Course, German Society for Gene Therapy, Cologne, September 2009.
"Gene Therapy of Immune Deficiencies"


Excellent feedback. Much interest generated
Year(s) Of Engagement Activity 2009
 
Description IATI Symposium, Granada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact IATI Symposium, Granada, 28th-29th June 2012
"Gene Therapies for Immunodeficiencies"


No feedback available to me
Year(s) Of Engagement Activity 2012
 
Description Inspiring Careers in Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact Inspiring Careers in Science - Educational Fellowship UCL Awayday, 7th May 2013.
Q&A session "Moral Dilemmas - how will rapid advances in science and medicine affect you?"


Very positive response and feedback. Enquiries from other schools regarding future events
Year(s) Of Engagement Activity 2012
 
Description JMF Network, Berlin 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Jeffrey Modell Centres Network, Berlin, 17-21 July 2013
"Progress in gene therapy from bench to clinic"


Opportunity for networking with other JMF Centres
Year(s) Of Engagement Activity 2013
 
Description Primary Immune Deficiency Treatment Consortium (PIDTC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Addressing Primary Immune Deficiency Treatment Consortium (PIDTC) "Vector optimization and strategies for targeted gene repair"

Networking
Year(s) Of Engagement Activity 2012
 
Description Stem Cell Clonality and Genotoxicity Retreat 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 4th Stem Cell Clonality and Genotoxicity Retreat, Boston, June 2008
X-linked severe combined immune deficiency trial / Clinical Trials for SCID past and future.

5th Stem cell clonality and genotoxicity retreat, ESGCT Hannover November 2009
"Gene therapy of severe combined immunodeficiency"

Stem Cell Clonality and Genome Stability Retreat, Madrid 24-25th October 2013
"Update on SCID-X1 Gene Therapy"


Always successful meetings generating much discussion
Year(s) Of Engagement Activity 2008,2009,2013
 
Description Tohoku University Hospital, Japan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Tohoku University Hospital, Japan, December 2007
Update on gene therapy trials for SCID


Generated much interest
Year(s) Of Engagement Activity 2007
 
Description Transatlantic Gene Therapy Consortium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Transatlantic Gene Therapy Consortium, San Diego, May 2009
"Vector Developments for PID"

Transatlantic Gene Therapy Consortium, 15th May 2012
"Update on Trials for SCID-X1"


Networking
Year(s) Of Engagement Activity 2009,2012
 
Description UK National Stem Cell Network meeting, York 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact UK National Stem Cell Network meeting, York 30-31 March 2011
"Successful genetic therapy for immunodeficiency"


Networking
Year(s) Of Engagement Activity 2010
 
Description UK-Israel Regenerative Medicine meetings, Israel 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact UK-Israel Regenerative Medicine Conference and Launch of the BIRAX Regenerative Medicine Initiative, Beer Sheva Israel, 22-23 November 2011
"Gene Therapy for Immunodeficiency"


Generated much interest, launch of BIRAX Regenerative Medicine Initiative.
Year(s) Of Engagement Activity 2011
 
Description UK-Japan Gene Therapy Workshop, Tokyo 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 2nd UK-Japan Gene Therapy Workshop, Tokyo October 2006
Gene therapy strategies for immunodeficiencies

Networking
Year(s) Of Engagement Activity 2006
 
Description University of Hong Kong 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Faculty of Medicine Departmental Research Meeting, University of Hong Kong, 22 January 2013
"A journey through WAS: Actin Cytoskeleton and the Immune Response"

Faculty of Medicine Departmental Grand Round, University of Hong Kong, 24 January 2013
"Current Clinical Applications of Gene Therapy in Childhood Diseases"

Stem Cell and Regenerative Medicine Consortium seminar, University of Hong Kong, 24 January 2013.
"Gene Therapy for Primary Immunodeficiencies: From Bench to Clinic"


Arrangements initiated for visiting clinician from Hong Kong to work in our labs for 2 years 2010-2012, and for Professorial visit by Prof Yu-Lung Lau in 2013.
Year(s) Of Engagement Activity 2010,2012