Gene therapy for immunodeficiency diseases
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Technology: Medical Biotechnology
Medical and Health Sciences: Immunology
Summary of the impact
Research at the UCL Institute of Child Health (ICH) has led to the successful treatment of children
with primary immunodeficiency diseases for whom there was little chance of "cure" by the only
other possible means: haematopoietic stem cell transplantation (HSCT). Beginning in 2002, we
have treated 32 patients with four different primary immunodeficiency disorders. In total we have
treated 12 patients with severe combined immunodeficiency (SCID-X1), 13 patients with adenosine
deaminase deficient severe combined immunodeficiency (ADA-SCID), 5 patients with chronic
granulomatous disease (CGD) and 2 patients with Wiskott-Aldrich syndrome (WAS). Most of the
patients have been successfully treated and are at home, off all therapy. We are now starting to
develop this technology to treat a wider range of related disorders.
Primary immunodeficiency disorders are a heterogeneous group of rare, inherited diseases, where
children are born with defective immune systems. In the most severe forms children are unable to
fight off even very mild infections and, without treatment, will usually die within the first 2 years of
With the discovery of the causative genes for several primary immunodeficiencies by our group
and others came the possibility of developing new and improved forms of treatment for these life-threatening diseases . Although earlier clinical trials of gene therapy had been conducted, these
had been largely unsuccessful.
Our strategy was to develop efficient methods for introducing therapeutic genes into
haematopoietic stem cells (HSCs). To this end we developed gammaretroviral vectors to transduce
HSCs, using technology that we had developed in-house (selection of HSCs using anti-CD34
monoclonal antibodies and novel vectors). Using CGD as a model disorder, we showed functional
correction of the defect in in vitro models . At the same time we developed immunodeficient
mouse models for testing functional correction in vivo. By 2000 we had developed gammaretroviral
vectors that were capable of delivering therapeutic genes under the control of constitutive viral
promoters that could transduce HSCs with high efficiency and which could be used for clinical trials
of gene therapy .
Following scale-up of these methods we initiated our first clinical trial of gene therapy for SCID-X1,
followed by clinical trials for ADA-SCID and CGD using gammaretroviral vectors in the early 2000s.
By measuring the quantity and quality of immune reconstitution using cellular and molecular
techniques we evaluated the success of these treatments, comparing them to the only other
alternative, HSCT. We have also analysed these patients using novel molecular methods for
investigating and mapping gene integration sites to assess the efficiency of transduction [4, 5].
Overall these clinical trials have been judged to be largely successful. However, following the
development of a T-cell leukaemia-like disease in 4 of 10 SCID-X1 patients in a French clinical
trial, there were concerns regarding the safety profile of the use of gammaretroviral vectors. Of
these patients 3 were successfully treated by chemotherapy and HSCT while unfortunately 1
patient died. One of our patients was similarly affected but responded to chemotherapy treatment.
These studies demonstrated that while gene correction of autologous HSCs was highly effective,
the use of gammaretroviral vectors utilising the viral promoter had a finite risk of insertional
Further research has shown that relatively simple modifications to design, such as the use of self-inactivating (SIN) vectors in which viral promoters are deleted and transcription is under the control
of an internal mammalian promoter, may significantly improve safety . To this end, we have
developed new SIN gammaretroviral vectors which incorporate additional safety features, including
self-inactivation and tissue specific promoters, and we have also developed SIN lentiviral vectors
based on HIV. Current clinical trials using these new vectors are being conducted for SCID-X1,
ADA-SCID, CGD and WAS.
References to the research
 Vetrie D, Vorechovský I, Sideras P, Holland J, Davies A, Flinter F, Hammarström L, Kinnon C,
Levinsky R, Bobrow M, et al. The gene involved in X-linked agammaglobulinaemia is a
member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226-33.
 Demaison C, Brouns G, Blundell MP, Goldman JP, Levinsky RJ, Grez M, Kinnon C, Thrasher
AJ. A defined window for efficient gene marking of severe combined immunodeficient-repopulating cells using a gibbon ape leukemia virus-pseudotyped retroviral vector. Hum Gene
Ther. 2000 Jan 1;11(1):91-100. http://dx.doi.org/10.1089/10430340050016184
 Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von
Kalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL,
Levinsky RJ, Ali RR, Kinnon C, Thrasher AJ. Gene therapy of X-linked severe combined
immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004 Dec 18-31;364(9452):2181-7. http://dx.doi.org/10.1016/S0140-6736(04)17590-9
 Gaspar HB, Bjorkegren E, Parsley K, Gilmour KC, King D, Sinclair J, Zhang F, Giannakopoulos
A, Adams S, Fairbanks LD, Gaspar J, Henderson L, Xu-Bayford JH, Davies EG, Veys PA,
Kinnon C, Thrasher AJ. Successful reconstitution of immunity in ADA-SCID by stem cell gene
therapy following cessation of PEG-ADA and use of mild preconditioning. Mol Ther. 2006
 Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman
MH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC, Adams S, Thornhill SI, Parsley KL,
Staal FJ, Gale RE, Linch DC, Bayford J, Brown L, Quaye M, Kinnon C, Ancliff P, Webb DK,
Schmidt M, von Kalle C, Gaspar HB, Thrasher AJ. Insertional mutagenesis combined with
acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1
patients. J Clin Invest. 2008 Sep;118(9):3143-50. http://dx.doi.org/10.1172/JCI35798
 Thornhill SI, Schambach A, Howe SJ, Ulaganathan M, Grassman E, Williams D, Schiedlmeier
B, Sebire NJ, Gaspar HB, Kinnon C, Baum C, Thrasher AJ. Self-inactivating gammaretroviral
vectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther. 2008
Selected research grant support
Wellcome Trust Senior Fellowship in Clinical Science. Development of novel therapeutic
approaches for primary immunodeficiency. 1999-2014. Over £4 million. Thrasher
Department of Health. Clinical trials of gene therapy for primary immunodeficiency. 2005-10.
£1,033,723. Thrasher, Kinnon & Gaspar
MRC Project Grant. Clinical trial of self-inactivating vectors for gene therapy of X-linked severe
combined immunodeficiency (SCID-X1). 2006-12. £727,647. Thrasher & Gaspar
Details of the impact
Impact on patients
The majority of our patients are well and off all prophylactic therapy. One SCID-X1 patient who
was atypical (adolescent at time of treatment and had previously undergone HSCT, which was
failing) was treated on compassionate grounds, but did not reconstitute. As discussed, we have
had one serious adverse event (leukaemia). This patient was successfully treated by
chemotherapy and HSCT [a].
The only alternative treatment for our patients would have been HSCT. Many patients who have
undergone this treatment suffer from additional complications such as long-term effects related to
chemotherapy, usually with alkylating agents (e.g. lack of growth, compromised fertility, secondary
malignancy, hearing loss, hypodontia). Our recent study suggests a high incidence of cognitive and
behavioural abnormalities in SCID patients following HSCT. Since many of our gene therapy
patients have not received chemotherapy we can reasonably expect to see a reduction in the
appearance of such debilitating side effects and a consequent improved quality of life compared to
patients who have had chemotherapy.
One parent whose child underwent gene therapy said:
"Guy is now doing brilliantly; he can do all of the things his friends can do and more. He is
able to play football and ride a pony. He wouldn't be here if it wasn't for the option of gene
therapy treatment. We are incredibly grateful to the whole team at Great Ormond Street
Hospital, but especially Adrian Thrasher and Bobby Gaspar who pioneered this work. To
other parents who find themselves in our situation we would say `go for it'" [b].
The cost of gene therapy compared to the only other comparable treatment, HSCT, is reduced
because the patient has a significantly shorter stay in hospital (4-6 weeks for gene therapy
compared to 8 weeks on average for HSCT). The cost of enzyme replacement for ADA-SCID is
estimated at £350,000 p.a. minimum cost for the life-time of a patient. A significant number of our
patients are now off enzyme replacement treatment, with gene therapy thus offering an overall total
cost saving of £5 million to date.
Input into guidelines and policy
Gaspar has been Chairman of the BMT and Gene Therapy Working Party of European Society for
Immunodeficiencies (ESID), Chairman of the Inborn Errors Working Party of the European Blood
and Marrow Transplantation Society (EBMT). He has been involved in developing the current
guidelines for the treatment of PIDs [c, d]. In 2006 we contributed to the European Primary
Immunodeficiency Consensus Conference and their guidelines, which are still current [e].
Thrasher has acted in an advisory capacity to the US Recombinant DNA Advisory Committee
(RAC), the US Federal Drugs Administration (FDA), the UK Gene Therapy Advisory Committee
(GTAC) [f], the Medicines Control Agency (MCA) and the European Medicines Evaluation Agency
We have worked extensively with national and international patients' groups including the Primary
Immunodeficiency Association (PIA) [g], the CGD Society, the International Patient Organisation
for Primary Immunodeficiency (IPOPI) and Rare Disease UK [h]. This has included speaking at
their meetings and contributing to newsletters. For example, Gaspar is Chairman of the IPOPI
Medical Advisory panel and is a member of the advisory panels for PID-UK and the Ataxia
We have publicised our work to the general public through our interactions with the GOSH
Children's Charity fundraising work, through talks, films and other promotional material. We have
also worked closely with the Jeans for Genes Campaign in schools and at other fundraising
events, speaking and appearing in films to raise awareness of our work. Our work has been
presented as part of a living exhibition to promote the public understanding of science. The
exhibition, "Health Matters", has been on continuous display in the Science Museum throughout
the 2008-13 period. Our work also appears as part of a science exhibition at Bristol Museum.
We have worked extensively with the media to publicise our work. We have promoted our research
through films, newspapers and television, including BBC News, Newsnight and Radio 4, ITN News
and Channel 4 News and also in numerous scientific documentaries, including BBC Horizon [i].
We have worked with the Science Media Centre in educating journalists about our work.
We are very active in scientific societies which relate to our work such as the British Society for
Gene and Cell Therapy (BSGCT). Thrasher has recently retired as the President of the BSGCT,
and has organised education days for junior scientists and the general public. We are hosting at
tent at the forthcoming Bloomsbury Festival to showcase our work. We have talked about our work
in schools, to students of all ages from primary through to `A' Level students. We have hosted
school children to visit our labs and to hear presentations on our work. We offer one week work
experience placements to students in our labs on a biannual basis.
Sources to corroborate the impact
[a] Patient data can be verified by Senior Consultant Immunologist, Chair of Research
Governance Advisory Committee, GOSH. Contact details provided.
[b] Patient testimonies available from Senior Press Officer, Great Ormond Street Hospital. Contact
[f] Corroboration can be obtained from former Chair of the Gene Therapy Advisory Committee
(GTAC). Contact details provided.
[g] Letter of testimony from David Webster, past Chairman of Trustees of the Primary
Immunodeficiency Association available on request.
[h] Corroborating testimony as to our work with patient groups can be obtained from the Chronic
Granulomatous Disease Society (CGD Society). Contact details provided.
[i] Media coverage: