Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID2)

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ClinicalTrials.gov Identifier: NCT01410019

Recruitment Status : Completed

First Posted : August 4, 2011

Last Update Posted : September 28, 2021

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

X-linked severe combined immunodeficiency (SCID-X1) is an inherited disorder that results in failure of development of the immune system in boys. This trial aims to treat SCID-X1 patients using gene therapy to replace the defective gene.

Condition or disease	Intervention/treatment	Phase
X-linked Severe Combined Immunodeficiency	Other: Gene transfer	Phase 1 Phase 2

Detailed Description:

The objective of this protocol is to reinitiate an ex vivo gene therapy clinical protocol to treat patients with SCID-X1 without HLA identical family donor nor HLA identical unrelated donor (bone marrow and cord blood) available in an adequate time with the clinical conditions of the patient at diagnosis (approximately 6 weeks). This clinical protocol No. 2 of SCID-X1 must be as efficient than the previous one but must involve a risk of insertional mutagenesis significantly reduced as compared to the first protocol.

The main purpose of the study is the study of toxicity: tolerance and incidence of serious adverse effects.

Secondary goals are the evaluation of immune reconstitution allowing the cure of infections present at the time of gene therapy, assessment of integration sites, and finally the long-term correction of immunosuppression.

safety assessment : clinical effects, possible emergence of clonal lymphocyte proliferation, potential activation of proto-oncogene;
efficacy assessment of ex vivo transduction of CD34 + hematopoietic stem cells of the patient through the use of retroviral vector pSRS11.EFS.IL2RG.pre;
assessment of immune reconstitution : phenotype, number and function of different T, NK and B cells subpopulations;
longitudinal evaluation of clinical effects in terms of improvement or complete restoration of immunity;
biological efficacy assessment of this new vector SIN, assessment of molecular characteristics of retroviral integration.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	5 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Protocol No. 2 of Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1) Using a Self Retroviral Vector - SCID2
Study Start Date :	December 2010
Actual Primary Completion Date :	June 16, 2015
Actual Study Completion Date :	June 16, 2015

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Adenosine deaminase deficiency X-linked severe combined immunodeficiency JAK3-deficient severe combined immunodeficiency Omenn syndrome ZAP70-related severe combined immunodeficiency Purine nucleoside phosphorylase deficiency

MedlinePlus related topics: Genes and Gene Therapy

Genetic and Rare Diseases Information Center resources: Severe Combined Immunodeficiency X-linked Severe Combined Immunodeficiency

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1 Gene transfer	Other: Gene transfer Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) GAMMARETROVIRAL vector pSRS11.EFS.IL2RG.pre

Outcome Measures

Primary Outcome Measures :

Assessment of immunological reconstitution at short term [ Time Frame: month 4 ]
T cells proliferation T cells and B cells repertory by immunofluorescence T, NK and B Lymphocytes phenotyping Immunoglobulins dosage IgG, A, M, E and antibody production

Secondary Outcome Measures :

Molecular characterization of gene transfer [ Time Frame: every 15 days during 3 months, once per month until 6 months, every 3 months until year 1, every year until year 10 ]
PCR of vector
Analysis of activated proto-oncogene s expression [ Time Frame: every 4 months during 2 years and every 6 months indefinitely ]
Immunofluorescence analysis of the relative expression of different families of TCR alpha beta et gamma delta LAM PCR analysis and sequencing of integration sites

Eligibility Criteria

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Ages Eligible for Study:	up to 12 Months (Child)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria :

Boys diagnosed during the first year of life
Diagnosis of classical SCID-X1 based on immunophenotype (absent, or reduced numbers of non-functional T lymphocytes) and confirmed by DNA sequencing
No HLA identical family donor and no HLA identical unrelated donor (10/10 antigens) found in the 6 weeks following the beginning of the search. This period could be shortened if the probability to find a donor is low or if the clinical situation (gravity) required
Presence of a severe infection: pneumonitis and / or chronic diarrhea, or infection with herpes viruses or parainfluenza type 3 or adenovirus, or disseminated BCG infection, or presence of severe diarrhea and a severe compromise of the general state with denutrition
Or failure of a HLA HAPLO-identical bone marrow transplant within 10 years after transplantation
In all cases:
- No family background of cancer in childhood.
- No cytogenetic abnormalities (medullary karyotype) and no detection of main rearrangements associated with acute leukemia of children
- Parental/guardian voluntary consent

Exclusion criteria :

Atypical health with autologous T> 500/ml3
Infection by HIV 1 or 2
Allogeneic HSC completed (excluding situations of failure)
Existence of an HLA identical family donor or HLA identical unrelated donor
No severe infections in a child with a preserved general state
Family background of cancer in childhood
Detection of cytogenetic abnormality and / or rearrangement associated with acute leukemia of children
No affiliation to a social security scheme (beneficiary or assignee)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01410019

Locations

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France
Hopital Necker
Paris, France, 75015

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

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Study Director:	Alain Fischer, MD, PhD	Assistance Publique - Hôpitaux de Paris

More Information

Publications of Results:

Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernandez KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med. 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588.

Other Publications:

Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000 Apr 28;288(5466):669-72. doi: 10.1126/science.288.5466.669.

Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S, Fischer A, Davies EG, Kuis W, Leiva L, Cavazzana-Calvo M. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002 Apr 18;346(16):1185-93. doi: 10.1056/NEJMoa012616.

Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debre M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2010 Jul 22;363(4):355-64. doi: 10.1056/NEJMoa1000164.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Clarke EL, Connell AJ, Six E, Kadry NA, Abbas AA, Hwang Y, Everett JK, Hofstaedter CE, Marsh R, Armant M, Kelsen J, Notarangelo LD, Collman RG, Hacein-Bey-Abina S, Kohn DB, Cavazzana M, Fischer A, Williams DA, Pai SY, Bushman FD. T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency. Genome Med. 2018 Sep 28;10(1):70. doi: 10.1186/s13073-018-0580-z.

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Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT01410019
Other Study ID Numbers:	P071204 2008-002380-14 ( EudraCT Number )
First Posted:	August 4, 2011 Key Record Dates
Last Update Posted:	September 28, 2021
Last Verified:	September 2021

Keywords provided by Assistance Publique - Hôpitaux de Paris:


X-linked Severe Combined Immunodeficiency (SCID-X1) severe infection gene therapy HLA identical family donor without HLA identical unrelated donor

Additional relevant MeSH terms:

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Severe Combined Immunodeficiency X-Linked Combined Immunodeficiency Diseases Immunologic Deficiency Syndromes Immune System Diseases Primary Immunodeficiency Diseases	Genetic Diseases, Inborn Infant, Newborn, Diseases DNA Repair-Deficiency Disorders Metabolic Diseases Genetic Diseases, X-Linked

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