Gene Therapy for X-linked Severe Combined Immunodeficiency

X-linked Severe Combined Immunodeficiency Clinical Trial

— SCID2  

Official title:

Protocol No. 2 of Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1) Using a Self Retroviral Vector - SCID2

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01410019
• Other study ID #: P071204
• Secondary ID: 2008-002380-14
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 2010
• Est. completion date: June 16, 2015

Study information

• Verified date: September 2021
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

1. safety assessment : clinical effects, possible emergence of clonal lymphocyte proliferation, potential activation of proto-oncogene;

2. efficacy assessment of ex vivo transduction of CD34 + hematopoietic stem cells of the patient through the use of retroviral vector pSRS11.EFS.IL2RG.pre;

3. assessment of immune reconstitution : phenotype, number and function of different T, NK and B cells subpopulations;

4. longitudinal evaluation of clinical effects in terms of improvement or complete restoration of immunity;

5. biological efficacy assessment of this new vector SIN, assessment of molecular characteristics of retroviral integration.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: June 16, 2015
• Est. primary completion date: June 16, 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A to 12 Months

Eligibility

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)

Related Conditions & MeSH terms

• Immunologic Deficiency Syndromes
• Severe Combined Immunodeficiency
• X-Linked Combined Immunodeficiency Diseases
• X-linked Severe Combined Immunodeficiency

Intervention

Other:
• Gene transfer
Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) GAMMARETROVIRAL vector pSRS11.EFS.IL2RG.pre

Locations

Country	Name	City	State
France	Hopital Necker	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (4)

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. — View Citation

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, Debré 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. — View Citation

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. — View Citation

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, Fernández KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, M — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of immunological reconstitution at short term	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	month 4
Secondary	Molecular characterization of gene transfer	PCR of vector	every 15 days during 3 months, once per month until 6 months, every 3 months until year 1, every year until year 10
Secondary	Analysis of activated proto-oncogene s expression	Immunofluorescence analysis of the relative expression of different families of TCR alpha beta et gamma delta LAM PCR analysis and sequencing of integration sites	every 4 months during 2 years and every 6 months indefinitely