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

Primary Purpose

X-linked Severe Combined Immunodeficiency

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Gene transfer
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for X-linked Severe Combined Immunodeficiency focused on measuring X-linked Severe Combined Immunodeficiency (SCID-X1), severe infection, gene therapy, HLA identical family donor, without HLA identical unrelated donor

Eligibility Criteria

undefined - 12 Months (Child)MaleDoes not accept healthy volunteers

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)

Sites / Locations

  • Hopital Necker

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

1

Arm Description

Gene transfer

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Molecular characterization of gene transfer
PCR of vector
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

Full Information

First Posted
June 21, 2011
Last Updated
September 22, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT01410019
Brief Title
Gene Therapy for X-linked Severe Combined Immunodeficiency
Acronym
SCID2
Official Title
Protocol No. 2 of Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1) Using a Self Retroviral Vector - SCID2
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
December 2010 (undefined)
Primary Completion Date
June 16, 2015 (Actual)
Study Completion Date
June 16, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
X-linked Severe Combined Immunodeficiency
Keywords
X-linked Severe Combined Immunodeficiency (SCID-X1), severe infection, gene therapy, HLA identical family donor, without HLA identical unrelated donor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Gene transfer
Intervention Type
Other
Intervention Name(s)
Gene transfer
Intervention Description
Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) GAMMARETROVIRAL vector pSRS11.EFS.IL2RG.pre
Primary Outcome Measure Information:
Title
Assessment of immunological reconstitution at short term
Description
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
Time Frame
month 4
Secondary Outcome Measure Information:
Title
Molecular characterization of gene transfer
Description
PCR of vector
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
Title
Analysis of activated proto-oncogene s expression
Description
Immunofluorescence analysis of the relative expression of different families of TCR alpha beta et gamma delta LAM PCR analysis and sequencing of integration sites
Time Frame
every 4 months during 2 years and every 6 months indefinitely

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alain Fischer, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
Facility Information:
Facility Name
Hopital Necker
City
Paris
ZIP/Postal Code
75015
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
10784449
Citation
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.
Results Reference
background
PubMed Identifier
11961146
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. doi: 10.1056/NEJMoa012616.
Results Reference
background
PubMed Identifier
20660403
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, 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.
Results Reference
background
PubMed Identifier
25295500
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, 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.
Results Reference
result
PubMed Identifier
30261899
Citation
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.
Results Reference
derived

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Gene Therapy for X-linked Severe Combined Immunodeficiency

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