Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1)

Gene Therapy for SCID-X1 Using a Self-inactivating (SIN) Gammaretroviral Vector

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.

Study Overview

• Status: Unknown
• Conditions: X-linked Severe Combined Immunodeficiency
• Intervention / Treatment: Genetic: Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. No HLA identical (A,B,C,DR,DQ) family donor and no HLA identical unrelated donor available within 3 months of diagnosis or patients whose underlying clinical problems and prognosis would be significantly compromised by chemotherapy conditioning (including persisting pneumonitis, protracted diarrhoea requiring parental nutrition, ongoing visceral viral infection (herpes viruses, HSV,VZV,CMV, EBV or adenovirus), systemic BCG infection, virus-induced lymphoproliferation.
2. Diagnosis of classical SCID-X1 based on immunophenotype (absent, or reduced numbers of non-functional T lymphocytes) and confirmed by DNA sequencing
3. Parental/guardian voluntary consent
4. Boys between the ages of 0 and 16

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single infusion of autologous CD34+ cells	Genetic: Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre; Single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) gammaretroviral vector pSRS11.EFS.IL2RG.pre

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological reconstitution	Immunophenotyping: detection of naïve CD3+ T-cell numbers, CD4, CD8, TCRαβ, TCRγδ, CD16+CD56+ NK & gamma chain expression. TRECs may be enumerated as surrogate marker for new thymic emigrants post-gene therapy; Lymphocyte proliferation assays to test function of T cells; Representation of TCR families by flow cytometry (Vβ phenotyping), & CDR3 PCR spectratyping (Vβ spectratyping) to monitor physiological & potentially pathological clonal expansions; Restoration of antibody production (IgA, IgM, IgG) & serological responses to vaccinations & natural infections.	1-18 months post-infusion,then annually

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse reactions	At each scheduled visit, adverse events that might have occurred since the previous visit or assessment will be elicited from the patient/parent/guardian. The investigators will maintain a record of all adverse events/occurrences in patients participating in the clinical trial. This record will be noted in the patient's medical notes. Adverse events that have a causal relationship to the IMP (ARs) and SAEs will be recorded on the AE reporting section of the CRF.	from consent until 5 years post-infusion of gene-modified cells
Molecular characterisation of gene transfer	Quantification of transgene copy numbers is determined on sorted cell populations by real-time PCR methodology. Detailed integration analysis may be used to investigate specific clonal expansions.	until 5 years post-infusion of gene-modified cells
Normalisation of nutritional status, growth, and development	Normalisation of nutritional status, growth, and development will be assessed at each follow-up visit by the investigator through clinical examinations.	until 5 years post-infusion of gene-modified cells

Collaborators and Investigators

• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust

Publications and helpful links

General Publications

• 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 Mar;16(3):590-8. doi: 10.1038/sj.mt.6300393. Epub 2008 Jan 8.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: July 29, 2010
• First Submitted That Met QC Criteria: August 3, 2010
• First Posted (Estimate): August 4, 2010

Study Record Updates

• Last Update Posted (Actual): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 31, 2017
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: X-linked severe combined immunodeficiency, gene therapy; Patients will be enrolled following diagnosis and referral to Great Ormond Street Immunology Service.
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency; X-Linked Combined Immunodeficiency Diseases
• Other Study ID Numbers: 06MI10

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No