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

Study Overview
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Brief Summary
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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.

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

Conditions
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X-linked Severe Combined Immunodeficiency

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Diagnosis of classical SCID-X1 based on immunophenotype (absent, or reduced numbers of non-functional T lymphocytes) and confirmed by DNA sequencing Parental/guardian voluntary consent Boys between the ages of 0 and 16

Ages Eligible for Study
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Maximum Age: 16 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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X-linked severe combined immunodeficiency, gene therapy, Patients will be enrolled following diagnosis and referral to Great Ormond Street Immunology Service.