Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency

NCT ID: NCT03601286

Last Updated: 2023-10-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-21
• Study Completion Date: 2026-08-31

Brief Summary

Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. SCID arises from a variety of molecular defects which affect lymphocyte development and function. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. SCID-X1 is caused by defects in the common cytokine receptor gamma chain, which was originally identified as a component of the high affinity interleukin-2 receptor (IL2RG).

Allogeneic haematopoietic stem cell transplantation (HSCT), which replaces the patient's bone marrow with that of a healthy donor, is the only treatment that definitively restores the normal function of the bone marrow. HSCT is the first choice of treatment for patients with signs of bone marrow failure and a fully-matched related donor. However, patients without a fully-matched related donor have much worse overall outcomes from HSCT.

This study will investigate whether patients with SCID-X1 without a fully matched related donor may benefit from gene therapy. To do this the investigators propose to perform a phase I/II clinical trial to evaluate the safety and efficacy (effect) of gene therapy for SCID-X1 patients using a lentivirus delivery system containing the IL2RG gene. Up to 5 eligible SCID-X1 patients will undergo mobilisation and harvest of their haematopoietic stem precursor cells (HPSCs). In the laboratory the disabled lentivirus will be used to insert a normal human IL2RG gene into the patient's harvested HPSCs. Patients will receive chemotherapy conditioning prior to cell infusion, in order to enhance grafting. The genetically corrected stem cells will then be re-infused into the patient. Patients will be followed up for 2 years. This trial will determine whether gene therapy for SCID-X1 using a lentiviral vector is safe, feasible and effective

Conditions

Severe Combined Immunodeficiency, X-Linked

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lentiviral vector transduced CD34+ cells

Single arm, non-randomised cohort of up to 5 patients with X-linked Severe Combined Immunodeficiency. CD34+ cells will be collected via bone marrow harvest or leukapheresis. The collected cells will then be purified, cultured and transduced with the G2SCID lentiviral vector. Transduced cells will be frozen. A minimum of 2.5 x 106/kg CD34+ cells after transduction with a minimum transduction efficiency of 0.7 copies/cell is required for infusion into the patient. The patient will receive non-myeloablative conditioning with intravenous busulfan the two or three days prior to cell infusion. The frozen cells will be thawed on the day of infusion and the cells administered according to hospital procedures. The patient will remain in hospital until sufficient cover of the patient's immune system

Group Type: EXPERIMENTAL

Lentiviral vector transduced CD34+ cells

Intervention Type: DRUG

Gene therapy for X-linked Severe Combined Immunodeficiency will be performed by introduction a normal copy of the IL2RG gene into the blood forming stem cells (CD34+ cells) of the patient's bone marrow by using a type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient.

Interventions

Lentiviral vector transduced CD34+ cells

Gene therapy for X-linked Severe Combined Immunodeficiency will be performed by introduction a normal copy of the IL2RG gene into the blood forming stem cells (CD34+ cells) of the patient's bone marrow by using a type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient.

Intervention Type: DRUG

Other Intervention Names

G2SCID lentiviral vector transduced CD34+ cells

Eligibility Criteria

Inclusion Criteria

1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG

2. Lack of an HLA identical (A, B, C, DR, DQ) related donor

3. Age <5 years

4. Signed informed consent

5. Documentation of willingness to follow up for 15 years post-infusion

6. If the patient has previously undergone allogeneic transplant or gene therapy, insufficiency of graft-derived T cell engraftment must be documented.

7. Age at least 8 weeks of age by the time of busulfan administration

Exclusion Criteria

1. Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).

1. Mechanical ventilation including continuous positive airway pressure

2. Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL

3. Shortening fraction on echocardiogram <25% or ejection fraction <50%

4. Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence

2. Uncontrolled seizure disorder

3. Encephalopathy

4. Documented coexistence of any disorder known to affect DNA repair

5. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease

6. Patients with evidence of infection with HIV-1

7. Previous allogeneic transplant with cytoreductive chemotherapy

8. Major (life-threatening) congenital anomalies. Examples of "major (life-threatening) congenital anomalies" include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.

9. Other conditions which in the opinion of the P.I. or Co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient's inability to follow the protocol. These may include for example clinical ineligibility to receive anaesthesia, severe deterioration of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship.

• Minimum Eligible Age: 8 Weeks
• Maximum Eligible Age: 5 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Great Ormond Street Hospital for Children NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Claire Booth, Dr

Role: PRINCIPAL_INVESTIGATOR

UCL Great Ormond Street Institute of Child Health

Adrian Thrasher, Prof

Role: PRINCIPAL_INVESTIGATOR

UCL Great Ormond Street Institute of Child Health

Locations

Great Ormond Street Hospital for Children NHS Foundation Trust

London, Greater London, United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Claire Booth, Dr

Role: CONTACT

c.booth@ucl.ac.uk

0207 905 2198

Karen Oprych, Dr

Role: CONTACT

k.gladwin@ucl.ac.uk

Facility Contacts

Claire Booth, MBBS, MRCPCH, MSc, PhD

Role: primary

c.booth@ucl.ac.uk

Karen Oprych, PhD

Role: backup

k.gladwin@ucl.ac.uk

Other Identifiers

16IC17

Identifier Type: -

Identifier Source: org_study_id