Gene therapy for X-linked severe combined immunodeficiency using targeted busulfan conditioning

Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning

This study is testing a new gene therapy for patients with X-linked severe combined immunodeficiency to see if it can help their immune system work better after a special treatment to prepare their bodies.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 0 Years to 5 Years
• Sex: Male
• Sponsor: Boston Children's Hospital (Academic / other)
• Locations: 4 sites (Los Angeles, California and 3 other locations)
• Trial ID: NCT03311503 on ClinicalTrials.gov

What this trial studies

This phase I/II open-label, multi-center study aims to treat patients with X-linked severe combined immunodeficiency (SCID-X1) through a single infusion of autologous CD34+ cells that have been genetically modified using a lentiviral vector. Patients will first undergo low-dose targeted busulfan conditioning to prepare their bodies for the infusion. The study will enroll up to 10 patients and will monitor their health and immune function for two years post-infusion, with long-term follow-up extending to 15 years. Key objectives include assessing event-free survival and T cell immune reconstitution, along with safety and efficacy measures.

Who should consider this trial

Good fit: Ideal candidates are children aged 5 years or younger diagnosed with SCID-X1 and lacking an HLA identical related donor.

Not a fit: Patients with active, therapy-resistant infections or those older than 5 years will not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve immune function and quality of life for patients with SCID-X1.

How similar studies have performed: Other studies using gene therapy for SCID have shown promising results, indicating potential success for this approach.

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 old or younger 4. Signed informed consent 5. Documentation of willingness to follow up for 15 years post-infusion as currently required by the FDA 6. If the patient has previously undergone allogeneic transplant, lack of donor T cell engraftment must be documented.

7\. Age at least 8 weeks 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. 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.
8. 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 anesthesia, severe deterioriation 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

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Where this trial is running

Los Angeles, California and 3 other locations

• Mattel Children's Hospital - UCLA — Los Angeles, California, United States (Recruiting)
• Emory University/Childrens Healthcare of Atlanta — Atlanta, Georgia, United States (Recruiting)
• Boston Childrens Hospital — Boston, Massachusetts, United States (Recruiting)
• Cincinnati Children's Hospital Medical Center — Cincinnati, Ohio, United States (Recruiting)

Study contacts

• Study coordinator: Colleen Dansereau

Conditions Severe Combined Immunodeficiency, X Linked; Gene Therapy; lentiviral; Gene therapy; busulfan