Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)
- X-linked severe combined immunodeficiency (XSCID) is caused by a genetic abnormality in the IL2RG gene that affects the growth and development of immune cells such as white blood cells. Individuals with XSCID have difficulty fighting infections, which may lead to chronic or severe illness and death. The primary treatment for XSCID is replacement of the patient s immune system with a normal immune system through a bone marrow transplant. The best outcomes in transplant patients are achieved when the bone marrow comes from a sibling, but parents and matching unrelated donors can provide bone marrow for transplant as well. However, because these transplant procedures are not always effective, researchers are studying gene transfer treatment as an approach to treating XSCID.
- Lentiviral gene transfer treatment uses good genes to replace defective genes. A lentivirus is a virus that has been modified to carry corrected genes into the blood through corrected stem cells. By collecting an individual s stem cells and modifying them with a lentivirus, the gene-corrected cells can be returned into the blood to help produce normal healthy immune cells. Gene transfer treatment with lentivirus vector has been used in humans but has never been studied in patients with XSCID.
- To determine the safety and effectiveness of lentiviral gene transfer as a treatment for children and adolescents with X-linked severe combined immunodeficiency.
- Children and adolescents between 2 and 20 years of age who have XSCID related to a defect in the IL2RG gene and who are not currently under treatment with strong immune-modulating or chemotherapy drugs.
- Participants will be screened with a medical history, physical examination, blood and urine tests, and bone marrow samples to collect stem cells for the procedure.
- Participants will be admitted to the National Institutes of Health Clinical Center 11 to 12 days before receiving gene-corrected blood stem cells.
- Participants will receive palifermin for 3 days, followed by busulfan for 2 days. Palifermin will help prevent side effects from busulfan, and busulfan will help suppress the immune system in preparation for the gene transfer. Participants will have regular blood tests during this preparation period.
- Participants will receive a transfer of their corrected blood stem cells about 36 to 48 hours after the second dose of busulfan. The cells will be injected over 5 to 10 minutes under close monitoring.
- The day after the transfer, participants will have 3 more days of palifermin.
- Participants will remain in the hospital for several weeks, possibly as long as 6 weeks, while the response to treatment is monitored.
- Participants will continue to be monitored for immune function and possible side effects after leaving the hospital, and will be followed for up to 15 years after the procedure to evaluate the long-term effects of gene transfer therapy. The monitoring will involve regular physical exams and blood samples.
X-linked Severe Combined Immunodeficiency
Gamma C-Deficient SCID
Other: Gene-modified CD34+ Hematopoietic stem cells
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Lentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age With X-Linked Severe Combined Immunodeficiency|
- The primary objective is to assess the efficacy of immune reconstitution in XSCID patients transplanted with autologous CD34 plus cells that have been transduced with a self-inactivating lentiviral vector expressing a Gamma C gene. [ Time Frame: Primary endpoint evaluation at 2 years ] [ Designated as safety issue: Yes ]
- To determine the incidence of serious side effects due to lentiviral gene transfer. [ Time Frame: Out to at least 5 years after treatment, though periodic follow-up will continue for 15 years as per FDA Guidance ] [ Designated as safety issue: Yes ]
- To determine the integration site distribution of the lentiviral vector in reconstituted peripheral blood cells. [ Time Frame: At intervals out to at least 5 years after treatment ] [ Designated as safety issue: No ]
|Study Start Date:||October 2010|
|Estimated Study Completion Date:||December 2025|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
Other: Gene-modified CD34+ Hematopoietic stem cells
Infusion of transduced autologous CD34+ Hematopoietic stem cellsDrug: Busulfan
Pre gene therapy conditioning regimen
This is a Phase I/II non-randomized clinical trial of ex vivo hematopoietic stem cell (HSC) gene transfer treatment for X-linked severe combined immunodeficiency (XSCID, also known as SCID-X1) using a self-inactivating lentiviral vector incorporating additional features to improve safety and performance. The study will treat 13 patients with XSCID who are between 2 and 30 years of age and who have clinically significant impairment of immunity. Patients will receive a total busulfan dose of 6 mg/kg/body weight to condition their bone marrow, and this will be followed by a single infusion of autologous transduced CD34 plus HSC. Patients will then be followed to evaluate engraftment, expansion, and function of gene corrected lymphocytes that arise from the transplant; to evaluate improvement in laboratory measures of immune function; to evaluate any clinical benefit that accrues from the treatment; and to evaluate the safety of this treatment. The primary endpoint of the study with respect to these outcomes will be at 2 years, though data relevant to these measures will be collected at intervals throughout the study and during the longer follow-up period of at least 15 years recommended by the FDA Guidance Gene Therapy Clinical Trials Observing Subjects for Delayed Adverse Events
Please refer to this study by its ClinicalTrials.gov identifier: NCT01306019
|Contact: April Engram||(301) firstname.lastname@example.org|
|Contact: Suk S De Ravin, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Suk S De Ravin, M.D.||National Institute of Allergy and Infectious Diseases (NIAID)|