- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00028236
Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
Ex Vivo Retroviral Gene Transfer For Treatment of X-Linked Severe Combined Immunodeficiency (XSCID)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is a Phase I/II clinical trial of ex vivo hematopoietic stem cell (HSC) gene therapy for X-linked severe combined immunodeficiency (XSCID). XSCID results from defects in the IL2RG gene encoding the common gamma chain (gc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. XSCID patients generally lack T-lymphocytes and NK cells, and their B-lymphocytes fail to make essential antibodies. XSCID is fatal in infancy without immune reconstitution, such as by allogeneic bone marrow transplantation (BMT). However, many transplanted patients achieve only partial immune reconstitution, and consequently have recurrent infections, autoimmunity and/or poor growth. Recent successful retroviral gene therapy instead of BMT for infants with XSCID indicates that ex vivo gene therapy can provide clinical benefit to XSCID patients.
We will enroll eight older XSCID patients (1.5-20 years-old; greater than or equal to 12 kg body weight), who have had attempted BMT, but who have persistent T-lymphocyte and B-lymphocyte impairments that compromise their quality of life. Prior to enrollment, these subjects will have had autologous CD34+ HSC mobilized by treatment with granulocyte colony stimulating factor (G-CSF), collected from peripheral blood by apheresis, immune selected and cryopreserved in sufficient numbers to achieve entry criteria (greater than or equal to 1.0 x 10(6) CD34+ HSC/kg body weight). HSC procurement will be conducted under a separate, approved and active NIH protocol, 94-I-0073, 'Recruitment of peripheral blood hematopoietic progenitors by granulocyte colony stimulating factor [G-CSF]'.
Autologous CD34+ HSC will be transduced ex vivo with the gibbon ape leukemia virus (GALV) envelope-pseudotyped, replication-defective, murine onco-retrovirus vector, MFGS-gc that encodes the common gamma chain. Transductions will occur in flexible gas-permeable plastic containers using serum-free medium supplemented with 1% human serum albumin and five recombinant growth factors (50 ng/mL Flt3-L, 50 ng/mL SCF, 50 ng/mL TPO, 25 ng/mL IL-6, and 5 ng/mL IL-3). Subjects who are older than the age of 3 will be given a conditioning regimen consisting of Fludarabine and Busulfan then they will receive a single infusion of transduced HSC. Prior to the chemotherapy, and following the infusion of the cells, the same patients will also be given Keratinocyte growth factor (KGF), also known as palifermin. Subjects will be monitored for safety and efficacy; the latter evidenced by new development of autologous transduced lymphocytes with functional gc. Study endpoints are (1) efficient and safe clinical-scale transduction of HSC from post-BMT XSCID subjects; (2) administration of a nonmyeloablative conditioning regimen to improve engraftment; (3) administration of transduced HSC to eight subjects; (4) administration of KGF to improve thymic function post transplant to improve T cell development; and (5) appropriate follow up of treated subjects to monitor vector sequence distribution, gc expression in hematopoietic lineages, and lymphocyte numbers and function; as well as general health and immune status.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Maryland
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Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
- INCLUSION CRITERIA:
Patients must have XSCID as defined by either a deleterious mutation in IL2RG, the absence of or less than 5% of normal detectable gc protein, or evidence of functionally defective gc protein.
Patients must be between 1.5 and 20 years of age.
Patients must weigh at least 12 kg.
Patients will have evidence of combined B-cell and T-cell immune deficiency over at least a 6 month period despite previous allogeneic BMT at least 12 months prior to study entry. T-cell immune deficiency is defined as one or more of the following: Total T-cell count less than 500/ul; less than 50% of normal value for in vitro mitogen stimulation; or absent proliferation in vitro to antigens. B-cell immune deficiency is defined as one or more of the following: IgM, IgA or IgE values which are 2 or more standard deviations below the established value for normal, IgG values falling to less than 30% of normal during unintended interruptions or delay in the periodic administration of IVIG; or documented failure to respond to a specific antigen challenge.
Patients must have less than or equal to 3% of their mobilized CD34+ cells deriving from their allogeneic bone marrow donor.
Willingness to remain hospitalized for several days to several weeks.
Have a primary care physician at home.
Consent to permit blood and/or tissue samples for storage.
EXCLUSION CRITERIA:
Any current or preexisting hematologic malignancy.
Current treatment with any chemotherapeutic agent.
Current treatment with any immunosuppressive agent, excluding corticosteroids.
Documented HIV-1 infection.
Documented Hepatitis B infection.
Childhood malignancy (occurring before 18 years of age) in the patient or a first degree relative, or known genotype of the subject conferring a predisposition to cancer.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
Collaborators and Investigators
Publications and helpful links
General Publications
- 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.
- Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147-57. doi: 10.1016/0092-8674(93)90167-o.
- Puck JM, Deschenes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, Henthorn PS. The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993 Aug;2(8):1099-104. doi: 10.1093/hmg/2.8.1099.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 020057
- 02-I-0057
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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