Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)

NCT00028236 | Completed Phase 1

• 2 other identifiers: 02005702-I-0057
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

This is a clinical trial of gene therapy for X-linked severe combined immunodeficiency (XSCID), a genetic disease caused by defects in a protein called the common gamma chain, which is normally on the surface of immune cells called lymphocytes. XSCID patients cannot make T lymphocytes, and their B lymphocytes fail to make essential antibodies for fighting infections. Without T and B lymphocytes patients develop fatal infections in infancy unless they are rescued by a bone marrow transplant from a healthy donor. However, even transplanted patients may achieve only partial immune recovery and still suffer from many infections, auto-immunity and/or and poor growth. A recent, successful trial in France used gene therapy instead of bone marrow transplantation for infants with XSCID. This experience indicates that gene therapy can provide clinical benefit to XSCID patients. We will enroll eight older XSCID patients (1.5-20 years-old), who have previously received at least one bone marrow transplant, but still have poor T and B lymphocyte function that compromises their quality of life. Before enrollment, these subjects will have had some of their own blood-forming stem cells harvested and frozen in a blood bank. These cells have a defective gene, but a correct copy of the gene will be inserted while the cells are grown in sterile conditions outside the patient's body. To do this, the cells will be unfrozen and exposed for four days in a row to growth factors and particles of a retrovirus we have constructed and tested called "GALV MFGS-gc." Retrovirus particles will attach to the patient cells and introduce a correct copy of the common gamma chain gene into cells capable of growing into all types of blood cells, including T and B lymphocytes. XSCID patients who are enrolled in the study will receive a single dose of their own cells that have been modified by the GALV MFGS-gc treatment and also will be given another drug called palifermin to help prevent side effects from the chemotherapy and possibly try to improve the development of the T cells. After this, the patients will be monitored to find out if the treatment is safe and to see if their immune function improves. Study endpoints are (1) efficient and safe clinical-scale transduction of HSC from post-BMT XSCID subjects; (2) administration of a nonmyeloablative conditioning regimen in older patients to improve engraftment; (3) administration of a 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 the treated subjects to monitor vector sequence distribution, gc expression in hematopoietic lineages, and lymphoctye numbers and function as well as general health and immune status.

Conditions

Severe Combined Immunodeficiency

Keywords

Peripheral Blood Stem Cells; Common Gamma Chain (GC); Immune Reconstitution; T Lymphocytes; B Lymphocytes; X-Linked Severe Combined Immune Deficiency (XSCID); Gene Therapy; NK Cell; Bone Marrow Transplantation; Engraftment; XSCID; Immune Deficiency; Immune System

Interventions

Gene-Transduced Autologous CD34+ Stem Cells DRUG

Eligibility Criteria

• Age: 18 Months - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 10784449 BACKGROUND

• 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.

  PMID: 8462096 BACKGROUND

• 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.

  PMID: 8401490 BACKGROUND

MeSH Terms

Conditions

Severe Combined Immunodeficiency; X-Linked Combined Immunodeficiency Diseases; Immunologic Deficiency Syndromes

Condition Hierarchy (Ancestors)

Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immune System Diseases; Genetic Diseases, X-Linked

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: December 17, 2001
• First Posted: December 18, 2001
• Study Start: December 10, 2001
• Primary Completion: July 25, 2011
• Study Completion: July 25, 2011
• Last Updated: July 2, 2017

Record last verified: 2011-07-25

Locations

US (1)