Protocol Number: 02-I-0057

Title:

Ex Vivo Retroviral Gene Transfer For Treatment of X-Linked Severe Combined Immunodeficiency (XSCID)

Number:

02-I-0057

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 six older XSCID patients (2-20 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 ymphocytes. Each XSCID patient enrolled in the study will receive a single dose of his own cells that have been modified by the GALV MFGS-gc treatment. 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 correction of cells from XSCID patients; (2) administration of treated cells to six subjects: and (3) year follow-up of the treated subjects to see how many of their cells have taken up the correct copy of the gene, how many new T and B lymphocytes express a normal common gamma chain, and whether the patients' immune function and general health improve.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

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 2 and 20 years of age.

Patients must weigh at least 15 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 18 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 less than or equal to 3% of their mobilized CD34+ cells deriving from their allogeneic bone marrow donor.

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.

Special Instructions: Currently Not Provided

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

Recruitment Keywords:

X-Linked Severe Combined Immune Deficiency (XSCID)

XSCID

Immune Deficiency

Immune System

Conditions:

Severe Combined Immunodeficiency

Investigational Drug(s):

Gamma Chain Transduced CD34+ Cells

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease

Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans

The interleukin-2 receptor gamma chain maps to Xq131 and is mutated in X-linked severe combined immunodeficiency, SCIDX1

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