Gene Therapy Approach for Chronic Granulomatous Disease

• INCLUSION CRITERIA:

Male or female; if concurrent infection is present or there has been recent multiple relapse of infection with likely potential for additional relapse, then subjects may include minors 5 to 17 years of age and adults of any age; if no concurrent infection is present at enrollment then subjects must be adults of any age or minors 16-17 years of age.

History of severe infections (two infections requiring hospitalization and intravenous antibiotics).

Confirmed diagnosis of Chronic Granulomatous Disease as defined by less than 2 percent of normal oxidant production by all circulating neutrophils.

Confirmed CGD genetic subtype of gp91(phox)-deficiency or p47(phox)-deficiency as defined by the absence or deficiency of the phox subunit protein using an antibody detection assay (western blot, ELISA, or flow cytometry) of patient granulocytes.

Subjects without current active infection or recent multiple recurrence of infections must have adequate organ function as defined by renal function (creatinine less than or equal to 2 mg per dl; less than or equal to 2+ proteinuria); hepatic function (bilirubin less than or equal to 1.5 mg per dl; prothrombin time less than or equal to 1.3 x control); hematologic function (WBC greater than or equal to 2500 per mm(3); granulocytes greater than or equal to 1200 per mm(3); platelet greater than or equal to 100,000; hematocrit greater than or equal to 26).

Successful mobilization as demonstrated by greater than or equal to 10 CD34+ cells per microliter in peripheral blood on the day of the planned apheresis.

Must weigh at least 15 kg.

If a female of childbearing potential, then the patient must have a negative serum pregnancy test within one week of beginning administration of combination flt3L and GM-CSF or single agent G-CSF. Both male and female must use a barrier or other effective form of contraception during marrow growth factor administration and for at least three months following the last reinfusion of the transduced CD34 + PBHP.

Written informed consent, conforming to institutional guidelines obtained from patient (and/or parent or guardian if a minor).

EXCLUSION CRITERIA:

Female patients who are pregnant or lactating as determined by history and/or positive pregnancy test.

While patients may have an active infection under treatment and still be included in the study, patients are excluded who are in shock, manifested by severe hypotension (less than 100 systolic or less than 60 diastolic) or severe hypoxia requiring mechanical ventilation and piO(2) greater than 40 percent.

HIV antibody/antigen positive or hepatitis B, C antigen positive. (Exceptions to this exclusion may be made on a case by case basis in consultation with the Transfusion Medicine staff where severe bacterial or fungal infection is present).

Any condition which in the opinion of the attending physician or the Apheresis Unit staff contraindicates apheresis procedures, such as cardiovascular instability, severe anemia (hematocrit/hemoglobin below less than 26/8), in adequate venous access, and/or severe coagulation disorder. Patients with severe infection who have a hematocrit/hemoglobin below less than 26/8 and might benefit clinically from participation in this protocol may undergo apheresis at the discretion of the physician in charge of the Apheresis Unit. In that setting RBC transfusion may be used to raise the hematocrit/hemoglobin to a level safe for apheresis.

Any condition which in the opinion of the principal investigator or the patient's primary physician contraindicates administration of bone marrow growth factors at the indicated doses, such as preexisting severe autoimmune vasculitis or other severe autoimmune inflammatory conditions where augmentation of immune responses or infiltration of granulocytes may exacerbate the condition.

History of severe allergic reactions to study medication Currently pregnant or breastfeeding Recent participation in another clinical trial within the last 30 days Presence of uncontrolled medical conditions that could affect safety