Lentiviral Gene Therapy for p47 AR-CGD

Inclusion criteria

• p47 AR-CGD patients > 23 months of age
• Molecular diagnosis confirmed by Deoxyribonucleic acid (DNA) sequencing and supported by laboratory evidence for absent or reduction > 95% of the biochemical activity of the NAHPD-oxidase
• At least one prior, ongoing or refractory severe infection and/or inflammatory complications requiring hospitalisation despite conventional therapy
• No 10/10 human leukocyte antigen (HLA)-matched donor available after initial search of National Marrow Donor Program (NMDP) registries performed within the last year
• No co-infection with Human Immunodeficiency Virus (HIV) or hepatitis B virus (HBsAg positive) or hepatitis C virus (HCV ribonucleic acid (RNA) positive), Cytomegalovirus (CMV), adenovirus, parvovirus B 19 or toxoplasmosis
• Written informed consent for adult patient
• Parental/guardian and, where appropriate, child's signed consent/assent

Exclusion criteria

• Age ≤ 23 months or > 35 kg body weight
• 10/10 HLA identical (A,B,C,DR,DQ) family or unrelated adult donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure
• Contraindication for leukapheresis (Haemoglobin <8g/dl, cardiovascular instability, severe coagulopathy)
• Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial.

a) Haematologic i) Anaemia (hemoglobin < 8 g/dl). ii) Neutropenia (absolute granulocyte count <1,000/mm3 iii) Thrombocytopenia (platelet count < 150,000/mm3). iv) Prothrombin Time (PT) or Partial thromboplastin time (PTT) > 2 X the upper limits of normal (ULN) (patients with a correctable deficiency controlled on medication will not be excluded).

v) Cytogenetic abnormalities known to be associated with haematopoietic defect on peripheral blood or bone marrow.

b) Infectious i) Evidence of infection with HIV-1 and -2, hepatitis B, Hepatitis C, adenovirus, parvovirus B 19 or toxoplasmosis within 8 weeks prior to mobilisation/pheresis or bone marrow harvest. CMV infection is allowable as long as the infection is under control.

c) Pulmonary i) Resting O2 saturation by pulse oximetry < 90% on room air. d) Cardiac i) Abnormal electrocardiogram (ECG) indicating cardiac pathology. ii) Uncorrected congenital cardiac malformation with clinical symptomatology. iii) Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, iv) Hypotension. v) Poor cardiac function as evidenced by Left Ventricular Ejection Fraction (LVEF) < 40% on echocardiogram.

e) Neurologic i) Significant neurologic abnormality by examination. ii) Uncontrolled seizure disorder. f) Renal i) Renal insufficiency: serum creatinine greater than or equal to 1.5 mg/dl, or greater than or equal to 3+ proteinuria ii) Abnormal serum sodium, potassium, calcium, magnesium at grade III or IV according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 g) Hepatic/GI: i) Serum transaminases > 5X the upper limit of normal (ULN). ii) Serum Bilirubin > 2X ULN. iii) Serum Glucose > 1.5x ULN. h) Oncologic i) Evidence of active malignant disease

• General

• Expected survival < 6 months.
• Major congenital anomaly.
• Ineligible for autologous Haematopoietic Stem Cell Transplant (HSCT) by the criteria at the clinical site.
• Contraindication for administration of conditioning medication
• Known sensitivity to Busulfan
• Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells
• Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period
• Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion
• Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements.