Lentiviral Gene Therapy for p47 AR-CGD

Chronic Granulomatous Disease (CGD) is a rare inherited disorder in which patients suffer from severe infection and inflammation. The first indications of disease usually appear in early childhood. The basic defect has been found to be lie in specialised white blood cells called phagocytic cells, which are responsible for engulfing and destroying germs. In CGD, there is a defect in an enzyme (known as the NADPH-oxidase) that is responsible for generating bleach like substances that are important for killing some important germs. In one form of the disease known as p47 AR-CGD (which accounts for 30% of patients), there are defined mistakes in a gene called NCF1. This gene is needed to form a key component of NADPH-oxidase.

In many cases, patients can be protected from infection by constant intake of antibiotics. However, in others potentially life-threatening infections break through. In some cases patients also develop serious inflammation requiring high doses of drugs such as steroids. CGD can be cured by bone marrow transplant and the best results are available when a matched sibling donor is available. Transplant from unmatched donors have a much worse outcome and as a result alternative treatments for patients without a matched donor are highly desirable.

Gene therapy of p47 AR-CGD is performed by introducing a normal copy of the human NCF-1 gene into the blood forming stem cells in the patients' bone marrow by using a gene carrier (in this study called a lentiviral vector). After treatment of the bone marrow cells in a specialised laboratory they are given back to the patient and will grow into functional phagocytic cells. There have been no previous clinical trials for patients with p47 AR-CGD however there have been previous gene therapy clinical trials conducted in the UK for patients with the most common form of CGD, known as X-CGD.


Eligibility Criteria:
Inclusion Criteria:

1. p47 AR-CGD patients \> 23 months of age
2. 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
3. At least one prior, ongoing or refractory severe infection and/or inflammatory complications requiring hospitalisation despite conventional therapy
4. 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
5. 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
6. Written informed consent for adult patient
7. Parental/guardian and, where appropriate, child's signed consent/assent

Exclusion Criteria:

1. Age ≤ 23 months or \> 35 kg body weight
2. 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
3. Contraindication for leukapheresis (Haemoglobin \<8g/dl, cardiovascular instability, severe coagulopathy)
4. 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
5. General

   1. Expected survival \< 6 months.
   2. Major congenital anomaly.
   3. Ineligible for autologous Haematopoietic Stem Cell Transplant (HSCT) by the criteria at the clinical site.
   4. Contraindication for administration of conditioning medication
   5. Known sensitivity to Busulfan
6. Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells
7. Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period
8. 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
9. Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements.