National Institute of Allergy and Infectious Diseases (NIAID)
Background: Chronic granulomatous disease (CGD) is a rare immune disorder caused by a mutation in the CYBB gene. People with CGD have white blood cells that do not work properly and are at greater risk of getting infections. Researchers want to know if gene therapy using the patient's own base-edited stem cells can improve the white cells' functioning and result in fewer CGD-related infections. Objective: To learn if base-edited stem cells will correct the white blood cells in people with CGD. Eligibility: Males aged 18 years and older with X-linked CGD. Design: This is a non-randomized study. Participants with the specific mutation under study will be screened during the initial phase. During the development phase, participants will undergo apheresis to collect stem cells for base-editing correction of the mutation. During the treatment phase, participants will first receive Campath (alemtuzumab) to reduce the risk of an immune response to the new protein expressed by the base-edited cells. This will be followed by conditioning chemotherapy with busulfan and subsequent infusion of the base-edited stem cells. Participants will be maintained on sirolimus to further reduce the risk of an immune response to the new protein expressed by the base-edited cells. Follow-up visits will continue for 15 years.
Study Description: Open-label, phase 1/2 trial to determine the safety, and efficacy of a single infusion of base-edited (BE) autologous hematopoietic stem and progenitor cells (HSPCs) for treatment of X-linked chronic granulomatous disease (X-CGD). Base editing is performed to repair CYBB missense gene mutations (eg, CYBB c.676C\>T). The study hypotheses are that 1) base editing can efficiently repair gene mutations in HSPCs; and 2) BE HSPCs can engraft and differentiate into functional phagocytes with restored nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. During the…
* INCLUSION CRITERIA: -\>= 18 years of age. * Confirmed CYBB c.676 C\>T mutation. * Male patients. * Clinically stable and eligible to undergo apheresis and conditioning chemotherapy. -\>=5 x 10\^6 cryopreserved cells/kg body weight available for study product manufacturing. * History of at least one prior serious infection or inflammatory complication requiring hospitalization despite conventional therapy. * In the experience of a qualified clinical investigator, the patient has a poor prognosis. * Able and willing to use a highly effective method of contraception, AND partner has commu…
Immunomodulating agent: Daily subcutaneous administration beginning Day -9 for 5 days to reduce the risk of an immune response to the protein expressed by the BE HSPCs.
Immunomodulating agent: Daily oral dosing beginning Day -1 for approximately 3 to 6 months to reduce the risk of an immune response to the protein expressed by the BE HSPCs.
Investigational/Study Agent: Base-edited autologous CD34 plus hematopoietic stem and progenitor cell product. The product is administered intravenously as a single infusion. This product is under an IND.
Transplant Conditioning Agent: An alkylating chemotherapy drug to enhance engraftment of the study agent (base-edited stem cells). Conditioning will be given intravenously over 3 days with an approximate total dose of 12mg/kg. Drug levels obtained will be obtained to achieve the targeted total busulfan AUC of 65,000 ng/mL x hr.
Mucositis Prophylaxis Agent: Intravenous infusion of keratinocyte growth factor (Palifermin) at 60 mcg/kg/day before (Days -7 to Day -5 administration of busulfan and (Days 1 to 3) post-busulfan administration to prevent oral mucositis.
Stem Cell Mobilizing Agent: Subcutaneous administration for 6 consecutive days. It is necessary to mobilize stem cells for collection.
Stem Cell Mobilizing Agent: Subcutaneous administration for 2 consecutive days to improve stem cell collection.