Base Editing Hematopoietic Stem Cell and T Cell Gene Therapy for CD40L-HyperIgM Syndrome: Single Patient Study

Study Description: This is a single participant gene therapy study to provide a participant with CD40L c.658C\>T; p.Q220X-Hyper IgM syndrome with autologous base-edited hematopoietic stem/progenitor cells (HSPC) and base-edited T cells (BE T). The study hypothesis is that base edited HSPCs will be repaired efficiently and safely to restore CD40L expression and improve immune function long term. BE T cells will provide functional T cells to support subject against immunodeficiency and lymphopenia. The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan administered once daily for 2 days with a daily target AUC of 4500 micromol\*min/L or a cumulative AUC of 9000 micromol\*min/L (approximately 6 mg/kg) and serotherapy (alemtuzumab (Campath)) 10 mg/m\^2 total dose divided over 3 days by subcutaneous injection on days -21, -20, and -19. Following infusion, the participant will be evaluated at months 3, 6, 9, 12, 18, 24. Long-term annual follow up will be performed on a separate protocol. Base edited autologous T cells will be administered at 2 weeks following BE HSPC infusion that function as 'donor lymphocyte infusions' to protect the patient from the diseaserelated T-cell immunodeficiency and alemtuzumab-related lymphopenia. Subsequent doses of BE T cells may be infused monthly as indicated to achieve T cell reconstitution for treatment of infections. Objectives: * Primary Objective: To determine the safety and efficacy of BE HSPC CD40L and BE T cells. * Secondary Objectives: To determine restoration of CD40L expression and immune function * Exploratory Objectives: * Assess for potential unintended edits * Kinetics of immune reconstitution Endpoints: * Primary Endpoint: * Efficacy determined by percentages of corrected alleles * Safety determined by toxicities related to infusion of Study Cell Product * Secondary Endpoints: * Level of CD40L expression in peripheral blood T cells * IgG production * Response to immunization * Exploratory Endpoints: * Repeat WES at 24 months after study cell product infusion * Evaluate for gene correction levels in peripheral blood CD34s and isolated immune cell lineages