National Institute of Allergy and Infectious Diseases (NIAID)
Background: X-linked hyper-IgM (HIGM) syndrome is caused by a mutation in the CD40 ligand (CD40L) gene. People with this disease have white blood cells that do not work properly. These people are at risk of severe infections and autoimmune diseases. Researchers want to know if these base-edited stem cells and T cells can help people with CD40L-HIGM syndrome. Objective: To test base-edited stem cells and base-edited T cells in 1 person with CD40L-HIGM syndrome. Eligibility: A single male with CD40L-HIGM syndrome. Design: A single participant is planned to receive a single dose of edited stem cells and supportive treatment with edited T cells. Participant stem and T cells will undergo base editing to repair the mutation. In preparation for the gene therapy, the participant will receive busulfan chemotherapy and alemtuzumab. After treatment, the participant will have follow-up visits every few months in the first 2 years after treatment. Long-term visits will continue annually for 15 years.
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…
* INCLUSION CRITERIA: This study is a single participant research study and to receive the study product, he needs to meet the following criteria: * Provision of signed and dated informed consent form * Stated willingness to comply with all study procedures and availability for the duration of the study * Has CD40L Q220X mutation * Defective class switching * Liver abnormalities (transaminases\>UL) * Portal hypertension * Consensus from Hepatology Consult to receive myeloid conditioning * Ability to take oral medication and be willing to adhere to the intervention regimen * Use of condoms or…
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning.
Serotherapy agent, 10 mg/m\^2 on days -21, -20 and -19
Immunophilin drug, will start on day -1, targeting a trough level between 4-12 ng/mL.
Mucositis prophylaxis agent, will be administered at 60 mcg/kg/day for 3 days before initiation of busulfan (days -6 to -4), as well as for the 3 days following study agent administration (days 1 to 3).
Myeloid conditioning agent, administered once daily (3 mg/kg) x 2 days, targeting a daily AUC of 4500 micromol\*min/L or a cumulative AUC of 9000 micromol\*min/L for the 2 days of therapy, if levels are available
The secondary study cell product is base edited autologous which will be administered as a one-time infusion two weeks following the infusion of the base-edited autologous HSPCs.
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