base editing hematopoietic stem cell gene therapy for cd40l-hyperigm syndrome: single patient study

Conditions: CD40L-HyperIgM Syndrome

Summary: background: x-linked hyper igm (higm) syndrome is caused by a mutation in the 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. stem cell transplant can cure this disease. however, transplanting stem cells donated by other people can have serious complications. another approach is gene therapy; this treatment repairs the mutation in a person's own stem cells by base editing. researchers want to know if these base-edited stem cells can help people with cd40l-higm syndrome. objective: to test base-edited stem cell transplant in 1 person with cd40l-higm syndrome. eligibility: a male with cd40l-higm syndrome. design: participant will be screened. tests will include medically indicated imaging scans, blood tests, and a sample of tissue and fluid (biopsy) may be taken from the bone marrow. participant may undergo apheresis to collect stem cells. the collected stem cells will undergo base editing to repair the mutation. for treatment, participant will be admitted to the hospital for 5 weeks or more. for 2 weeks he will receive drugs to prepare his body for receiving the stem cells. after receiving the edited stem cells, he will remain in the hospital until his cell counts recover. participant will have follow-up visits every few months in the first 2 years after treatment. the bone marrow biopsy will be repeated after 2 years. 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). the study hypothesis is that base edited hspcs will be repaired efficiently and safely to restore cd40l expression and improve immune function. 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. objectives: * primary objective: to determine the safety and efficacy of be hspc cd40l * 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

Eligibility criteria:
* inclusion criteria this study is a single participant research study and to receive the study product, he needs to meet the following criteria: 1. provision of signed and dated informed consent form 2. stated willingness to comply with all study procedures and availability for the duration of the study 3. has cd40l q220x mutation 4. defective class switching 5. liver abnormalities (transaminases\>ul) 6. portal hypertension 7. consensus from hepatology consult to receive myeloid conditioning 8. ability to take oral medication and be willing to adhere to the intervention regimen 9. use of condoms or other methods to ensure effective contraception with partner 10. ability of subject to understand and the willingness to sign a written informed consent document exclusion criteria an individual who meets any of the following criteria will be excluded from participation in this study: 1. known allergic reactions to components of the be hspc study product 2. febrile illness within two weeks of hospital admission for treatment 3. unwilling to submit their information as part of the alemtuzumab \[campath(r)\] distribution program application or the distribution program committee has determined the participant is not qualified to receive alemtuzumab. note: alemtuzumab (campath) (iv formulation) is no longer distributed commercially. to receive product, the physician must contact the program for the participant. if the participant is not willing to consent to submit their info (demographics, contact information, and rationale for use) to the program such that we can obtain the drug, then we cannot proceed with conditioning; therefore no transplant will occur on this protocol. http://www.campath.com/ co-enrollment guidelines: co-enrollment in other trials is restricted, other than enrollment on observational studies and nih protocols 94-i-0073 and 05-i-0213. consideration for coenrollment in trials evaluating the use of a licensed medication will require the approval of the principal investigator in consultation with the medical monitor. study staff should be notified of co-enrollment on any other protocol as it may require the approval of the principal investigator (in consultation with the medical monitor).

Keywords: base editing gene editing