CRISPR-Edited HLA Donor Kidney Transplant to Reduce Rejection Risk

Inclusion Criteria:

• Adult patients, age 16 to 85 years, with end-stage renal disease (ESRD) who arecandidates for kidney transplantation. This includes patients on dialysis orapproaching dialysis who have been evaluated and listed for transplant.

• Eligible for transplant surgery based on medical assessment (i.e., nocontraindications to major surgery and transplantation). The patient's overallhealth status must be sufficient to undergo the transplant procedure and therequired immunosuppression.

• Suitable donor organ available: A deceased-donor kidney that meets standardacceptable criteria for transplant (e.g., adequate organ function and anatomy) andis ABO blood type compatible with the recipient. The donor kidney must be allocatedto the trial and available for ex vivo gene editing prior to transplantation.

• Informed consent: The patient (or legally authorized representative) is able tounderstand the experimental nature of the study and has voluntarily signed theinformed consent form. The patient must be willing to comply with all studyprocedures, follow-up visits, and laboratory tests.

• Negative crossmatch (if applicable): No pre-existing anti-donor reactivity thatwould cause immediate graft failure. (All recipients should have a negative T and Bcell crossmatch with the donor organ prior to transplant, as per standard practice,to ensure no strong baseline donor-specific antibodies, especially against anyremaining donor HLA such as HLA-C.)

• Women of childbearing potential must have a negative pregnancy test and must agreeto use effective contraception during the study and for a period after (to bespecified, e.g., 1 year post-transplant), given the use of immunosuppressants andthe unknown effects of gene-edited organ transplantation on pregnancy. Men withpartners of childbearing potential should also agree to use contraception.

• High immunologic risk patients are eligible: Patients with high panel reactiveantibody (PRA) levels or a history of sensitization (from prior transplants, bloodtransfusions, or pregnancies) are allowed and even anticipated in this trial, as theintervention is designed to benefit patients with broad HLA sensitization. Forinstance, patients with calculated PRA > 80% (who have difficulty finding matcheddonors) can be included. (Such patients must still meet the crossmatch criterionabove - any existing antibodies should not target the antigens remaining on theedited graft.)

• Geographic availability: Patients must be available for long-term follow-up in thestudy center in China or able to travel for scheduled follow-up visits. They shouldbe willing to remain in proximity to the transplant center for the initialpost-operative period as per standard transplant care.

Exclusion Criteria:

• Active infection: Any ongoing severe infection that would contraindicatetransplantation or be exacerbated by immunosuppression (e.g., active tuberculosis,untreated Hepatitis B or C, HIV with uncontrolled viremia, etc.). Patients withcontrolled HIV (on stable antiretroviral therapy with undetectable viral load) maybe considered on a case-by-case basis, but active uncontrolled infection isexcluded.

• Pregnancy or breastfeeding: Pregnant women are excluded due to the need forimmunosuppressive drugs and the unknown risks of the investigational intervention ona fetus. Women who are breastfeeding are also excluded due to potential drugexcretion in milk and unknown risks to the infant.

• Multi-organ transplant need: Patients requiring more than one organ transplantsimultaneously (e.g., kidney + liver, or kidney + heart) are excluded, as this trialfocuses on isolated kidney transplant outcomes. (A history of a prior transplant isnot an automatic exclusion if the patient now only needs a kidney, but concurrentmulti-organ requirements are excluded.)

• Severe co-morbidities that would significantly increase transplant risk or confoundresults: for example, uncontrolled cardiovascular disease (e.g., recent myocardialinfarction, severe heart failure), uncontrolled diabetes with end-organ damagebeyond ESRD, severe liver dysfunction, or other life-threatening illnesses unrelatedto kidney failure. Such conditions could make the surgery unsafe or the outcome hardto interpret.

• Contraindications to immunosuppression: Patients with conditions that precludestandard immunosuppressive therapy (for instance, a history of anaphylaxis totacrolimus or mycophenolate that cannot be managed, or chronic infection that wouldbe fatally worsened by immunosuppression) are excluded. The trial still relies onbaseline immunosuppressants, so patients must be able to tolerate them.

• Inability to follow the protocol: Patients with significant psychiatric disorders,cognitive impairment, or social situations that would make adherence to the studyprotocol and follow-up unlikely. This includes inability to give informed consent orlack of support for the intensive follow-up (for example, if the patient isincarcerated or has no fixed address, etc.).

• Prior gene therapy or organ experiment participation: Patients who have previouslyreceived any investigational gene therapy, or who have a donor-specific toleranceinduction or other experimental transplant treatments ongoing, may be excluded toavoid confounding effects. (This is a precaution to attribute outcomes specificallyto the CRISPR-edited organ intervention.)

• Laboratory abnormalities: Any clinically significant abnormalities in baseline labsthat would pose added risk - for instance, severe leukopenia or thrombocytopeniathat could worsen with immunosuppression, or uncontrolled coagulopathy that raisessurgical risk.

• Donor-related exclusions: If the donor kidney, upon retrieval, is found unsuitablefor gene editing or transplant (e.g., poor organ quality, unexpected disease in theorgan, or if the CRISPR editing fails to achieve sufficient knockout of targetgenes), the transplant to that patient will not proceed under the study (the patientmay either receive a standard transplant off-study or wait for another opportunity).In such a case, the patient might be withdrawn or deferred, but this is a proceduralconsideration rather than a characteristic of the patient.