Phase 1/2, Single-Arm, Open-Label Trial to Evaluate the Safety, Feasibility, and Immunogenicity of Ex Vivo CRISPR-Cas9 Gene-Edited Donor Kidneys (Knockout of HLA-A, HLA-B, and CIITA) in Human Renal Transplant Recipients
This clinical trial investigates the transplantation of donor kidneys that have been genetically modified ex vivo using CRISPR-Cas9 genome editing to reduce immunogenicity and transplant rejection. Donor kidney grafts will have key human leukocyte antigen (HLA) genes disrupted - specifically, knockout of HLA class I heavy chains HLA-A and HLA-B, along with disabling HLA class II expression by targeting the CIITA gene (a master regulator of HLA-DR/DQ/DP). Approximately 90 adult end-stage renal disease patients will receive a CRISPR-edited donor kidney transplant. The primary objectives are to assess the safety and feasibility of this novel intervention, while secondary objectives evaluate the reduction in immune responses (immunogenicity), graft function, and the practicality of implementing ex vivo gene-edited organ transplantation in humans. By knocking out major donor HLA molecules, the trial aims to reduce T-cell and antibody-mediated recognition of the graft, potentially lowering rejection rates and reliance on high-dose immunosuppressants. Safety, including any off-target effects or unanticipated immune reactions, will be closely monitored, and transplant outcomes will be tracked for one year post-transplant.
• Adult patients, age 16 to 85 years, with end-stage renal disease (ESRD) who are candidates for kidney transplantation. This includes patients on dialysis or approaching dialysis who have been evaluated and listed for transplant.
• Eligible for transplant surgery based on medical assessment (i.e., no contraindications to major surgery and transplantation). The patient's overall health status must be sufficient to undergo the transplant procedure and the required immunosuppression.
• Suitable donor organ available: A deceased-donor kidney that meets standard acceptable criteria for transplant (e.g., adequate organ function and anatomy) and is ABO blood type compatible with the recipient. The donor kidney must be allocated to the trial and available for ex vivo gene editing prior to transplantation.
• Informed consent: The patient (or legally authorized representative) is able to understand the experimental nature of the study and has voluntarily signed the informed consent form. The patient must be willing to comply with all study procedures, follow-up visits, and laboratory tests.
• Negative crossmatch (if applicable): No pre-existing anti-donor reactivity that would cause immediate graft failure. (All recipients should have a negative T and B cell crossmatch with the donor organ prior to transplant, as per standard practice, to ensure no strong baseline donor-specific antibodies, especially against any remaining donor HLA such as HLA-C.)
• Women of childbearing potential must have a negative pregnancy test and must agree to use effective contraception during the study and for a period after (to be specified, e.g., 1 year post-transplant), given the use of immunosuppressants and the unknown effects of gene-edited organ transplantation on pregnancy. Men with partners of childbearing potential should also agree to use contraception.
• High immunologic risk patients are eligible: Patients with high panel reactive antibody (PRA) levels or a history of sensitization (from prior transplants, blood transfusions, or pregnancies) are allowed and even anticipated in this trial, as the intervention is designed to benefit patients with broad HLA sensitization. For instance, patients with calculated PRA \> 80% (who have difficulty finding matched donors) can be included. (Such patients must still meet the crossmatch criterion above - any existing antibodies should not target the antigens remaining on the edited graft.)
• Geographic availability: Patients must be available for long-term follow-up in the study center in China or able to travel for scheduled follow-up visits. They should be willing to remain in proximity to the transplant center for the initial post-operative period as per standard transplant care.