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.
Active infection: Any ongoing severe infection that would contraindicate transplantation or be exacerbated by immunosuppression (e.g., active tuberculosis, untreated Hepatitis B or C, HIV with uncontrolled viremia, etc.). Patients with controlled HIV (on stable antiretroviral therapy with undetectable viral load) may be considered on a case-by-case basis, but active uncontrolled infection is excluded.
Pregnancy or breastfeeding: Pregnant women are excluded due to the need for immunosuppressive drugs and the unknown risks of the investigational intervention on a fetus. Women who are breastfeeding are also excluded due to potential drug excretion in milk and unknown risks to the infant.
Multi-organ transplant need: Patients requiring more than one organ transplant simultaneously (e.g., kidney + liver, or kidney + heart) are excluded, as this trial focuses on isolated kidney transplant outcomes. (A history of a prior transplant is not an automatic exclusion if the patient now only needs a kidney, but concurrent multi-organ requirements are excluded.)
Severe co-morbidities that would significantly increase transplant risk or confound results: for example, uncontrolled cardiovascular disease (e.g., recent myocardial infarction, severe heart failure), uncontrolled diabetes with end-organ damage beyond ESRD, severe liver dysfunction, or other life-threatening illnesses unrelated to kidney failure. Such conditions could make the surgery unsafe or the outcome hard to interpret.
Single group
Ex Vivo CRISPR-Cas9 Gene Editing of Donor Kidney
Biological/VaccineThe donor kidney is treated outside the body with CRISPR-Cas9 ribonucleoprotein complexes targeting the genes HLA-A, HLA-B, and CIITA. This genetic intervention knocks out HLA-A/B on donor cells and disables expression of HLA-DR, -DQ, -DP by disrupting CIITA (essential for class II antigen presentation). The goal is to create a transplanted organ with greatly reduced immunogenic surface proteins. (This is a one-time genetic manipulation applied to the donor organ prior to transplantation; no direct gene therapy is given to the patient's own cells.)
Kidney Transplantation with Standard Care
Procedure/SurgeryAfter gene editing, the donor kidney is implanted into the recipient in a surgical transplant procedure. Standard peri-operative care is provided. All patients will receive standard immunosuppressive therapy post-transplant (such as tacrolimus, mycophenolate, and prednisone, per center protocol) to prevent rejection, though the regimen may be tailored based on the edited graft's expected lower immunogenicity. Patients will be hospitalized for transplant and monitored closely during the immediate post-op period, then followed in clinic frequently for transplant aftercare.
Incidence of Treatment-Related Serious Adverse Events
Number of participants who experience any serious adverse event (SAE) that is possibly related to the gene-edited transplant procedure within the first 12 months post-transplant.
Graft Survival at 6 Months
Proportion of transplanted gene-edited kidneys that remain viable and functional at 6 months post-transplant. Graft survival is defined as the kidney graft not being lost to rejection or other causes (i.e., the recipient is alive with a functioning transplant, not returning to chronic dialysis) Unit of Measure: Participants with functioning graft (n, %)
Acute Rejection Episodes
Incidence of acute rejection events within the first 12 months post-transplant. This will be measured as the number of episodes of biopsy-confirmed acute allograft rejection (acute T-cell mediated rejection or antibody-mediated rejection) per patient, and the proportion of patients who experience at least one rejection. Unit of Measure: Episodes per participant
Donor-Specific Antibody (DSA) Development
Number of participants who develop de-novo anti-donor HLA antibodies (MFI ≥1000). Time Frame: Baseline to Month 12 Unit of Measure: Participants with de-novo DSA (n, %)
Mean eGFR at Month 12
Average eGFR calculated by CKD-EPI at Month 12 ±7 days. Unit: mL/min/1.73 m² (mean ± SD)
Frequency of Donor-Reactive IFN-γ Producing T Cells (ELISPOT)
Spot-forming cells per 10⁶ PBMC in ELISPOT assay at Month 6 compared with baseline. Unit: Spot-forming cells/10⁶ PBMC (mean ± SD)
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