CRISPR-Edited HLA Donor Kidney Transplant to Reduce Rejection Risk

NCT07053462 | Recruiting Phase 1 DMC

• 1 other identifier: AOTCRI-101
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

End-Stage Renal Disease; End Stage Renal Disease on Dialysis; End Stage Renal Disease With Renal Transplant; Kidney Transplant Rejection; Kidney Tumor; Kidney Failure; Kidney Ischemia

Keywords

HLA Mismatch Immunogenicity; Transplant Rejection (Immunologic); Kidney Transplantation (Allograft); Kidney Failure; CRISPR-Cas9; Kidney Transplant; Human Leukocyte Antigen (HLA); Immunogenicity Reduction; Graft Rejection Prevention

Outcome Measures

Primary Outcomes (2)

• 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.

  Day 0 to Day 365 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, %)

  6 months

Secondary Outcomes (6)

• Acute Rejection Episodes

  12 months

• Donor-Specific Antibody (DSA) Development

  12 months

• Mean eGFR at Month 12

  12 months

• Frequency of Donor-Reactive IFN-γ Producing T Cells (ELISPOT)

  12 months

• Percentage of HLA-A Alleles with Indel Mutation (NGS)

  30 days

Study Arms (1)

CRISPR-Edited Donor Kidney Transplant

EXPERIMENTAL

All enrolled participants will receive a kidney allograft that has undergone ex vivo CRISPR-Cas9 gene editing to disrupt HLA-A and HLA-B (class I) and the CIITA gene (to broadly suppress HLA class II expression). The edited kidney is then transplanted into the patient using standard surgical techniques. Participants are maintained on a conventional post-transplant immunosuppressive regimen (with possible adjustments as appropriate for reduced graft immunogenicity). Arm description: Single-arm trial, wherein each patient is in the experimental group receiving the gene-edited kidney graft.

Biological: Ex Vivo CRISPR-Cas9 Gene Editing of Donor Kidney; Procedure: Kidney Transplantation with Standard Care

Interventions

Ex Vivo CRISPR-Cas9 Gene Editing of Donor Kidney BIOLOGICAL

The 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.)

CRISPR-Edited Donor Kidney Transplant

Kidney Transplantation with Standard Care PROCEDURE

After 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.

CRISPR-Edited Donor Kidney Transplant

Eligibility Criteria

• Age: 16 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• Contraindications to immunosuppression: Patients with conditions that preclude standard immunosuppressive therapy (for instance, a history of anaphylaxis to tacrolimus or mycophenolate that cannot be managed, or chronic infection that would be fatally worsened by immunosuppression) are excluded. The trial still relies on baseline 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 study protocol and follow-up unlikely. This includes inability to give informed consent or lack of support for the intensive follow-up (for example, if the patient is incarcerated or has no fixed address, etc.).
• Prior gene therapy or organ experiment participation: Patients who have previously received any investigational gene therapy, or who have a donor-specific tolerance induction or other experimental transplant treatments ongoing, may be excluded to avoid confounding effects. (This is a precaution to attribute outcomes specifically to the CRISPR-edited organ intervention.)
• Laboratory abnormalities: Any clinically significant abnormalities in baseline labs that would pose added risk - for instance, severe leukopenia or thrombocytopenia that could worsen with immunosuppression, or uncontrolled coagulopathy that raises surgical risk.

Sponsors & Collaborators

• AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC: lead

Study Sites (1)

Peking University Health Science Center (PKUHSC)

Beijing, Changping, 102206, China

RECRUITING

MeSH Terms

Conditions

Kidney Failure, Chronic; Carcinoma, Renal Cell; Renal Insufficiency

Interventions

Kidney Transplantation; Standard of Care

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Renal Replacement Therapy; Therapeutics; Organ Transplantation; Transplantation; Surgical Procedures, Operative; Urologic Surgical Procedures; Urogenital Surgical Procedures; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Central Study Contacts

Andrew R Linehan

CONTACT

+1 (302) 615-8388; clinical-trials@aotcri.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single Group Assignment (Open-Label, Non-Randomized) - All participants receive the experimental CRISPR-edited kidney transplant; there is no control arm. This is a single-arm feasibility and safety study in an early phase setting.

Study Record Dates

• First Submitted: June 8, 2025
• First Posted: July 8, 2025
• Study Start: June 1, 2025
• Primary Completion (Estimated): December 18, 2027
• Study Completion (Estimated): December 28, 2028
• Last Updated: July 8, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)