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

Plain English Summary

CRISPR-Edited HLA Donor Kidney Transplant to Reduce Rejection Risk is a Phase 2 clinical trial sponsored by AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC studying 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. This trial tests genetically modified donor kidneys using CRISPR technology to reduce the risk of rejection after transplant. It is for adult patients with end-stage kidney disease who are candidates for a kidney transplant. Participation involves receiving a specially edited donor kidney and undergoing regular medical check-ups and tests for one year. Alternatives include standard kidney transplantation with lifelong immunosuppression or remaining on dialysis. The trial aims to enroll 90 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 16-85 with end-stage kidney disease who need a transplant can join. You must be healthy enough for transplant surgery and able to follow study instructions. Patients with a history of high immune responses (high PRA) are welcome. You cannot join if you have an active severe infection, need multiple organ transplants, or have severe health problems unrelated to kidney failure. This trial is studying 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, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcomes measure how safe the treatment is and whether the transplanted kidney continues to work well for at least six months, meaning patients can expect a potentially safer and more dura The specific primary outcome measures are: Incidence of Treatment-Related Serious Adverse Events (Day 0 to Day 365 post-transplant); Graft Survival at 6 Months (6 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial matters because it aims to reduce kidney transplant rejection by genetically modifying donor organs, potentially leading to better long-term outcomes and less need for strong anti-rejection Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets 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, where improved treatment options are needed.

Investor Insight

This trial represents a significant advancement in organ transplantation, potentially opening a new market for gene-edited organs and offering a competitive edge in reducing transplant rejection. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of receiving a gene-edited kidney. Understand that you will need to attend regular follow-up appointments and undergo various tests for a year after your transplant. Be prepared for potential travel if the study center is not local, as long-term follow-up is crucial. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 90 participants

Interventions

• BIOLOGICAL: Ex Vivo CRISPR-Cas9 Gene Editing of Donor Kidney — 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 dir
• PROCEDURE: Kidney Transplantation with Standard Care — 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

Primary Outcomes

• Incidence of Treatment-Related Serious Adverse Events (Day 0 to Day 365 post-transplant)
• Graft Survival at 6 Months (6 months)

Secondary Outcomes

• 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)

Full Eligibility Criteria

Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.
* 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

Trial Locations

• Peking University Health Science Center (PKUHSC), Beijing, Changping, China

Frequently Asked Questions

Related Conditions

• End-Stage Renal Disease
• Kidney Transplant
• Organ Transplantation
• Immunosuppression
• Gene Editing
• CRISPR Technology
• Autoimmune Diseases
• Renal Failure
• Dialysis
• Kidney Disease

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