CRISPR-edited donor liver transplant to reduce rejection

A Phase 1/2, Open-Label, Single-Arm Study to Evaluate the Safety, Immunogenicity Reduction, Transplant Function, and Feasibility of Ex Vivo CRISPR-Cas9 Gene-Edited Donor Liver Transplantation Targeting HLA Class I (HLA-A, HLA-B) and Class II (Via CIITA) Genes.

This trial will try transplanting deceased-donor livers that have had key HLA genes removed with CRISPR to see if they cause less rejection in adults needing a liver transplant.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 90 (estimated)
• Ages: 16 Years to 85 Years
• Sex: All
• Sponsor: American Organ Transplant and Cancer Research Institute LLC (Academic / other)
• Locations: 1 site (Beijing, Changping)
• Trial ID: NCT07053488 on ClinicalTrials.gov

What this trial studies

Deceased-donor livers are edited ex vivo with CRISPR-Cas9 to knock out HLA-A and HLA-B and disable HLA class II expression by targeting CIITA, then transplanted into adults with end-stage liver disease or acute liver failure. The trial is an early-phase (Phase 1/2) interventional protocol focused on safety and feasibility of transplanting a gene-edited whole organ and monitoring graft function. Investigators will monitor for acute rejection, anti-donor T cell activation, graft function over time, and standard post-transplant complications while patients receive standard immunosuppression. Outcomes will include measures of immune response, feasibility of the editing and transplant workflow, and short- to mid-term organ performance.

Who should consider this trial

Good fit: Adults aged about 16–85 with end-stage liver disease or acute liver failure who are eligible for deceased-donor liver transplantation, have been allocated a donor graft for use in the protocol, and can consent and tolerate standard immunosuppressive therapy are ideal candidates.

Not a fit: Patients who have fully HLA-matched living donors, those who are not surgical transplant candidates, or those with uncontrolled active infections or other contraindications to transplantation are unlikely to benefit.

Why it matters

Potential benefit: If successful, this approach could reduce immune rejection of donor livers and lower the need for intensive long-term immunosuppression.

How similar studies have performed: Preclinical cell and animal studies have shown that removing class I and class II HLA components can greatly reduce T-cell activation and prolong graft survival, but ex vivo CRISPR editing of whole human donor organs for clinical transplant is novel and untested in humans.

Eligibility criteria

Inclusion Criteria:

* Adults aged 16-85 (inclusive) with end-stage liver disease or acute liver failure who are eligible for liver transplantation.
* Require a liver transplant and have been allocated a donor liver graft (from a deceased donor) that will be used in the study after gene editing.
* No immediately available fully HLA-matched donor (since the study targets patients who would otherwise receive an HLA-mismatched organ; standard allocation generally does not consider HLA matching for liver, so most patients will qualify).
* Medically suitable for transplant surgery and able to tolerate standard immunosuppressive therapy (no contraindications to transplant such as uncontrolled infection or other active serious disease that would preclude surgery).
* Informed Consent: Able to understand the investigational nature of the trial and provide written informed consent. Patients (and their legal representatives if applicable) must consent to the use of a genetically modified organ and to long-term follow-up including multiple biopsies and immune monitoring.
* Willingness to comply with all study procedures and availability for the duration of follow-up (including frequent monitoring visits).

Exclusion Criteria:

* Active uncontrolled infection (e.g., sepsis, active tuberculosis) that would severely increase transplant risk or confound interpretation of immune-related outcomes.
* Uncontrolled HIV or chronic viral infections that are not well-managed. (Note: Patients with hepatitis B or C may be included if adequately treated or under control, as these are common in liver failure, but such patients should not have active, replicating virus at transplant if possible.)
* Multi-organ transplant requirement: Patients needing more than a liver alone (e.g., liver-kidney dual transplant) are excluded, as the trial is only evaluating single organ (liver) outcomes.
* Pregnancy or breastfeeding: Female participants of childbearing potential must have a negative pregnancy test prior to transplant and must agree to use effective contraception. The effects of a gene-edited organ transplant on a fetus/infant are unknown, and immunosuppressive drugs can also harm a pregnancy.
* Severe concurrent illness not related to liver disease that would limit survival to \<1 year or make the patient an unsuitable candidate (e.g., advanced heart failure, uncontrolled diabetes with complications, etc.).
* Allergy or hypersensitivity to study-related products: If any components used in the ex vivo gene editing (such as a specific vehicle or enzyme) have known severe allergies in the recipient, they will be excluded. (For instance, although unlikely, if a patient had a documented severe immune reaction to Streptococcus pyogenes Cas9 or similar proteins, they would not be enrolled.)
* Inability to follow the protocol or comply with follow-up: this includes psychiatric, social or logistical factors that would prevent adhering to the intense monitoring schedule (for example, lack of reliable transportation or support).

Where this trial is running

Beijing, Changping

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

Study contacts

• Study coordinator: Andrew R Linehan

Conditions Liver Diseases; Liver Cancer; Liver Cirrhosis; Liver Failure; Liver Metastases; Liver Transplant Rejection; Liver Steatoses; End-Stage Liver Disease requiring transplantation