CRISPR-Edited HLA Donor Liver Transplant to Reduce Rejection

NCT07053488 | Recruiting Phase 1 DMC

• 1 other identifier: AOTCRI-102
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

This early-phase clinical trial will assess the use of ex vivo CRISPR-Cas9 genome editing on donor liver grafts to reduce immunogenicity before transplantation. Donor livers will have HLA-A and HLA-B genes knocked out, and HLA class II expression disabled (by targeting the CIITA transactivator gene), aiming to create a "hypoimmunogenic" organ less prone to rejection. The edited liver is then transplanted into patients with end-stage liver disease. The primary focus is on safety and feasibility - determining whether a CRISPR-edited liver can be transplanted successfully and function normally - as well as evaluating reductions in immune response (acute rejection, anti-donor T cell activation) and graft function over time.

Conditions

Liver Diseases; Liver Cancer; Liver Cirrhosis; Liver Failure; Liver Metastases; Liver Transplant Rejection; Liver Steatoses

Keywords

End-Stage Liver Disease requiring transplantation; Prevention of Allograft Rejection in Liver Transplantation; CRISPR-Cas9; Gene Editing; Liver Transplant; Organ Transplantation; Immunogenicity Reduction; HLA Knockout; Hypoimmunogenic Graft; Allograft Rejection; Universal Donor Organ

Outcome Measures

Primary Outcomes (3)

• Incidence of Grade ≥3 Treatment-Emergent Adverse Events (TEAEs)

  Number of participants experiencing ≥1 CTCAE v5.0 Grade 3-5 TEAE judged related to the gene-edited liver transplant procedure

  Day 1 to Day 90

• Feasibility of Ex Vivo HLA Gene Editing

  Proportion of donor livers that achieve the desired editing criteria (e.g., \>90% knockout efficiency of HLA-A/B and abolition of class II expression) and are successfully transplanted into recipients. Feasibility is further indicated by the absence of technical issues during organ editing and transplantation.

  Day1 to Day 90

• Graft Failure Rate at Day 90

  Proportion of participants requiring re-transplant, graft explant, or returning to listing due to primary non-function.Unit of Measure :Participants with graft failure (n, %)

  Day1 to Day 90

Secondary Outcomes (6)

• Incidence of Acute Rejection at 6 and 12 Months

  Day 1 - Month 12

• Immunologic Markers of Alloreactivity

  Day 1 - Month 12

• Graft Survival and Function at 1 Year

  Day 1 - Month 12

• Patient Survival at 1 Year

  12 months

• Immunosuppression Reduction Feasibility

  12 months

Study Arms (1)

CRISPR-Edited Donor Liver Transplant

EXPERIMENTAL

Participants undergo orthotopic liver transplantation using a donor liver that has been ex vivo gene-edited by CRISPR-Cas9 to knock out HLA class I (A, B) and class II (via CIITA) genes. There is no comparator arm; outcomes will be compared to historical norms of unedited transplants for context.

Biological: Ex Vivo CRISPR-Cas9 Gene Editing of Donor Liver

Interventions

Ex Vivo CRISPR-Cas9 Gene Editing of Donor Liver BIOLOGICAL

Donor liver tissue is perfused outside the body with a CRISPR-Cas9 RNP complex targeting HLA-A, HLA-B, and CIITA, to create a hypoimmunogenic graft. After confirming successful gene knockout, the liver is transplanted into the patient following standard surgical techniques. Post-operative care includes routine immunosuppressive therapy with planned adjustments based on the patient's tolerance and evidence of graft immunogenicity.

CRISPR-Edited Donor Liver 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:

• 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).

You may not qualify if:

• 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).

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

Liver Diseases; Liver Neoplasms; Liver Cirrhosis; Liver Failure; Fatty Liver

Condition Hierarchy (Ancestors)

Digestive System Diseases; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hepatic Insufficiency

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: All enrolled participants receive the experimental intervention (no control arm). The trial is Open-Label (no blinding) and designed as a combined Phase 1/2 study focusing on safety and preliminary efficacy.

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)