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.
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).
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.
Single group
Ex Vivo CRISPR-Cas9 Gene Editing of Donor Liver
Biological/VaccineDonor 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.
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
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.
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, %)
Incidence of Acute Rejection at 6 and 12 Months
The proportion of patients experiencing biopsy-confirmed acute cellular rejection episodes within 6 months and within 12 months post-transplant. The severity of rejection (graded by standard criteria) and response to treatment will also be recorded. A lower-than-expected rejection rate or milder rejection would indicate a successful immunogenicity reduction.
Immunologic Markers of Alloreactivity
Levels of anti-donor HLA antibodies in recipient blood (donor-specific antibodies, DSA) and T-cell alloimmune reactivity (e.g., in vitro mixed lymphocyte reaction or ELISPOT assays against donor cells) at 3, 6, and 12 months. We will compare these immunologic markers to baseline and to typical post-transplant profiles. We hypothesize that patients with edited grafts will show attenuated T cell responses to donor antigens.
Graft Survival and Function at 1 Year
Number of patients with the original transplanted liver surviving at 12 months with no graft loss.
Patient Survival at 1 Year
Overall survival of participants at 1 year post-transplant.
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