A Phase 1/2 interventional study of Ex Vivo CRISPR-Cas9 Gene Editing of Donor Liver in Liver Diseases, Liver Cancer and Liver Cirrhosis, sponsored by AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC. Recruiting at 1 site in China. Open to participants aged 16 Years to 85 Years. Per ClinicalTrials.gov, last updated 2025-07-08.
Sponsored by AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC · Phase 1/2, Interventional, and Treatment
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.
Organ transplant rejection is primarily driven by immune recognition of donor HLA (human leukocyte antigen) molecules as foreign. Mismatches in HLA-A and HLA-B (class I) in particular are strongly immunogenic and can provoke T-cell mediated graft rejection. HLA class II molecules (HLA-DR, DQ, DP), expressed on donor antigen-presenting cells, can also activate CD4⁺ T cells and contribute to rejection. Current therapy relies on immunosuppressive drugs, which carry significant risks. Preclinical research has shown that genetically "erasing" HLA molecules from donor cells can blunt immune responses: for example, cells with HLA-A, HLA-B, and HLA-DR knocked out via CRISPR elicited little to no T cell proliferation in vitro, indicating greatly reduced immunogenicity. Similarly, in xenotransplant models, triple knockout of genes (including class I and the class II regulator CIITA) in donor animals significantly weakened human T-cell activation and prolonged graft survival. These findings provide a strong rationale that an HLA-edited donor organ could evade the human immune system to a large extent, potentially reducing or delaying rejection.
Gene-Editing of Donor Liver Ex Vivo: In this trial, deceased-donor livers will undergo ex vivo CRISPR-Cas9 genome editing prior to transplantation. The editing targets are HLA-A and HLA-B (to eliminate the major class I alloantigens) and CIITA (class II transactivator, whose knockout abolishes HLA-DR/DQ/DP expression on donor cells). By knocking out HLA-A and -B, while leaving HLA-C expression intact, the goal is to remove the most immunogenic class I molecules yet maintain some HLA presence to mitigate natural killer cell "missing-self" responses. Disabling CIITA will prevent expression of HLA class II proteins, thus reducing CD4⁺ T cell activation against the graft. The CRISPR editing is performed during machine perfusion of the donor liver (a period in which the organ is kept alive outside the body). A CRISPR-Cas9 ribonucleoprotein (Cas9 enzyme complexed with guide RNAs for HLA-A, HLA-B, and CIITA) is delivered into the liver tissue through the perfusion circuit. Editing takes place ex vivo, avoiding direct in vivo gene therapy to the recipient. Before transplantation, the graft is assessed for successful gene knockout (for example, by biopsy immunostaining or flow cytometry to confirm absence of HLA-A/B/DR on the cell surface). Only livers with confirmed high-efficiency editing (e.g. >90% target gene disruption) are used for transplant to ensure maximal immune-evasion benefit.
824 studies on the registry are indexed under Liver Diseases; 152 are open to participants now.
This study's planned enrollment of 90 is above the median of 52 across 521 interventional studies indexed under Liver Diseases.
Browse Liver Diseases studies →AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC is the lead sponsor of 2 studies on the registry; 2 are open to participants now.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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.
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
Time frame: 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.
Time frame: 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, %)
Time frame: Day1 to Day 90
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.
Time frame: Day 1 - Month 12
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.
Time frame: Day 1 - Month 12
Graft Survival and Function at 1 Year
Number of patients with the original transplanted liver surviving at 12 months with no graft loss.
Time frame: Day 1 - Month 12
Patient Survival at 1 Year
Overall survival of participants at 1 year post-transplant.
Time frame: 12 months
Immunosuppression Reduction Feasibility
Among patients with stable graft function, ability to taper down immunosuppressive therapy by 6-12 months post-transplant without precipitating rejection. This will be measured by the proportion of patients successfully maintaining graft health on reduced immunosuppressant dosage or simpler regimen.
Time frame: 12 months
Off-target Effects Assessment
trial will evaluate any evidence of off-target gene editing effects manifesting in the graft (for example, unexpected histological changes, or aberrant liver function that could hint at unintended gene disruptions). Genomic analyses of edited tissue will be done to characterize off-target mutation frequency.
Time frame: 24 months
Plan to share: No
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