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.

Plain English Summary

CRISPR-Edited HLA Donor Liver Transplant to Reduce Rejection is a Phase 2 clinical trial sponsored by AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC studying Liver Diseases, Liver Cancer, Liver Cirrhosis, Liver Failure, Liver Metastases, Liver Transplant Rejection, Liver Steatoses. This trial tests a new method using gene editing (CRISPR-Cas9) to modify donor livers before transplant, aiming to reduce the risk of rejection. It is for adults with end-stage liver disease or acute liver failure who need a liver transplant and are eligible for surgery. Participation involves receiving a gene-edited donor liver and undergoing extensive monitoring, including biopsies and immune tests, for up to a year. Currently, standard liver transplants rely on powerful immunosuppressant drugs to prevent rejection; this trial explores a biological approach to reduce the need for such drugs. The trial aims to enroll 90 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 16-85 who need a liver transplant and are medically fit for surgery can join. You cannot join if you have an active, uncontrolled infection, certain poorly managed viral infections, or need more than just a liver transplant. Women who are pregnant or breastfeeding cannot participate due to unknown risks to the fetus/infant and potential harm from immunosuppressants. Individuals with severe illnesses unrelated to liver disease that would limit survival to less than a year are also excluded. This trial is studying Liver Diseases, Liver Cancer, Liver Cirrhosis, Liver Failure, Liver Metastases, Liver Transplant Rejection, Liver Steatoses, 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 gene-edited liver transplant is, whether the gene editing process can be successfully done, and if the new liver works well without failing in the first 90 da The specific primary outcome measures are: Incidence of Grade ≥3 Treatment-Emergent Adverse Events (TEAEs) (Day 1 to Day 90); Feasibility of Ex Vivo HLA Gene Editing (Day1 to Day 90); Graft Failure Rate at Day 90 (Day1 to Day 90). 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 create a 'hypoimmunogenic' donor liver, potentially reducing organ rejection and the need for lifelong immunosuppression, addressing a major challenge in liver tr Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Liver Diseases, Liver Cancer, Liver Cirrhosis, Liver Failure, Liver Metastases, Liver Transplant Rejection, Liver Steatoses, where improved treatment options are needed.

Investor Insight

This trial represents a significant advancement in transplant technology, targeting a large market of patients with end-stage liver disease and potentially offering a competitive edge by reducing reje 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 gene-editing process, potential risks of gene-edited organs, and what the long-term monitoring will involve. Be prepared for frequent visits for blood tests, imaging, and potentially liver biopsies to check how the new liver is functioning and how your body is responding. Understand that you will need to provide informed consent for the use of a genetically modified organ and commit to long-term follow-up. 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 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.

Primary Outcomes

• Incidence of Grade ≥3 Treatment-Emergent Adverse Events (TEAEs) (Day 1 to Day 90)
• Feasibility of Ex Vivo HLA Gene Editing (Day1 to Day 90)
• Graft Failure Rate at Day 90 (Day1 to Day 90)

Secondary Outcomes

• 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)

Full 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).

Trial Locations

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

Frequently Asked Questions

Related Conditions

• Liver Diseases
• Liver Cancer
• Liver Cirrhosis
• Liver Failure
• Liver Metastases
• Liver Transplant Rejection
• Liver Steatoses
• Hepatitis
• Autoimmune Liver Disease
• Genetic Liver Disorders

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