Trials / Recruiting

RecruitingNCT07053462

CRISPR-Edited HLA Donor Kidney Transplant to Reduce Rejection Risk

Phase 1/2, Single-Arm, Open-Label Trial to Evaluate the Safety, Feasibility, and Immunogenicity of Ex Vivo CRISPR-Cas9 Gene-Edited Donor Kidneys (Knockout of HLA-A, HLA-B, and CIITA) in Human Renal Transplant Recipients

Status: Recruiting
Phase: Phase 1 / Phase 2
Study type: Interventional
Enrollment: 90 (estimated)

Sponsor: AMERICAN ORGAN TRANSPLANT AND CANCER RESEARCH INSTITUTE LLC · Academic / Other
Sex: All
Age: 16 Years – 85 Years
Healthy volunteers: Not accepted

Summary

This clinical trial investigates the transplantation of donor kidneys that have been genetically modified ex vivo using CRISPR-Cas9 genome editing to reduce immunogenicity and transplant rejection. Donor kidney grafts will have key human leukocyte antigen (HLA) genes disrupted - specifically, knockout of HLA class I heavy chains HLA-A and HLA-B, along with disabling HLA class II expression by targeting the CIITA gene (a master regulator of HLA-DR/DQ/DP). Approximately 90 adult end-stage renal disease patients will receive a CRISPR-edited donor kidney transplant. The primary objectives are to assess the safety and feasibility of this novel intervention, while secondary objectives evaluate the reduction in immune responses (immunogenicity), graft function, and the practicality of implementing ex vivo gene-edited organ transplantation in humans. By knocking out major donor HLA molecules, the trial aims to reduce T-cell and antibody-mediated recognition of the graft, potentially lowering rejection rates and reliance on high-dose immunosuppressants. Safety, including any off-target effects or unanticipated immune reactions, will be closely monitored, and transplant outcomes will be tracked for one year post-transplant.

Detailed description

In organ transplantation, differences in HLA genes between donor and recipient are a primary driver of allorecognition and graft rejection. Mismatched donor HLA antigens are identified as "non-self" by the recipient's immune system, provoking CD8\<sup\>+\</sup\> cytotoxic T lymphocyte responses, CD4\<sup\>+\</sup\> T-helper responses, and natural killer (NK) cell activation that can damage the graft. While immunosuppressive drugs can mitigate rejection, patients remain at risk for rejection if donor HLAs are unfamiliar, and life-long immunosuppression carries significant morbidities (infection, malignancy, etc.). Complete HLA matching is rarely achievable for all patients, especially for highly sensitized individuals with pre-formed anti-HLA antibodies. To address this, researchers have proposed rendering donor tissues "hypoimmunogenic" by removing or reducing expression of the most immunogenic HLA molecules. Preclinical studies show that eliminating key HLA class I and II antigens can prevent immune recognition and rejection of allogeneic cells. For example, genome editing of induced pluripotent stem cells to knock out HLA-A, HLA-B, and HLA-DR (via the DRA gene) successfully created universal cell grafts that evade T cell responses. Similarly, in animal models, silencing of major histocompatibility complex (MHC) genes in donor organs dramatically prolonged transplant survival. In a recent porcine study, donor lungs with reduced MHC (SLA gene) expression had markedly improved outcomes: \~71% of treated pigs survived long-term (2 years) with little to no rejection, whereas all control pigs receiving unmodified organs rejected within 3 months. Treated animals showed reduced donor-specific antibody production and T-cell reactivity, demonstrating that lowering graft antigenicity can ameliorate rejection. These findings provide a strong rationale that knocking out donor HLA genes can reduce human allograft immunogenicity and potentially allow better graft survival with less immunosuppression. This trial is a applying ex vivo CRISPR-Cas9 gene editing to donor organs to reduce HLA expression prior to transplantation. The editing strategy targets the donor kidney's HLA class I and II pathways: both HLA-A and HLA-B genes will be knocked out (biallelic disruption), while HLA class II expression is ablated by knocking out CIITA, a transcriptional activator required for HLA-DR, -DQ, and -DP expression. The intended result is a kidney graft largely devoid of classical HLA class I and II molecules. Notably, HLA-C (a class I gene) may be partially retained (e.g. only one allele knocked out) to maintain a low level of class I expression - this strategy can help avoid NK cell-mediated "missing-self" responses that occur when all class I is absent. By preserving minimal HLA-C or non-polymorphic HLA-E/G expression, the graft may evade NK cell attack while still lacking the highly polymorphic HLA-A/B and class II antigens that elicit T-cell and antibody responses. The overall hypothesis is that such CRISPR-edited "stealth" kidneys will be significantly less immunogenic, leading to fewer acute rejection episodes and reduced anti-graft antibody formation, thereby improving transplant success.

Conditions

Interventions

Type	Name	Description
BIOLOGICAL	Ex Vivo CRISPR-Cas9 Gene Editing of Donor Kidney	The donor kidney is treated outside the body with CRISPR-Cas9 ribonucleoprotein complexes targeting the genes HLA-A, HLA-B, and CIITA. This genetic intervention knocks out HLA-A/B on donor cells and disables expression of HLA-DR, -DQ, -DP by disrupting CIITA (essential for class II antigen presentation). The goal is to create a transplanted organ with greatly reduced immunogenic surface proteins. (This is a one-time genetic manipulation applied to the donor organ prior to transplantation; no direct gene therapy is given to the patient's own cells.)
PROCEDURE	Kidney Transplantation with Standard Care	After gene editing, the donor kidney is implanted into the recipient in a surgical transplant procedure. Standard peri-operative care is provided. All patients will receive standard immunosuppressive therapy post-transplant (such as tacrolimus, mycophenolate, and prednisone, per center protocol) to prevent rejection, though the regimen may be tailored based on the edited graft's expected lower immunogenicity. Patients will be hospitalized for transplant and monitored closely during the immediate post-op period, then followed in clinic frequently for transplant aftercare.

Timeline

Start date: 2025-06-01
Primary completion: 2027-12-18
Completion: 2028-12-28
First posted: 2025-07-08
Last updated: 2025-07-08

Locations

1 site across 1 country: China

Source: ClinicalTrials.gov record NCT07053462. Inclusion in this directory is not an endorsement.