First-in-human trial will test patients' own reprogrammed liver cells against advanced cirrhosis
Japanese researchers will transplant patients' own chemically reprogrammed liver progenitor cells into the portal vein in a first-in-human cirrhosis safety trial.
Summary
People with decompensated cirrhosis who cannot receive a liver transplant have few options, and survival after decompensation is often about two years. A Japanese team is launching the first human trial of a new approach. Surgeons remove about 30 grams of a patient's own liver, and lab scientists use three small molecules to turn mature liver cells into expandable progenitor cells called CLiPs. After 12 to 16 weeks of growth and strict safety testing, including checks for hidden cancer and genetic damage, about 100 million cells are infused into the liver's portal vein. Only three patients with Child–Pugh class B disease will be treated, and the main goal is safety through one month. Liver function and scarring markers are tracked for a year as exploratory outcomes. No patient has been transplanted yet, so there are no results. Animal studies, including a large-animal fatty liver model, showed reduced scarring and no tumors.
Detailed Summary
Decompensated cirrhosis is the terminal stage of chronic liver disease. Once ascites, variceal bleeding or hepatic encephalopathy appear, median survival is about 2 years without transplantation. Historical one-year survival is roughly 80% in Child–Pugh class B and 45% in class C. Transplantation is the only curative option, but donor shortages, surgical risk, lifelong immunosuppression and strict eligibility rules exclude many patients. Earlier cell therapies, including hematopoietic stem cells, mesenchymal stromal cells and primary hepatocytes, appeared feasible and safe but produced modest, transient benefit, largely because the cells do not persist or function in the hostile cirrhotic liver.
This paper is a protocol, not a results report. It describes the first-in-human phase I/II study of autologous chemically induced liver progenitor cells (CLiPs), which are produced by culturing mature hepatocytes with three small molecules (Y-27632, A-83-01 and CHIR99021). The resulting cells are proliferative and bipotent, meaning they can mature toward hepatocytes or biliary epithelial cells. Because the cirrhotic microenvironment may steer that fate, the authors state openly that they do not know whether human transplanted CLiPs will mature into hepatocytes as efficiently as in animals, and this trial cannot directly answer that.
Manufacturing and safety screening are central to the design. About 30 g of liver tissue is removed laparoscopically from segment 3 or 5/6 and expanded for 12–16 weeks in a certified cell processing center at Nagasaki University Hospital. Patients first undergo contrast-enhanced CT and gadoxetic acid MRI, and the harvested tissue must show no malignancy on histology. Copy-number variation analysis compares starting hepatocytes with a CLiP intermediate. A cancer-gene panel is run on blood DNA, starting hepatocytes and the intermediate. Sterility, mycoplasma, endotoxin, viability and surface-marker tests gate release. Prolonged passaging is avoided, and the target cell number has been reached by passage 6.
The preclinical case spans several models. Rat CLiPs reduced fibrosis and ALT in diet-induced MASH. Human CLiPs, including those derived from cirrhotic liver, matured into albumin-positive cells, lowered AST and ALT, and reduced collagen and fibrosis genes in immunodeficient MASH mice. CLiPs also improved regeneration after partial hepatectomy in aged mice. In a porcine MASLD model, autologous portal venous transplantation was well tolerated and reduced steatosis, stellate cell activation and collagen, with no ectopic tissue formation or tumorigenesis. One caution is that 2 of 3 rat CLiP lines showed aneuploidy and translocations at passages 15–20.
Three adults aged 20–80 with Child–Pugh class B cirrhosis (score 7–9 on two assessments at least 90 days apart) will be enrolled. Eligible causes are HBV on stable therapy, HCV after sustained virological response, MASH, or alcohol-associated disease with at least 6 months of abstinence. Exclusions include prior or suspected liver cancer, portal vein thrombosis, moderate or severe ascites, bilirubin of 5.0 mg/dL or higher, and eGFR of 30 or below. The target dose is 1 × 10^8 cells (minimum 5 × 10^7) in 100 mL, infused over about 10 minutes via ileocolic vein cut-down. An independent committee must review the first patient's 1-month safety data before others proceed.
The primary endpoint is adverse events and product deficiencies from tissue harvest to 1 month after transplant. Safety is followed to 12 months. Exploratory outcomes include Child–Pugh and ALBI change, MELD, fibrosis biomarkers (P-III-P, hyaluronic acid, M2BPGi, Pro-C3), elastography, FIB-4, encephalopathy testing and ascites. With no control arm, no sample size calculation and no hypothesis testing, efficacy cannot be inferred. The dose is a conservative translational estimate (about 0.1% cell-to-liver ratio), not a proven effective or maximum tolerated dose. At submission, enrollment had begun but no participant had been transplanted.
Key Findings
- Planned enrollment is only 3 adults with Child–Pugh class B decompensated cirrhosis (score 7–9 on two assessments at least 90 days apart) who are not transplant candidates
- Each patient provides about 30 g of liver tissue, and manufacturing of the CLP-001 cell product takes 12–16 weeks
- Target dose is 1 × 10^8 cells in 100 mL infused over about 10 minutes into the portal vein, with a minimum acceptable dose of 5 × 10^7 cells
- Background survival without transplantation is poor: about 80% one-year survival in Child–Pugh B, 45% in class C, and a median of about 2 years after decompensation
- In earlier rat work, 2 of 3 CLiP lines showed aneuploidy and translocations at passages 15–20, so the clinical process avoids prolonged passaging and reaches the target cell number by passage 6
- In a porcine MASLD model, autologous portal venous CLiP transplantation reduced steatosis, stellate cell activation and collagen with no tumorigenesis or ectopic tissue formation
- Primary endpoint is safety from tissue harvest to 1 month after transplant, with follow-up to 12 months, and no participant had been transplanted at submission
Methodology
This is a protocol for a single-center (Nagasaki University Hospital), open-label, single-arm, first-in-human phase I/II study under Japan's Act on the Safety of Regenerative Medicine (jRCTa070250146). It will enroll 3 patients with no concurrent control group, no formal sample size calculation and no hypothesis testing. An independent safety committee must review the first patient's 1-month data before further enrollment. Follow-up includes inpatient assessments through day 7 after transplant and outpatient visits at 1, 3, 6 and 12 months.
Study Limitations
The authors note that the trial is exploratory, with only three patients, no control arm and no formal statistical testing, so efficacy findings are descriptive only. The fate of transplanted CLiPs in the human liver cannot be directly established, and the dose is a conservative estimate rather than a validated effective or maximum tolerated dose. Early-passage karyotyping does not prove genomic stability after longer culture. The excerpt provided does not include a conflict-of-interest statement.
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