Adult liver progenitor cells for treating acute-on-chronic liver failure

A technology for acute liver failure and progenitor cells, applied in animal cells, organic active ingredients, vertebrate cells, etc., can solve problems such as coagulation factor consumption and severe bleeding

Pending Publication Date: 2021-11-19
PROMETHERA THERAPEUTICS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of these cells express procoagulant activity associated with expression of tissue factor that activates the coagulation cascade and leads to depletion of coagulation factors leading to severe bleeding

Method used

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  • Adult liver progenitor cells for treating acute-on-chronic liver failure
  • Adult liver progenitor cells for treating acute-on-chronic liver failure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Embodiment 1: the preparation of HALPC

[0158] HALPC were prepared from livers of healthy cadaveric or beating donors as described in EP 3140393 or WO2017 / 149059. Briefly, hepatocyte preparations were resuspended in Williams'E medium supplemented with 10% FBS, 10 mg / ml INS, 1 mM DEX. primary cells in Flasks were incubated at 37 °C in 5% CO 2 cultivated in a completely humidified atmosphere. After 24 hours, the medium was changed to remove unattached cells, and refreshed twice a week thereafter while the cultures were followed microscopically daily. After 12-16 days the medium was changed to high glucose DMEM supplemented with 9% FBS. Cell types with mesenchymal-like morphology emerge and proliferate. When reaching 70-95% confluency, trypsinize cells with recombinant trypsin and 1 mM EDTA and dilute at 1-10x10 3 cells / cm 2 Density re-plated. At each passage, cells were trypsinized when they were 80-90% confluent.

[0159] Tests on the cells confirmed that they...

Embodiment 2

[0160] Example 2: Administration of HALPC to patients (interim results)

[0161] Eight patients with confirmed acute-on-chronic liver failure (ACLF) and seven patients with acute decompensation (AD) at risk of developing ACLF were treated with HALPC prepared according to Example 1 using the dosage regimen of the present invention. Cells were counted using the manual method described above. The MELD scores of the patients before treatment ranged from 18 to 35, with an average of about 27. Serum concentrations of total bilirubin were greater than 6 mg / dL (>100 umol / L) in each patient; between patients, they ranged from about 7 to about 43 mg / dL, with a mean of about 22 mg / dL. All patients received standard medical care (SMT) as required by their clinical status, but without concomitant anticoagulant therapy.

[0162] For each administration of HALPC, the vial containing the cells prepared according to Example 1 was thawed and diluted with 45 mL of a sterile liquid vehicle cont...

Embodiment 3

[0168] Example 3: Administration of HALPC to patients (full results)

[0169] The clinical trial of Example 2 was continued until a total of 22 patients were treated with the present invention. Cell counts and doses for this example were provided by the automated method described above using a Nucleocounter NC-200. In summary, patients are treated as follows:

[0170] One patient did not receive cells due to technical issues. Three patients received one infusion of approximately 600,000 cells / kg. Three additional patients received two infusions of approximately 600,000 cells / kg approximately 7 days apart. Three additional patients received a single infusion of approximately 800,000 cells / kg. Four patients received one infusion of approximately 1,200,000 cells / kg. Eight patients received two infusions of approximately 1,200,000 cells / kg approximately 7 days apart. In all cases, the infused cells were contained in a composition containing only pharmacologically insignifica...

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Abstract

The invention relates to the use of a composition comprising human adult liver- derived progenitor cells, such as heterologous human adult liver-derived progenitor cells (HALPC), for the treatment of a patient who has developed acute-on-chronic liver failure (ACLF) or is at risk of developing ACLF, wherein the treatment comprises a step of administering to the patient an amount of the composition which comprises a dose of 0.25 to 2.5 million the progenitor cells per kg body weight; the composition is substantially free of an effective amount of an anticoagulant, and the patient does not receive any co-treatment with an anticoagulant.

Description

[0001] The present invention relates to adult hepatic progenitor cells generated using primary hepatocytes for the treatment of acute-on-chronic liver failure. Background technique [0002] The liver is a major organ regulating homeostasis and the site of many metabolic pathways of life. Damage to just one protein in a complex metabolic pathway can be very harmful. The presence of important liver enzymes in large quantities greatly increases the risk of developing a variety of liver diseases. In total, there are 200 different birth defects of liver metabolism, affecting 1 in 2500 live births. Neither current treatment nor long-term management is effective enough. Orthotopic liver transplantation (OLT) is highly invasive, irreversible, limited by a shortage of donor grafts, and requires state-of-the-art surgical techniques. Liver cell transplantation (LCT) may only be effective in the short to medium term due to the quality of the hepatocyte preparation. Further improvement...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/0775C12N5/071A61K35/407A61P1/16A61K31/727
CPCA61K35/407A61P1/16A61K9/0019A61K47/42A61K47/02
Inventor N·维勒曼斯V·巴塞尔E·索卡尔J·通纳德N·贝尔蒙特Y·瓦尼洛维奇
Owner PROMETHERA THERAPEUTICS SA
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