Trail receptor agonists for treatment of fibrotic disease
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Publication Number
US-9901620-B2
Publication Date
2018-02-27
Expiration Date
Abstract
Pro-apoptotic agents such as ligands and agonists of agonistic TRAIL receptors can induce or increase apoptosis of cells that cause fibrosis and underlying diseases such as liver, pancreatic, lung and skin diseases characterized by fibrosis, cirrhosis, or complications thereof. The compositions and methods can be used to selectively remove activated hepatic stellate cells (HSCs), the originators of liver fibrosis and cirrhosis, and activated pancreatic stellate cells (PSCs), the originators of pancreas fibrosis and pancreatitis, and can be effective to reduce or prevent further chronic fibrosis by simultaneously reducing multiple fibrosis-associated molecules secreted or induced by such activated stellate cells. The compositions are typically effective to target agonistic TRAIL receptors such as TRAIL-R1/DR4 and TRAIL-R2/DR5 that are selectively expressed in activated HSCs and PSCs in physiological conditions. Ligands and agonists that can be used to target agonistic TRAIL receptors include, but are not limited to, TRAIL-R1/DR4 and/or TRAIL-R2/DR5 agonists.
Core Innovation
The invention provides a method for reversing tissue fibrosis in a subject by administering an effective amount of a pro-apoptotic TNF-related apoptosis-inducing ligand (TRAIL)-R1/DR4 or TRAIL-R2/DR5 receptor agonist. The method is directed to inducing apoptosis in hepatic stellate cells (HSCs), pancreatic stellate cells (PSCs), and activated myofibroblasts that produce or induce an excess amount of extracellular matrix resulting in fibrosis of an organ or tissue or cirrhosis.
The therapeutic concept selectively targets originator stellate cells that are associated with fibrosis and reduces multiple fibrosis-associated molecules by acting on cells responsible for fibrosis progression and maintenance. TRAIL receptor agonists include TRAIL forms and PEGylated TRAIL modalities, including full length TRAIL and TRAIL functional fragments with specified amino acid regions.
Representative TRAIL-based modalities include PEGylated TRAIL (PEG-TRAIL) and related formulations intended to deliver a pro-apoptotic TRAIL receptor agonist. The document describes TRAIL/PEG-TRAIL inducing apoptosis in activated HSCs and activated PSCs, with higher sensitivity in activated states, and describes preventing liver fibrosis, reversing established liver fibrosis, ameliorating cirrhosis with reduced ascites incidence/volume, and reducing pancreatic fibrosis.
For pancreatic disease, the document describes an alcohol-induced chronic pancreatitis model in which PEG-TRAIL reduces pancreatic fibrosis and upregulates cleaved caspase-8. The described outcomes are associated with apoptosis-related markers and fibrosis-related changes, including increased cleaved caspase-8 and detection of apoptosis in activated stellate-cell populations.
Claims Coverage
The partial content identifies one independent claim directed to a method for reversing tissue fibrosis. The independent claim contains multiple inventive elements, including selecting a specific TRAIL receptor agonist (TRAIL-R1/DR4 or TRAIL-R2/DR5), selecting among full length TRAIL/functional fragments and N-terminal PEGylated variants, and using this to induce apoptosis in specific fibrosis-driving cell populations to reverse fibrosis or cirrhosis.
Pro-apoptotic TRAIL receptor agonist for reversing fibrosis
Administering by injection to the subject an effective amount of a pro-apoptotic TNF-related apoptosis-inducing ligand (TRAIL)-R1/DR4 or TRAIL-R2/DR5 receptor agonist to reverse tissue fibrosis in the subject.
Selected TRAIL forms and N-terminal PEGylated variants
Selecting the receptor agonist from the group consisting of full length TRAIL comprising amino acids 1 to 281 of SEQ ID NO:1, full length TRAIL comprising amino acids 1 to 281 of SEQ ID NO:1 pegylated at the N-terminus, TRAIL functional fragments comprising at least amino acids 114-281 of SEQ ID NO:1, and TRAIL functional fragments comprising at least amino acids 114-281 of SEQ ID NO:1 pegylated at the N-terminus.
Apoptosis in fibrosis-producing stellate cells and activated myofibroblasts
Inducing apoptosis in hepatic stellate cells, pancreatic stellate cells, and activated myofibroblasts that produce or induce an excess amount of extracellular matrix resulting in fibrosis of an organ or tissue or cirrhosis.
Overall, claim coverage centers on an injected, pro-apoptotic TRAIL-R1/DR4 or TRAIL-R2/DR5 receptor agonist selected from specified full length TRAIL, TRAIL functional fragments, and N-terminal PEGylated variants, used to induce apoptosis in hepatic stellate cells, pancreatic stellate cells, and activated myofibroblasts that generate excess extracellular matrix leading to fibrosis or cirrhosis.
Stated Advantages
Reversing tissue fibrosis in a subject.
Inducing apoptosis in hepatic stellate cells, pancreatic stellate cells, and activated myofibroblasts that produce or induce excess extracellular matrix resulting in fibrosis or cirrhosis.
Preventing liver fibrosis.
Reversing established liver fibrosis.
Ameliorating cirrhosis.
Reducing ascites incidence/volume.
Reducing pancreatic fibrosis.
Documented Applications
Reversing tissue fibrosis, including fibrosis of an organ or tissue and cirrhosis, by administering pro-apoptotic TRAIL receptor agonists to induce apoptosis in hepatic stellate cells, pancreatic stellate cells, and activated myofibroblasts.
Liver fibrosis: preventing liver fibrosis in CCl4 rats and reversing established liver fibrosis.
Cirrhosis: ameliorating cirrhosis and reducing ascites incidence/volume.
Pancreatic fibrosis: reducing pancreatic fibrosis in an alcohol-induced chronic pancreatitis model and upregulating cleaved caspase-8.
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