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Botulinum toxin cell binding domain polypeptides and methods of use for treatments of fibrosis associated disorders

A botulinum toxin, binding domain technology, applied in fusion polypeptides, chemical instruments and methods, biochemical equipment and methods, etc.

Pending Publication Date: 2021-02-09
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Existing drug formulations contain full-length Clostridial toxin

Method used

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  • Botulinum toxin cell binding domain polypeptides and methods of use for treatments of fibrosis associated disorders
  • Botulinum toxin cell binding domain polypeptides and methods of use for treatments of fibrosis associated disorders
  • Botulinum toxin cell binding domain polypeptides and methods of use for treatments of fibrosis associated disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0346] Effects of the exemplary polypeptide of SEQ ID NO: 19 on cellular gene expression in normal human primary fibroblasts

[0347] With 10nM, 100nM or 1μM with the binding domain of BoNT / A (H C / A) Treat normal human primary fibroblasts with polypeptides having substantially the same amino acid sequence for 1 day (24 hours), resulting in significant dose-dependent changes in the expression of 16 fibroblast genes based on qPCR. Briefly, adult human dermal fibroblasts (HDFa) (ThermoFisher Scientific, catalog number C0135C) were cultured in MEM medium containing 2% FBS for 2 weeks, and then treated with 10 nM, 100 nM or 1 μM of SEQ ID NO: 19 peptides were treated for 1 day (24 hours). Expression of genes known to be expressed in fibroblasts and involved in ECM organization, inflammation or epidermal self-renewal (keratinocyte stem cell factor) was evaluated. cDNA was generated by reverse transcription using the SUPERSCRIPT VILO cDNA Synthesis Kit (Thermo Scientific #11754050),...

Embodiment 2

[0349] Effect of the exemplary polypeptide of SEQ ID NO: 21 on cellular gene expression in pimple scar-derived human primary fibroblasts

[0350] With the N-terminal half (H CN Treatment of pimple scar primary human fibroblasts with a polypeptide (SEQ ID NO: 21) having substantially the same amino acid sequence as / A) produced significant dose-dependent changes in the expression of six (6) fibroblast genes based on qPCR . Briefly, human dermal fibroblasts (KF116R) (cellResearchCorp Pte Ltd) were cultured in MEM medium containing 2% FBS for 2 weeks, and then treated with 1 nM, 10 nM or 1 μM of the polypeptide of SEQ ID NO: 211 day (24 hours). The expression of six (6) fibroblast-associated genes known to be involved in ECM organization and remodeling (MMP1, MMP3, and TIMP1), and epidermal differentiation and self-renewal (FGFR1, FGF7, and TP63) were evaluated. cDNA was generated by reverse transcription using the SUPERSCRIPT VILO cDNA Synthesis Kit (Thermo Scientific #117540...

Embodiment 3

[0352] Effect of the exemplary polypeptide of SEQ ID NO: 19 on collagen secretion from human primary fibroblasts derived from pimple scars

[0353] With 1μM with the binding domain of BoNT / A (H C / A) Polypeptide (SEQ ID NO: 19) with substantially the same amino acid sequence treats pimple scar human primary fibroblasts, so that the type I precursor secreted by pimple scar human primary fibroblasts into a medium containing 10% FBS Collagen C-peptide (PIP) was significantly reduced by about 30%. This reduction was similar to that observed after treatment with 0.1 μM antibody to TGF-β (approximately 20%) or 1 μM antibody to CTGF (approximately 30%). Briefly, human dermal pimple fibroblasts (KF116R) were regularly cultured in MEM medium containing 2% FBS. For experiments, cells were kept in 2% FBS medium or switched to medium containing 10% FBS with or without 1 μM of the polypeptide of SEQ ID NO: 19, 0.1 μM of anti-TGF-β mAb or 1 μM of anti-CTGF mAb deal with. After 24 hours,...

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Abstract

A polypeptide having an amino acid sequence corresponding to a binding domain of a botulinum toxin is described. The polypeptide modulates expression of genes involved in, for example, collagen production and extra cellular matrix organization, and finds use, therefore in treating or reducing the occurrence of a disease such as a disease of the ECM, a connective or epithelial tissue disease, an endothelial disease or a fibrotic disease, e.g., a fibrotic disease of the ECM, connective tissue, or endothelium. Nucleic acids encoding the polypeptide, as well as vectors, host cells, and systems comprising the nucleic acids, are further described.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 608,119, filed December 20, 2017, and U.S. Provisional Application No. 62 / 727,640, filed September 6, 2018, the entire contents of which are incorporated herein by reference. [0003] sequence listing [0004] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy was created on December 19, 2018, named 19980-US-A-NTB_SL.txt, and was 71,997 bytes in size. technical field [0005] The present disclosure relates generally to polypeptides from the cell-binding domain of botulinum toxin and uses of said polypeptides in therapeutic applications, including diseases and conditions associated with fibrosis. Background technique [0006] The anaerobic gram-positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, bo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/33A61K38/48
CPCC12N9/52A61K38/4893C12Y304/24069A61P35/00A61P13/10A61P13/08A61P1/18A61P17/02A61P17/10A61P37/00A61P17/06A61P17/08A61P29/00C07K14/33Y02A50/30A61Q19/007A61Q19/08A61Q19/008A61K9/0014A61K9/0019C07K2319/00C07K14/315A61P43/00
Inventor B·P·杰克伊A·布里多安德森H·尤D·E·弗雷尔M·F·布林
Owner ALLERGAN INC
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