Modulation of ciliogenesis

a ciliogenesis and cell technology, applied in the field of ciliogenesis in cells, can solve the problems of high mortality rate and inefficient mucociliary clearance, and achieve the effect of improving their physical properties

Pending Publication Date: 2022-05-05
ACADEMISCH ZIEKENHUIS BIJ DE UNIV VAN AMSTERDAM ACADEMISCH MEDISCH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds restore or enhance ciliogenesis, improving mucociliary clearance and addressing the underlying cause of COPD symptoms, potentially reducing mortality by promoting the formation and function of ciliated cells in the bronchial epithelium.

Problems solved by technology

Loss of ciliated cells leads to inefficient mucociliary clearance, in particular in patients suffering from COPD.
This ineffective clearance mechanism will cause severe symptoms (including coughing, bronchopulmonary infections and inefficient gas exchange in the lung), resulting in a high mortality rate.

Method used

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  • Modulation of ciliogenesis
  • Modulation of ciliogenesis
  • Modulation of ciliogenesis

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0096]1.1: Binding of R2R1 Proteins (FAM25 Protein Family) to Polycomb Group PRC1 (Through Subunit RNF2) and Trithorax Group TrxG-MLL (Through Subunits DPY-30 and ASH2L) Chromatin Binding / Remodelling Complexes is an On / Off Switch for Ciliogenesis in the Human Pulmonary Bronchial Epithelium.

[0097]R2R1 is essential for maintenance and regeneration of the pulmonary epithelium, more particular the basal cell program. Experiments in submerged Primary Bronchial Epithelial Cells (PBECs) uncovered this function. The submerged culture conditions are characterized by rapid cell proliferation of undifferentiated PBECs. Hence, submerged culture conditions are ideal for the study of basal cells (the stem cells of the human bronchial pulmonary (‘airway’) epithelium.

[0098]Follow-up experiments were performed in order to study the function of R2R1 in differentiating / differentiated PBECs. PBECs were grown in Air Liquid Interface (‘ALI’) conditions. shRNA mediated knockdown of R2R1 gene expression in...

example 2

[0117]2.1: Restoration of ciliogenesis in COPD donor-derived PBECs in ALI conditions.

[0118]First we must determine that ciliogenesis due to the absence of R2R1 isn't limited to PBECs derived from non-COPD donors. Therefore we have to establish that:[0119](a) The expression of R2R1 can be reliably up- or downregulated in PBECs from a COPD and non-COPD donor.[0120](b) The expression of the R2R1 protein is related to the expression of the R2R1 (transcript).[0121](c) Knockdown of R2R1 expression triggers the ciliary gene expression program in PBECs from a COPD and non-COPD donor. Conversely, upregulation of R2R1 expression leads to suppression of the ciliary transcriptome.[0122](d) The transcriptomic changes need to be mirrored in the cellular phenotype. The ciliogenesis transcriptome should lead to an increase in the number of ciliated cells in ALI cultures of COPD-derived PBECs.

[0123]The following experiment demonstrates points 2.1 (a), 2.1 (b), 2.1(c) and 2.1 (d) above.

[0124]PBECs de...

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Abstract

The disclosure is based on the finding that compounds capable of binding to (or interacting with) chromatin binding / remodelling complexes (for example Polycomb group PRC1 and Trithorax group MLL) and / or modulation of the same can be used to modulate (for example switch on / off) ciliogenesis as may occur, for example, in the human pulmonary bronchial epithelium. Provided are compounds, compositions, methods and medicaments which may be used to treat and / or prevent diseases and / or conditions associated with aberrant or defective ciliogenesis.

Description

STATEMENT REGARDING ELECTRONIC FILING OF A SEQUENCE LISTING[0001]A Sequence Listing in ASCII text format, submitted under 37 C.F.R. § 1.821, entitled 9013-161CT_ST25, 11,874 bytes in size, generated on Jul. 2, 2021, and filed via EFS-Web, is provided in lieu of a paper copy. This Sequence Listing is hereby incorporated herein by reference into the specification for its disclosures.FIELD OF THE INVENTION[0002]The present invention concerns ciliogenesis in cells and provides compounds, compositions, uses, medicaments and methods to be exploited in the modulation of ciliogenesis and in the prevention and / or treatment of diseases associated with the same.BACKGROUND OF THE INVENTION[0003]The protein designated R2R1 belongs to the FAM25 protein family and is essential for maintenance and regeneration of the pulmonary epithelium, more particular the basal cell program. Experiments in submerged Primary Bronchial Epithelial Cells (PBECs) uncovered this function. The submerged culture conditi...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/7088A61K38/17A61P9/00A61P11/00C12N15/113A61K45/06A61K45/00
CPCA61K31/7088A61K38/1709A61P9/00A61P11/00C12N2310/14A61K45/06A61K45/00C12N2310/531C12N15/113
InventorVAN BREMPT, RONALD KAREL LOUISA
OwnerACADEMISCH ZIEKENHUIS BIJ DE UNIV VAN AMSTERDAM ACADEMISCH MEDISCH CENT