Means and methods for modulating NOTCH3 protein expression and/or the coding region of NOTCH3; compositions and use thereof in the treatment of CADASIL

Patent metadata

Field	Value
Publication number	US-9353169-B2
Application number	US-201514738593-A
Country	US
Kind code	B2
Filing date	Jun 12, 2015
Priority date	Jan 26, 2009
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The invention among other provides means and methods for modulating NOTCH3 expression and/or protein coding domain. In one aspect the invention provides a method for at least reducing an elevated level of NOTCH3 protein in a NOTCH3 expressing cell or the immediate vicinity thereof said method comprising providing said cell with an anti-sense oligonucleotide specific for NOTCH3 mRNA or pre-mRNA thereby decreasing production of said NOTCH3 protein or thereby altering the protein coding region in said NOTCH3 mRNA or pre-mRNA.

First claim

The invention claimed is:

1. A method for producing an mRNA encoding a NOTCH3 protein having EGFL repeats with even numbers of cysteine residues from a pre-mRNA encoding a mutant NOTCH3 protein having an EGFL repeat with an uneven number of cysteine residues, comprising providing a cell expressing said pre-mRNA with at least one anti-sense oligonucleotide that is complementary to and hybridizes with an exon independently selected from 2-5 of said pre-mRNA thereby producing an mRNA encoding a NOTCH3 protein having EGFL repeats with an even number of cysteine residues.

2. A method according to claim 1 , wherein said pre-mRNA encodes a NOTCH3 protein with a mutation Arg133Cys, Cys134Trp, Arg141Cys, Cys144Phe, Arg153Cys, Cys162Trp, Arg182Cys, Tyr189Cys, Arg207Cys, Cys224Tyr, Arg207Cys, Cys224Tyr or a combination thereof.

3. A method according to claim 1 , wherein said antisense oligonucleotide comprises a modification that renders the duplex formed by the antisense oligonucleotide and the target pre-mRNA resistant to RNAseH.

4. A method according to claim 1 , wherein said oligonucleotide comprises between 15-40 nucleotides specific for said NOTCH3 mRNA or pre-mRNA.

Assignees

• Academisch Ziekenhuis Leiden

Inventors

• Lesnik Oberstein Saskia Anne-Marie Jenny
• Van Ommen Garrit-Jan Boudewijn
• Rus Adriana Marie
• Dauwerse Johannes Gregorius

Classifications

• A61P9/10

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