Academisch Ziekenhuis Leiden

Biomarin Technologies B.v.

Academisch Ziekenhuis Leiden (h.o.d.n. Lumc)

Rijksuniversiteit Te Leiden

Prosensa Technologies B.v.

Academisch Ziekenbuls Leiden

Prosensa Holding Bv

Prosensa B.v.

Garrit-Jan Boudewijn Van Ommen

Annemieke Aartsma-Rus

Judith Christina Theodora Van Deutekom

Josephus Johannes De Kimpe

Gerard Johannes Platenburg

Adriana Marie Rus

Johannes Theodorus Den Dunnen

Wilhelmina M C Van Roon-Mom

Melvin Maurice Evers

Barry Antonius Pepers

Johannes Gregorius Dauwerse

Peter Devilee

Egbert Bakker

Anne Petrij-Bos

Saskia Anne-Marie Jenny Lesnik Oberstein

Gerardus Johannes Platenburg

Judith C T Van Deutekom

Wilhelmina Maria Clasina Van Roon-Mom

Judith Christina T Van Deutekom

Aliye Seda Ylmaz-Elis

Joseph Stephan Verbeek

Peter Abraham Christiaan 'T Hoen

Petronella Johanna Elisabeth Sterrenberg

Aliye Seda Yilmaz-Elis

The. invention relates to a method for inducing or promoting skipping of exon 45 of DMD pre-mRNA in a Duchenne Muscular Dystrophy patient, preferably in an isolated (muscle) cell, the method comprising providing said cell with an antisense molecule that binds to a continuous stretch of at least 21 nucleotides within said exon. The invention further relates to such antisense molecule used in said method.

Methods and means for efficient skipping of exon 45 in Duchenne muscular dystrophy pre-mRNA

The invention provides means and methods for alleviating one or more symptom(s) of Duchenne Muscular Dystrophy and/or Becker Muscular Dystrophy. Therapies using compounds for providing patients with functional muscle proteins are combined with at least one adjunct compound for reducing inflammation, preferably for reducing muscle tissue inflammation, and/or at least one adjunct compound for improving muscle fiber function, integrity and/or survival.

Means and methods for counteracting muscle disorders

Described are methods for removing a proteolytic cleavage site, the HCHWA-D mutation or the amino acids encoded by a trinucleotide repeat expansion from a protein comprising providing a cell that expresses pre-mRNA encoding the protein with an anti-sense oligonucleotide that induces skipping of the exonic sequence that comprises the proteolytic cleavage site, HCHWA-D mutation or trinucleotide repeat expansion, respectively, the method further comprising allowing translation of mRNA produced from the pre-mRNA.

Antisense oligonucleotide directed removal of proteolytic cleavage sites, the HCHWA-D mutation, and trinucleotide repeat expansions

The invention relates to means and methods for removing a proteolytic cleavage site from a protein comprising providing a cell that expresses pre-mRNA encoding the protein with an anti-sense oligonucleotide that induces skipping of the exonic sequence that encodes the proteolytic cleavage site, the method further comprising allowing translation of mRNA produced from the pre-mRNA.

Antisense oligonucleotide directed removal of proteolytic cleavage sites from proteins

The invention relates to a nucleic acid molecule that binds and/or is complementary to the nucleotide molecule having sequence 5'-GUGGCUAACAGAAGCU (SEQ ID NO 1) and to its use in a method for inducing skipping of exon 44 of the DMD gene in a DMD patient.

Method for efficient exon (44) skipping in duchenne muscular dystrophy and associated means

The invention relates to oligonucleotides for inducing skipping of exon 53 of the dystrophin gene. The invention also relates to methods of inducing exon 53 skipping using the oligonucleotides.

Modulation of exon recognition in pre-mRNA by interfering with the secondary RNA structure

The invention relates to a method for inducing or promoting skipping of exon 45 of DMD pre-mRNA in a Duchenne Muscular Dystrophy patient, preferably in an isolated (muscle) cell, the method comprising providing an isolated muscle cell with a molecule that binds to a continuous stretch of at least 21 nucleotides within said exon. The invention further relates to such molecule used in the method.

The invention provides a method for generating an oligonucleotide with which an exon may be skipped in a pre-mRNA and thus excluded from a produced mRNA thereof. Further provided are methods for altering the secondary structure of an mRNA to interfere with splicing processes and uses of the oligonucleotides and methods in the treatment of disease. Further provided are pharmaceutical compositions and methods and means for inducing skipping of several exons in a pre-mRNA.

Described are means and methods for removing a proteolytic cleavage site from a protein, the method comprising providing a cell that expresses pre-mRNA encoding the protein with an anti-sense oligonucleotide that induces skipping of the exonic sequence that encodes the proteolytic cleavage site, and allowing translation of mRNA produced from the pre-mRNA.

The invention relates to a method for inducing or promoting skipping of exon 45 of DMD pre-mRNA in a Duchenne Muscular Dystrophy patient, preferably in an isolated (muscle) cell, the method comprising providing an isolated muscle cell with a molecule that binds to a continuous stretch of at least 21 nucleotides within the exon. The invention further relates to such molecule used in the method.

Methods and means for efficient skipping of exon 45 in duchenne muscular dystrophy pre-mRNA

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.

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

The invention relates to oligonucleotides that bind to and induce skipping of exon 44 in the human dystrophin pre-mRNA, and methods of use.

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 m RNA or pre-m RNA thereby decreasing production of said NOTCH3 protein or thereby altering the protein coding region in said NOTCH3 m RNA or pre-m RNA.

The invention provides two types of oligonucleotides for treating an inflammatory disorder: an oligonucleotide which is able of altering the splicing of a pre-mRNA encoding a C5 in order to decrease the amount of a C5a and an oligonucleotide which is able of altering the splicing of a pre-mRNA encoding a IL-1RAcP in order to increase the amount of a soluble IL-1RAcP. The invention further provides the use of said oligonucleotides for preventing or treating an inflammatory disorder.

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Amsterdam, Netherlands

Garrit-Jan Boudewijn Van Ommen