EXON SKIPPING THERAPY FOR DYSTROPHIC EPIDERMOLYSIS BULLOSA

• US 20140288155A1
• Filed: 10/11/2012
• Published: 09/25/2014
• Est. Priority Date: 10/11/2011
• Status: Active Grant

• Current Assignee: Assistance Publique - Hopitaux De Paris, Association Francaise Contre Les Myopathies, Inserm (institut national de la sant et de la recherche mdicale, Universite Paris CITE
• Original Assignee: Inserm (institut national de la sant et de la recherche mdicale, Université Paris Descartes
• Inventors: Hovnanian, Alain, Titeux, Matthias, Turczynski, Sandrina
• Granted Patent: US 9,340,783 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

The present invention also relates to an antisense oligonucleotide complementary to a nucleic acid sequence of COL7A1 gene that is necessary for correct splicing of one or more exons which encode amino acid sequence of type VII collagen implicated in dysfunction of a mutated type VII collagen wherein said exons are selected from the group consisting of exon 73, 74 or 80 of the COL7A1 gene. The present invention also relates to a method for the treatment of a patient suffering from Dystrophic Epidermolysis Bullosa caused by a dysfunction of a mutated type VII collagen, comprising the step of administering to said patient a least one antisense oligonucleotide according to the invention.

Claims

1. A method for restoring the function of a mutated type VII collagen comprising the step of preventing splicing of one or more exons which encode amino acid sequence of type VII collagen implicated in dysfunction of a mutated type VII collagen wherein said exons are selected from the group consisting of exon 73, 74 or 80 of the COL7A1 gene.

2. An antisense oligonucleotide complementary to a nucleic acid sequence of COL7A1 gene that is necessary for correct splicing of one or more exons which encode amino acid sequence of type VII collagen implicated in dysfunction of a mutated type VII collagen wherein said exons are selected from the group consisting of exon 73, 74 or 80 of the COL7A1 gene.

3. The antisense oligonucleotide according to claim 2 which is selected from the group consisting of sequences ESE73.3 (SEQ ID NO:

1), ESE73.7 (SEQ ID NO;

2), SA+ESE-74 (SEQ ID NO;

3), SA+ESE-74_R2063W (SEQ ID NO;

4), ESE-74.2+SD (SEQ ID NO;

5), ESE-80.3 (SEQ ID NO;

6) and ESE80-3_Q2170X (SEQ ID NO;

7).

4. The antisense oligonucleotide according to claim 2 which is inserted in a vector.

6. A pharmaceutical composition comprising at least one antisense oligonucleotide according to claim 2.

5. (canceled)

7. A method of treating a patient suffering from Dystrophic Epidermolysis Bullosa comprising the step of

administering to the patient, in an amount sufficient to ameliorate symptoms of said Dystrophic Epidermolysis Bullosa, an antisense oligonucleotide complementary to a nucleic acid sequence of COL7A1 gene that is necessary for correct splicing of one or more exons which encode amino acid sequence of type VII collagen implicated in dysfunction of a mutated type VII collagen wherein said exons are selected from the group consisting of exon 73, 74 or 80 of the COL7A1 gene.

8. The method of claim 7, wherein said antisense oligonucleotide is selected from the group consisting of sequences ESE73.3 (SEQ ID NO:

1), ESE73.7 (SEQ ID NO;

2), SA+ESE-74 (SEQ ID NO;

3), SA+ESE-74_R2063W (SEQ ID NO;

4), ESE-74.2+SD (SEQ ID NO;

5), ESE-80.3 (SEQ ID NO;

6) and ESE80-3_Q2170X (SEQ ID NO;

7).