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

Abstract

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 13 / 814,203, filed Apr. 12, 2013, pending, which application is a national phase entry under 35 U.S.C. §371 of International Patent Application PCT / NL2011 / 050549, filed Aug. 4, 2011, designating the United States of America and published in English as International Patent Publication WO 2012 / 018257 A1 on Feb. 9, 2012, which claims the benefit under Article 8 of the Patent Cooperation Treaty and under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 61 / 370,855, filed Aug. 5, 2010, and to European Patent Application Serial No. 10172076.1, filed Aug. 5, 2010, the entire disclosure of each of which is hereby incorporated herein by this reference.STATEMENT ACCORDING TO 37 C.F.R. §1.821(c) or (e)—SEQUENCE LISTING SUBMITTED AS A TXT AND PDF FILES[0002]Pursuant to 37 C.F.R. §1.821(c) or (e), files containing a TXT version and a PDF version of the Sequen...

AI Technical Summary

Benefits of technology

This patent is about a new way to reduce the harmful effects of a mutant protein called ataxin-3, which is associated with a neurodegenerative disorder called spinocerebellar ataxia (SCA). The method involves using special RNA molecules called AONs to stop the production of ataxin-3 by specifically targeting a part of the gene that codes for the protein. This approach does not require modifying the gene itself, but rather prevents the production of harmful parts of the protein. By doing this, it is possible to reduce the toxic properties of ataxin-3 while maintaining its normal functions. This patent is useful for treating individuals with SCA and other neurodegenerative disorders caused by the buildup of harmful proteins.

Problems solved by technology

Although this can be done in the laboratory, it is difficult to implement such strategies in the clinic, if only because gene therapy applications that rely on the introduction of a complete gene are, at present, not very efficient, and the original gene associated with the problem is not removed.

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