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Oligonucleotide comprising an inosine for treating dmd

a technology of inosine and oligonucleotide, which is applied in the field of molecular biology and medicine, can solve the problems of calcium-activated proteases and fiber necrosis, progressive muscle wasting and weakness, and/or abnormal formation of dystrophins

Inactive Publication Date: 2016-09-15
BIOMARIN TECH BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the use of certain compounds in oligonucleotides to prevent the formation of multimers or aggregates, which can decrease the efficiency of the oligonucleotides. The compounds in question are inosine and / or compounds that can form a wobble base pair. The use of these compounds can also help alleviate symptoms associated with Duchenne Muscle Dystrophy (DMD) and other muscle-related diseases. The patent also describes the use of an ACE inhibitor, such as perindopril, which can help lower blood pressure, in a combination with other compounds for the treatment of DMD. The patent provides a method for reducing the multimerization of oligonucleotides and suggests compounds that can enhance their efficiency.

Problems solved by technology

In Duchenne dystrophin is absent, whereas in Becker some dystrophin is present but its production is most often not sufficient and / or the dystrophin present is abnormally formed.
The frameshift in the DMD gene's transcript (mRNA) results in the production of a truncated non-functional dystrophin protein, resulting in progressive muscle wasting and weakness.
In the absence of dystrophin, mechanical stress leads to sarcolemmal ruptures, causing an uncontrolled influx of calcium into the muscle fiber interior, thereby triggering calcium-activated proteases and fiber necrosis.
For most genetic muscular dystrophies no clinically applicable and effective therapies are currently available.
Hence, exon skipping techniques applied on the dystrophin gene result in the generation of at least partially functional—albeit shorter—dystrophin protein in DMD patients.

Method used

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  • Oligonucleotide comprising an inosine for treating dmd
  • Oligonucleotide comprising an inosine for treating dmd

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example 1

Materials and Methods

[0158]AON design was based on (partly) overlapping open secondary structures of the target exon RNA as predicted by the m-fold program, on (partly) overlapping putative SR-protein binding sites as predicted by the ESE-finder software. AONs were synthesized by Prosensa Therapeutics B.V. (Leiden, Netherlands), and contain 2′-O-methyl RNA and full-length phosphorothioate (PS) backbones.

[0159]Tissue Culturing, Transfection and RT-PCR Analysis

[0160]Myotube cultures derived from a healthy individual (“human control”) (examples 1, 3, and 4; exon 43, 50, 52 skipping) or a DMD patient carrying an exon 45 deletion (example 2; exon 46 skipping) were processed as described previously (Aartsma-Rus et al., Neuromuscul. Disord. 2002; 12: S71-77 and Hum Mol Genet 2003; 12(8): 907-14). For the screening of AONs, myotube cultures were transfected with 200 nM for each AON (PS220 and PS305). Transfection reagent UNIFectylin (Prosensa Therapeutics BV, Netherlands) was used, with 2 μ...

example 2

Materials and Methods

[0164]AON design was based on (partly) overlapping open secondary structures of the target exon 45 RNA as predicted by the m-fold program, on (partly) overlapping putative SR-protein binding sites as predicted by the ESE-finder software. AONs were synthesized by Prosensa Therapeutics B.V. (Leiden, Netherlands), and contain 2′-O-methyl RNA, full-length phosphorothioate (PS) backbones and one inosine for guanosine substitution.

[0165]Tissue Culturing, Transfection and RT-PCR Analysis

[0166]Myotube cultures derived from a healthy individual (“human control”) were processed as described previously (Aartsma-Rus et al., Neuromuscul. Disord. 2002; 12: S71-77 and Hum Mol Genet 2003; 12(8): 907-14). For the screening of AONs, myotube cultures were transfected with 200 nM for each AON. Transfection reagent UNIFectylin (Prosensa Therapeutics BV, Netherlands) was used, with 2 μl UNIFectylin per μg AON. Exon skipping efficiencies were determined by nested RT-PCR analysis using...

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Abstract

The invention provides an oligonucleotide comprising an inosine, and / or a nucleotide containing a base able to form a wobble base pair or a functional equivalent thereof, wherein the oligonucleotide, or a functional equivalent thereof, comprises a sequence which is complementary to at least part of a dystrophin pre-m RNA exon or at least part of a non-exon region of a dystrophin pre-m RNA said part being a contiguous stretch comprising at least 8 nucleotides. The invention further provides the use of said oligonucleotide for preventing or treating DMD or BMD.

Description

FIELD OF THE INVENTION[0001]The invention relates to the fields of molecular biology and medicine.BACKGROUND OF THE INVENTION[0002]A muscle disorder is a disease that usually has a significant impact on the life of an individual. A muscle disorder can have either a genetic cause or a non-genetic cause. An important group of muscle diseases with a genetic cause are Becker Muscular Dystrophy (BMD) and Duchenne Muscular Dystrophy (DMD). These disorders are caused by defects in a gene for a muscle protein.[0003]Becker Muscular Dystrophy and Duchenne Muscular Dystrophy are genetic muscular dystrophies with a relatively high incidence. In both Duchenne and Becker muscular dystrophy the muscle protein dystrophin is affected. In Duchenne dystrophin is absent, whereas in Becker some dystrophin is present but its production is most often not sufficient and / or the dystrophin present is abnormally formed. Both diseases are associated with recessive X-linked inheritance. DMD results from a frame...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113
CPCC12N15/113C12N2320/33C12N2310/11C12N2310/3231C12N2310/321C12N2310/315C12N2310/333C12N15/111C12N2310/331A61P21/00A61P29/00C12N2310/3521A61K48/00C12N2310/3181C12N2310/336
Inventor VAN DEUTEKOM, JUDITH CHRISTINA THEODORADE KIMPE, JOSEPHUS JOHANNESPLATENBURG, GERARD JOHANNES
Owner BIOMARIN TECH BV
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