Compositions and methods for reducing spliceopathy and treating RNA dominance disorders

An endogenous, exonic technology, applied in the field of composition of genetic diseases, can solve the problem of lack of successful treatment and mitigation

Pending Publication Date: 2021-03-09
UNIV OF WASHINGTON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Available strategies to successfully treat and alleviate the symptoms of myotonic dystrophy, other than those associated with RNA dominance, are lacking and there remains a need for effective therapies against these diseases

Method used

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  • Compositions and methods for reducing spliceopathy and treating RNA dominance disorders
  • Compositions and methods for reducing spliceopathy and treating RNA dominance disorders
  • Compositions and methods for reducing spliceopathy and treating RNA dominance disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Example 1. Development and evaluation of adeno-associated viral vectors encoding miRNA constructs for the treatment of RNA-dominantly associated diseases

[0203] Purpose

[0204] This example describes a series of experiments performed to characterize the encoding of LR Development and evaluation of rAAV vectors for miRNA constructs, the murine HSA LR Expressed in a mouse model of the RNA-dominant disease, myotonic dystrophy. Myotonic dystrophy (DM) is caused by the expansion of microsatellite repeats, which results in the expression of toxic expanded repeat mRNAs. Another RNA-dominant disorder, facial scapulohumeral dystrophy (FSHD), is caused by a reduction in the D4Z4 david satellite repeat, which leads to expression of the toxic protein DUX4 in adult muscle. The aim of the experiments described in this example was to develop AAV vectors encoding miRNA constructs targeting muscle DM and FSHD-associated mRNAs, thereby preventing muscle dysfunction and loss in affe...

Embodiment 2

[0219] Example 2. Treatment of Myotonic Dystrophy in Human Patients by Administration of Viral Vectors Encoding miRNAs Against DMPK

[0220] Using the compositions and methods described herein, one skilled in the art can administer a viral vector encoding an miRNA that anneals to a mutant DMPK RNA transcript containing an expanded CUG repeat region to a patient with myotonic dystrophy type I. and reduce its expression. The vector may be an AAV vector, such as a pseudotyped AAV2 / 8 or AAV2 / 9 vector. The vector can be administered by one or more of the routes of administration described herein, eg, by intravenous, intrathecal, intracerebroventricular, intraparenchymal, intracisternal, intramuscular or subcutaneous injection. The encoded miRNA may be a miRNA characterized herein, such as a miRNA having a nucleic acid sequence of any one of SEQ ID NO: 40-161.

[0221] Following administration of the vector, physicians can monitor disease progression and therapeutic efficacy by as...

Embodiment 3

[0222] Example 3. Treatment of myotonic dystrophy in human patients by administration of siRNA oligonucleotides against DMPK

[0223] Using the compositions and methods described herein, one skilled in the art can administer to patients with myotonic dystrophy type I siRNA oligos that anneal to and reduce expression of mutant DMPK RNA transcripts comprising expanded CUG repeat regions. Nucleotides. The oligonucleotide can have, for example, the nucleic acid sequence of any one of SEQ ID NO: 3-39.

[0224] Following administration of the oligonucleotides, physicians can monitor disease progression and treatment efficacy by assessing, for example, the concentration of correctly spliced ​​mRNA transcripts encoding SERCA1, CLCN1 and / or ZASP using the RNA detection techniques described herein. Physicians can also monitor the concentration of functional SERCA1, CLCN1 and / or ZASP protein products produced from correctly spliced ​​transcripts. Additionally or alternatively, the phys...

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Abstract

The disclosure features compositions and methods for the treatment of disorders associated with improper ribonucleic acid (RNA) splicing, including disorders characterized by nuclear retention of RNAtranscripts containing aberrantly expanded repeat regions that bind and sequester splicing factor proteins. Disclosed herein are interfering RNA constructs that suppress the expression of RNA transcripts containing expanded repeat regions, as well as viral vectors, such as adeno-associated viral vectors, encoding such interfering RNA molecules. For example, the disclosure features interfering RNAmolecules, such as siRNA, miRNA, and shRNA constructs, that anneal to dystrophia myotonica protein kinase (DMPK) RNA transcripts and attenuate the expression of DMPK RNA containing expanded CUG trinucleotide repeats. Using the compositions and methods described herein, a patient having an RNA dominance disorder, such as a human patient having myotonic dystrophy, among other conditions described herein, may be administered an interfering RNA construct or vector containing the same so as to reduce the occurrence of spliceopathy in the patient, thereby treating an underlying etiology of the disease.

Description

[0001] government license [0002] This invention was made with Government support under Grant No. R03 AR056107 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0003] The present invention relates to the field of nucleic acid biotechnology, and provides compositions and methods for treating genetic diseases related to incorrect ribonucleic acid splicing. Background technique [0004] The expression and nuclear retention of endogenous ribonucleic acid (RNA) transcripts containing abnormally expanded repeat regions leads to the development of RNA dominance, which is a variety of heritable genetic disorders, including ankylosing Pathological basis of muscular dystrophy type 1, etc.). Myotonic dystrophy is the most common form of muscular dystrophy, with an estimated frequency of about 1 in 7500 adults. RNA dominance results from gain-of-function mutations in RNA transcripts that confer undesired biologi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7105A61K48/00A61P21/00C12N15/113C12N15/63C12N15/85C12N15/86
CPCA61K31/7105A61P21/00C12N15/86C12N15/1137C12N2310/14C12N2320/32C12N2750/14143A01K2227/105A01K2267/0306A01K2217/072A61K48/00C12N9/12C12N2310/122C12N2310/141C12N2310/531C12N2750/14171C12Y207/11001
Inventor J·张伯伦
Owner UNIV OF WASHINGTON
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