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Compounds and methods for modulating smn2

a technology of smn2 and rna, applied in the field of compounds, methods and pharmaceutical compositions for modulating smn2 rna, can solve the problems of inefficient inclusion of exon 7 in smn2 transcripts, and achieve the effects of reducing neuromuscular activity, reducing muscle strength, and reducing the inability or reducing the ability to stand upright, walk, and/or stand

Pending Publication Date: 2022-03-03
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for treating a neurodegenerative disease called SMA, which causes symptoms such as muscle weakness, difficulty in sitting, walking, and respiratory problems. The treatment involves using modified oligonucleotides, which are small molecules that can regulate the expression of genes. The invention provides a way to ameliorate the symptoms of SMA and improve the lives of those affected by the disease.

Problems solved by technology

SMA is an autosomal recessive disease of early onset and is a leading genetic cause of death among infants.
SMN2 contains a translationally silent mutation at position+6 of exon 7, which results in inefficient inclusion of exon 7 in SMN2 transcripts.

Method used

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  • Compounds and methods for modulating smn2
  • Compounds and methods for modulating smn2
  • Compounds and methods for modulating smn2

Examples

Experimental program
Comparison scheme
Effect test

example 1

Modified Oligonucleotides Complementary to a Human SMN2 Nucleic Acid

[0286]Modified oligonucleotides complementary to a human SMN2 nucleic acid were designed and synthesized as indicated in the tables below.

[0287]The modified oligonucleotides in the tables below are 16, 17, 18, 19, or 20 nucleosides in length, as specified. The modified oligonucleotides comprise 2′-MOE sugar moieties, 2′-NMA sugar moieties, cEt sugar moieties, 2′-OMe sugar moieties, and / or 2′β-D-deoxyribosyl sugar moieties, as specified. Each internucleoside linkage throughout the modified oligonucleotides is either a phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage, as specified. Cytosines are either non-methylated cytosines or 5-methyl cytosines, as specified.

[0288]Each modified oligonucleotide listed in the tables below is 100% complementary to SEQ ID NO: 1 (GENBANK Accession No. NT_006713.14 truncated from nucleotides 19939708 to Ser. No. 19 / 967,777), unless specifically stated...

example 2

of Modified Oligonucleotides Complementary to Human SMN2 in Transgenic Mice, Single Dose (35 μg)

[0307]Activity of selected modified oligonucleotides described above was tested in human SMN2 transgenic mice. Taiwan strain of SMA Type III mice were obtained from The Jackson Laboratory (Bar Harbor, Me.). These mice lack mouse SMN and are homozygous for human SMN2 (mSMN− / −; hSMN2+ / +; FVB.Cg-Tg(SMN2)2HungSMN1tm1Hung / J, stock number 005058; Bar Harbor, Me.), or are heterozygous for mouse SMN and heterozygous for human SMN2(mSMN+ / −; hSMN2+ / −; FVB.Cg-Tg(SMN2)2HungSMN1tm1Hung / J) obtained by breeding HOM / HOM (stock #00005058) to FVB / NJ (Stock #001800).

Treatment

[0308]Homozygous or heterozygous transgenic mice were divided into groups of 4 mice each. Each mouse received a single ICV bolus of 35 μg of modified oligonucleotide. Comparator Compound Nos. 387954, 396442, and 396443 were also tested in this assay. A group of 4 mice received PBS as a negative control.

RNA Analysis

[0309]Two weeks post t...

example 3

of Modified Oligonucleotides Complementary to Human SMN2 in Transgenic Mice, Single Dose (15 μg)

[0311]Activity of selected modified oligonucleotides described above was tested in human SMN2 transgenic mice essentially as described above in Example 2. Comparator Compound Nos. 396443 and 819735 were also tested in this assay. The transgenic mice were divided into groups of 4 mice each. Each mouse received a single ICV bolus of 15 μg of modified oligonucleotide. A group of 4 mice received PBS as a negative control. Two weeks post treatment, mice were sacrificed and RNA was extracted from cortical brain tissue and spinal cord for real-time qPCR analysis of SMN2 RNA. Results are presented as fold change in RNA levels relative to PBS control, normalized to total SMN2 levels. Each of Tables 19-23 represents a different experiment.

TABLE 19Effect of modified oligonucleotideson human SMN2 RNA splicing in homozygous transgenic miceCompoundDoseCORTEXSPINAL CORDNo.(μg)exon 7+exon 7−exon 7+exon 7...

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Abstract

Provided are compounds, methods, and pharmaceutical compositions for modulating SMN2 RNA and / or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a neurodegenerative disorder. Such symptoms include reduced muscle strength; inability or reduced ability to sit upright, to stand, and / or walk; reduced neuromuscular activity; reduced electrical activity in one or more muscles; reduced respiration; inability or reduced ability to eat, drink, and / or breathe without assistance; loss of weight or reduced weight gain; and / or decreased survival.

Description

SEQUENCE LISTING[0001]The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0367USSEQ_ST25.txt, created on Feb. 26, 2021, which is 44 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.FIELD[0002]Provided are compounds, methods, and pharmaceutical compositions for modulating SMN2 RNA in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a neurodegenerative disorder. Such symptoms include reduced muscle strength; inability or reduced ability to sit upright, to stand, and / or walk; reduced neuromuscular activity; reduced electrical activity in one or more muscles; reduced respiration; inability or reduced ability to eat, drink, and / or breathe without assistance; loss of weight or reduced weight gain; and / or decreased survival.BACKGROUND[0003]Pro...

Claims

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Application Information

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IPC IPC(8): C12N15/113
CPCC12N15/113C12N2310/11C12N2310/3341C12N2310/321C12N2310/315C12N2310/322A61K31/712A61K31/7125A61K31/713C12N2310/3515C12N2310/345C12N2310/346C12N2320/33C12N2310/3521C12N2310/3525A61K48/00A61P25/28
Inventor RIGO, FRANKPRAKASH, THAZHA P.LING, KAR YUN KARENWAN, W. BRADDRURY, III, WILLIAM JOHN
Owner IONIS PHARMA INC