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Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy

一种反义寡核苷酸、肌强直性的技术，应用在用于肌强直性营养不良治疗的肽连接吗啉代反义寡核苷酸领域

Pending Publication Date: 2015-08-12
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this treatment modality has been shown to be effective for HSA LR Correction of the DM1-like phenotype in mice, but a systemic delivery strategy that allows multiple tissues, including multiple tissue types, to be exposed to active morpholino oligonucleotides targeting the toxic DMPK RNA transcript responsible for DM1 is still needed

Method used

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  • Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy
  • Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy
  • Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0054] In preparation of the formulations, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is usually adjusted by milling to provide a substantially homogeneous distribution in the formulation, eg about 40 mesh.

[0055] Some examples of suitable excipients or carriers include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, Cellulose, Sterile Water, Syrup and Methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and prop...

Embodiment 1

[0114] Example 1: Intramuscular injection of two different PPMO conjugates into the tibialis anterior muscle to correct abnormal RNA splicing

[0115] The large expansion of CUG trinucleotide sequences provides the basis for the gain-of-function of toxic RNAs leading to detrimental changes in RNA metabolism. Such a CUG repeat element is normally located in the 3' untranslated region of the protein kinase DMPK, but when expanded it becomes the genetic lesion of myotonic dystrophy type I (DM1), an inherited neuromuscular disease. Pathogenic DMPK transcripts containing CUG expansions are retained in ribonuclear foci as part of complexes with RNA-binding proteins such as muscle blindness-like 1 (MBNL1), leading to aberrant splicing of numerous RNA transcripts and physiological abnormalities including myotonia.

[0116] In this example, a condensation synthesis reaction was performed to generate CAG25 comprising a morpholine based on the 25 mg mer CAG sequence (Wheeler et al., ...

Embodiment 2

[0130] Example 2: Repeated IV injections of PPMO-B and PPMO-K are effective in ameliorating splicing diseases in vivo

[0131] Having confirmed that modification of CAG25 with peptides B or K does not abolish its biological activity, this example evaluates whether PPMO-B and PPMO-K can modulate HSA using an IV dosing regimen LR Effects of toxic RNA in mice.

[0132] Materials and methods

[0133] HSA LR Systematic Delivery Studies in

[0134] CAG25, PPMO-B and PPMO-K were dissolved in saline and administered to male and female HSA via tail vein IV injection at a dose of 30 mg / kg body weight LR Homozygous mice, once a week for six weeks. Blood was collected by orbital bleeding 24 hours after the last dose. Approximately one week after the final dose, mice were assessed for the presence of myotonia as described in the electromyography procedure. Mice were subsequently sacrificed and muscle sections were either frozen in liquid nitrogen for RNA analysis or embedded ...

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Abstract

Provided herein are peptide-linked morpholino (PPMO) antisense oligonucleotides that target the poly CUG repeat tract in the 3' untranslated region of the gene encoding dystrophia myotonica-protein kinase (DMPK) and methods for systemic administration of the same for the treatment of mytonic dystrophy type I (DM1).

Description

field of invention [0001] The present invention relates to cationic peptide-linked morpholino (PPMO) transfectants targeting a poly CUG repeat tract in the 3' untranslated region of the gene encoding dystrophic dystrophy protein kinase (DMPK). Sense oligonucleotides and their systemic administration for the treatment of myotonic dystrophy type I (DM1). Background of the invention [0002] Myotonic dystrophy type 1 is an autosomal dominant disorder characterized primarily by neuromuscular disease but may also involve cardiac, endocrine, gastrointestinal, and central nervous system dysfunction. A hallmark symptom of DM1 is myotonia, a defect in muscle relaxation after contraction, detected by electromyography (EMG) by persistently running repetitive action potentials in the muscle. The genetic lesion in DM1 consists of an unstable CUG trinucleotide repeat element in the 3' untranslated region of the gene encoding the protein kinase termed myotonic dystrophy protein kinas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113
CPCC12N15/113C12N2320/32C12N2310/11C12N2310/3233C12N2310/3513A61K31/712A61K47/64A61P21/00A61P21/02
Inventor A·莱杰B·温特沃思C·A·纳尔逊T·E·韦登N·克莱顿S·程
Owner GENZYME CORP
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