RNA-mediated therapies in myotonic dystrophy

Overby, Sarah; Cerro-Herreros, Estefanía; Llamusí, Beatriz; Artero, Rubén

doi:10.1016/j.drudis.2018.08.004

Cited by 39 publications

(32 citation statements)

References 62 publications

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“…Myotonic dystrophy type 1 (DM1) is a neuromuscular diseases caused by inherited CTG repeat expansion in the gene encoding DM Protein Kinase (DMPK) (7). The CTG repeats in the gene are transcribed into mRNA which cause hairpins to form and bind with high affinity to the muscle blind-like (MBNL) family of proteins.…”

Section: Resultsmentioning

confidence: 99%

“…ASOs show robust gene silencing in extrahepatic tissues such as muscle after systemic administration but higher doses are required (6). Development of Ionis DMPK-2.5 Rx was recently discontinued because of inadequate therapeutic benefit in short-term clinical trials in patients with myotonic dystrophy type 1 (DM1) (7). We envisage that more potent ASOs with improved muscle delivery technologies would ameliorate poor efficacy of this drug in patients.…”

Section: Introductionmentioning

confidence: 99%

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Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle

Prakash

Mullick

Lee

et al. 2019

Nucleic Acids Research

104

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Enhancing the functional uptake of antisense oligonucleotide (ASO) in the muscle will be beneficial for developing ASO therapeutics targeting genes expressed in the muscle. We hypothesized that improving albumin binding will facilitate traversal of ASO from the blood compartment to the interstitium of the muscle tissues to enhance ASO functional uptake. We synthesized structurally diverse saturated and unsaturated fatty acid conjugated ASOs with a range of hydrophobicity. The binding affinity of ASO fatty acid conjugates to plasma proteins improved with fatty acid chain length and highest binding affinity was observed with ASO conjugates containing fatty acid chain length from 16 to 22 carbons. The degree of unsaturation or conformation of double bond appears to have no influence on protein binding or activity of ASO fatty acid conjugates. Activity of fatty acid ASO conjugates correlated with the affinity to albumin and the tightest albumin binder exhibited the highest activity improvement in muscle. Palmitic acid conjugation increases ASO plasma Cmax and improved delivery of ASO to interstitial space of mouse muscle. Conjugation of palmitic acid improved potency of DMPK, Cav3, CD36 and Malat-1 ASOs (3- to 7-fold) in mouse muscle. Our approach provides a foundation for developing more effective therapeutic ASOs for muscle disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle

Prakash

Mullick

Lee

et al. 2019

Nucleic Acids Research

104

View full text Add to dashboard Cite

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“…Since DM1 is incurable and fatal there is an urgent need for designing effective medicaments to delay and eventually cease the progression of the disease especially life-threatening atrophy of respiratory muscles and heart failure. Many methods for screening potential medicaments have been studied on DNA, RNA, and protein levels [ 304 , 305 ]. The most numerous and promising group of potential therapeutics is composed of small compounds and antisense oligonucleotides which release sequestered proteins from RNP inclusions due to their high affinity or complementarity to toxic repeats and sometimes induction of degradation of toxic RNA [ 305 , 306 , 307 , 308 , 309 ].…”

Section: Splicing-related Diseases Mediated By Rna Structural Arramentioning

confidence: 99%

“…Many methods for screening potential medicaments have been studied on DNA, RNA, and protein levels [ 304 , 305 ]. The most numerous and promising group of potential therapeutics is composed of small compounds and antisense oligonucleotides which release sequestered proteins from RNP inclusions due to their high affinity or complementarity to toxic repeats and sometimes induction of degradation of toxic RNA [ 305 , 306 , 307 , 308 , 309 ]. An antisense oligonucleotide-based reagent, ISIS-DMPK-2.5 RX , was the first potential DM1-specific drug which underwent clinical research [ 304 , 310 ].…”

Section: Splicing-related Diseases Mediated By Rna Structural Arramentioning

confidence: 99%

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Taylor

Sobczak

2020

IJMS

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Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this review, we describe the principles of RNA structural arrangement and briefly decipher its cis- and trans-acting cellular modulators which serve as crucial determinants of biological functionality of the RNA structure. Subsequently, we engage in a discussion about the RNA structure-mediated mechanisms of alternative splicing regulation. On one hand, the impairment of formation of optimal RNA structures may have critical consequences for the splicing outcome and further contribute to understanding the pathomechanism of severe disorders. On the other hand, the structural aspects of RNA became significant features taken into consideration in the endeavor of finding potential therapeutic treatments. Both aspects have been addressed by us emphasizing the importance of ongoing studies in both fields.

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“…DM1 is also characteristically multisystemic and degenerative, affecting body systems such as the heart and the brain (1). Several candidate therapies have been tested in DM1 models but none has reached clinical practice (2) revealing a need to find new drugs against DM1.…”

mentioning

confidence: 99%

Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

Bargiela

Sabater-Arcis

Espinosa-Espinosa

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSALR) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSALR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.

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RNA-mediated therapies in myotonic dystrophy

Cited by 39 publications

References 62 publications

Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle

Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

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