Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
Accepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceproves muscle pathology of adult mdx miceNgoc Lu-Nguyen. Alberto Malerba. Linda Popplewell. Fred Schnell. Gunnar Hanson.George DicksonPll:S2162-2531(16)30367-5DOI:10.1016/j.omtn.2016.11.009Reference:OMTN 10To appear in:Molecular Therapy: Nucleic AcidReceived Date: 31 October 2016Revised Date: 21 Nov Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceember 2016Accepted Date: 21 November 2016Please cite this article as: Lu-Nguyen N. Malerba A, Popplewell L. Schnell F. Hanson G. Dickson G. Systemic iSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
ntravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation improves muscle pathology of aduAccepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceed for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be disc Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceovered which could affect the content, and all legal disclaimers that apply to the journal pertain.ACCEPTED MANUSCRIPTAbstractAntisense-mediated exonSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
skipping is a promising approach for the treatment of Duchenne muscular dystrophy (DMD), a rare life-threatening genetic disease due to dystrophin defAccepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micentisense therapy can be used to induce destructive skipping of myostatin pre-niRXA. knocking-down myostatin expression to enhance muscle strength and reduce fibrosis. We have previously reported that intramuscular or intraperitoneal antisense administration inducing dual exon skipping of dystrophin Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceand myostatin pre-mRNAs was beneficial in mdx mice, a mouse model of DMD. although therapeutic effects were muscletype restricted, possibly due to theSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
delivery routes used. Here, following systemic intravascular antisense treatment, muscle strength and body activity- of treated adult ntíỉx mice incrAccepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceing therapy, as compared to those receiving dystrophin antisense therapy alone. Our results support the translation of antisense therapy for dystrophin restoration and myostatin inhibition into the clinical setting for DMD.Keywords: antisense oligonucleotides. Duchenne muscular dystrophy, dystrophin Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice, exon skipping, myostatin2ACCEPTED MANUSCRIPTIntroductionDuchenne muscular dystrophy (DMĐ) is the most common fatal muscular disease in children, affSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
ecting approximately 1 in 3500 male births1. This X-hnked recessive disorder is characterized by the absence of dystrophin protein due to mutations inAccepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceintain muscle integrity3-4. The absence of dystrophin makes myofibers extremely susceptible to injury during muscle contraction that leads to progressive muscle deterioration and weakness, respirator}' insufficiency, cardiac failure, and premature death5 6.Since the identification of the genetic cau Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micese of DMD almost 30 years ago2, many strategies have been developed for symptomatic treatment of the disease, but none has yet pl oven to be curative.Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
Cun ent therapies are able to address several dystrophinopathy symptoms to improve the quality of life for DMD patients or delay the disease developmAccepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micehown abilities to collect the faulty D.\iD gene1112, to add a modified form of the D1\£D gene13-10, or to generate myofibers from engrafted mesoangioblasts1 Among these, antisense therapy has been considered as one of the most promising approaches1819 and so far the only genetic therapy to be condit Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceionally approved by FDA for DMD treatment (i.e. EXONDYS 51™ - Eteplirsen. Sarepta Therapeutic Inc.). The approach uses small antisense oligonucleotideSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
s designed to silence enhancer motifs on out-of-fiame exons in rhe DMD pre-mRNA to restore the DMD reading frame and recover production of dystrophin Accepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micePTmodels of DMD2-23. However, such approach suffers rhe limitation of DMD being often diagnosed when skeletal muscles are severely wasted and only a minor portion of muscle tissue remains. Furthermore, multiple problems developed in advanced stages of the disease (i.e. muscle infiltration with fat a Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micend connective tissue, respiratory and cardiac dysftmction. and reduced muscle function as a consequence of substantial muscle fiber loss6,24-*8) are vSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
ery challenging for this treatment. Hence, several adjunctive therapies have been recently investigated, in particular for entrancing muscle strength Accepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micegrowth and differentiation*9, an enhancer of muscle fibroblast proliferation30, and an indirect modulator of adipogenesis31. Myostatin downregulation has been reported to increase muscle mass and muscle strength in a mdx mouse model of DMD through the use of niyostatill-blocking agents like monoclon Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx miceal antibodies3233, recombinant myostatin propeptides34,35, myostatin antagonists36'37, or soluble myostatin receptors38. We and others have demonstratSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
ed that it is possible to employ antisense therapy inducing destructive exon skipping of myostatin pre-mRNA for inhibiting myostatui expression. This Accepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micerial therapy with an antisense approach restoring dystrophin in md.x mice, tlirough intramuscular41 or intraperitoneal injection22, enhanced the therapeutic benefits offered by dystrophin restoration alone.Heie we performed intravenous systemic delivery of phosphorodiainidate morpholino oligomers co Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micenjugated with B peptide (BPMOs). an arginine-rich cell-penetrating peptide, for open-reading4ACCEPTED MANUSCRIPTframe rescue of dystrophm and destructSystemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx mice
ive exon skipping of myostatin. Following ten consecutive weeks of treatment. treated rndx mice displayed increase in muscle strength to comparable leAccepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation imp Systemic antisense therapeutics for dystrophin and myostatin exon splice modulation improve muscle pathology of adult mdx micewide dystrophin restoration is combined with myostatin inhibition, compared to the single dystrophin therapy.5Accepted ManuscriptSystemic intravenous administration of antisense therapeutics for combinatorial dystrophin and myostatin exon splice modulation impGọi ngay
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