Sequence 951 (Pip6d)

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Sequence Pip6d
Target n/a
Description Control
Design cell-penetrating peptide
Chemistry Amino acids
Sequence RXRRBRRXRQFLRXRBRXRB
Application delivery
Name Pip6d

References

Pip6-PMO, a new generation of peptide-oligonucleotide conjugates with improved cardiac exon skipping activity for DMD treatment. Betts C, Saleh AF, Arzumanov AA, Hammond SM, Godfrey C, Coursindel T, Gait MJ, Wood MJ. Mol Ther Nucleic Acids. 2012 Aug 14;1:e38.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Comments

Background

Description. The DMD gene encodes dystrophin, a large muscle protein that is mutant in Duchenne (OMIM 310200) and Becker (OMIM 300376) muscular dystrophy, defined as progressive deterioration of muscle tissue and resultant weakness.

Gene Function. Prochniewicz et al. (2009) noted that utrophin (128240) and dystrophin bind actin with similar affinities, but the molecular contacts are different. Dystrophin utilizes 2 low-affinity actin-binding sites, whereas utrophin utilizes a continuous actin-binding domain. Using transient phosphorescence anisotropy, they showed that both proteins restricted the amplitude and increased the rate of actin bending and twisting. However, utrophin had a much greater effect than dystrophin in reducing actin torsional rigidity, particularly with high actin saturation. Utrophin, like dystrophin, had no effect on actin aggregation or bundling. Prochniewicz et al. (2009) hypothesized that, in addition to stabilizing actin filaments from depolymerization, dystrophin and utrophin provide greater resistance to actin filament breakage due to stretching or twisting.

Animal Model. To identify potential nonmechanical roles of dystrophin, Rafael et al. (2000) tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and utrophin. Restoration of the dystrophin-associated protein complex (DAPC) with Dp71 did not prevent the structural abnormalities of the postsynaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, was able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. The authors concluded that in addition to a mechanical role, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle.

Dystrophin-deficient muscles show large reductions in expression of nitric oxide synthase (NOS1; 163731), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, Wehling et al. (2001) proposed that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented most of the muscle membrane injury that was detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. The data also showed that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. The data showed, furthermore, that depletion of macrophages by antibody in mdx mice causes significant reductions in muscle membrane injury.

Revertant fibers are muscle fibers containing a low percentage of dystrophin-positive cells. These are present in the dystrophin-deficient mdx mouse, and are believed to result from alternative splicing or second mutation events that bypass the mutation and restore an open reading frame. Crawford et al. (2001) found that newborn transgenic mice displayed approximately the same number of revertant fibers as newborn mdx mice, indicating that expression of a functional dystrophin does not suppress the initiation of revertant fiber formation. However, when the transgene encoded a functional dystrophin, revertant fibers were not detected in adult or old mdx mice. In contrast, adult transgenic mice expressing a nonfunctional dystrophin accumulated increasing numbers of revertant fibers, similar to mdx mice, suggesting that positive selection is required for the persistence of revertant fibers. The authors further provided evidence that the loss of revertant dystrophin in transgenic mdx muscle fibers overexpressing a functional dystrophin resulted from displacement of the revertant protein by the transgene-encoded dystrophin.

With a view to developing gene therapy for DMD with the adeno-associated virus vector, which can accommodate a gene of only limited length, Sakamoto et al. (2002) generated a series of rod-truncated microdystrophin cDNAs and used them, driven by a CAG promoter, to produce transgenic mdx mice. The authors showed that all 3 microdystrophins localized at the sarcolemma together with the expression of dystrophin-associated proteins. One of them, containing 4 rod repeats, greatly improved dystrophic phenotypes of mdx mice, and contractile force of the diaphragm in particular was restored to normal. The second of them, containing 3 rod repeats, resulted in modest amelioration of the dystrophic pathology, but a third, containing 1 rod repeat, showed no improvement.

Harper et al. (2002) performed a detailed functional analysis of dystrophin structural domains and showed that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, revealed that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins were fully protected against damage caused by muscle activity and were not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice resulted in a striking reversal of histopathologic features of the disease. Harper et al. (2002) concluded that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.

Previous demonstrations that the enteroviral protease 2A cleaves dystrophin (Badorff et al., 1999; Badorff et al., 2000; Lee et al., 2000) led Xiong et al. (2002) to hypothesize that dystrophin deficiency would predispose to enterovirus-induced cardiomyopathy. In dystrophin-deficient mice infected with enterovirus, Xiong et al. (2002) observed more severe cardiomyopathy, worsening over time, and greater viral replication than in infected wildtype mice. The difference appeared to be a result of more efficient release of the virus from dystrophin-deficient myocytes. In addition, Xiong et al. (2002) found that expression of wildtype dystrophin in cultured cells decreased the cytopathic effect of enteroviral infection and the release of virus from the cell. They also found that expression of a cleavage-resistant mutant dystrophin further inhibited the virally mediated cytopathic effect and viral release. The results indicated that viral infection can influence the severity and penetrance of the cardiomyopathy that occurs in the hearts of dystrophin-deficient individuals.

Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.

Fabb et al. (2002) designed an adeno-associated viral (AAV) vector containing a micro-dystrophin cDNA gene construct that is less than 3.8 kb. This construct, driven by a CMV promoter, was introduced into the skeletal muscle of 12-day-old nude/mdx mice, resulting in specific sarcolemmal expression of micro-dystrophin in more than 50% of myofibers up to 20 weeks of age, and effective restoration of the DAP complex components. Additionally, evaluation of central nucleation indicated a significant inhibition of degenerative dystrophic muscle pathology.

Warner et al. (2002) constructed transgenic mice expressing Dp260 in skeletal muscle. Dp260 lacks the N-terminal domain and a significant portion of the rod domain, but retains the rod domain actin-binding domain. Expression of the abbreviated protein restored a stable association between costameric actin and the sarcolemma, fostered assembly of the dystrophin-glycoprotein complex, and significantly slowed the progression of the dystrophy in the dystrophin-deficient mdx mouse. Although Dp260 muscles showed normal resistance to contraction-induced injury, these muscles showed dramatic reductions in force generation, similar to mdx muscles. Morphologically, Dp260 muscles displayed reduced amounts of inflammation and fibrosis, but still showed a significant, albeit reduced, amount of degeneration/regeneration. The authors concluded that data protection from contraction-induced injury may dramatically ameliorate, but not completely halt, the dystrophic process. They speculated that a nonmechanical defect, attributed to the loss of the N terminus of dystrophin, is likely responsible for the residual dystrophy observed.

Bogdanovich et al. (2002) blocked endogenous myostatin (MSTN; 601788) in mdx mice by intraperitoneal injections of blocking antibodies for 3 months and found increase in body weight, muscle mass, muscle size, and absolute muscle strength along with a significant decrease in muscle degeneration and concentrations of serum creatine kinase. Bogdanovich et al. (2002) concluded that myostatin blockade provides a novel, pharmacologic strategy for treatment of diseases associated with muscle wasting such as DMD, and circumvents the major problems associated with conventional gene therapy in these disorders.

To explore the hypothesis that the dystrophin rod domain acts as a spacer region, Harper et al. (2002a) expressed a chimeric microdystrophin transgene containing the 4-repeat rod domain of alpha-actinin-2 (102573) in mdx mice. The chimeric transgene was incapable of correcting the morphologic pathology of the mdx mouse, but still functioned to assemble the dystrophin-glycoprotein complex at the membrane and provided some protection from contraction-induced injury. The authors concluded that different spectrin-like repeats are not equivalent, and suggested that the dystrophin rod domain is not merely a spacer but likely contributes an important mechanical role to overall dystrophin function.

Most mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. Lu et al. (2003) tested this idea in vivo in the mdx dystrophic mouse by combining a potent transfection protocol with an antisense oligoribonucleotide designed to promote skipping of the mutated exon 23. The treated mice showed persistent production of dystrophin at normal levels in large numbers of muscle fibers and showed functional improvement of the treated muscle. Repeated administration enhanced dystrophin expression without eliciting immune responses. The data established the practicality of an approach that is applicable, in principle, to a majority of cases of severe dystrophinopathy.

Bertoni et al. (2003) tested the ability of chimeric RNA/DNA oligonucleotides (chimeraplasts) to alter key bases in specific splice sequences in the dystrophin gene to induce exon skipping. In mdx mouse cells, chimeraplast-mediated base conversion in the intron 22/exon 23 splice junction induced alternative splicing and the production of in-frame transcripts. Multiple alternative transcripts were induced, several of which were predicted to produce in-frame dystrophin transcripts with internal deletions. Multiple forms of dystrophin protein were observed by Western blot analysis, and the functionality of the products was demonstrated by the restoration of expression and localization of alpha-dystroglycan (DAG1; 128239) in differentiated cells. Bertoni et al. (2003) concluded that chimeraplasts can induce exon skipping by altering splice site sequences at the genomic level.

The abnormal retinal neurotransmission observed in patients with Duchenne muscular dystrophy and in some genotypes of mice lacking dystrophin has been attributed to altered expression of short products of the dystrophin gene. Dalloz et al. (2003) investigated the potential role of Dp71, the most abundant C-terminal dystrophin gene product, in retinal electrophysiology. Comparison of the scotopic ERGs between Dp71-null mice and wildtype littermates revealed a normal ERG in Dp71-null mice with no significant changes of the b-wave amplitude and kinetics. Analysis of Dmd gene products, utrophin (UTRN; 128240), and dystrophin-associated proteins (DAPs) showed that Dp71 and utrophin were localized around the blood vessels, in the ganglion cell layer (GCL), and at the inner limiting membrane (ILM). Dp71 deficiency was accompanied by an increased level of utrophin and decreased level of beta-dystroglycan (DAG1; 128239) localized in the ILM, without any apparent effect on the other DAPs. Dp71 deficiency was also associated with an impaired clustering of 2 Muller glial cell proteins: the inwardly rectifying potassium channel Kir4.1 (KCNJ10; 602208) and the water pore aquaporin-4 (AQP4; 600308). Immunostaining of both proteins decreased around blood vessels and in the ILM of Dp71-null mice, suggesting that Dp71 plays a role in the clustering and/or stabilization of the 2 proteins.

Porter et al. (2003) used temporal gene expression profiling to identify and correlate diverse transcriptional patterns in dystrophin-deficient mdx mice. Although 719 transcripts were differentially expressed at 1 or more ages in leg muscle, only 56 genes were altered in the spared extraocular muscles (EOM). Contrasting molecular signatures of affected versus spared muscles provided evidence that the absence of dystrophin alone was necessary but not sufficient to cause the patterned fibrosis, inflammation, and failure of muscle regeneration characteristic of dystrophinopathy. An aggregate disease load index (DLI) highlighted the divergent responses of EOM and leg muscle groups. Cellular process-specific DLIs in leg muscle identified positively correlated temporal expression profiles for some gene classes, and the independence of others, that are linked to major disease components. Porter et al. (2004) characterized temporal expression profiles of the diaphragm in mdx mice between postnatal days 7 and 112 and contrasted these data with hindlimb muscle findings reported by Porter et al. (2003). The 2 muscle groups principally differed in expression levels of differentially regulated genes, as opposed to nonconserved induced/repressed transcripts defining fundamentally distinct mechanisms. A postnatal divergence of the 2 wildtype muscle group expression profiles was identified that temporally correlated with the onset and progression of the dystrophic process. Porter et al. (2004) hypothesized that conserved disease mechanisms interacting with baseline differences in muscle group-specific transcriptomes may underlie their differential response to DMD.

ADAM12 (602714) is a disintegrin and metalloprotease demonstrated to prevent muscle cell necrosis in the mdx mouse (Kronqvist et al., 2002). Moghadaszadeh et al. (2003) found that transgenic mice overexpressing ADAM12 exhibited only mild myopathic changes and accelerated regeneration following acute injury. Only small changes in gene expression profiles were found between mdx/ADAM12 transgenic mice and mdx mice, suggesting that significant changes in mdx/ADAM12 muscle might occur posttranscriptionally. By immunostaining and immunoblotting, Moghadaszadeh et al. (2003) detected a 2-fold increase in expression and extrasynaptic localization of alpha-7B integrin (ITGA7; 600536) and utrophin (128240), the functional homolog of dystrophin. Expression of dystrophin-associated glycoproteins was also increased.

Using TO-2 hamsters, Toyo-Oka et al. (2004) demonstrated age-dependent cleavage and translocation of myocardial dystrophin from the sarcolemma to the myoplasm, increased sarcolemmal permeability in situ, and a correlation between the loss of dystrophin and hemodynamic indices, and between the amount of dystrophin and the survival rate. Transfer of the missing delta-sarcoglycan gene to degrading cardiomyocytes in vivo ameliorated all of the pathologic features. The authors demonstrated dystrophin disruption in rats with acute heart failure from isoproterenol toxicity or with chronic heart failure after coronary ligation. They also found dystrophin cleavage in human hearts from patients with dilated cardiomyopathy of unidentified etiology. Toyo-Oka et al. (2004) proposed a common mechanism for heart failure involving sarcolemmal instability, dystrophin cleavage, and translocation of dystrophin from the sarcolemma to the myoplasm, irrespective of whether the disease is acute or chronic, or hereditary or acquired in origin. Goyenvalle et al. (2004) achieved persistent exon skipping that removed the mutated exon on the dystrophin mRNA of the mdx mouse by single administration of an adeno-associated virus (AAV) vector expressing antisense sequences linked to a modified U7 small nuclear RNA. Goyenvalle et al. (2004) reported the sustained production of functional dystrophin at physiologic levels in entire groups of muscles and the correction of the muscular dystrophy.

Yue et al. (2004) generated female heterozygous mdx mice that persistently expressed the full-length dystrophin gene in 50% of cardiomyocytes. Heart function of mdx mice was normal in the absence of external stress. Using beta-isoproterenol challenge in 3-month-old mice, they showed that cardiomyocyte sarcolemma integrity was significantly impaired in mdx but not in heterozygous mdx and C57BL/10 mice. In vivo closed-chest hemodynamic assays revealed normal left ventricular function in beta-isoproterenol-stimulated heterozygous mdx mice. The nonuniform dystrophin expression pattern in heterozygous mdx mice resembled the pattern seen in viral gene transfer studies. Yue et al. (2004) concluded that gene therapy correction in 50% of heart cells may be sufficient to treat cardiomyopathy in mdx mice.

ARC (NOL3; 605235) is an abundant protein in human muscle that can inhibit both hypoxia and CASP8 (601763)-induced apoptosis, as well as protect cells from oxidative stress. To investigate a potential role for ARC in protecting muscle fiber from dystrophic breakdown, Abmayr et al. (2004) cloned and characterized murine Arc and studied its expression in normal and dystrophic mouse muscle. Arc expression levels were normal in mdx mice, and overexpression of Arc in mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by Arc does not significantly contribute to myofiber death.

Some patients with dystrophin mutations suffer from X-linked dilated cardiomyopathy (CMD3B; 302045) but are devoid of skeletal muscle myopathy. The absence of skeletal muscle symptoms has been attributed to expression of the brain and cerebellar Purkinje (CP) isoforms of dystrophin in skeletal, but not cardiac, muscles of CMD3B patients. Brain and cerebellar Purkinje dystrophin promoter upregulation has been attributed to activity of the dystrophin muscle enhancer-1 (DME1). De Repentigny et al. (2004) demonstrated that the mouse dystrophin CP promoter drove expression of a reporter gene specifically to the cerebellar Purkinje cell layer, but not to skeletal or cardiac muscle of transgenic mice. When the mouse counterpart of DME1 was present in the transgene construct, the dystrophin CP promoter was activated in skeletal muscle, but not in cardiac muscle.

Yasuda et al. (2005) showed that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer-188 corrects these defects in vitro. In vivo administration of poloxamer-188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Yasuda et al. (2005) suggested that once issues relating to optimal dosing and long-term effects of poloxamer-188 in humans have been resolved, chemical-based membrane sealants could represent a therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.

Both dystrophin and alpha-7/beta-1 (ITGB1; 135630) integrin have critical roles in the maintenance of muscle integrity by providing mechanical links between muscle fibers and the basement membrane. Guo et al. (2006) created Dmd/Itga7 double-knockout mice (DKO), which appeared normal at birth, but died within the first month of life with severe muscular dystrophy, endomysial fibrosis, and ectopic calcification. Progressive muscle wasting in the DKO mice was likely due to inadequate muscle regeneration, and the premature death appeared to be due to cardiac and/or respiratory failure.

Bellinger et al. (2009) found that the calcium channel Ryr1 (180901) in skeletal muscle from mdx mice showed increased inducible nitric oxide (NOS2A; 163730)-mediated S-nitrosylation of cysteine residues, which depleted the channel complex of calstabin-1 (FKBP12; 186945). This resulted in leaky channels with increased calcium flux. These changes were age-dependent and coincided with dystrophic changes in muscle. Prevention of calstabin-1 depletion from Ryr1 with S107, a compound that binds the Ryr1 channel and enhances binding affinity, inhibited sarcoplasmic reticulum calcium leak, reduced biochemical and histologic evidence of muscle damage, improved muscle function, and increased exercise performance in mdx mice. Bellinger et al. (2009) proposed that the increased calcium flux via a defective Ryr1 channel contributes to muscle weakness and degeneration in DMD by increasing calcium-activated proteases.

Li et al. (2009) generated delta-sarcoglycan (SGCD; 601411)/dystrophin double-knockout mice (delta-Dko) in which residual sarcoglycans were completely eliminated from the sarcolemma. Utrophin (UTRN; 128240) levels were increased in these mice but did not mitigate disease. The clinical manifestation of delta-Dko mice was worse than that of mdx mice. They showed characteristic dystrophic signs, body emaciation, macrophage infiltration, decreased life span, less absolute muscle force, and greater susceptibility to contraction-induced injury. Li et al. (2009) suggested that subphysiologic sarcoglycan expression may play a role in ameliorating muscle disease in mdx mice. Li et al. (2009) investigated the role and the mechanisms by which increased levels of matrix metalloproteinase-9 (MMP9; 120361) protein cause myopathy in dystrophin-deficient mdx mice. MMP9 levels but not tissue inhibitor of MMPs were drastically increased in skeletal muscle of mdx mice. Infiltrating macrophages also contributed to the elevated levels of MMP9 in dystrophic muscle. In vivo administration of NFKB-inhibitory peptide NBD blocked the expression of MMP9 in dystrophic muscle of mdx mice. Deletion of the Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation, and fiber necrosis. Inhibition of MMP9 increased the levels of cytoskeletal protein beta-dystroglycan and Nos1 and reduced the amounts of caveolin-3 (CAV3; 601253) and transforming growth factor-beta (TGFB1; 190180) in myofibers of mdx mice. Genetic ablation of MMP9 significantly augmented the skeletal muscle regeneration in mdx mice. Pharmacologic inhibition of MMP9 activity also ameliorated skeletal muscle pathogenesis and enhanced myofiber regeneration in mdx mice.

Wehling-Henricks et al. (2009) tested whether the loss of neuronal nitric oxide synthase, nNOS (NOS1; 163731), contributes to the increased fatigability of mdx mice. The expression of a muscle-specific nNOS transgene increased the endurance of mdx mice and enhanced glycogen metabolism during treadmill running, but did not affect vascular perfusion of muscles. The specific activity of phosphofructokinase (PFK; 610681), the rate-limiting enzyme in glycolysis, was positively affected by nNOS in muscle; PFK-specific activity was significantly reduced in mdx muscles and the muscles of nNOS-null mutants, but significantly increased in nNOS transgenic muscles and muscles from mdx mice that expressed the nNOS transgene. PFK activity measured under allosteric conditions was significantly increased by nNOS, but unaffected by endothelial NOS or inducible NOS. The specific domain of nNOS that positively regulates PFK activity was assayed by cloning and expressing different domains of nNOS and assaying their effects on PFK activity. This approach yielded a polypeptide that included the flavin adenine dinucleotide (FAD)-binding domain of nNOS as the region of the molecule that promotes PFK activity. A 36-amino acid peptide in the FAD-binding domain was identified in which most of the positive allosteric activity of nNOS for PFK resides. Wehling-Henricks et al. (2009) proposed that defects in glycolytic metabolism and increased fatigability in dystrophic muscle may be caused in part by the loss of positive allosteric interactions between nNOS and PFK. Miura et al. (2009) found that GW501516, a peroxisome proliferator-activated receptor PPAR-beta/delta (PPARD; 600409) agonist, stimulated utrophin A (UTRN; 128240) mRNA levels in mdx muscle cells, through an element in the utrophin A promoter. Expression of PPARD was greater in skeletal muscles of mdx versus wildtype mice. Over a 4-week trial, treatment increased the percentage of muscle fibers expressing slower myosin heavy chain isoforms and stimulated utrophin A mRNA levels, leading to its increased expression at the sarcolemma. Expression of alpha-1-syntrophin (SNTA1; 601017) and beta-dystroglycan (DAG1; 128239) was also restored to the sarcolemma. The mdx sarcolemmal integrity was improved, and treatment also conferred protection against eccentric contraction-induced damage of mdx skeletal muscles.

Long et al. (2014) used clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9)-mediated genome editing to correct the Dmd mutation in the germline of mdx mice, and then monitored muscle structure and function. Genome editing produced genetically mosaic animals containing 2 to 100% correction of the Dmd gene. The degree of muscle phenotypic rescue in mosaic mice exceeded the efficiency of gene correction, likely reflecting an advantage of the corrected cells and their contribution to regenerating muscle. Long et al. (2014) anticipated technologic advances that would facilitate genome editing of postnatal somatic cells, a strategy that may allow correction of disease-causing mutations in the muscle tissue of patients with Duchenne muscular dystrophy.

Goyenvalle et al. (2015) demonstrated for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice by the systemic delivery of exon-skipping tricyclo-DNA (tcDNA) antisense oligonucleotides. The treament promoted a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain.

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