Treatment Of Duchenne Muscular Dystrophy Research Articles

Systemic Injection of Peptide-PMOs into Humanized DMD Mice and Evaluation by RT-PCR and ELISA.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder due to the lack of dystrophin production. The disease is characterized by muscle wasting, with the most common causes of death being respiratory failure or heart failure. Recently, exon skipping using a phosphorodiamidate morpholino oligomer (PMO) isused as an FDA approved treatment for DMD. Peptide-conjugated PMOs (PPMOs) are used to increase exon skipping efficacy in the heart and are a promising therapy for DMD. Researchers have previously relied on high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC/MS) methods for detecting PPMO uptake, but an enzyme-linked immunosorbent assay (ELISA) has been shown to have greater sensitivity. Here, we present methodologies to determine the uptake efficiency of a PPMO into the heart and efficacy of exon 51 skipping by a PPMO injected retro-orbitally into a humanized DMD mouse model via ELISA and RT-PCR, respectively.

Advances in the treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy(DMD)is the most common fx-linked recessive inherited myopathy, which is characterized by progressive aggravation, debilitating and lethal prognosis.There is no effective curative treatment for DMD.Classical corticosteroids therapy combined with physical training and multi-disciplinary comprehensive healthcare can effectively slow the disease progression and prolong life expectancy effectively.However, it can't change the outcome of patients.New alternative cell therapy, such as bone marrow mesenchymal stem cell transplantation has a certain effect, but there are many complications and the efficacy is uncertain.Skeletal muscle satellite cell transplantation is facing the problem of cell survival and migration.Gene therapy is the most promising treatment for DMD.Traditional methods include viral-mediated mini- or micro-DMD gene replacement, exon skipping strategies.CRISPR/Cas9-based genome editing technique is a promising treatment to cure the disease.Additionally, some new treatment targets of DMD such as gene Jagged1 and P2RX7, as well as small molecular therapies such as ARM210 and SMT C1100 have also been studied.In this review, recent progress in the treatment of DMD was summarized. Key words: Duchenne muscular dystrophy; Glucocorticoid; Cell transplantation; Gene therapy

RNA-Seq Analysis of an Antisense Sequence Optimized for Exon Skipping in Duchenne Patients Reveals No Off-Target Effect.

Non-coding uridine-rich small nuclear RNAs (UsnRNAs) have emerged in recent years as effective tools for exon skipping for the treatment of Duchenne muscular dystrophy (DMD), a degenerative muscular genetic disorder. We recently showed the high capacity of a recombinant adeno-associated virus (rAAV)-U7snRNA vector to restore the reading frame of the DMD mRNA in the muscles of DMD dogs. We are now moving toward a phase I/II clinical trial with an rAAV-U7snRNA-E53, carrying an antisense sequence designed to hybridize exon 53 of the human DMD messenger. As observed for genome-editing tools, antisense sequences present a risk of off-target effects, reflecting partial hybridization onto unintended transcripts. To characterize the clinical antisense sequence, we studied its expression and explored the occurrence of its off-target effects in human in vitro models of skeletal muscle and liver. We presented a comprehensive methodology combining RNA sequencing and in silico filtering to analyze off-targets. We showed that U7snRNA-E53 induced the effective exon skipping of the DMD transcript without inducing the notable deregulation of transcripts in human cells, neither at gene expression nor at the mRNA splicing level. Altogether, these results suggest that the use of the rAAV-U7snRNA-E53 vector for exon skipping could be safe in eligible DMD patients.

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology due to lack of dystrophin and characterized by progressive muscle degeneration, impaired locomotion and premature death. The chronic presence of inflammatory cells, fibrosis and fat deposition are hallmarks of DMD muscle tissue. Many different therapeutic approaches to DMD have been tested, including cell-based and gene-based approaches, exon skipping, induction of expression of the dystrophin paralogue, utrophin, and, most recently the application of the CASPR/Cas9 genome editing system. However, corticosteroid treatment remains the gold standard therapy, even if corticosteroids have shown multiple undesirable side effects. Sertoli cells (SeC) have long been known for their ability to produce immunomodulatory and trophic factors, and have been used in a plethora of experimental models of disease. Recently, microencapsulated porcine SeC (MC-SeC) injected intraperitoneally in dystrophic mice produced morphological and functional benefits in muscles thanks to their release into the circulation of anti-inflammatory factors and heregulin β1, a known inducer of utrophin expression, thus opening a new avenue in the treatment of DMD. In order to stress the potentiality of the use of MC-SeC in the treatment of DMD, here, we examine the principal therapeutic approaches to DMD, and the properties of SeC (either nude or encapsulated into alginate-based microcapsules) and their preclinical and clinical use. Finally, we discuss the potential and future development of this latter approach.

An industry update: the latest developments in therapeutic delivery.

This industry update covers the period from 1 September through 30 September 2017, and is based on information sourced from company press releases, scientific literature, patents and various news websites. The month saw the US FDA approve three new molecular entities, Aliqopa (copanlisib dihydrochloride) (Bayer Healthcare); Solosec (secnidazole) (Symbiomix Therapeutics) and Verzenio (abemaciclib) (Eli Lilly and Co). Intarcia Therapeutics Inc. has its application for approval of a novel drug device combination of exenatide for the treatment of diabetes rejected by FDA but said that it will work to address the concerns and refile the application. The impact of biosimilars in the market is steadily increasing with seven biosimilars approved in the USA and Sandoz hoping to add to this with its announcement that FDA has accepted its Biologics License Application for a biosimilar version of Roche's Rituxan. Circassia announced positive top line results of a respiratory drug, Duaklir (for the treatment of chronic obstructive pulmonary disease) and Sarepta (for its new treatment for Duchenne muscular dystrophy). Axovant Sciences Ltd announced the failure if its drug Intepirdine in the treatment of Alzheimer's, adding to a growing list of drug failures in this area. There were a number of developments in the area of oncology with Bristol-Myers Squibb and Infinity Pharmaceuticals announcing an expansion of their collaboration looking at combination treatments, as well as Eli Lilly and Co's approval for Verzenio. Rani Therapeutics and Intra-Cellular Therapies announced successful funding rounds to support their drug programs. Allergan announced a novel licensing deal for its dry eye drug, Restasis, which it hopes would allow it to stave off patent challenges from several companies looking to develop generic versions of the drug. New research suggests that loss of sense of smell can be linked to an increased risk of developing Parkinson's disease.

Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle

Duchenne muscular dystrophy (DMD) is a debilitating X-linked disorder that is fatal. DMD patients lack the expression of the structural protein dystrophin caused by mutations within the DMD gene. The absence of functional dystrophin protein results in excessive damage from normal muscle use due to the compromised structural integrity of the dystrophin associated glycoprotein complex. As a result, DMD patients exhibit ongoing cycles of muscle destruction and regeneration that promote inflammation, fibrosis, mitochondrial dysfunction, satellite cell (SC) exhaustion and loss of skeletal and cardiac muscle function. The nuclear receptor REV-ERB suppresses myoblast differentiation and recently we have demonstrated that the REV-ERB antagonist, SR8278, stimulates muscle regeneration after acute injury. Therefore, we decided to explore whether the REV-ERB antagonist SR8278 could slow the progression of muscular dystrophy. In mdx mice SR8278 increased lean mass and muscle function, and decreased muscle fibrosis and muscle protein degradation. Interestingly, we also found that SR8278 increased the SC pool through stimulation of Notch and Wnt signaling. These results suggest that REV-ERB is a potent target for the treatment of DMD.

Timed function tests, motor function measure, and quantitative thigh muscle MRI in ambulant children with Duchenne muscular dystrophy: A cross-sectional analysis

The development of new therapeutic agents for the treatment of Duchenne muscular dystrophy has put a focus on defining outcome measures most sensitive to capture treatment effects. This cross-sectional analysis investigates the relation between validated clinical assessments such as the 6-minute walk test, motor function measure and quantitative muscle MRI of thigh muscles in ambulant Duchenne muscular dystrophy patients, aged 6.5 to 10.8 years (mean 8.2, SD 1.1). Quantitative muscle MRI included the mean fat fraction using a 2-point Dixon technique, and transverse relaxation time (T2) measurements. All clinical assessments were highly significantly inter-correlated with p < 0.001. The strongest correlation with the motor function measure and its D1-subscore was shown by the 6-minute walk test. Clinical assessments showed no correlation with age. Importantly, quantitative muscle MRI values significantly correlated with all clinical assessments with the extensors showing the strongest correlation. In contrast to the clinical assessments, quantitative muscle MRI values were highly significantly correlated with age. In conclusion, the motor function measure and timed function tests measure disease severity in a highly comparable fashion and all tests correlated with quantitative muscle MRI values quantifying fatty muscle degeneration.

Real‐World Evidence, Public Participation, and the FDA

For observers of pharmaceutical regulation and the Food and Drug Administration, these are uncertain times. Events in late 2016 raised concerns that the FDA's evidentiary standards were being weakened, compromising the agency's ability to adequately perform its regulatory and public health responsibilities. Two developments most directly contributed to these fears-the approval of eteplirsen, a treatment for Duchenne muscular dystrophy, against the recommendations of both FDA staff and an advisory committee and the December 2016 signing of the 21st Century Cures Act, which encouraged greater use by the FDA of "real-world" evidence not obtained through randomized controlled trials. The arrival of the Trump administration-with its deregulatory, industry-friendly approach-has only amplified concerns over the future of the FDA. It is too early to know whether the recent developments are truly harbingers of an FDA less likely to prevent unsafe or ineffective products from reaching the market. But elements in the two events-the role of patient narratives in deliberations regarding eteplirsen and the enthusiasm for real-world evidence in the 21st Century Cures Act-raise critical issues for the future of evidence in the FDA's work. The rigorous, inclusive approach under way to consider issues related to real-world evidence provides a model for a similarly needed inquiry regarding public participation in FDA decision-making.

The Use of Antisense Oligonucleotides for the Treatment of Duchenne Muscular Dystrophy.

Antisense oligonucleotides (AONs) hold great promise for therapeutic splice-switching correction in many genetic diseases and in particular for Duchenne muscular dystrophy (DMD), where AONs can be used to reframe the dystrophin transcript and give rise to a partially deleted but yet functional dystrophin protein. Many different chemistries of AONs can be used for splice switching modulation, and some of them have been evaluated in clinical trials for DMD. However, despite advances in AON chemistry and design, systemic use of AONs is limited due to poor tissue uptake, and sufficient therapeutic efficacy is difficult to achieve. Therefore, there is still a critical need to develop efficient AONs able to restore the expression of dystrophin in all relevant tissues and international efforts are currently on going to develop new compounds or alternative chemistries with higher therapeutic potential. Here, we describe the methods to evaluate the potency of antisense oligonucleotides, and in particular of tricyclo-DNA (tcDNA)-AONs, a novel class of AONs which displays unique pharmacological properties and unprecedented uptake in many tissues after systemic administration. We focus on the most widely used mouse model for DMD, the mdx mouse and detail methods to analyze the skipping of the mouse exon 23 both in vitro in H2K mdx cells and in vivo in the mdx mouse model.

PMO Delivery System Using Bubble Liposomes and Ultrasound Exposure for Duchenne Muscular Dystrophy Treatment.

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration, caused by nonsense or frameshift mutations in the dystrophin (DMD) gene. Antisense oligonucleotides can be used to induce specific exon skipping; recently, a phosphorodiamidate morpholino oligomer (PMO) has been approved for clinical use in DMD. However, an efficient PMO delivery strategy is required to improve the therapeutic efficacy in DMD patients. We previously developed polyethylene glycol (PEG)-modified liposomes containing ultrasound contrast gas, "Bubble liposomes" (BLs), and found that the combination of BLs with ultrasound exposure is a useful gene delivery tool. Here, we describe an efficient PMO delivery strategy using the combination of BLs and ultrasound exposure to treat muscles in a DMD mouse model (mdx). This ultrasound-mediated BL technique can increase the PMO-mediated exon-skipping efficiency, leading to significantly increased dystrophin expression. Thus, the combination of BLs and ultrasound exposure may be a feasible PMO delivery method to improve therapeutic efficacy and reduce the PMO dosage for DMD treatment.

Respiratory involvement in neuromuscular disorders.

In numerous neuromuscular disorders (NMDs), respiratory muscle weakness is present, and acute or chronic respiratory failure may evolve. Very often, respiratory involvement substantially adds to the burden of disease, impairs quality of life, or reduces life expectancy. This article summarizes new aspects of both diagnosis and management of respiratory muscle weakness in patients with NMDs. Drugs like deflazacort, ataluren, eteplirsen, and nusinersen are now approved treatments for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, and others are on their way in NMDs. Although observing how innovative drugs will change the natural history of these diseases, including respiratory function over time, adequate symptomatic treatment remains meaningful and is strongly recommended. Physicians should systematically take respiratory involvement into account to improve patients' quality of life and prognosis. First, it is outlined in which subtypes of NMD respiratory muscle dysfunction is particularly relevant. Second, new developments regarding diagnostic procedures, including respiratory muscle strength testing, spirometry, and sleep studies, are covered. Third, this article gives an overview on current concepts of ventilatory support and management of secretions in patients with NMD.

The FDA Approval of Eteplirsen – Necessary Flexibility or a Worrying Precedent?

In November 2016, eteplirsen received FDA-accelerated approval for the treatment of Duchenne muscular dystrophy (DMD). This was controversial; a small, non-comparative dataset demonstrated what FDA reviewers considered to be minor benefits in a surrogate marker (dystrophin). The FDA advisory panel voted against approval but their advice wasn’t followed. This research will evaluate eteplirsen’s FDA-approval in the context of its two main competitors: drisapersen (FDA-rejected), and ataluren (not accepted for FDA-review, but EMA-approved). Publically-available FDA Summary Review documentation on the DMD appraisals were analysed and compared. Drisapersen was FDA-rejected primarily due to lack of efficacy in phase 3, despite significantly improving 6-minute walk distance (6MWD) versus placebo in phase 2. Ataluren claimed positive phase 2b data based on increasing dystrophin versus baseline, but a follow-on placebo-controlled phase 3 trial did not meet its primary endpoint of significantly improving 6MWD. The FDA judged the company’s filing incomplete, not warranting review. Eteplirsen was FDA-approved on the basis of a statistically significant improvement in dystrophin levels from a non-comparative dataset versus baseline and compared with historical controls, however the analysis methodology and its clinical significance were questioned. The FDA-approval of eteplirsen is arguably problematic given that other putative DMD treatments showed benefits in Phase 2 that was not confirmed in Phase 3. But how strong should the level of evidence be for a positive benefit–risk profile? With eteplirsen’s benign toxicity profile and the severe unmet need, arguably this could be set quite low. Additionally, by receiving FDA-accelerated approval, market withdrawal may follow if phase 3 data is not confirmatory. Nevertheless, approvals based on non-comparative datasets with claimed improvements in surrogate endpoints and where the link to clinical benefit has not been shown may set a worrying precedent that could undermine the FDA’s credibility, reflected in the denials/restrictions eteplirsen’s coverage by some payers.

Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues.

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience.

Management Of Duchenne Muscular Dystrophy (DMD): Results From A Global Survey Of Healthcare Providers From Nine Countries

Assess the physician perception and dynamics of management of patients with DMD. A quantitative survey was implemented in May 2017 in the U.S, Europe5(Germany/France/Italy/Spain/UK), Turkey, Colombia, Brazil among specialists treating a minimum threshold of DMD patients; physicians must have been in practice between 2-35yrs and spent >=25% of time in direct patient care. Fifty-minute survey (in local languages) captured physicians/site characteristics, perceptions of early intervention and disease management, as well as the dynamics of patient diagnostics, genetic testing, specific DMD treatment attributes and stakeholder interactions. Descriptive statistics were computed. Preliminary analysis included 170 physicians (pediatric neurologist: 51.8%; neuromuscular specialist: 28.2%; adult neurologist: 12.4%; US: 24.7%, Europe5: 45.3%, Turkey: 7.6%, Colombia: 8.8%, Brazil: 13.5%) completing the survey. Mean number of DMD patients in practice: 43.0, mean number of patients personally managed within previous12mo: 26.9; 80.6% & 80.0% physicians were affiliated with muscle centers and hospitals, respectively. Physicians used diverse pathways to treat DMD patients (not mutually-exclusive): Physical therapy/rehabilitation (92.9%), pulmonary/respiratory care (92.4%), orthopedic/orthotics (86.5%), prescription medications (84.1%), symptom management/supportive care (82.9%), cardiac care (81.8%), scoliosis management (80.0%), nutritionals/vitamins (76.5%), psychological (74.1%), palliative care (48.2%). Key physician perceptions of DMD management (rated >=5 on a likert scale of 1(strongly-disagree)-7(strongly-agree)): preserving functionality at all stages of disease is key (91.2%), delaying loss of ambulation is a meaningful outcome (90.6%), pressing need for earlier detection of DMD (87.7%) and earlier start of treatment (86.5%), early diagnosis/treatment could meaningfully delay irreversible muscle damage (84.5%); 84.1% discussed genetic-test results with patients; 68.8%, 57.7% and42.9% reported using timed function tests, 6-minute walk test and north star ambulatory assessment to measure disease progression, respectively. This cohort of physicians highlighted the diversity in DMD disease management. Majority of physicians highlighted the importance of early DMD diagnosis/treatment, preserving functionality and delay loss of ambulation.

LB1000 Differentiation of dermal papilla cells into a myogenic lineage for the treatment of duchenne muscular dystrophy

LB1000 Differentiation of dermal papilla cells into a myogenic lineage for the treatment of duchenne muscular dystrophy

Eteplirsen for the Treatment of Duchenne Muscular Dystrophy: Quality of Evidence Concerns-an Alternative Viewpoint.

We read the paper by Reinig AM and colleagues entitled “Advances in the Treatment of Duchenne Muscular Dystrophy: New and Emerging Pharmacotherapies” with great interest.1 The authors discuss several novel therapies to increase production of dystrophin in myocytes, of which, eteplirsen (Exondys) is the only currently approved by the US Food & Drug Administration (FDA).2 Pharmacologic management of Duchenne muscular dystrophy (DMD) centers on the use of glucocorticoids which works by decreasing inflammation and reducing immune system activity. Steroid therapy only slows disease progression and therefore, there is a clear need for additional therapeutic options.3 This article is protected by copyright. All rights reserved.

P.393 - Computational alignment of duplex immunohistochemically-stained muscle sections in support of therapies for Duchenne muscular dystrophy

Continuous expression of utrophin protein by a utrophin modulator could be a disease modifying treatment for Duchenne muscular dystrophy (DMD) patients regardless of their dystrophin mutation. At least 3 biomarkers (a fibre identification biomarker, a regeneration biomarker, and utrophin biomarker) are needed to separate utrophin expression resulting from therapeutic intervention with a utrophin modulator from the pathophysiologic utrophin expression associated with muscle fibre regeneration. Technical challenges of multiplex assay development and analytical validation for 3 or more biomarkers limit the utility of such assays in clinical trials. Having successfully completed the analytical validation of utrophin-laminin α2 (merosin) and developmental myosin heavy chain (MHCd)-laminin α2 duplex immunohistochemical-Computational Tissue Analysis (IHC-cTA™) based assays, we have developed a fibre-based image analysis software to co-register consecutive and non-consecutive serial biopsy sections. The co-registration assay was developed utilising DMD, Becker muscular dystrophy (BMD), and control muscle biopsy sections obtained from the Wellstone Muscular Dystrophy Cooperative Research Center stained with each duplex assay highlighted above. Co-registration quality was numerically evaluated, and visually assessed by a veterinary pathologist. We demonstrate that the cTA™ approach reproducibly detects biomarker signal features (e.g., mean signal intensities), tissue morphometrics (e.g., fibre minimum diameter), and fibre classification (e.g., utrophin+/MHCd-) in whole-slide images of muscle cryosections at an individual muscle fibre resolution. This facilitates understanding of architectural and functional relationships between multiple biomarkers throughout biopsy specimens, and may provide valuable assessment of therapeutic efficacy in on-going and future clinical trials.

P.310 - A novel drug screening approach to identify new drug candidates for the treatment of Duchenne muscular dystrophy

P.310 - A novel drug screening approach to identify new drug candidates for the treatment of Duchenne muscular dystrophy

P.400 - Stunning pharmacological properties of DS-5141b, an antisense oligonucleotide consisting of 2'-O,4'-C-ethylene-bridged nucleic acids and 2'-O-methyl RNA, on dystrophin mRNA exon skipping

DS-5141b is an antisense oligonucleotide (ASO) consisting of 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) and 2'-O-methyl RNA that induces dystrophin mRNA exon 45 skipping for treatment of Duchenne muscular dystrophy (DMD). As sufficient efficacy and safety had been observed in previous non-clinical studies of DS-5141b, DS-5141b currently has been in Ph1/2 clinical trial in Japan. In a repeated dosing study once a week for 4 weeks, DS-5141b showed clear exon 45 skipping at doses over 3 mg/kg in all examined tissues, anterior tibial muscles, diaphragm, and heart in mdx mice. It was remarkable that the exon 45 skipping in heart was detected at such a low dose. Based on the results and the past reports, we are persuaded that DS-5141b is the most potent exon skipping compound among ASOs in mdx mice. On the other hand, a phosphorodiamidate morpholino oligomer (PMO) with the same nucleotide sequence as that of DS-5141b did not induce the exon skipping in the all examined tissues at doses up to 30 mg/kg. 2'-O-methyl RNA with the same nucleotide sequence as that of DS-5141b showed much weaker exon skipping at 30 mg/kg compared to DS-5141b. Therefore, it was suggested that the stunning pharmacological properties of DS-5141b could be caused mainly by ENA. One of the most possible reasons of this differentiation is that ASOs containing ENA show extremely higher affinity to complementary mRNA than PMOs and 2'-O-methyl RNAs. However, the mechanisms responsible for the potent activity of DS-5141b are not fully understood. In order to make it clear in human dystrophin gene, now we are comparing effectiveness of exon 51 skipping of ASOs consisting of ENA and 2'-O-methyl RNA to eteplirsen, recently approved for DMD treatment by FDA, using mice expressing human dystrophin by a human artificial chromosome vector.

P.239 - Identification of serum protein biomarkers for utrophin based DMD therapy

Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic.