DOCSLIB.ORG

Pediatric Pharmacotherapy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pediatric Pharmacotherapy PEDIATRIC PHARMACOTHERAPY Volume 21 Number 2 February 2015 New Drugs for Children in the Food and Drug Administration Pipeline Marcia L. Buck, PharmD, FCCP, FPPAG everal drugs in development have the was initiated at 0.4 mg/kg given twice daily for S potential to benefit children. New Drug the first week, followed by 0.8 mg/kg twice daily Applications (NDA) and preliminary filings with for week 2 and 1.6 mg/kg twice daily for week 3. the Food and Drug Administration (FDA) in the Down-titration was done in the same manner for past 4 months include a new antiepileptic, weeks 4 and 5. The results of the study have not several long-awaited drugs for the treatment of yet been published. Several other studies of Duchenne muscular dystrophy, a brivaracetam are currently enrolling patients, chemotherapeutic agent for neuroblastoma, a including a pediatric follow-up study.4 CFTR corrector to be used in combination with ivacaftor in patients with cystic fibrosis, and a Drugs for Duchenne Muscular Dystrophy monoclonal antibody for patients with severe Ataluren eosinophilic asthma. On December 23, 2014, PTC Therapeutics announced that it will begin a rolling NDA Brivaracetam submission for ataluren (Translarna®), a new On January 21, 2015, UCB announced therapy for Duchenne muscular dystrophy regulatory filings at the FDA and the European (DMD).5 The rolling submission allows the Medicines Agency (EMA) for brivaracetam.1 manufacturer to submit completed portions of This drug, structurally similar to levetiracetam, the NDA for review by the FDA on an ongoing has a more than 30-fold higher affinity for basis, potentially avoiding delays in the approval synaptic vesicle protein 2A (SV2A) ligand in the process. Ataluren is a protein restoration therapy human cerebral cortex. Both oral and intravenous for patients with genetic diseases caused by a formulations are under investigation. Three nonsense mutation.5,6 It is estimated that 13% of phase 3 studies, enrolling over 3,000 adults and boys with DMD have a nonsense mutation in the children, have been conducted to establish the dystrophin gene. Ataluren enables a readthrough safety and efficacy of brivaracetam. A recently of the premature stop codon in the mRNA of published phase 3 randomized, double-blind, DMD patients, leading to production of full- placebo-controlled trial conducted in 398 adults length functional dystrophin protein. found that a dose of 100 mg/kg/day reduced baseline-adjusted focal seizures by 11.7% over In 2013, Finkel and colleagues published the placebo (p = 0.004).2 Thirty-six percent of results of a phase 2a open-label dose-ranging patients receiving brivaracetam achieved a study of ataluren in 38 boys with nonsense reduction in seizure frequency of 50% or greater. mutation DMD.6 Six patients (the first cohort) received ataluren at 4 mg/kg in the morning, 4 An open-label pharmacokinetic, safety, and mg/kg at midday, and 8 mg/kg in the evening for efficacy study of brivaracetam as adjunctive 28 days. The second cohort (20 children) therapy in 101 children (1 month-16 years of received 10, 10, and 20 mg/kg. The third (12 age) with epilepsy was completed in 2014.3 In children) received 20, 20, and 40 mg/kg. The patients younger than 8 years of age, primary endpoint for the study was the change in brivaracetam was initiated at a dose of 0.5 mg/kg full-length dystrophin protein expression, based given twice daily for the first week. The dose on immunostaining of muscle biopsy specimens. was increased to 1 mg/kg twice daily for week 2 Sixty-one percent of the boys demonstrated and 2 mg/kg twice daily for week 3. Patients increases in dystrophin expression. The increase were evaluated for the presence of treatment- was not associated with age, type of nonsense emergent adverse effects, change in seizure mutation, or exon location. Target ataluren frequency, and treatment adherence at the end of plasma concentrations (2-10 mcg/mL) were week 3. After assessment, the dose was reduced consistently achieved. There were no serious in the same stepwise manner on weeks 4 and 5. adverse events. Mild adverse effects included For patients 8 years of age and older, the dose nausea, vomiting, diarrhea, and abdominal pain. A phase 2b randomized, double-blind, placebo- groups at both centers, suggesting a possible controlled trial of ataluren was published in adverse effect on growth. Cataracts were more 2014.7 A total of 174 patients were enrolled of also common in the deflazacort groups. one of 37 sites. Patients were randomized to receive placebo, ataluren at a dose of 10, 10, 20 In 2013, Lebel and colleagues at Toronto’s mg/kg (40 mg/kg/day) or 20, 20, 40 mg/kg (80 Hospital for Sick Children published a long-term mg/kg/day). At week 48, the mean decline in follow-up of deflazacort in 54 boys with DMD.11 predicted 6-minute walk test (6MWT) was 7.6% The decision to initiate deflazacort was made by in the placebo group, compared to 2.7% in the the patients’ families. Patients were evaluated ataluren 40 mg/kg/day group (p = 0.055). Mean every 4-6 months for up to 15 years. Five boys in decline in the 80 mg/kg/day group was 7.7%, the non-treatment group and one in the similar to placebo, suggesting a bell-shaped deflazacort group died during follow-up. Of the exposure-response relationship. Ataluren was survivors, 6 (20%) in the deflazacort group and well tolerated, with no serious adverse effects. 22 (92%) of the controls developed scoliosis and underwent spinal surgery. There was no In the January 2015 issue of Neuromuscular difference in the frequency of long bone Disorders, Haas and colleagues published a fractures. Height, however, was impacted by review of the ataluren study data submitted to the treatment, with the patients receiving deflazacort EMA which led to the granting of a conditional measuring a mean of 17 cm less than the marketing authorization in the European Union controls. The incidence of cataracts was also on August 5, 2014.8 This excellent review significantly higher in the treatment group (70% provides not only a detailed analysis of the study versus zero). The authors concluded that the data, but also a concise review of the drug’s long-term use of glucocorticoids was associated mechanism of action and adverse effect profile, with a substantial decrease in the need for spinal as well as a benefit to risk assessment. surgery for scoliosis. Deflazacort Drisapersen On January 19, 2015, Marathon Pharmaceuticals On October 10, 2014, Prosensa announced that announced that the FDA had given deflazacort, the FDA had given drisapersen, another agent for an oxazoline derivative of prednisolone, a Fast DMD, a Fast Track designation.12 The Track designation for the treatment of patients manufacturer has begun a rolling NDA with DMD.9 The Fast Track designation was submission and anticipates completion in 2015. developed to facilitate the approval process by Drisapersen is an antisense oligonucleotide providing earlier and more frequent interaction which induces skipping of exon 51 of the human between the manufacturer and the FDA. The dystrophin pre-mRNA, resulting in production of FDA ruling also makes the drug eligible for the more function dystrophin protein.13 More than Accelerated Approval and Priority Review 300 patients from more than 25 countries have process. The drug was previously granted participated in drisapersen trials, with mixed Orphan Drug status for the treatment of patients results. While several phase 2 trials gave with DMD. The Orphan Drug designation is promising results, an unpublished 48-week given by the FDA to drug products used to treat placebo-controlled trial failed to show significant rare diseases, defined as those affecting fewer benefit in the 6MWT.14 than 200,000 patients in the U.S. Marathon anticipates filing the completed NDA in 2016. The results of the DEMAND II trial, a randomized double-blind, placebo-controlled Although it has never been approved in the U.S., phase 2 study of drisapersen for the treatment of deflazacort is widely prescribed in Canada and a DMD, were published last year by Voit and number of European countries. When compared colleagues.15 Fifty-three patients (mean age 7 to prednisone, deflazacort has been shown to years) were enrolled at 13 centers in nine cause fewer adverse effects and to better countries. Patients received either drisapersen 6 preserve bone density with long-term use. In mg/kg or placebo subcutaneously either weekly 2012, McAdam and colleagues published a or intermittently (9 doses over 10 weeks). At review of the Canadian experience with week 25, the mean 6MWT had increased by 31.5 deflazacort in DMD, using data from Montreal meters from baseline for weekly drisapersen, and Toronto to compare patients treated with with a mean difference in the change from deflazacort with those not given steroids. baseline of 35.09 meters (95% CI 7.59, 62.6, p = Deflazacort was found to slow the time to loss of 0.014) versus placebo. There was no significant ambulation in the Montreal data, from 9.6 + 1.4 improvement with intermittent dosing. The most years in the controls to 11.5 + 1.9 years. The common adverse effects were injection site percentage of DMD patients who developed reactions and subclinical proteinuria. The authors scoliosis was lower with treatment, 27% suggest the benefit of drisapersen seen in their compared to 67% of controls in Montreal and study may reflect use in a younger patient 10% versus 90% of controls in Toronto. Rates of population compared to previous studies.
Load more

Recommended publications
  • Opportunities and Challenges for Antisense Oligonucleotide Therapies
    Received: 10 January 2020 Revised: 23 April 2020 Accepted: 8 May 2020 DOI: 10.1002/jimd.12251 REVIEW ARTICLE Opportunities and challenges for antisense oligonucleotide therapies Elsa C. Kuijper1 | Atze J. Bergsma2,3 | W.W.M. Pim Pijnappel2,3 | Annemieke Aartsma-Rus1 1Department of Human Genetics, Leiden University Medical Center, Leiden, The Abstract Netherlands Antisense oligonucleotide (AON) therapies involve short strands of modi- 2Department of Pediatrics, Center for fied nucleotides that target RNA in a sequence-specific manner, inducing Lysosomal and Metabolic Diseases, targeted protein knockdown or restoration. Currently, 10 AON therapies Erasmus Medical Center, Rotterdam, The Netherlands have been approved in the United States and Europe. Nucleotides are chem- 3Department of Clinical Genetics, Center ically modified to protect AONs from degradation, enhance bioavailability for Lysosomal and Metabolic Diseases, and increase RNA affinity. Whereas single stranded AONs can efficiently Erasmus Medical Center, Rotterdam, The Netherlands be delivered systemically, delivery of double stranded AONs requires capsulation in lipid nanoparticles or binding to a conjugate as the uptake Correspondence enhancing backbone is hidden in this conformation. With improved chem- Annemieke Aartsma-Rus, LUMC Postzone S4-P, Albinusdreef 2, 2333 ZA istry, delivery vehicles and conjugates, doses can be lowered, thereby reduc- Leiden, The Netherlands. ing the risk and occurrence of side effects. AONs can be used to knockdown Email: [email protected] or restore levels of protein. Knockdown can be achieved by single stranded Communicating Editor: Carla E. Hollak or double stranded AONs binding the RNA transcript and activating RNaseH-mediated and RISC-mediated degradation respectively. Transcript binding by AONs can also prevent translation, hence reducing protein levels.
    [Show full text]
  • The Use of Ataluren in the Effective Management of Duchenne Muscular Dystrophy
    Review Neuromuscular Diseases Early Diagnosis and Treatment – The Use of Ataluren in the Effective Management of Duchenne Muscular Dystrophy Eugenio Mercuri,1 Ros Quinlivan2 and Sylvie Tuffery-Giraud3 1. Catholic University, Rome, Italy; 2. Great Ormond Street Hospital and National Hospital for Neurology and Neurosurgery, London, UK; 3. Laboratory of Genetics of Rare Diseases (LGMR), University of Montpellier, Montpellier, France DOI: https://doi.org/10.17925/ENR.2018.13.1.31 he understanding of the natural history of Duchenne muscular dystrophy (DMD) is increasing rapidly and new treatments are emerging that have the potential to substantially improve the prognosis for patients with this disabling and life-shortening disease. For many, Thowever, there is a long delay between the appearance of symptoms and DMD diagnosis, which reduces the possibility of successful treatment. DMD results from mutations in the large dystrophin gene of which one-third are de novo mutations and two-thirds are inherited from a female carrier. Roughly 75% of mutations are large rearrangements and 25% are point mutations. Certain deletions and nonsense mutations can be treated whereas many other mutations cannot currently be treated. This emphasises the need for early genetic testing to identify the mutation, guide treatment and inform genetic counselling. Treatments for DMD include corticosteroids and more recently, ataluren has been approved in Europe, the first disease-modifying therapy for treating DMD caused by nonsense mutations. The use of ataluren in DMD is supported by positive results from phase IIb and phase III studies in which the treatment produced marked improvements in the 6-minute walk test, timed function tests such as the 10 m walk/run test and the 4-stair ascent/descent test compared with placebo.
    [Show full text]
  • Are Speci C Symptoms and Signs That Will Enable the Clinician to Recognise Disease Patterns That Will Narrow Down the Differenti
    CHILDHOOD DEVELOPMENTAL SCREENING 2020 https://doi.org/10.33591/sfp.46.5.u5 UNIT NO. 5 Brumbaugh D, Case LE, Clemens PR, Hadjiyannakis S, Pandya S, Street CHILDHOOD NEUROMUSCULAR DISORDERS examiner’s hands under the armpits and assessed for any arm periodic paralysis) and the rate of progression. An acute or delay/hypotonia, neuroimaging with MRI brain and aordable gene panels targeting neuromuscular disorders promising, with near-normal motor development in some receptor but reduced transcriptional activation and therefore 3. Orthopaedic Care neuromuscular diseases has resulted in faster and more accurate slip sign, and an attempt should be made to see if the infant can subacute onset of symptoms may be suggestive of an endocrine appropriate chromosomal/genetic testing can be considered. which are faster and less costly than whole exome or whole infants. is has resulted in new recommendations for neonatal has less side eects of other steroids. Clinical trials are still Prevention of contractures may be aected with appropriate diagnosis. Furthermore, new treatments are in the pipeline or N. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointes- A/Prof Stacey Tay Kiat Hong bear weight on both legs. e infant is then put into ventral or inammatory myositis, the chronic onset of symptoms may 2. If the child has evidence of lower limb involvement and genome sequencing. e choice of whole exome or whole newborn screening of SMA as well as a treatment algorithm for underway for head-to-head comparison of Vamorolone and resting splints of the ankles. Proper seating is also key to are already available for certain neuromuscular disorders, and 11 20 tinal and nutritional management.
    [Show full text]
  • PRAC Draft Agenda of Meeting 14-17 March 2016
    14 March 2016 EMA/PRAC/199507/2016 Corr.∗ Procedure Management and Committees Support Division Pharmacovigilance Risk Assessment Committee (PRAC) Draft agenda for the meeting on 14-17 March 2016 Chair: June Raine – Vice-Chair: Almath Spooner 14 March 2016, 13:00 – 19:00, room 3/A 15 March 2016, 08:30 – 19:00, room 3/A 16 March 2016, 08:30 – 19:00, room 3/A 17 March 2016, 08:30 – 16:00, room 3/E Organisational, regulatory and methodological matters (ORGAM) 31 March 2016, 10:00 - 12:00, room 7/B, via Adobe Connect Health and safety information In accordance with the Agency’s health and safety policy, delegates are to be briefed on health, safety and emergency information and procedures prior to the start of the meeting. Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also change during the course of the review. Additional details on some of these procedures will be published in the PRAC meeting highlights once the procedures are finalised. Of note, this agenda is a working document primarily designed for PRAC members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted.
    [Show full text]
  • Annexes to the Annual Report of the European Medicines Agency 2014
    Annexes to the annual report of the European Medicines Agency 2014 Table of contents Annex 1 – Members of the Management Board ............................................................................. 2 Annex 2 – Members of the Committee for Medicinal Products for Human Use ................................... 4 Annex 3 – Members of the Pharmacovigilance Risk Assessment Committee ...................................... 6 Annex 4 – Members of the Committee for Medicinal Products for Veterinary Use ............................... 8 Annex 5 – Members of the Committee on Orphan Medicinal Products ............................................ 10 Annex 6 – Members of the Committee on Herbal Medicinal Products .............................................. 12 Annex 07 – Committee for Advanced Therapies .......................................................................... 14 Annex 8 – Members of the Paediatric Committee ........................................................................ 16 Annex 9 – Working parties and working groups .......................................................................... 18 Annex 10 – CHMP opinions in 2014 on medicinal products for human use ...................................... 22 Annex 11 – CVMP opinions in 2014 on medicinal products for veterinary use .................................. 36 Annex 12 – COMP opinions in 2014 on designation of orphan medicinal products ............................ 41 Annex 13 – HMPC European Union herbal monographs in 2014....................................................
    [Show full text]
  • Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease
    fgene-11-00731 July 14, 2020 Time: 11:18 # 1 REVIEW published: 14 July 2020 doi: 10.3389/fgene.2020.00731 Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease Marc Suñé-Pou1†, María J. Limeres2†, Cristina Moreno-Castro3, Cristina Hernández-Munain4, Josep M. Suñé-Negre1, María L. Cuestas2 and Carlos Suñé3* 1 Drug Development Service (SDM), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain, 2 Institute of Research in Microbiology and Medical Parasitology (IMPaM), Faculty of Medicine, University of Buenos Aires-CONICET, Buenos Aires, Argentina, 3 Department of Molecular Biology, Institute of Parasitology and Biomedicine “López-Neyra” (IPBLN-CSIC), Granada, Spain, 4 Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine “López-Neyra” (IPBLN-CSIC), Granada, Spain Alternative splicing of pre-mRNA contributes strongly to the diversity of cell- and tissue- Edited by: specific protein expression patterns. Global transcriptome analyses have suggested Rosanna Asselta, Humanitas University, Italy that >90% of human multiexon genes are alternatively spliced. Alterations in the Reviewed by: splicing process cause missplicing events that lead to genetic diseases and pathologies, Dario Balestra, including various neurological disorders, cancers, and muscular dystrophies. In recent University of Ferrara, Italy Mauricio Fernando Budini, decades, research has helped to elucidate the mechanisms regulating alternative University of Chile, Chile splicing
    [Show full text]
  • Curriculum Vitae
    Curriculum Vitae PERSONAL INFORMATION Ulrike Schara WORK EXPERIENCE 1991- 1997 Education in Paediatrics Paediatric Outpatient Centre,City Hospital Gelsenkirchen. (Germany) Paediatric Outpatient Centre. City Hospital Gelsenkirchen.<br/>Childrens Hospital, Ruhr University Bochum<br/> 1998- 2002 Senior Neuropediatrics Children&apos;s University Hospital Bochum (Germany) . 2002- 2003 Head of Neuropediatrics Children&apos;s University Hospital Bochum (Germany) 2004- 2006 Head of Neuropediatrics Children&apos;s Hospital, City of Neuss (Germany) 2007- Present Head of the Neuropaediatric Outpatient Centre and Consultant for Neuropaediatrics University of Essen (Germany) EDUCATION AND TRAINING 1991- 2012 MD, Professor Ruhr University of Bochum, Germany University of Essen (Germany) ADDITIONAL INFORMATION Expertise Publications Publcations of the past 5 years 1.Rudnik-Schöneborn S, Tölle D, Senderek J, Eggermann K, Elbracht M, Kornak U, von der Hagen M, Kirschner J, Leube B, Müller-Felber W, Schara U, von Au K, Wieczorek D, Bußmann C, Zerres K. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet. 2016 Jan;89(1):34-43 2.Byrne S, Jansen L, U-King-Im JM, Siddiqui A, Lidov HG, Bodi I, Smith L, Mein R, Cullup T, Dionisi-Vici C, Al-Gazali L, Al-Owain M, Bruwer Z, Al Thihli K, El-Garhy R, Flanigan KM, Manickam K, Zmuda E, Banks W, Gershoni-Baruch R, Mandel H, Dagan E, Raas-Rothschild A, Barash H, Filloux F, Creel D, Harris M, Hamosh A, Kölker S, Ebrahimi-Fakhari D, Hoffmann GF, Manchester D, Boyer PJ, Manzur AY, Lourenco CM, Pilz DT, Kamath A, Prabhakar P, Rao VK, Rogers RC, Ryan MM, Brown NJ, McLean CA, Said E, Schara U, Stein A, Sewry C, Travan L, Wijburg FA, Zenker M, Mohammed S, Fanto M, Gautel M, Jungbluth H.
    [Show full text]
  • 213026Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213026Orig1s000 CLINICAL REVIEW(S) Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping CLINICAL REVIEW Application Type NME, original NDA Application Number(s) NDA 213,026 (IND 118,086) Priority or Standard Priority Submit Date(s) 1/10/20 (submission 1 [clinical, nonclinical]) 6/25/20 (submission 2 [quality, complete NDA]) Received Date(s) 1/10/20; 6/25/20 PDUFA Goal Date 2/25/21 Division/Office DN1 / ON / OND / CDER Reviewer Name(s) David Hosford, ; Xiang Ling (Biometrics); Thomas Biel, Ashutosh Rao (Office of Biotechnology Products [OBP]) Review Completion Date 2/15/21 Established/Proper Name Casimersen (Proposed) Trade Name Amondys 45 Applicant Sarepta Therapeutics, Inc. (Cambridge, MA) Dosage Form(s) concentrated solution in a single use-vial for IV infusion Applicant Proposed Dosing 30mg/kg weekly Regimen(s) Applicant Proposed For the treatment of Duchenne muscular dystrophy (DMD) in Indication(s)/Population(s) patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping Recommendation on Accelerated Approval Regulatory Action Recommended For the treatment of Duchenne muscular dystrophy (DMD) in Indication(s)/Population(s) patients who have a confirmed mutation of the DMD gene that (if applicable) is amenable to exon 45 skipping 1 Reference ID: 4751845 Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping Table of Contents Glossary ........................................................................................................................................11 1. Executive Summary...............................................................................................................14 1.1. Product Introduction......................................................................................................14 1.2.
    [Show full text]
  • Systematic Mining of Gene Co-Expression Network Suggesting a New Drug Repositioning for the Effective Treatment of Duchenne Muscular Dystrophy
    Iranian Journal of Pharmaceutical Sciences 2021: 17 (1): 1-18 www.ijps.ir Original Article Systematic Mining of Gene Co-Expression Network Suggesting a New Drug Repositioning for the Effective Treatment of Duchenne Muscular Dystrophy Afshin Derakhshania, Maryam Moosavib, Saeed Nasserib, Ebrahim Miri-Moghaddamc, Hossein Safarpourb*, Behzad Baradarana,d aImmunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, bCellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran, cMolecular Medicine Department, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran, dDepartment of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Abstract Duchenne Muscular Dystrophy (DMD) is one of the most common inherited disorders worldwide. As there is currently no absolute treatment, the present systems biology study aimed to propose a new drug repositioning for DMD therapy. A microarray dataset of 16 DMD and 6 control samples were analyzed and 208 differentially expressed genes were screened. Weighted gene co-expression network analysis (WGCNA) algorithm, was applied to obtain co-expressed gene networks for the establishment of transcriptional modules related to clinical and demographic data of DMD patients. Results indicated that a maximum of 11 co-expression modules is present in datasets with a varying number of genes. Turquoise module with 3334 genes was strongly correlated with collagen fibril organization as a positive regulator in DMD pathogenesis (r=0.98, p-value=2/00E-15) through which other DMD related hub-genes were identified as COL1A1, FZD10, COL1A2, CRISPLD1, FMO1, COL5A1, COL3A1, COL5A2, TP53I3, PLAGL1, RIPK2, SBF1, MLXIP, CFAP46, and TYRP1. Drug repositioning of the turquoise module identified some candidate drugs which are not presently approved for the treatment of DMD.
    [Show full text]
  • What Is the Level of Dystrophin Expression Required for Effective
    RVC OPEN ACCESS REPOSITORY – COPYRIGHT NOTICE This is the author’s accepted manuscript. The version of record is available online via the Journal of Muscle Research and Cell Motility: https://doi.org/10.1007/s10974-019-09535-9. The full details of the published version of the article are as follows: TITLE: What is the level of dystrophin expression required for effective therapy of Duchenne muscular dystrophy? AUTHORS: DJ Wells JOURNAL TITLE: Journal of Muscle Research and Cell Motility PUBLICATION DATE: 9 July 2019 PUBLISHER: Springer Nature DOI: 10.1007/s10974-019-09535-9 What is the level of dystrophin expression required for effective therapy of Duchenne muscular dystrophy? Dominic J. Wells. Neuromuscular Diseases Group, Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street NW1 0TU, UK. [email protected] orcid.org/0000-0002-1425-6344 Abstract Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease. The disease is due to mutations in the DMD gene that encodes for a large intracellular protein called dystrophin. Dystrophin plays a critical role in linking the internal cytoskeleton of the striated muscle cell with the extracellular matrix as well as having cell signalling functions. In its absence muscle contraction is associated with cycles of damage, repair, inflammation and fibrosis with eventual loss of muscle and replacement with fat. Experiments in animal models of DMD have generated a number of different approaches to the induction of dystrophin including viral vector mediated delivery of a recombinant dystrophin gene, antisense oligonucleotide mediated exon-skipping to restore the open reading frame in the dystrophin mRNA, read-through of premature stop mutations, genome modification using CRISPR-Cas9 or cell based transfer of a functional dystrophin gene.
    [Show full text]
  • Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy
    Journal of Clinical Medicine Review Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy Fernanda Fortunato †, Rachele Rossi † , Maria Sofia Falzarano ‡ and Alessandra Ferlini *,‡ Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; [email protected] (F.F.); [email protected] (R.R.); fl[email protected] (M.S.F.) * Correspondence: fl[email protected] † Co-first authors. ‡ Co-last authors. Abstract: Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second- generation drugs now entering in clinical trials as gene therapy, potentially providing a further Citation: Fortunato, F.; Rossi, R.; effective approach to the condition. Falzarano, M.S.; Ferlini, A. Innovative Therapeutic Approaches for Duchenne Keywords: Duchenne muscular dystrophy; dystrophin restoration; antisense oligonucleotide Muscular Dystrophy.
    [Show full text]
  • Deoxyuridine Nucleotides Induce Exon-Skipping I
    RSC Advances View Article Online PAPER View Journal | View Issue Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-20-deoxyuridine Cite this: RSC Adv.,2017,7, 54542 nucleotides induce exon-skipping in vitro† Bao T. Le,ab Mick Hornum, c Pawan K. Sharma,d Poul Nielsen c and Rakesh N. Veedu *ab Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have been explored for exon-skipping applications. Herein, for the first time, we have investigated the potential of nucleobase-modified antisense oligonucleotides to induce exon-skipping. For this purpose, we have synthesised 5-(phenyltriazol)-20-deoxyuridine-modified 20-O-methyl mixmer antisense Received 5th October 2017 b oligonucleotides, and evaluated their efficacy to induce exon-23 skipping in H-2K -tsA58 (H2K) mdx Accepted 21st November 2017 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. mouse myotubes as a model system. Our results showed that the phenyltriazol base-modified AOs DOI: 10.1039/c7ra10964d successfully induced efficient exon-skipping in a DMD transcript. Our findings open up the exploration rsc.li/rsc-advances of novel base-modified antisense oligonucleotides for exon-skipping applications. 0 0 Introduction drug candidate drisapersen composed of 2 -O-methyl (2 -O-Me) nucleotides on a phosphorothioate (PS) backbone entered Antisense oligonucleotide (AO)-based therapy has now been phase-3 clinical trials, and was later rejected by the FDA based established as one of the most promising approaches for the on poor efficacy and toxicity issues.
    [Show full text]