Systematic Mining of Gene Co-Expression Network Suggesting a New Drug Repositioning for the Effective Treatment of Duchenne Muscular Dystrophy Drug repositioning for the effective treatment of Duchenne Muscular Dystrophy
Iranian Journal of Pharmaceutical Sciences,
Vol. 17 No. 1 (2021),
15 January 2021
,
Page 1-18
https://doi.org/10.22037/ijps.v17.40292
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. The targets in the turquoise module indicated that some drugs might greatly affect DMD disease. Furthermore, drug repositioning introduced Zoledronic acid as a potent antagonist for COL1A1.
- Systems biology
- Duchenne Muscle Dystrophy
- WGCNA
- Co-expression network
- Drug Repositioning
- Data analysis
- COL1A1
How to Cite
References
[2] Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, Case LE, Clemens PR, Hadjiyannakis S, Pandya S, Street N, Tomezsko J, Wagner KR, Ward LM, Weber DR. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. (2018) 17(3): 251-267.
[3] Lionarons JM, Hellebrekers DMJ, Klinkenberg S, Faber CG, Vles JSH, Hendriksen JGM. Methylphenidate use in males with Duchenne muscular dystrophy and a comorbid attention-deficit hyperactivity disorder. Eur. J. Paediatr. Neurol. (2019) 23(1):152‐157.
[4] Amoasii L, Long C. Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci. Transl. Med. (2017)
[5] Akpulat U, Wang H, Becker K, Contreras A, Partridge TA, Novak JS, Cirak S. Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD. Mol. Ther. Nucleic Acids. (2018) 13:534-542.
[6] Min YL, Bassel-Duby R, Olson EN. CRISPR Correction of Duchenne Muscular Dystrophy. Annu Rev. Med. (2019) 70:239-255.
[7] Rancourt A, Dufresne SS, St-Pierre G, Levesque JC, Nakamura H, Kikuchi Y, Satoh MS, Frenette J, Sato S. Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy. Faseb j. (2018) fj201701151RRR.
[8] McAdam LC, Mayo AL, Alman BA, Biggar WD. The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy. Acta Myol. (2012) 31(1):16-20.
[9] Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A, Han J, Escolar DM, Florence JM, Clemens PR, Hoffman EP, McDonald CM. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. (2013) 48(1): 55-67.
[10] Wong BL, Christopher C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J. Child Neurol. (2002) 17(3): 183-190.
[11] Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. (2008) (1): CD003725.
[12] Ricotti V, Ridout DA, Scott E, Quinlivan R, Robb SA, Manzur AY, Muntoni F. Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy. J Neurol. Neurosurg. Psychiatry. (2013) 84(6): 698-705.
[13] Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, De Kimpe SJ, Eagle M, Guglieri M, Hood S, Liefaard L, Lourbakos A, Morgan A, Nakielny J, Quarcoo N, Ricotti V, Rolfe K, Servais L, Wardell C, Wilson R, Wright P, Kraus JE. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol. (2014) 13(10): 987-96.
[14] Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann. Neurol. (2016) 79(2): 257-71.
[15] Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, Connolly AM, Day JW, Flanigan KM, Goemans N, Jones KJ, Mercuri E, Quinlivan R, Renfroe JB, Russman B, Ryan MM, Tulinius M, Voit T, Moore SA, Lee Sweeney H, Abresch RT, Coleman KL, Eagle M, Florence J, Gappmaier E, Glanzman AM, Henricson E, Barth J, Elfring GL, Reha A, Spiegel RJ ,O'Donnell M W, Peltz SW, McDonald CM. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. (2014) 50(4): 477-87.
[16] Wang Z, Storb R, Halbert CL, Banks GB, Butts TM, Finn EE, Allen JM, Miller AD, Chamberlain JS, Tapscott SJ. Successful regional delivery and long-term expression of a dystrophin gene in canine muscular dystrophy: a preclinical model for human therapies. Mol. Ther. (2012) 20(8): 1501-7.
[17] Nik-Ahd F, Bertoni C. Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy. Stem Cells. (2014) 32(7): 1817-30.
[18] Nelson MD, Rader F, Tang X, Tavyev J, Nelson SF, Miceli MC, Elashoff RM, Sweeney HL, Victor RG. PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology. (2014) 82(23): 2085-91.
[19] Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol. Ther. (2015) 23(1): 192-201.
[20] Campbell C, McMillan HJ, Mah JK, Tarnopolsky M, Selby K, McClure T, Wilson DM, Sherman ML, Escolar D, Attie KM. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle Nerve. (2017) 55(4): 458-464.
[21] Ricotti V, Spinty S, Roper H, Hughes I, Tejura B, Robinson N, Layton G, Davies K, Muntoni F, Tinsley J. Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy. PLoS One. (2016) 11(4): e0152840.
[22] Guiraud S, Squire SE, Edwards B, Chen H, Burns DT, Shah N, Babbs A, Davies SG, Wynne GM, Russell AJ, Elsey D, Wilson FX, Tinsley JM, Davies KE. Second-generation compound for the modulation of utrophin in the therapy of DMD. Hum. Mol. Genet. (2015) 24(15): 4212-24.
[23] Victor RG, Sweeney HL, Finkel R, McDonald CM, Byrne B, Eagle M, Goemans N, Vandenborne K, Dubrovsky AL, Topaloglu H, Miceli MC, Furlong P, Landry J, Elashoff R, Cox D. A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. Neurology. (2017) 89(17): 1811‐1820.
[24] Guiraud S, Edwards B, Squire SE, Babbs A, Shah N, Berg A, Chen H, Davies KE. Identification of serum protein biomarkers for utrophin based DMD therapy. Sci. Rep. (2017) 7: 43697.
[25] Chen J, Piquette‐Miller M, Smith B. Network medicine: finding the links to personalized therapy. Clin. Pharmacol. Ther. (2013) 94(6): 613‐616.
[26] Wang X, Song P, Huang C, Yuan N, Zhao X, Xu C. Weighted gene co‑expression network analysis for identifying hub genes in association with prognosis in Wilms tumor. Mol. Med. Rep. (2019) 19(3): 2041-2050.
[27] Chen W, Chen X, Wang Y, Liu T, Liang Y, Xiao Y, Chen L. Construction and Analysis of lncRNA-Mediated ceRNA Network in Cervical Squamous Cell Carcinoma by Weighted Gene Co-Expression Network Analysis. Med. Sci. Monit. (2019) 25: 2609‐2622.
[28] Huayan L, Runhong T. Identification of Temporal Characteristic Networks of peripheral blood changes in Alzheimer’s disease Based on Weighted correlation network analysis. Front. Aging Neurosci. (2019) 11:83.
[29] Guo N, Zhang N, Yan L, Lian Z, Wang J, Lv F, Wang Y, Cao X. Weighted gene co‑expression network analysis in identification of key genes and networks for ischemic-reperfusion remodeling myocardium. Mol. Med. Rep. (2018) 18(2):1955-1962.
[30] Langfelder P, Horvath S. Eigengene networks for studying the relationships between co-expression modules. BMC Syst. Biol. (2007) 1:54.
[31] https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE38417.
[32] Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC bioinformatics. (2008) 9(1): 559.
[33] Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol. (2005) 4: Article17.
[34] Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT ,Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. (2003) 13(11): 2498-504.
[35] Cao W, Wu W, Yan M, Tian F, Ma C, Zhang Q, Li X, Han P, Liu Z, Gu J, Biddle FG. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma. Oncogenesis. (2015) 4(11): e175-e175.
[36] Benchaouir R, Meregalli M, Farini A, D'Antona G, Belicchi M, Goyenvalle A, Battistelli M, Bresolin N, Bottinelli R, Garcia L, Torrente Y. Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice. Cell Stem Cell. (2007) 1(6): 646-57.
[37] Arechavala-Gomeza V, Anthony K, Morgan J, Muntoni F. Antisense oligonucleotide-mediated exon skipping for Duchenne muscular dystrophy: progress and challenges. Curr. Gene Ther. (2012) 12(3): 152-60.
[38] Rinaldi C, Wood MJA. Wood, Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat. Rev. Neurol. (2018) 14(1): 9-21.
[39] Komaki H, Nagata T. Nagata. Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci. Transl. Med. (2018) 10(437): eaan0713.
[40] U.S. Food and Drug Administration (FDA),)D.A.P.E.I., w.a.f.g.d.d.n. (eteplirsen) (FDA, and TOC.cfm.
[41] Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. (2004) 3(8): 673-83.
[42] Foidart M, Foidart JM ,Engel WK. Collagen localization in normal and fibrotic human skeletal muscle. Arch. Neurol. (1981) 38(3): 152-7.
[43] Smith LR, Meyer G, Lieber RL. Systems analysis of biological networks in skeletal muscle function. Wiley Interdiscip. Rev. Syst. Biol. Med. (2013) 5(1): 55-71.
[44] Zanotti S, Gibertini S, Curcio M, Savadori P, Pasanisi B, Morandi L, Cornelio F, Mantegazza R, Mora M. Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy. Biochim. Biophys. Acta. (2015) 1852(7): 1451-64.
[45] Hantai D, Labat-Robert J, Grimaud JA, Fardeau M. Fibronectin, laminin, type I, III and IV collagens in Duchenne's muscular dystrophy, congenital muscular dystrophies and congenital myopathies: an immunocytochemical study. Connect. Tissue Res. (1985) 13(4): 273-81.
[46] Porter JD, Merriam AP, Leahy P, Gong B, Feuerman J, Cheng G, Khanna S. Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy. Hum. Mol. Genet. (2004) 13(3): 257-269.
[47] Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J ,Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N. Engl. J. Med. (2007) 357(18): 1799-1809.
[48] Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Hegmans JP, Aerts JG. Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br. J. Cancer. (2010) 103(5): 629-641.
[49] Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. (2014) 6: 13.
[50] Vidal B, Serrano AL, Tjwa M, Suelves M, Ardite E, De Mori R, Baeza-Raja B, Martínez de Lagrán M, Lafuste P, Ruiz-Bonilla V, Jardí M, Gherardi R, Christov C, Dierssen M, Carmeliet P, Degen JL, Dewerchin M, Muñoz-Cánoves P. Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway. Genes Dev. (2008) 22(13):1747-1752.
- Abstract Viewed: 99 times
- IJPS_Volume 17_Issue 1_Pages 1-18 Downloaded: 35 times