The potential and benefits of repurposing existing drugs to treat rare muscular dystrophies

References

• Engel AG, Yamamoto M, Fischbeck KH. Dystrophinopathies. In: Engel AG, Franzini-Armstrong C, editors. Basic and clinical myology. Vol. 2. 2nd ed. New York: McGraw-Hill, Inc; 1994. p. 1133–1187.
   Google Scholar
• Arahata K. Muscular dystrophy. Neuropathol. 2000;20:S34–S41.
   PubMed Web of Science ®Google Scholar
• Kaplan JC, Hamroun D. The 2016 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2015 Dec;25(12):991–1020. PubMed PMID: 27563712.
   PubMed Web of Science ®Google Scholar
• Cohn RD, Campbell KP. Molecular basis of muscular dystrophies. Muscle Nerve. 2000;23(10):1456–1471.
   PubMed Web of Science ®Google Scholar
• Rahimov F, Kunkel LM. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol. 2013 May 13;201(4):499–510. PubMed PMID: 23671309; PubMed Central PMCID: PMCPMC3653356.
   PubMed Web of Science ®Google Scholar
• Emery AEH. The muscular dystrophies. The Lancet. 2002 2 23;359(9307):687–695.
   PubMed Web of Science ®Google Scholar
• Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010 Feb;9(2):177–189. PubMed PMID: 19945914.
   PubMed Web of Science ®Google Scholar
• Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010 Jan;9(1):77–93. PubMed PMID: 19945913.
   PubMed Web of Science ®Google Scholar
• Emery AE. Muscle histology and creatine kinase levels in the foetus in Duchenne muscular dystrophy. Nature. 1977 Mar 31;266(5601):472–473. PubMed PMID: 859617.
   PubMed Web of Science ®Google Scholar
• Hoffman EP, Brown RHJ, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919–928.
   PubMed Web of Science ®Google Scholar
• Hoffman EP, Schwartz L. Dystrophin and disease. Mol Aspects Med. 1991;12(3):175–194.
   PubMed Web of Science ®Google Scholar
• Hoffman EP, Dressman D. Molecular pathophysiology and targeted therapeutics for muscular dystrophy. Trends Pharmacol Sci. 2001 Sep;22(9):465–470. PubMed PMID: 11543874.
   PubMed Web of Science ®Google Scholar
• Blake DJ, Weir A, Newey SE, et al. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev. 2002 April 1;82(2):291–329.
   PubMed Web of Science ®Google Scholar
• Hopf FW, Turner PR, Steinhardt RA. Calcium misregulation and the pathogenesis of muscular dystrophy [Review]. Subcell Biochem. 2007;45:429–464. PubMed PMID: 18193647; eng.
   PubMedGoogle Scholar
• Allen DG, Whitehead NP, Yeung EW. Mechanisms of stretch-induced muscle damage in normal and dystrophic muscle: role of ionic changes. J Physiol. 2005 September 15;567(Pt 3):723–735. PubMed PMID: 16002444.
   PubMed Web of Science ®Google Scholar
• Dogra C, Srivastava D, Kumar A. Protein–DNA array-based identification of transcription factor activities differentially regulated in skeletal muscle of normal and dystrophin-deficient mdx mice. Mol Cell Biochem. 2008 May;312(1):17–24.
   PubMed Web of Science ®Google Scholar
• Angelis A, Tordrup D, Kanavos P. Socio-economic burden of rare diseases: a systematic review of cost of illness evidence. Health Policy. 2015 Jul;119(7):964–979. PubMed PMID: 25661982.
   PubMed Web of Science ®Google Scholar
• Rosenberg T, Jacobs HK, Thompson R, et al. Cost-effectiveness of neonatal screening for Duchenne muscular dystrophy–how does this compare to existing neonatal screening for metabolic disorders? Soc Sci Med. 1993 Aug;37(4):541–547. PubMed PMID: 8211266.
   PubMed Web of Science ®Google Scholar
• Van der Riet AA, Van Hout BA, Rutten FF. Cost effectiveness of DNA diagnosis for four monogenic diseases. J Med Genet. 1997 Sep;34(9):741–745. PubMed PMID: 9321760; PubMed Central PMCID: PMCPMC1051058.
   PubMed Web of Science ®Google Scholar
• Koch SJ, Arego DE, Bowser B. Outpatient rehabilitation for chronic neuromuscular diseases. Am J Phys Med. 1986 Oct;65(5):245–257. PubMed PMID: 3766710.
   PubMedGoogle Scholar
• Landfeldt E, Lindgren P, Bell CF, et al. Quantifying the burden of caregiving in Duchenne muscular dystrophy. J Neurol. 2016 May;263(5):906–915. PubMed PMID: 26964543; PubMed Central PMCID: PMCPMC4859858.
   PubMed Web of Science ®Google Scholar
• Landfeldt E, Lindgren P, Bell CF, et al. The burden of Duchenne muscular dystrophy: an international, cross-sectional study. Neurology. 2014 Aug 05;83(6):529–536. PubMed PMID: 24991029; PubMed Central PMCID: PMCPMC4141999.
   PubMed Web of Science ®Google Scholar
• Landfeldt E, Alfredsson L, Straub V, et al. Economic evaluation in Duchenne muscular dystrophy: model frameworks for cost-effectiveness analysis. Pharmacoeconomics. 2017 Feb;35(2):249–258. PubMed PMID: 27798808.
   PubMed Web of Science ®Google Scholar
• Odom GL, Gregorevic P, Chamberlain JS. Viral-mediated gene therapy for the muscular dystrophies: successes, limitations and recent advances. Biochim Biophys Acta. 2007 February;1772(2):243–262.
   PubMed Web of Science ®Google Scholar
• Shin JH, Pan X, Hakim CH, et al. Microdystrophin ameliorates muscular dystrophy in the canine model of duchenne muscular dystrophy. Mol Therapy J Am Soc Gene Ther. 2013 Apr;21(4):750–757. PubMed PMID: 23319056; PubMed Central PMCID: PMC3616540.
   PubMed Web of Science ®Google Scholar
• Bengtsson NE, Seto JT, Hall JK, et al. Progress and prospects of gene therapy clinical trials for the muscular dystrophies. Human Molecular Genetics. 2016 Apr 15;25(R1):R9–17. PubMed PMID: 26450518; PubMed Central PMCID: PMCPMC4802376.
   PubMedGoogle Scholar
• Barton-Davis ER, Cordier L, Shoturma DI, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Investig. 1999;104(4):375–381.
   PubMed Web of Science ®Google Scholar
• Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87–91.
   PubMed Web of Science ®Google Scholar
• McDonald CM, Campbell C, Torricelli RE, et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2017 Sep 23;390(10101):1489–1498. PubMed PMID: 28728956.
   PubMed Web of Science ®Google Scholar
• Aartsma-Rus A, Bremmer-Bout M, Janson AAM, et al. Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy. Neuromuscul Disord. 2002 October;12(Supplement 1):S71–S77.
   PubMedGoogle Scholar
• Béroud C, Tuffery-Giraud S, Matsuo M, et al. Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Human Mutation. 2007;28(2):196–202.
   PubMed Web of Science ®Google Scholar
• Anthony K, Feng L, Arechavala-Gomeza V, et al. Exon skipping quantification by quantitative reverse-transcription polymerase chain reaction in Duchenne muscular dystrophy patients treated with the antisense oligomer eteplirsen. Hum Gene Ther Methods. 2012 Oct;23(5):336–345. PubMed PMID: 23075107.
   PubMed Web of Science ®Google Scholar
• Hammond SM, Wood MJ. PRO-051, an antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy. Curr Opin Mol Ther. 2010 Aug;12(4):478–486. PubMed PMID: 20677099.
   PubMed Web of Science ®Google Scholar
• Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017;11: 533–545. PubMed PMID: 28280301; PubMed Central PMCID: PMCPMC5338848.
   PubMed Web of Science ®Google Scholar
• Kole R, Krieg AM. Exon skipping therapy for Duchenne muscular dystrophy. Adv Drug Deliv Rev. 2015 Jun 29;87:104–107. PubMed PMID: 25980936.
   PubMed Web of Science ®Google Scholar
• Gee P, Xu H, Hotta A. Cellular reprogramming, genome editing, and alternative CRISPR Cas9 technologies for precise gene therapy of Duchenne muscular dystrophy. Stem Cells Int. 2017;2017:8765154. PubMed PMID: 28607562; PubMed Central PMCID: PMCPMC5451761.
   PubMedGoogle Scholar
• Amoasii L, Long C, Li H, et al. Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci Transl Med. 2017 Nov 29;9(418). PubMed PMID: 29187645; PubMed Central PMCID: PMCPMC5749406.
   PubMed Web of Science ®Google Scholar
• Law PK, Yap JL. New muscle transplant method produces normal twitch tension in dystrophic muscle. Muscle Nerve. 1979;2(5):356–363.
   PubMed Web of Science ®Google Scholar
• Partridge TA, Morgan JE, Coulton GR, et al. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature. 1989 January 12;337(6203):176–179.
   PubMed Web of Science ®Google Scholar
• Gussoni E, Pavlath GK, Lanctot AM, et al. Normal dystrophin transcripts detected in Duchenne muscular dystrophy patients after myoblast transplantation. Nature. 1992;356(6368):435–438.
   PubMed Web of Science ®Google Scholar
• Mendell JR, Kissel JT, Amato AA, et al. Myoblast transfer in the treatment of Duchenne’s muscular dystrophy. N Engl J Med. 1995 Sep 28;333(13):832–838. PubMed PMID: 7651473.
   PubMed Web of Science ®Google Scholar
• Konieczny P, Swiderski K, Chamberlain JS. Gene and cell-mediated therapies for muscular dystrophy. Muscle Nerve. 2013 May;47(5):649–663. PubMed PMID: 23553671.
   PubMed Web of Science ®Google Scholar
• Meregalli M, Farini A, Parolini D, et al. Stem cell therapies to treat muscular dystrophy: progress to date. BioDrugs. 2010 Aug 1;24(4):237–247. PubMed PMID: 20623990.
   PubMed Web of Science ®Google Scholar
• Guiraud S, Davies KE. Pharmacological advances for treatment in Duchenne muscular dystrophy. Curr Opin Pharmacol. 2017 May 06;34:36–48. PubMed PMID: 28486179.
   PubMed Web of Science ®Google Scholar
• Reinig AM, Mirzaei S, Berlau DJ. Advances in the treatment of Duchenne muscular dystrophy: new and emerging pharmacotherapies. Pharmacotherapy. 2017 Apr;37(4):492–499. PubMed PMID: 28152217.
   PubMed Web of Science ®Google Scholar
• Ruegg UT. Pharmacological prospects in the treatment of Duchenne muscular dystrophy. Curr Opin Neurol. 2013 Oct;26(5):577–584. PubMed PMID: 23995279.
   PubMed Web of Science ®Google Scholar
• Leijendekker WJ, Passaquin AC, Metzinger L, et al. Regulation of cytosolic calcium in skeletal muscle cells of the mdx mouse under conditions of stress. Br J Pharmacol. 1996;118(3):611–616.
   PubMed Web of Science ®Google Scholar
• Metzinger L, Passaquin AC, Leijendekker WJ, et al. Modulation by prednisolone of calcium handling in skeletal muscle cells. Br J Pharmacol. 1995 Dec;116(7):2811–2816. PubMed PMID: 8680710; PubMed Central PMCID: PMC1909214.
   PubMed Web of Science ®Google Scholar
• Angelini C. The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve. 2007 Oct;36(4):424–435. PubMed PMID: 17541998.
   PubMed Web of Science ®Google Scholar
• St-Pierre SJ, Chakkalakal JV, Kolodziejczyk SM, et al. Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway. Faseb J. 2004 Dec;18(15):1937–1939. PubMed PMID: 15456738.
   PubMed Web of Science ®Google Scholar
• Bonifati MD, Ruzza G, Bonometto P, et al. A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve. 2000;23(9):1344–1347.
   PubMed Web of Science ®Google Scholar
• Griggs RC, Herr BE, Reha A, et al. Corticosteroids in Duchenne muscular dystrophy: major variations in practice. Muscle Nerve. 2013 Jul;48(1):27–31. PubMed PMID: 23483575.
   PubMed Web of Science ®Google Scholar
• Gloss D, Moxley RT 3rd, Ashwal S, et al. Practice guideline update summary: corticosteroid treatment of duchenne muscular dystrophy: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2016 Feb 2;86(5):465–472. PubMed PMID: 26833937; PubMed Central PMCID: PMCPMC4773944.
   PubMed Web of Science ®Google Scholar
• Huynh T, Uaesoontrachoon K, Quinn J, et al. Selective modulation through the glucocorticoid receptor ameliorates muscle pathology in mdx mice. J Pathol. 2013 October;231(2):223–235.
   PubMed Web of Science ®Google Scholar
• Patel K, Amthor H. The function of myostatin and strategies of myostatin blockade-new hope for therapies aimed at promoting growth of skeletal muscle. Neuromuscul Disord. 2005 Feb;15(2):117–126. PubMed PMID: 15694133.
   PubMed Web of Science ®Google Scholar
• Wagner KR, Liu X, Chang X, et al. Muscle regeneration in the prolonged absence of myostatin. Proc Natl Acad Sci USA. 2005 February 15;102(7):2519–2524.
   PubMed Web of Science ®Google Scholar
• Li ZB, Kollias HD, Wagner KR. Myostatin directly regulates skeletal muscle fibrosis. J Biol Chem. 2008 July 11;283(28):19371–19378.
   PubMed Web of Science ®Google Scholar
• Amthor H, Macharia R, Navarrete R, et al. Lack of myostatin results in excessive muscle growth but impaired force generation. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1835–1840. PubMed PMID: 17267614; PubMed Central PMCID: PMC1794294. eng.
   PubMed Web of Science ®Google Scholar
• Dorchies OM, Reutenauer-Patte J, Dahmane E, et al. The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy. Am J Pathol. 2013 Feb;182(2):485–504. PubMed PMID: 23332367.
   PubMed Web of Science ®Google Scholar
• Cozzoli A, Capogrosso RF, Sblendorio VT, et al. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Pharmacol Res. 2013 Jun;72:9–24. PubMed PMID: 23523664.
   PubMed Web of Science ®Google Scholar
• Louis M, Raymackers JM, Debaix H, et al. Effect of creatine supplementation on skeletal muscle of mdx mice. Muscle Nerve. 2004 May;29(5):687–692.
   PubMed Web of Science ®Google Scholar
• Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve. 1997;20(12):1502–1509.
   PubMed Web of Science ®Google Scholar
• Dorchies OM, Wagner S, Vuadens O, et al. Green tea extract and its major polyphenol (-)-epigallocatechin gallate improve muscle function in a mouse model for Duchenne muscular dystrophy. Am J Physiol-Cell Ph. 2006 Feb;290(2):C616–C625. PubMed PMID: WOS:000234531500032.
   PubMed Web of Science ®Google Scholar
• Hafner P, Bonati U, Rubino D, et al. Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial. Trials. 2016 Aug 03;17(1):389. PubMed PMID: 27488051; PubMed Central PMCID: PMCPMC4973063.
   PubMed Web of Science ®Google Scholar
• Spencer MJ, Mellgren RL. Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. Human Molecular Genetics. 2002 October 2;11(21):2645–2655.
   PubMed Web of Science ®Google Scholar
• Badalamente MA, Stracher A. Delay of muscle degeneration and necrosis in mdx mice by calpain inhibition. Muscle Nerve. 2000;23(1):106–111.
   PubMed Web of Science ®Google Scholar
• Briguet A, Erb M, Courdier-Fruh I, et al. Effect of calpain and proteasome inhibition on Ca2+-dependent proteolysis and muscle histopathology in the mdx mouse. Faseb J. 2008 Dec;22(12):4190–4200. PubMed PMID: 18728218.
   PubMed Web of Science ®Google Scholar
• Pan Y, Chen C, Shen Y, et al. Curcumin alleviates dystrophic muscle pathology in mdx mice. Mol Cells. 2008 June 30;25(4):531–537.
   PubMed Web of Science ®Google Scholar
• Grounds MD, Torrisi JO. Anti-TNFα (Remicade®) therapy protects dystrophic skeletal muscle from necrosis. Faseb J. 2004 April 1;18(6):676–682.
   PubMed Web of Science ®Google Scholar
• Buyse GM, Goemans N, Henricson E, et al. CINRG pilot trial of oxatomide in steroid-naïve Duchenne muscular dystrophy. Eur J Paediatric Neurol. 2007 November;11(6):337–340.
   PubMed Web of Science ®Google Scholar
• De Luca A, Nico B, Liantonio A, et al. A multidisciplinary evaluation of the effectiveness of cyclosporine A in dystrophic mdx mice. Am J Pathol. 2005 February 1;166(2):477–489.
   PubMed Web of Science ®Google Scholar
• Kirschner J, Schessl J, Schara U, et al. Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurol. 2010 Nov;9(11):1053–1059. PubMed PMID: 20801085.
   PubMed Web of Science ®Google Scholar
• Allen DG, Whitehead NP, Froehner SC. Absence of dystrophin disrupts skeletal muscle signaling: roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physiol Rev. 2016 Jan;96(1):253–305. PubMed PMID: 26676145; PubMed Central PMCID: PMCPMC4698395.
   PubMed Web of Science ®Google Scholar
• Emery AEH, Skinner R, Howden LC, et al. Verapamil in Duchenne muscular dystrophy. The Lancet. 1982;319(8271):559.
   Google Scholar
• Bertorini TE, Palmieri GM, Griffin JW, et al. Effect of chronic treatment with the calcium antagonist diltiazem in Duchenne muscular dystrophy. Neurology. 1988;38:609–613.
   PubMed Web of Science ®Google Scholar
• Yasuda S, Townsend D, Michele DE, et al. Dystrophic heart failure blocked by membrane sealant poloxamer. Nature. 2005 August 18;436(7053):1025–1029.
   PubMed Web of Science ®Google Scholar
• Terry RL, Kaneb HM, Wells DJ. Poloxamer [corrected] 188 has a deleterious effect on dystrophic skeletal muscle function. PloS One. 2014;9(3): e91221. PubMed PMID: 24642557; PubMed Central PMCID: PMCPMC3958340.
   PubMed Web of Science ®Google Scholar
• Whitehead NP, Streamer M, Lusambili LI, et al. Streptomycin reduces stretch-induced membrane permeability in muscles from mdx mice. Neuromuscul Disord. 2006 Dec;16(12):845–854. PubMed PMID: 17005404; eng.
   PubMed Web of Science ®Google Scholar
• Ismail HM, Dorchies OM, Perozzo R, et al. Inhibition of iPLA2 beta and of stretch-activated channels by doxorubicin alters dystrophic muscle function. Br J Pharmacol. 2013 Aug;169(7):1537–1550. PubMed PMID: 23849042; PubMed Central PMCID: PMC3724110.
   PubMed Web of Science ®Google Scholar
• Buetler TM, Renard M, Offord EA, et al. Green tea extract decreases muscle necrosis in mdx mice and protects against reactive oxygen species. Am J Clin Nutr. 2002 Apr;75(4):749–753. PubMed PMID: 11916763.
   PubMed Web of Science ®Google Scholar
• Dorchies OM, Wagner S, Buetler TM, et al. Protection of dystrophic muscle cells with polyphenols from green tea correlates with improved glutathione balance and increased expression of 67LR, a receptor for (-)-epigallocatechin gallate. Biofactors. 2009 May-Jun;35(3):279–294. PubMed PMID: 19322813; eng.
   PubMed Web of Science ®Google Scholar
• Hibaoui Y, Reutenauer-Patte J, Patthey-Vuadens O, et al. Melatonin improves muscle function of the dystrophic mdx5Cv mouse, a model for Duchenne muscular dystrophy [Research support, Non-U.S. Gov’t]. J Pineal Res. 2011 Sep;51(2):163–171. PubMed PMID: 21486366; eng.
   PubMed Web of Science ®Google Scholar
• Whitehead NP, Pham C, Gervasio OL, et al. N-Acetylcysteine ameliorates skeletal muscle pathophysiology in mdx mice. J Physiol. 2008 Apr 1;586(7):2003–2014. PubMed PMID: 18258657; PubMed Central PMCID: PMC2375717.
   PubMed Web of Science ®Google Scholar
• Kim JH, Lawler JM. Amplification of proinflammatory phenotype, damage, and weakness by oxidative stress in the diaphragm muscle of mdx mice. Free Radic Biol Med. 2012 May 1;52(9):1597–1606. PubMed PMID: 22330042.
   PubMed Web of Science ®Google Scholar
• Kim JH, Kwak HB, Thompson LV, et al. Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy. J Muscle Res Cell M. 2013 Feb;34(1):1–13. PubMed PMID: 23104273; eng.
   PubMed Web of Science ®Google Scholar
• Ismail HM, Scapozza L, Ruegg UT, et al. Diapocynin, a dimer of the NADPH oxidase inhibitor apocynin, reduces ROS production and prevents force loss in eccentrically contracting dystrophic muscle. PloS One. 2014;9(10):e110708.
   PubMed Web of Science ®Google Scholar
• Capdeville R, Buchdunger E, Zimmermann J, et al. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002 Jul;1(7):493–502. PubMed PMID: 12120256.
   PubMed Web of Science ®Google Scholar
• Langedijk J, Mantel-Teeuwisse AK, Slijkerman DS, et al. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discov Today. 2015 Aug;20(8):1027–1034. PubMed PMID: 25975957.
   PubMed Web of Science ®Google Scholar
• Hernandez JJ, Pryszlak M, Smith L, et al. Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics. Front Oncol. 2017;7:273, PubMed PMID: 29184849; PubMed Central PMCID: PMCPMC5694537
   PubMed Web of Science ®Google Scholar
• Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004 Aug;3(8):711–715. PubMed PMID: 15286737.
   PubMed Web of Science ®Google Scholar
• Mullard A. Could pharma open its drug freezers? Nat Rev Drug Discov. 2011 Jun;10(6):399–400. PubMed PMID: 21629278.
   PubMed Web of Science ®Google Scholar
• Mullard A. Drug repurposing programmes get lift off. Nat Rev Drug Discov. 2012 Jun 29;11(7):505–506. PubMed PMID: 22743966.
   PubMed Web of Science ®Google Scholar
• Shim JS, Liu JO. Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci. 2014;10(7): 654–663. PubMed PMID: 25013375; PubMed Central PMCID: PMCPMC4081601.
   PubMed Web of Science ®Google Scholar
• Sun W, Sanderson PE, Zheng W. Drug combination therapy increases successful drug repositioning. Drug Discov Today. 2016 Jul;21(7):1189–1195. PubMed PMID: 27240777; PubMed Central PMCID: PMCPMC4907866.
   PubMed Web of Science ®Google Scholar
• Weiss A, Nowak-Sliwinska P. Current trends in multidrug optimization: an alley of future successful treatment of complex disorders. SLAS Technol. 2017 Jun;22(3):254–275. PubMed PMID: 28027446.
   PubMed Web of Science ®Google Scholar
• Nowak-Sliwinska P, Weiss A, Ding X, et al. Optimization of drug combinations using feedback system control. Nat Protoc. 2016 Feb;11(2):302–315. PubMed PMID: 26766116.
   PubMed Web of Science ®Google Scholar
• Buyse GM, Voit T, Schara U, et al. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. The Lancet. 2015 May 2;385(9979):1748–1757. PubMed PMID: 25907158.
   PubMed Web of Science ®Google Scholar
• Meekings KN, Williams CS, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today. 2012 Jul;17(13–14):660–664. PubMed PMID: 22366309.
   PubMed Web of Science ®Google Scholar
• Silverman E. No price pressure on orphan drugs (Yet). Managed Care (Langhorne, Pa). 2017 Jun;26(6):20. PubMed PMID: 28661836; eng.
   PubMedGoogle Scholar
• Murphy SM, Puwanant A, Griggs RC, et al. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol. 2012 Oct;72(4):481–490. PubMed PMID: 23109143; PubMed Central PMCID: PMCPMC3490440.
   PubMed Web of Science ®Google Scholar