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Mini-Review Article

Angelman综合征的基因治疗：当代方法和未来的努力。

卷 19, 期 6, 2019

页: [359 - 366] 页: 8

弟呕挨: 10.2174/1566523220666200107151025

价格: $65

摘要

背景：Angelman综合征（AS）是一种先天性非遗传性神经发育障碍。当代的AS管理是有症状的，基因治疗可能在AS的治疗中起关键作用。 目的：本研究的目的是总结现有的和建议的天使疗法综合症的基因治疗方法。 方法：这是一篇文献综述。研究了Pubmed和Scopus数据库中的关键字（基因治疗，安格曼综合症，神经系统疾病，新生儿）。同行评议的研究与Angelman综合征的基因疗法密切相关，并提供英语，希腊语，乌克兰语或印尼语版本。 2000年之前发表的研究被排除在外，并且与上述标准不符。 结果：UBE3A在信号传递和降解过程中起着多种作用。尽管恢复UBE3A表达而不是靶向分子的已知活性将是最佳的治疗目标，但迄今为止尚不可能。恢复父系UBE3A似乎是一个适当的选择。这可以通过施用拓扑异构酶-I抑制剂或降低UBE3A反义转录物（UBE3A-ATS）（使父系UBE3A沉默的分子）来实现。 结论：了解UBE3A印记揭示了AS病因治疗的途径。在小鼠身上测试的基因治疗模型似乎没有预期的有效，指出父系UBE3A的激活不能抵消现有的CNS缺陷。另一方面，靶向异常下游细胞信号通路已经提供了有希望的拯救作用。也许，将父本UBE3A表达的恢复与异常信号通路导向的治疗结合起来可以提供更好的治疗效果。然而，在药物经济学和伦理学背景下，AS基因疗法仍存在争议。

关键词: Angelman综合征，基因治疗，神经发育障碍，先天性，UBE3A，CNS，ATF。

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[1]
NORD (National Organization for Rare Disorders) Angelman Syndrome - NORD (National Organization for Rare Disorders). 2019.Available from: https://rarediseases.org/rare-diseases/ angelman-syndrome/
[2]
Jamieson AC, Miller JC, Pabo CO. Drug discovery with engineered zinc-finger proteins. Nat Rev Drug Discov 2003; 2(5): 361-8.
[http://dx.doi.org/10.1038/nrd1087] [PMID: 12750739]
[3]
Eisenstein M. Sangamo’s lead zinc-finger therapy flops in diabetic neuropathy. Nat Biotechnol 2012; 30(2): 121-3.
[http://dx.doi.org/10.1038/nbt0212-121a] [PMID: 22318013]
[4]
Chamberlain SJ, Lalande M. Angelman syndrome, a genomic imprinting disorder of the brain. J Neurosci 2010; 30(30): 9958-63.
[http://dx.doi.org/10.1523/JNEUROSCI.1728-10.2010] [PMID: 20668179]
[5]
Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997; 15(1): 70-3.
[http://dx.doi.org/10.1038/ng0197-70] [PMID: 8988171]
[6]
Rougeulle C, Glatt H, Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet 1997; 17(1): 14-5.
[http://dx.doi.org/10.1038/ng0997-14] [PMID: 9288088]
[7]
Prakash V, Moore M, Yáñez-Muñoz RJ. Current progress in therapeutic gene editing for monogenic diseases. Mol Ther 2016; 24(3): 465-74.
[http://dx.doi.org/10.1038/mt.2016.5] [PMID: 26765770]
[8]
Chamberlain SJ, Lalande M. Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13. Neurobiol Dis 2010; 39(1): 13-20.
[http://dx.doi.org/10.1016/j.nbd.2010.03.011] [PMID: 20304067]
[9]
Rodwell C, Aymé S. Report on the state of the art of rare disease activities in europe part ii: Key developments in the field of rare diseases in Europe 2014; 1-90.Available from: http:// www.eucerd.eu/upload/file/Reports/2014ReportStateofArtRDActi- vities.pdf In:
[10]
Hacein-Bey-Abina S, Hauer J, Lim A, et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2010; 363(4): 355-64.
[http://dx.doi.org/10.1056/NEJMoa1000164] [PMID: 20660403]
[11]
Ylä-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther 2012; 20(10): 1831-2.
[http://dx.doi.org/10.1038/mt.2012.194] [PMID: 23023051]
[12]
Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman Syndrome. 2015 Neurotherapeutics 2015; 12(3): 641-50.
[http://dx.doi.org/10.1007/s13311-015-0361-y] [PMID: 26040994]
[13]
Sonzogni M, Wallaard I, Santos SS, et al. A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants. Mol Autism 2018; 9(1): 47.
[http://dx.doi.org/10.1186/s13229-018-0231-7] [PMID: 30220990]
[14]
Tan WH, Bird LM, Sadhwani A, et al. A randomized controlled trial of levodopa in patients with Angelman syndrome. Am J Med Genet A 2018; 176(5): 1099-107.
[http://dx.doi.org/10.1002/ajmg.a.38457] [PMID: 28944563]
[15]
Balaj K, Nowinski L, Walsh B, et al. Buspirone for the treatment of anxiety-related symptoms in Angelman syndrome: a case series. Psychiatr Genet 2019; 29(2): 51-6.
[http://dx.doi.org/10.1097/YPG.0000000000000218] [PMID: 30681431]
[16]
Ruiz-Antoran B, Sancho-López A, Cazorla-Calleja R, et al. A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman syndrome (A-MANECE study). Orphanet J Rare Dis 2018; 13(1): 144.
[http://dx.doi.org/10.1186/s13023-018-0891-6] [PMID: 30126448]
[17]
Ciarlone SL, Grieco JC, D’Agostino DP, Weeber EJ. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiol Dis 2016; 96: 38-46.
[http://dx.doi.org/10.1016/j.nbd.2016.08.002] [PMID: 27546058]
[18]
Bird LM, Tan W-H, Bacino CA, et al. A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome. Am J Med Genet A 2011; 155A(12): 2956-63.
[http://dx.doi.org/10.1002/ajmg.a.34297] [PMID: 22002941]
[19]
Doetschman T, Georgieva T, With GE. Gene editing with CRISPR/Cas9 RNA-directed nuclease. Circ Res 2017; 120(5): 876-94.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309727] [PMID: 28254804]
[20]
Philpot BD, Thompson CE, Franco L, Williams CA. Angelman syndrome: advancing the research frontier of neurodevelopmental disorders. J Neurodev Disord 2011; 3(1): 50-6.
[http://dx.doi.org/10.1007/s11689-010-9066-z] [PMID: 21484597]
[21]
Baron CA, Tepper CG, Liu SY, et al. Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Hum Mol Genet 2006; 15(6): 853-69.
[http://dx.doi.org/10.1093/hmg/ddl004] [PMID: 16446308]
[22]
Bramham CR, Alme MN, Bittins M, et al. The Arc of synaptic memory. Exp Brain Res 2010; 200(2): 125-40.
[http://dx.doi.org/10.1007/s00221-009-1959-2] [PMID: 19690847]
[23]
Chamberlain SJ, Bourgois-Rocha F, Lemtiri-Chlieh F, et al. Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proc Natl Acad Sci USA 2010; 107(41): 17668-73.
[http://dx.doi.org/10.1073/pnas.1004487107]
[24]
Christian SL, Brune CW, Sudi J, et al. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry 2008; 63(12): 1111-7.
[http://dx.doi.org/10.1016/j.biopsych.2008.01.009] [PMID: 18374305]
[25]
Dindot SV, Antalffy BA, Bhattacharjee MB, et al. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 2008; 17(1): 111-8.
[http://dx.doi.org/10.1093/hmg/ddm288] [PMID: 17940072]
[26]
Lee HM, Clark EP, Kuijer MB, Cushman M, Pommier Y, Philpot BD. Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome. Mol Autism 2018; 9(1): 45.
[http://dx.doi.org/10.1186/s13229-018-0228-2] [PMID: 30140420]
[27]
Pelc K, Cheron G, Dan B. Behavior and neuropsychiatric manifestations in Angelman syndrome. Neuropsychiatr Dis Treat 2008; 4(3): 577-84.
[PMID: 18830393]
[28]
Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003; 40(2): 87-95.
[http://dx.doi.org/10.1136/jmg.40.2.87] [PMID: 12566516]
[29]
Dan B. Angelman syndrome: current understanding and research prospects. Epilepsia 2009; 50(11): 2331-9.
[http://dx.doi.org/10.1111/j.1528-1167.2009.02311.x] [PMID: 19874386]
[30]
Williams CA. Neurological aspects of the Angelman syndrome. Brain Dev 2005; 27(2): 88-94.
[http://dx.doi.org/10.1016/j.braindev.2003.09.014] [PMID: 15668046]
[31]
Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci 2011; 34(6): 293-303.
[http://dx.doi.org/10.1016/j.tins.2011.04.001] [PMID: 21592595]
[32]
Liu Y, Johe K, Sun J, et al. Enhancement of synaptic plasticity and reversal of impairments in motor and cognitive functions in a mouse model of Angelman Syndrome by a small neurogenic molecule, NSI-189. Neuropharmacology 2019; 144: 337-44.
[http://dx.doi.org/10.1016/j.neuropharm.2018.10.038] [PMID: 30408487]
[33]
Allen BD, Acharya MM, Lu C, et al. Remediation of radiation-induced cognitive dysfunction through oral administration of the neuroprotective compound NSI-189. Radiat Res 2018; 189(4): 345-53.
[http://dx.doi.org/10.1667/RR14879.1] [PMID: 29351056]
[34]
Barry RJ, Leitner RP, Clarke AR, Einfeld SL. Behavioral aspects of Angelman syndrome: a case control study. Am J Med Genet A 2005; 132A(1): 8-12.
[http://dx.doi.org/10.1002/ajmg.a.30154] [PMID: 15578589]
[35]
Baudry M, Kramar E, Xu X, et al. Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome. Neurobiol Dis 2012; 47(2): 210-5.
[http://dx.doi.org/10.1016/j.nbd.2012.04.002] [PMID: 22525571]
[36]
Beaudet AL, Meng L. Gene-targeting pharmaceuticals for single-gene disorders. Hum Mol Genet 2016; 25(R1): R18-26.
[http://dx.doi.org/10.1093/hmg/ddv476] [PMID: 26628634]
[37]
Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 2015; 518(7539): 409-12.
[http://dx.doi.org/10.1038/nature13975] [PMID: 25470045]
[38]
Dagli A, Buiting K, Williams C. Molecular and clinical aspects of angelman syndrome. Mol Syndromol 2012; 2(3-5): 100-12.
[http://dx.doi.org/10.1159/000328837] [PMID: 22670133]
[39]
Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of Angelman syndrome. Genet Med 2010; 12(7): 385-95.
[http://dx.doi.org/10.1097/GIM.0b013e3181def138] [PMID: 20445456]
[40]
Meng L, Person RE, Beaudet AL. Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Hum Mol Genet 2012; 21(13): 3001-12.
[http://dx.doi.org/10.1093/hmg/dds130] [PMID: 22493002]
[41]
Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 2012; 14(1): 10-26.
[http://dx.doi.org/10.1038/gim.0b013e31822bead0] [PMID: 22237428]
[42]
Allensworth M, Saha A, Reiter LT, Heck DH. Normal social seeking behavior, hypoactivity and reduced exploratory range in a mouse model of Angelman syndrome. BMC Genet 2011; 12: 7.
[http://dx.doi.org/10.1186/1471-2156-12-7] [PMID: 21235769]
[43]
Rotaru DC, van Woerden GM, Wallaard I, Elgersma Y. Adult Ube3a gene reinstatement restores the electrophysiological deficits of prefrontal cortex layer 5 Neurons in a mouse model of angelman syndrome. J Neurosci 2018; 38(37): 8011-30.
[http://dx.doi.org/10.1523/JNEUROSCI.0083-18.2018] [PMID: 30082419]
[44]
Adhikari A, Lerner TN, Finkelstein J, et al. Basomedial amygdala mediates top-down control of anxiety and fear. Nature 2015; 527(7577): 179-85.
[http://dx.doi.org/10.1038/nature15698] [PMID: 26536109]
[45]
Aghakhanyan G, Bonanni P, Randazzo G, et al. From cortical and subcortical grey matter abnormalities to neurobehavioral phenotype of angelman syndrome: A voxel-based morphometry study. PLoS One 2016; 11(9): e0162817
[http://dx.doi.org/10.1371/journal.pone.0162817] [PMID: 27626634]
[46]
Auger C, Marty A. Quantal currents at single-site central synapses. J Physiol 2000; 526(Pt 1): 3-11.
[http://dx.doi.org/10.1111/j.1469-7793.2000.t01-3-00003.x] [PMID: 10878094]
[47]
Babst M. Quality control: quality control at the plasma membrane: one mechanism does not fit all. J Cell Biol 2014; 205(1): 11-20.
[http://dx.doi.org/10.1083/jcb.201310113] [PMID: 24733583]
[48]
Balleine BW, O’Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology 2010; 35(1): 48-69.
[http://dx.doi.org/10.1038/npp.2009.131] [PMID: 19776734]
[49]
Khatri N, Man H. The autism and angelman syndrome protein Ube3A/E6AP: The gene, E3 ligase ubiquitination targets and neurobiological functions. Front Mol Neurosci 2019; 12: 109.
[http://dx.doi.org/10.3389/fnmol.2019.00109] [PMID: 31114479]
[50]
Adelman JP, Maylie J, Sah P. Small-conductance Ca2+-activated K+ channels: form and function. Annu Rev Physiol 2012; 74: 245-69.
[http://dx.doi.org/10.1146/annurev-physiol-020911-153336] [PMID: 21942705]
[51]
Born HA, Dao AT, Levine AT, et al. Strain-dependence of the Angelman Syndrome phenotypes in Ube3a maternal deficiency mice. Sci Rep 2017; 7(1): 8451.
[http://dx.doi.org/10.1038/s41598-017-08825-x] [PMID: 28814801]
[52]
Azevedo FA, Carvalho LR, Grinberg LT, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 2009; 513(5): 532-41.
[http://dx.doi.org/10.1002/cne.21974] [PMID: 19226510]
[53]
Berrios J, Stamatakis AM, Kantak PA, et al. Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation. Nat Commun 2016; 7(1): 10702.
[http://dx.doi.org/10.1038/ncomms10702] [PMID: 26869263]
[54]
Borgatti R, Piccinelli P, Passoni D, et al. Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients. Pediatr Neurol 2001; 24(2): 111-6.
[http://dx.doi.org/10.1016/S0887-8994(00)00244-7] [PMID: 11275459]
[55]
Cassels C. ASH Annual Meetings April 2020; .Washington DC, USA..
[56]
Pyles B, Bailus BJ, O’Geen H, Segal DJ. Purified protein delivery to activate an epigenetically silenced allele in mouse brain. Methods Mol Biol 2018; 1767: 227-39.
[http://dx.doi.org/10.1007/978-1-4939-7774-1_12] [PMID: 29524138]
[57]
Blancafort P, Segal DJ, Barbas CF III. Designing transcription factor architectures for drug discovery. Mol Pharmacol 2004; 66(6): 1361-71.
[http://dx.doi.org/10.1124/mol.104.002758] [PMID: 15340042]
[58]
Polstein LR, Perez-Pinera P, Kocak DD, et al. Genome-wide specificity of DNA binding, gene regulation, and chromatin remodeling by TALE- and CRISPR/Cas9-based transcriptional activators. Genome Res 2015; 25(8): 1158-69.
[http://dx.doi.org/10.1101/gr.179044.114] [PMID: 26025803]
[59]
Thakore PI, Black JB, Hilton IB, Gersbach CA. Editing the epigenome: technologies for programmable transcription and epigenetic modulation. Nat Methods 2016; 13(2): 127-37.
[http://dx.doi.org/10.1038/nmeth.3733] [PMID: 26820547]
[60]
Thakore PI, Gersbach CA. Design, assembly, and characterization of TALE-Based transcriptional activators and repressors. Methods Mol Biol 2016; 1338: 71-88.
[http://dx.doi.org/10.1007/978-1-4939-2932-0_7] [PMID: 26443215]
[61]
Cearley CN, Wolfe JH. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol Ther 2006; 13(3): 528-37.
[http://dx.doi.org/10.1016/j.ymthe.2005.11.015] [PMID: 16413228]
[62]
Riemens RJM, Soares ES, Esteller M, Delgado-Morales R. Stem Cell technology for (Epi)genetic brain disorders. Adv Exp Med Biol 2017; 978: 443-75.
[http://dx.doi.org/10.1007/978-3-319-53889-1_23] [PMID: 28523560]
[63]
Horvath P, Aulner N, Bickle M, et al. Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 2016; 15(11): 751-69.
[http://dx.doi.org/10.1038/nrd.2016.175] [PMID: 27616293]
[64]
Fernández-Santiago R, Ezquerra M. Epigenetic research of neurodegenerative disorders using patient iPSC-based models. 2015. Stem Cells Int 2016; 2016: 1-16.
[http://dx.doi.org/10.1155/2016/9464591] [PMID: 26697081]
[65]
Takahashi K, Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 2016; 17(3): 183-93.
[http://dx.doi.org/10.1038/nrm.2016.8] [PMID: 26883003]
[66]
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4): 663-76.
[http://dx.doi.org/10.1016/j.cell.2006.07.024] [PMID: 16904174]
[67]
Rubin LL. Stem cells and drug discovery: the beginning of a new era? Cell 2008; 132(4): 549-52.
[http://dx.doi.org/10.1016/j.cell.2008.02.010] [PMID: 18295572]
[68]
Liu C, Zhang X, Wang J, et al. Genetic testing for Prader-Willi syndrome and Angelman syndrome in the clinical practice of Guangdong Province, China. Mol Cytogenet 2019; 12(1): 7.
[http://dx.doi.org/10.1186/s13039-019-0420-x] [PMID: 30820248]
[69]
Wheeler AC, Sacco P, Cabo R. Unmet clinical needs and burden in Angelman syndrome: a review of the literature. Orphanet J Rare Dis 2017; 12(1): 164.
[http://dx.doi.org/10.1186/s13023-017-0716-z] [PMID: 29037196]
[70]
Beckung E, Steffenburg S, Kyllerman M. Motor impairments, neurological signs, and developmental level in individuals with Angelman syndrome. Dev Med Child Neurol 2004; 46(4): 239-43.
[http://dx.doi.org/10.1111/j.1469-8749.2004.tb00478.x] [PMID: 15077701]
[71]
Williams CA, Dagli A. Angelman Syndrome Management of genetic syndromes. 3rd ed. Hoboken, NJ: Wiley-Blackwell 2010.
[http://dx.doi.org/10.1002/9780470893159.ch6]
[72]
Khan N, Cabo R, Tan WH, Tayag R, Bird LM. Healthcare burden among individuals with Angelman syndrome: Findings from the Angelman syndrome natural history study. Mol Genet Genomic Med 2019; 7(7): e00734
[http://dx.doi.org/10.1002/mgg3.734] [PMID: 31090212]
[73]
Landers M, Calciano MA, Colosi D, Glatt-Deeley H, Wagstaff J, Lalande M. Maternal disruption of Ube3a leads to increased expression of Ube3a-ATS in trans. Nucleic Acids Res 2005; 33(13): 3976-84.
[http://dx.doi.org/10.1093/nar/gki705] [PMID: 16027444]
[74]
Sell GL, Margolis SS. From UBE3A to Angelman syndrome: A substrate perspective. Front Neurosci 2015; 9: 322.
[http://dx.doi.org/10.3389/fnins.2015.00322] [PMID: 26441497]
[75]
Silva-Santos S, van Woerden GM, Bruinsma CF, et al. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J Clin Invest 2015; 125(5): 2069-76.
[http://dx.doi.org/10.1172/JCI80554] [PMID: 25866966]
[76]
Sonzogni M, Hakonen J, Bernabé Kleijn M, et al. Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes. Mol Autism 2019; 10(1): 23.
[http://dx.doi.org/10.1186/s13229-019-0277-1] [PMID: 31143434]
[77]
Bi X, Sun J, Ji AX, Baudry M. Potential therapeutic approaches for Angelman syndrome. Expert Opin Ther Targets 2016; 20(5): 601-13.
[http://dx.doi.org/10.1517/14728222.2016.1115837] [PMID: 26558806]
[78]
Lalande M, Calciano MA. Molecular epigenetics of Angelman syndrome. Cell Mol Life Sci 2007; 64(7-8): 947-60.
[http://dx.doi.org/10.1007/s00018-007-6460-0] [PMID: 17347796]
[79]
Cyranoski D. CRISPR-baby scientist fails to satisfy critics. Nature 2018; 564(7734): 13-4.
[http://dx.doi.org/10.1038/d41586-018-07573-w] [PMID: 30514937]
[80]
Cyranoski D, Ledford H. How the genome-edited babies revelation will affect research. Nature 2018; 2018
[http://dx.doi.org/10.1038/d41586-018-07559-8]
[81]
Burley J, Harris J, Eds. A companion to genethics. Blackwell Publishers 2004.
[http://dx.doi.org/10.1002/9780470756423]
[82]
Bodrogi J, Kaló Z. Principles of pharmacoeconomics and their impact on strategic imperatives of pharmaceutical research and development. Br J Pharmacol 2010; 159(7): 1367-73.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00550.x]
[83]
Bettio F, Plantenga J. Comparing care regimes in Europe. Feminist Economics Taylor & Francis Ltd 2004; 10(1): 85-113.
[http://dx.doi.org/10.1080/1354570042000198245]
[84]
Haycox A, Pirmohamed M, McLeod C, Houten R, Richards S. Through a glass darkly: economics and personalised medicine. Pharmacoeconomics 2014; 32(11): 1055-61.
[http://dx.doi.org/10.1007/s40273-014-0190-6] [PMID: 25118988]
[85]
Turner L. The tyranny of ‘genethics’. Nat Biotechnol 2003; 21(11): 1282-2.
[http://dx.doi.org/10.1038/nbt1103-1282] [PMID: 14595353]
[86]
Chatzichronis S, Alexiou A, Simou P, et al. Neurocognitive assessment software for enrichment sensory environments. J Proteomics Bioinform 2019; 12: 018-28.
[http://dx.doi.org/10.4172/0974-276X.1000492]
[87]
Alexiou A, Soursou G, Yarla NS, Md Ashraf G. Proteins commonly linked to autism spectrum disorder and alzheimer’s disease. Curr Protein Pept Sci 2018; 19(9): 876-80.
[http://dx.doi.org/10.2174/1389203718666170911145321] [PMID: 28901249]
[88]
Mantzavinos V, Alexiou A. Biomarkers for alzheimer’s disease diagnosis. Curr Alzheimer Res 2017; 14(11): 1149-54.
[http://dx.doi.org/10.2174/1567205014666170203125942] [PMID: 28164766]

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