Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome

被引：18

作者：

Lee, Sarah E. ^{[1
]}

Duran-Martinez, Monica ^{[1
]}

Khantsis, Sabina ^{[1
]}

Bianchi, Diana W. ^{[1
,2
]}

Guedj, Faycal ^{[1
]}

机构：

[1] NHGRI, Med Genet Branch, Prenatal Genom & Therapy Sect, NIH, Bethesda, MD 20892 USA

[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA

来源：

TRENDS IN MOLECULAR MEDICINE | 2020年 / 26卷 / 02期

基金：

美国国家卫生研究院;

关键词：

PLURIPOTENT STEM-CELLS; TS65DN MOUSE MODEL; DOUBLE-BLIND; PHARMACOLOGICAL INTERVENTIONS; MITOCHONDRIAL DYSFUNCTION; NEUROGENESIS IMPAIRMENT; BRAIN TRANSCRIPTOME; OXIDATIVE STRESS; AMNIOTIC-FLUID; YOUNG-ADULTS;

D O I：

10.1016/j.molmed.2019.10.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choke of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.

引用

页码：150 / 169

页数：20

共 143 条

[1] Impaired myelination of the human hippocampal formation in Down syndrome [J].

Abraham, Hajnalka ;

Vincze, Andras ;

Veszpremi, Bela ;

Kravjak, Andras ;

Gomori, Eva ;

Kovacs, Gabor G. ;

Seress, Laszlo .

INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, 2012, 30 (02) :147-158

[2] iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases [J].

Abud, Edsel M. ;

Ramirez, Ricardo N. ;

Martinez, Eric S. ;

Healy, Luke M. ;

Nguyen, Cecilia H. H. ;

Newman, Sean A. ;

Yeromin, Andriy V. ;

Scarfone, Vanessa M. ;

Marsh, Samuel E. ;

Fimbres, Cristhian ;

Caraway, Chad A. ;

Fote, Gianna M. ;

Madany, Abdullah M. ;

Agrawal, Anshu ;

Kayed, Rakez ;

Gylys, Karen H. ;

Cahalan, Michael D. ;

Cummings, Brian J. ;

Antel, Jack P. ;

Mortazavi, Ali ;

Carson, Monica J. ;

Poon, Wayne W. ;

Blurton-Jones, Mathew .

NEURON, 2017, 94 (02) :278-+

[3] The PsychENCODE project [J].

Akbarian, Schahram ;

Liu, Chunyu ;

Knowles, James A. ;

Vaccarino, Flora M. ;

Farnham, Peggy J. ;

Crawford, Gregory E. ;

Jaffe, Andrew E. ;

Pinto, Dalila ;

Dracheva, Stella ;

Geschwind, Daniel H. ;

Mill, Jonathan ;

Nairn, Angus C. ;

Abyzov, Alexej ;

Pochareddy, Sirisha ;

Prabhakar, Shyam ;

Weissman, Sherman ;

Sullivan, Patrick F. ;

State, Matthew W. ;

Weng, Zhiping ;

Peters, Mette A. ;

White, Kevin P. ;

Gerstein, Mark B. ;

Amiri, Anahita ;

Armoskus, Chris ;

Ashley-Koch, Allison E. ;

Bae, Taejeong ;

Beckel-Mitchener, Andrea ;

Berman, Benjamin P. ;

Coetzee, Gerhard A. ;

Coppola, Gianfilippo ;

Francoeur, Nancy ;

Fromer, Menachem ;

Gao, Robert ;

Grennan, Kay ;

Herstein, Jennifer ;

Kavanagh, David H. ;

Ivanov, Nikolay A. ;

Jiang, Yan ;

Kitchen, Robert R. ;

Kozlenkov, Alexey ;

Kundakovic, Marija ;

Li, Mingfeng ;

Li, Zhen ;

Liu, Shuang ;

Mangravite, Lara M. ;

Mattei, Eugenio ;

Markenscoff-Papadimitriou, Eirene ;

Navarro, Fabio C. P. ;

North, Nicole ;

Omberg, Larsson .

NATURE NEUROSCIENCE, 2015, 18 (12) :1707-1712

[4] Senescence in amniocytes and placentas from trisomy 21 pregnancies [J].

Amiel, Aliza ;

Fejgin, Moshe D. ;

Liberman, Meytal ;

Sharon, Yehudit ;

Kidron, Dvora ;

Biron-Shental, Tal .

JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2013, 26 (11) :1086-1089

[5] Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro [J].

Araujo, Bruno H. S. ;

Kaid, Carolini ;

De Souza, Janaina S. ;

da Silva, Sergio Gomes ;

Goulart, Ernesto ;

Caires, Luiz C. J. ;

Musso, Camila M. ;

Torres, Laila B. ;

Ferrasa, Adriano ;

Herai, Roberto ;

Zatz, Mayana ;

Okamoto, Oswaldo K. ;

Cavalheiro, Esper A. .

MOLECULAR NEUROBIOLOGY, 2018, 55 (07) :5962-5975

[6] Future of Rare Diseases Research 2017-2027: An IRDiRC Perspective [J].

Austin, Christopher P. ;

Cutillo, Christine M. ;

Lau, Lilian P. L. ;

Jonker, Anneliene H. ;

Rath, Ana ;

Julkowska, Daria ;

Thomson, David ;

Terry, Sharon F. ;

de Montleau, Beatrice ;

Ardigo, Diego ;

Hivert, Virginie ;

Boycott, Kym M. ;

Baynam, Gareth ;

Kaufmann, Petra ;

Taruscio, Domenica ;

Lochmuller, Hanns ;

Suematsu, Makoto ;

Incerti, Carlo ;

Draghia-Akli, Ruxandra ;

Norstedt, Irene ;

Wang, Lu ;

Dawkins, Hugh J. S. .

CTS-CLINICAL AND TRANSLATIONAL SCIENCE, 2018, 11 (01) :21-27

[7] Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome [J].

Aziz, Nadine M. ;

Guedj, Faycal ;

Pennings, Jeroen L. A. ;

Olmos-Serrano, Jose Luis ;

Siegel, Ashley ;

Haydar, Tarik F. ;

Bianchi, Diana W. .

DISEASE MODELS & MECHANISMS, 2018, 11 (06)

[8] Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection [J].

Balani, SK ;

Miwa, GT ;

Gan, LS ;

Wu, JT ;

Lee, FW .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (11) :1033-1038

[9]

BECKER L, 1991, PROG CLIN BIOL RES, V373, P133

[10] An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome [J].

Belichenko, Pavel V. ;

Madani, Rime ;

Rey-Bellet, Lorianne ;

Pihlgren, Maria ;

Becker, Ann ;

Plassard, Adeline ;

Vuillermot, Stephanie ;

Giriens, Valerie ;

Nosheny, Rachel L. ;

Kleschevnikov, Alexander M. ;

Valletta, Janice S. ;

Bengtsson, Sara K. S. ;

Linke, Gordon R. ;

Maloney, Michael T. ;

Hickman, David T. ;

Reis, Pedro ;

Granet, Anne ;

Mlaki, Dorin ;

Lopez-Deber, Maria Pilar ;

Do, Long ;

Singhal, Nishant ;

Masliah, Eliezer ;

Pearn, Matthew L. ;

Pfeifer, Andrea ;

Muhs, Andreas ;

Mobley, William C. .

PLOS ONE, 2016, 11 (03)

← 1 2 3 4 5 6 7 8 9 10 →