Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome

被引：250

作者：

Berry-Kravis, Elizabeth M. ^{[1
,2
]}

Lindemann, Lothar

Jonch, Aia E. ^{[4
,5
]}

Apostol, George ^{[6
]}

Bear, Mark F. ^{[7
]}

Carpenter, Randall L. ^{[7
]}

Crawley, Jacqueline N. ^{[8
,9
]}

Curie, Aurore ^{[10
]}

Des Portes, Vincent ^{[10
]}

Hossain, Farah ^{[11
]}

Gasparini, Fabrizio ^{[12
]}

Gomez-Mancilla, Baltazar ^{[12
,13
]}

Hessl, David ^{[8
,9
]}

Loth, Eva ^{[14
]}

Scharf, Sebastian H. ^{[15
]}

Wang, Paul P. ^{[16
]}

Von Raison, Florian ^{[17
]}

Hagerman, Randi ^{[8
,18
]}

Spooren, Will ^{[3
]}

Jacquemont, Sebastien ^{[19
,20
,21
]}

机构：

[1] Rush Univ, Dept Pediat, Med Ctr, 1725 West Harrison St,Suite 718, Chicago, IL 60612 USA

[2] Rush Univ, Dept Neurol Sci & Biochem, Med Ctr, 1725 West Harrison St,Suite 718, Chicago, IL 60612 USA

[3] Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev Discovery Neuro, Grenzacherstr 124, CH-4070 Basel, Switzerland

[4] Odense Univ Hosp, Dept Clin Genet, Sdr Blvd 29, Odense C, Denmark

[5] Univ Southern Denmark, Dept Clin Res, Human Genet, JB Winslows Vej 19, DK-5000 Odense C, Denmark

[6] Novartis Pharma AG, Neurosci Dev, Fabrikstr 2, CH-4056 Basel, Switzerland

[7] MIT, Picower Inst Learning & Memory, 43 Vassar St, Cambridge, MA 02139 USA

[8] Univ Calif Davis, Sch Med, MIND Inst, 2825 50th St, Sacramento, CA 95817 USA

[9] Univ Calif Davis, Sch Med, Dept Psychiat & Behav Sci, 4625 2nd Ave, Sacramento, CA 95817 USA

[10] Univ Lyon, CNRS UMR 5304, Inst Sci Cognit, Hosp Civils Lyon,Hop Femme Mere Enfant,Natl Refer, Blvd Pinel 67, F-69675 Bron, France

[11] Novartis Pharmaceutical Corp, Neurosci Dev, 1 Hlth Plaza, E Hanover, NJ 07936 USA

[12] Novartis Inst Biomed Res, Neurosci Res, CH-4002 Basel, Switzerland

[13] McGill Univ, Dept Neurol & Neurosurg, 845 Sherbrook St West, Montreal, PQ H3A 0G4, Canada

[14] Kings Coll London, Inst Psychiat Psychol & Neurosci, Sackler Inst Translat Neurodev, De Crespigny Pk,Denmark Hill, London SE5 8AF, England

[15] Roche Innovat Ctr Basel, Pharmaceut Res & Early Dev, Grenzacherstr 124, CH-4070 Basel, Switzerland

[16] Simons Fdn, 160 Fifth Ave,7th Floor, New York, NY 10010 USA

[17] Novartis Pharma AG, Neurosci Dev, Fabrikstr 2, CH-4056 Basel, Switzerland

[18] Univ Calif Davis, Dept Pediat, Med Ctr, 2516 Stockton Blvd, Sacramento, CA 95817 USA

[19] CHU Vaudois, Serv Gen Med, Rue Bugnon 46, CH-1011 Lausanne, Switzerland

[20] Univ Lausanne, Lausanne, Switzerland

[21] Univ Montreal, CHU St Justine Res Ctr, 3175 Chemin Cote St Catherine, Montreal, PQ H3T 1C5, Canada

来源：

NATURE REVIEWS DRUG DISCOVERY | 2018年 / 17卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

MENTAL-RETARDATION PROTEIN; GLUTAMATE-RECEPTOR; 5; AUTISM SPECTRUM DISORDERS; FMR1 KO MICE; MOUSE MODEL; SYNAPTIC PLASTICITY; DOUBLE-BLIND; INTELLECTUAL DISABILITIES; ENDOCANNABINOID SYSTEM; CONTROLLED TRIAL;

D O I：

10.1038/nrd.2017.221

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

引用

页码：280 / 298

页数：19

共 150 条

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