Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome.,Nature Reviews Drug Discovery

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Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome.
Nature Reviews Drug Discovery ( IF 122.7 ) Pub Date : 2017-12-08 , DOI: 10.1038/nrd.2017.221
Elizabeth M Berry-Kravis ₁ , Lothar Lindemann ₂ , Aia E Jønch _{3,

4} , George Apostol ₅ , Mark F Bear ₆ , Randall L Carpenter ₆ , Jacqueline N Crawley _{7,

8} , Aurore Curie ₉ , Vincent Des Portes ₉ , Farah Hossain ₁₀ , Fabrizio Gasparini ₁₁ , Baltazar Gomez-Mancilla _{11,

12} , David Hessl _{7,

8} , Eva Loth ₁₃ , Sebastian H Scharf ₁₄ , Paul P Wang ₁₅ , Florian Von Raison ₁₆ , Randi Hagerman _{7,

17} , Will Spooren ₂ , Sébastien Jacquemont _{18,

19}

Affiliation

Departments of Pediatrics, Neurological Sciences and Biochemistry, Rush University Medical Center, 1725 West Harrison Street, Suite 718, Chicago, Illinois 60612, USA.
Roche Pharmaceuticals Research and Early Development, Discovery Neuroscience, Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark.
Human Genetics, Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000 Odense C, Denmark.
Formerly at Neuroscience Development, Novartis Pharma AG, Fabrikstrasse 2, 4056 Basel, Switzerland.
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar St, Cambridge, Massachusetts 02139, USA.
MIND Institute, University of California Davis School of Medicine, 2825 50th Street, Sacramento, California 95817, USA.
Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, 4625 2nd Avenue, Sacramento, California 95817, USA.
National Reference Center for Rare Diseases with Intellectual Disability, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Université de Lyon, Institut des Sciences Cognitives, CNRS UMR 5304, Boulevard Pinel 67, 69675 Bron Cedex, France.
Neuroscience Development, Novartis Pharmaceutical Corporation, 1 Health Plaza, East Hanover, New Jersey 07936, USA.
Novartis Institutes for Biomedical Research, Neuroscience Research, Postfach, 4002 Basel, Switzerland.
Department of Neurology & Neurosurgery, McGill University, 845 Sherbrook Street West, Montreal, Quebec H3A 0G4, Canada.
Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Simons Foundation, 160 Fifth Avenue, 7th Floor, New York, New York 10010, USA.
Neuroscience Development, Novartis Pharma AG, Fabrikstrasse 2, 4056 Basel, Switzerland.
Department of Pediatrics, University of California Davis Medical Center, 2516 Stockton Boulevard, Sacramento, California 95817, USA.
Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, 1011 Lausanne and University of Lausanne, Switzerland.
CHU Sainte-Justine Research Centre, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada.

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.

中文翻译：

神经发育障碍的药物开发：从脆弱的X综合征中吸取的教训。

诸如脆性X综合征（FXS）之类的神经发育障碍会导致终生的认知和行为缺陷，并构成主要的公共健康负担。FXS是智力残疾和自闭症最常见的单基因形式，与其致病基因FMR1相关的潜在病理生理学一直是研究的重点。已经使用遗传和药理学方法在FXS动物模型中表征并挽救了被认为是这种神经发育障碍基础的突触功能的关键改变。这些可靠的临床前发现导致实施了迄今为止针对遗传学上定义的神经发育障碍的最全面的药物开发计划，包括代谢型谷氨酸受体5（mGluR5）拮抗剂的IIb期试验和GABAB受体激动剂的III期试验。但是，没有一项试验能够明确地证明疗效，并且它们也突出了针对FXS和其他神经发育障碍的药物开发中知识差距的程度。在本综述中，我们研究了先前研究中的潜在问题以及临床前和临床试验的未来方向。FXS处于开发用于神经发育障碍药物的最前沿，并且在此过程中获得的经验教训对于此类疾病也很重要。他们还强调了FXS和其他神经发育障碍药物开发中知识差距的程度。在本综述中，我们研究了先前研究中的潜在问题以及临床前和临床试验的未来方向。FXS处于开发用于神经发育障碍药物的最前沿，并且在此过程中获得的经验教训对于此类疾病也很重要。他们还强调了FXS和其他神经发育障碍药物开发中知识差距的程度。在本综述中，我们研究了先前研究中的潜在问题以及临床前和临床试验的未来方向。FXS处于开发用于神经发育障碍药物的最前沿，并且在此过程中汲取的经验教训对于此类疾病也很重要。

更新日期：2018-12-10

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