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

Nature Reviews Drug Discovery volume 17, pages 280–299 (2018)Cite this article

Subjects

Key Points

  • Fragile X syndrome is a monogenic neurodevelopmental disorder associated with intellectual disability and autism spectrum disorders.

  • Animal models have provided insights into the neurobiological mechanisms and enabled the identification of novel drug targets.

  • Promising targets include metabotropic glutamate receptor 5 (mGluR5), GABA receptors and proteins that are regulated or regulate fragile X mental retardation protein 1 (FMRP).

  • Many compounds have been extensively investigated in preclinical studies and are able to rescue altered levels of protein synthesis, synaptic plasticity and behaviour. Behavioural phenotypes in Fmr1-knockout mice are difficult to measure, and the rescue of these deficits has been inconsistent across these different drugs.

  • Subsequent clinical trials in humans were unable to demonstrate any improvement using behavioural measures as primary end points.

  • Objective measures of core phenotypes such as direct assessments of cognition and language rather than secondary behaviours need to be implemented in future trials.

  • Very young patients have not yet been included in clinical trials, and this may be the only group in which effects of a disease-modifying agent targeting cognition and development can be seen. Efforts may need to be redirected towards the implementation of longer trials in younger children accompanied by learning interventions measuring cognitive and developmental outcomes.

Abstract

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.

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Figure 1: Drug targets in fragile X syndrome under investigation.
Figure 2: Clinical trials performed since 2002 in fragile X syndrome.

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Acknowledgements

The authors acknowledge the patients, caregivers and global fragile X syndrome community of scientists and investigators who contribute to the body of knowledge that continues to inform the treatment and care of this special patient population. The authors thank Spectrum and artist N. Rapp for Fig. 2. Selected research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies' in kind contribution. V.D.P. and A.C. thank the Clinical Center of Investigation (CIC), 1407 INSERM, Hospices Civils de Lyon, 69002, Lyon, France. Some work presented here has been facilitated by the Fragile X Clinical and Research Consortium (FXCRC) in the USA. E.B.K. is supported by U01NS096767. A.E.J. is the recipient of grants from Odense University Hospital Free Research Fund (grant number 15-A857) and of the Region of Zealand and Region of Southern of Denmark joint research fund (journal no. 14-001308) as well as a PhD scholarship from the Region of Southern of Denmark and the Faculty of Health Sciences, University of Southern of Denmark. M.F.B. acknowledges past and ongoing support and encouragement from FRAXA and NIH grant number R01-MH106469. J.N.C. is the recipient of NIH grant numbers R01NS085709 and U54HD079125-04 and Autism Speaks PACT targeted grant number 8603. E.L. is supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (grant FP7/2007-2013), from the European Federation of Pharmaceutical Industries and Associations. R.H. is funded by The MIND Institute IDDRC U54 HD079125, HRSA grants R40MC22641 and R40MC27701 and DOD PR101054. S.J. is the recipient of a Bursary Professor fellowship of the Swiss National Science Foundation (SNSF), the Jeanne et Jean Louis Levesque Research Chair and the Canadian Research Chair.

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  1. Sébastien Jacquemont

    Present address: Present address: CHU Sainte-Justine Research Centre, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada.,

Authors and Affiliations

  1. Departments of Pediatrics, Neurological Sciences and Biochemistry, Rush University Medical Center, 1725 West Harrison Street, Suite 718, Chicago, 60612, Illinois, USA

    Elizabeth M. Berry-Kravis

  2. Roche Pharmaceuticals Research and Early Development, Discovery Neuroscience, Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel, 4070, Switzerland

    Lothar Lindemann & Will Spooren

  3. Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark

    Aia E. Jønch

  4. Department of Clinical Research, Human Genetics, University of Southern Denmark, J.B. Winsløws Vej 19, Odense C, 5000, Denmark

    Aia E. Jønch

  5. Formerly at Neuroscience Development, Novartis Pharma AG, Fabrikstrasse 2, Basel, 4056, Switzerland

    George Apostol

  6. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar St, Cambridge, 02139, Massachusetts, USA

    Mark F. Bear & Randall L. Carpenter

  7. MIND Institute, University of California Davis School of Medicine, 2825 50th Street, Sacramento, 95817, California, USA

    Jacqueline N. Crawley, David Hessl & Randi Hagerman

  8. Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, 4625 2nd Avenue, Sacramento, 95817, California, USA

    Jacqueline N. Crawley & David Hessl

  9. 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, Bron Cedex, 69675, France

    Aurore Curie & Vincent Des Portes

  10. Neuroscience Development, Novartis Pharmaceutical Corporation, 1 Health Plaza, East Hanover, 07936, New Jersey, USA

    Farah Hossain

  11. Novartis Institutes for Biomedical Research, Neuroscience Research, Postfach, Basel, 4002, Switzerland

    Fabrizio Gasparini & Baltazar Gomez-Mancilla

  12. Department of Neurology & Neurosurgery, McGill University, 845 Sherbrook Street West, Montreal, H3A 0G4, Quebec, Canada

    Baltazar Gomez-Mancilla

  13. Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    Eva Loth

  14. Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel, 4070, Switzerland

    Sebastian H. Scharf

  15. Simons Foundation, 160 Fifth Avenue, 7th Floor, New York, 10010, New York, USA

    Paul P. Wang

  16. Neuroscience Development, Novartis Pharma AG, Fabrikstrasse 2, Basel, 4056, Switzerland

    Florian Von Raison

  17. Department of Pediatrics, University of California Davis Medical Center, 2516 Stockton Boulevard, Sacramento, 95817, California, USA

    Randi Hagerman

  18. Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne, 1011

    Sébastien Jacquemont

  19. University of Lausanne, Switzerland

    Sébastien Jacquemont

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Competing interests

E.B.K. has received funding from Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum, GW, Marinus, Edison and Neurotrope Pharmaceuticals to consult on trial design and development strategies and/or conduct clinical trials in fragile X syndrome (FXS), Vtesse to run clinical trials in Niemann–Pick type C, and from Asuragen Inc. to develop testing standards for FMR1 testing. L.L. is a full-time employee of F. Hoffmann-La Roche AG, he owns stock and stock options in F. Hoffmann-La Roche AG, and he is a co-inventor on patents originating in his work at F. Hoffmann-La Roche AG. A.E.J. participated in clinical trials led by Novartis Pharmaceuticals and has no further competing interests to declare. G.A. was a former full-time employee of Novartis Pharma and is currently an employee of Shire Pharmaceuticals. M.F.B. declares no competing interests. R.L.C. was a former full-time employee of Seaside Therapeutics and declares no further competing interests. J.N.C. declares no competing interests. A.C. participated in clinical trials led by Novartis Pharma and has no further competing interests to declare. V.D.P. participated in clinical trials led by Novartis Pharma and has no further competing interests to declare. F.H. is a former employee of Novartis Pharmaceutical Corporation and is currently employed by Celgene. F.G. is an employee and a shareholder of Novartis. B.G.M. is an employee of Novartis Institutes for Biomedical Research. D.H. has provided paid consultation regarding clinical trials in FXS to Novartis, Roche and Seaside Therapeutics. E.L. declares no competing interests. S.H.S. is a full-time employee of F. Hoffmann-La Roche AG. P.W. declares no competing interests. F.V.R. is a full-time employee and shareholder of Novartis Pharma. R.H. has received funding from Novartis, Roche/Genentech, Alcobra, Marinus and Neuren for clinical trials in FXS and has consulted with Roche/Genentech, Zynerba and Novartis regarding fragile X treatment and clinical trial design. W.S. is an employee of F. Hoffman-La Roche. S.J. has served on the Novartis Fragile X Advisory Board and has consulted for Novartis and WG Pharma.

PowerPoint slides

Glossary

Mosaicism

The presence of cell populations with a full mutation or premutation expansions. Methylation mosaicism is defined as some cells carrying fully methylated alleles and others carrying unmethylated alleles. Approximately 40% of male patients with fragile X syndrome present with size-mosaicism.

Rotarod

A performance test in which the rodent is placed on a rotating rod to examine motor skills and coordination.

Aberrant Behaviour Checklist

(ABC). A caregiver-rated symptom checklist that assesses problem behaviours via a 58-item and 5-subscale questionnaire. Each item is attributed a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”), resulting in total score ranks from 0 to 174.

Endophenotypes

Phenotypes that bear a closer relationship to the biological processes underlying the clinical manifestation.

ABC-CFX Social Avoidance subscale

The ABC-CFX is a modified version of the ABC-C, with 55 items and 6 subscales (irritability, lethargy/withdrawal, stereotypic behaviour, hyperactivity, inappropriate speech and social avoidance). The total score ranks from 0 to165, and a negative change from baseline indicates improvement.

Vineland Adaptive Behavior Scale

(VABS). A test that measures adaptive behaviour across lifespan and contains five domains (communication, daily living skills, socialization, motor skills and maladaptive behaviour) each with 2–3 subdomains, such as expressive language.

Audiogenic seizures

Convulsions caused by prolonged exposure to high frequency sound in, for example, rodents.

National Institutes of Health Toolbox

A battery of extensively validated computer-administered cognitive, emotional, motor and sensory tests with utility across the lifespan.

Cancellation task

A test of attention span in which the participants cancel the target figure and leave all other figures uncancelled (in other words, it is a test of the number of correct detections).

Wechsler Intelligence Scale for Children

(WISC). An intelligence test for children between 6 and 16 years of age.

Stanford–Binet

A cognitive ability and intelligence test used for individuals aged 2 to 85+ years.

Jadad score

A score that ranks the quality of clinical trials with respect to randomization, blinding and placebo control on a score from 0–5, with 5 being the maximum score.

Open label

A type of clinical trial in which the treatment being administered is known to both the researchers and participants.

Bayesian Design trials

A theory of statistical inference in clinical trials.

Sequential studies

Studies that combine longitudinal and cross-sectional designs by following several different age cohorts over time.

Test–retest validation

A measure of reliability obtained by administering the same test twice over a period of time to a group of individuals.

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Berry-Kravis, E., Lindemann, L., Jønch, A. et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat Rev Drug Discov 17, 280–299 (2018). https://doi.org/10.1038/nrd.2017.221

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