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  • Review Article
  • Published:

Priorities in Parkinson's disease research

Nature Reviews Drug Discovery volume 10, pages 377–393 (2011)Cite this article

Subjects

Key Points

  • Despite recent advances in the treatment of Parkinson's disease (PD), dyskinesia and motor fluctuations still make a substantial contribution to the reduced quality of life of patients with advanced-stage PD. Additionally, non-motor signs such as depression, dementia, sleep abnormalities and autonomic failure are increasingly being recognized as challenges to effective treatment as they dominate the clinical, caregiver and financial burden of the later stages of PD.

  • The translational value of current preclinical models of neurodegeneration remains unsatisfactory. Current limitations could be overcome in a number of ways; for example, by obtaining combinations of mutations by breeding mice with single or dual mutations, or by challenging existing models with environmental stressors such as neurotoxins or neuroinflammation inducers in animals with an established and stable background.

  • Novel drug targets will be uncovered through pathophysiological insights gained from the identification of the role of genetic mutations that are responsible for hereditary forms of PD, and future therapies targeted towards these mutations will have broader efficacy against sporadic PD than the currently available symptomatic treatments.

  • Many of the therapies that are currently under development — both dopaminergic and non-dopaminergic compounds — are focused on improving motor control, fluctuations and dyskinesias. Far fewer approaches address the other two key unmet clinical needs: specifically, alleviating non-motor symptoms, and disease modification and/or neuroprotection.

  • The most promising strategy to achieve disease modification or neuroprotection seems to be a combination of compounds that interfere simultaneously with different key events of PD pathology. This approach would require collaboration between the pharmaceutical companies that hold the patent rights of the different compounds.

  • Primary end points in past and ongoing trials of potential disease-modifying or neuroprotective drugs rely on clinical assessment scales. Additional efforts are therefore urgently needed to establish validated biomarkers in PD.

Abstract

The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinson's disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.>

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Figure 1: Drugs in development for the treatment of Parkinson's disease.
Figure 2: The 'delayed start' and the 'N of 1' clinical study designs.

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Acknowledgements

This Review summarises the main outcomes of an International Symposium that was held in Bordeaux, France, between May 4 and 5 2010. We are indebted to the devotion and efficiency of N. Vignais in helping to organize the Symposium.

Author information

Authors and Affiliations

  1. Service de Neurologie et Centre de référence atrophie multisystématisée, CHU de Bordeaux, Avenue Magellan, F-33604, Pessac, France

    Wassilios G. Meissner, François Tison & Erwan Bezard

  2. Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France

    Wassilios G. Meissner & François Tison

  3. CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France

    Wassilios G. Meissner, François Tison & Erwan Bezard

  4. Michael J. Fox Foundation for Parkinson's Research, New York, 10004, New York, USA

    Mark Frasier

  5. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen and DZNE — German Center for Neurodegenerative Diseases, D-72076, Tübingen, Germany

    Thomas Gasser

  6. Department of Neurological Sciences, Rush University Medical Center, Chicago, 60612, Illinois, USA

    Christopher G. Goetz

  7. Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, M5T 2S8, Ontario, Canada

    Andres Lozano

  8. Centre for Neuroscience, Imperial College London, London, SW7 2AZ, UK

    Paola Piccini

  9. Neurosciences Division, and Department of Neurology and Neurosurgery, Movement Disorders Group, CIMA, Clínica Universitaria and CIBERNED, University of Navarra, 31008, Pamplona, Spain

    José A. Obeso

  10. Departments of Clinical Pharmacology and Neurosciences, INSERM CIC9302, University Hospital of Toulouse, 31000, Toulouse, France

    Olivier Rascol

  11. Department of Clinical Neurosciences, Institute of Neurology, University College London, NW3 2PF, London, UK

    Anthony Schapira

  12. Behavioral and Clinical Neurosciences Institute, University of Cambridge, CB2 0SZ, Cambridge, UK

    Valerie Voon

  13. EMD Serono, Rockland, 02370, Massachusetts, USA

    David M. Weiner

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  1. Wassilios G. Meissner
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  8. Olivier Rascol
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Corresponding author

Correspondence to Wassilios G. Meissner.

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Competing interests

Wassilios G. Meissner receives his salary from the University of Bordeaux and the University Hospital Bordeaux. He has received teaching honoraria and travel grants from Lundbeck, Boehringer Ingelheim, Novartis and GlaxoSmithKline. He has received research funding from the Michael J. Fox Foundation (MJFF), the University Hospital Bordeaux and APTES (French Patients Association for Essential Tremor).

Mark Frasier is an employee of the MJFF.

Thomas Gasser serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Mendelian Forms of Parkinsonism). He has received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cephalon Pharma and Merck-Serono. He holds a patent concerning the LRRK2 gene and neurodegenerative disorders.

Christopher G. Goetz receives his salary from Rush University Medical Center and has received honoraria for consulting and advisory board membership at the following pharmaceutical companies: Addex Pharmaceuticals, Asubio Pharmaceuticals, Biovail Technologies, Cleveland Medical Devices, CNS Therapeutics, Curry Rockefeller Group, Decision Resources, Dixon Group, ICON Clinical Research, Impax Pharmaceuticals, Ingenix, Intec Pharmaceuticals, Kenes International, Medical Education Global Solutions, Ono Pharmaceuticals, Oxford BioMedica, Santhera Pharmaceuticals, United Bioscience Corporation and UCB Pharma. He has received research funding from the US National Institutes of Health and the MJFF. He is Director of the Rush Parkinson's Disease Research Center, which receives support from the PD Foundation. He also directs the translation programme for the MDS-UPDRS and UDysRS and receives funds from the MDS for this effort. He has received honoraria from the Movement Disorder Society (MDS), American Academy of Neurology, University of Miami, University of Pennsylvania, University of Montreal and the Neurological Society. He receives royalties from Oxford University Press, Elsevier Publishers, Wolters Kluwer Health, Lippincott and Wilkins and Williams.

Andres Lozano is a consultant for Medtronic, St Jude and Boston Scientific as well as Functional Neurosciences.

Paola Piccini has received grants from the MJFF, Parkinson's UK, the CHDI and European commission (FP7).

José A. Obeso has served previously in the advisory board of GlaxoSmithKline (UK), and received honorarium for lecturing in meetings organized by GlaxoSmithKline (Spain), Lundbeck/Teva and UCB Pharma. He received research funding from the Spanish Science and Education Ministry and the European Union (REPLACES).

Olivier Rascol reports having received data monitoring committee membership or consultancy/advisory honoraria from Abbott-Solvay, Addex, Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Merck-Serono, Oxford BioMedica, UCB Pharma, Impax, Teva and Lundbeck. Olivier Rascol has received grants from the Michael J, Fox Foundation for Parkinson's Research, French Ministry of Health, INSERM, the Movement Disorders Society, France-Parkinson, and Merz Pharma. He has also received lecture fees from the Movement Disorders Society and UCB Pharma, royalties for the Handbook of Neurology and payment for the development of educational presentations from the Movement Disorders Society and First Class.

Anthony Schapira has either received honoraria for educational symposia or undertaken consultancy work for BI, GlaxoSmithKline, Teva/Lundbeck, Orion-Novartis and MSD-Serono.

Valerie Voon does not declare any competing financial interests.

David Weiner was employed by EMD Serono at the time the manuscript was written.

François Tison has received honoraria for consulting and advisory board membership at the following pharmaceutical companies: Boehringer Ingelheim, Novartis, Lundbeck and GlaxoSmithKline. François Tison has also received travel grants from Novartis and UCB Pharma.

Erwan Bezard is employed by INSERM (France), owns stocks in Motac Holding (Manchester, UK), receives consultancy from Motac Neuroscience (Manchester, UK), has received grants from the Agence Nationale de la Recherche (France), the MJFF and the European Commission, and is a member of the scientific advisory board of the MJFF and of the France Parkinson Association.

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FURTHER INFORMATION

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Boehringer Ingelheim

CheckOrphan

ClinicalTrials.gov

IMPAX Laboratories

Santhera Pharmaceuticals

The Merck Group

The Michael J. Fox Foundation for Parkinson's Research

Glossary

Bradykinesia

Abnormally slow voluntary movements.

Rigidity

Increased muscle tone during passive limb movements, which is frequently associated with a 'cogwheel' phenomenon.

Dyskinesia

Levodopa-induced involuntary movements that affect the head, trunk and limbs.

Paradoxic kinesis

A sudden and brief relief of motor signs due to a sudden stress — for example, a fire alarm.

Off-period dystonia

Sustained muscle contractions and postures during off-periods. Off-period dystonia relates to subtherapeutic levels of levodopa and is both caused and relieved by levodopa. It frequently manifests as early-morning foot dystonia or diphasic painful dystonia of the lower limbs.

Subthalamic nucleus

A glutamatergic relay within the basal ganglia that becomes overactive in Parkinson's disease. Overexpression of glutamic acid decarboxylase — the key enzyme of GABA (γ-aminobutyric acid) synthesis — may dampen the overactivity of subthalamic neurons.

α-synuclein

A protein with unknown physiological function that forms abnormal intraneuronal aggregates in Parkinson's disease.

Sporadic PD

A form of Parkinson's disease (PD) that is unrelated to genetic mutations or other known aetiologies.

Prodromal phase

The early phase of the disease before the appearance of full-blown symptoms. In Parkinson's disease, it means the time before the onset of motor signs.

Delayed washout

A prolonged symptomatic benefit that exceeds the time taken for the elimination of the administered drug from the body.

Longitudinal data

Data that are collected at several time points in order to monitor disease progression over time.

Diffusion tensor imaging

A magnetic resonance imaging technique that measures the preferred direction of water diffusion in fibre tracts. It informs about white matter connectivity between different brain areas. Loss of neuronal axons or white matter modifies measures of diffusion tensor imaging.

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Meissner, W., Frasier, M., Gasser, T. et al. Priorities in Parkinson's disease research. Nat Rev Drug Discov 10, 377–393 (2011). https://doi.org/10.1038/nrd3430

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