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      Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

      review-article
      Author(s): , PharmD, PhD 1 , , , MD 2 , , MD, PhD 3
      Publication date (Electronic):
      Journal: Movement Disorders
      Publisher: John Wiley and Sons Inc.
      Keywords: SNCA, GBA LRRK2, α‐synuclein, glucocerebrosidase, clinical trial

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          Abstract

          The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α‐synuclein, glucocerebrosidase, and leucine‐rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease‐modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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          Most cited references61

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          TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.

          Mickael Decressac, Bengt Mattsson, Pia Weikop … (2013)
          The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.
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            Technology in Parkinson's disease: Challenges and opportunities.

            Alberto Espay, Paolo Bonato, Fatta B. Nahab … (2016)
            The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.
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              The Synaptic Function of α-Synuclein

              Jacqueline Burré (2015)
              α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals, and is strongly linked genetically and pathologically to Parkinson’s disease and other neurodegenerative diseases. While the accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases called “synucleinopathies”, its cellular function has remained largely unclear, and is the subject of intense investigation. In this review, I focus on the structural characteristics of α-synuclein, its cellular and subcellular localization, and discuss how this relates to its function in neurons, in particular at the neuronal synapse.
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                Author and article information

                Contributors
                S. Pablo Sardi:
                ORCID: http://orcid.org/0000-0001-9805-3677
                Pablo.Sardi@sanofi.com
                Journal
                Journal ID (nlm-ta): Mov Disord
                Journal ID (iso-abbrev): Mov. Disord
                Journal ID (doi): 10.1002/(ISSN)1531-8257
                Journal ID (publisher-id): MDS
                Title: Movement Disorders
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0885-3185
                ISSN (Electronic): 1531-8257
                Publication date (Electronic): 27 April 2018
                Publication date (Print): May 2018
                Volume: 33
                Issue: 5 ( doiID: 10.1002/mds.v33.5 )
                Pages: 684-696
                Affiliations
                [ 1 ] Neuroscience Therapeutic Area Sanofi Framingham MA USA
                [ 2 ] Neurology Early Clinical Development Biogen Cambridge MA USA
                [ 3 ] Center for Neurodegenerative Science Van Andel Research Institute Grand Rapids MI USA
                Author notes
                [*] [* ] Corresponding author: S. Pablo Sardi, Neuroscience Therapeutic Area, Sanofi, 49 New York Ave., Framingham, MA 01701; Pablo.Sardi@ 123456sanofi.com
                Author information
                http://orcid.org/0000-0001-9805-3677
                Article
                Publisher ID: MDS27414
                DOI: 10.1002/mds.27414
                PMC ID: 6282975
                PubMed ID: 29704272
                SO-VID: 3439a430-b41c-48e9-965c-0d732a5d7d0b
                Copyright © © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 02 February 2018
                Date revision received : 20 March 2018
                Date accepted : 23 March 2018
                Page count
                Figures: 1, Tables: 1, Pages: 14, Words: 9642
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id mds27414
                cover-date May 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:06.12.2018

                ScienceOpen disciplines: Medicine
                Keywords: snca,gba lrrk2,α‐synuclein,glucocerebrosidase,clinical trial
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: snca, gba lrrk2, α‐synuclein, glucocerebrosidase, clinical trial

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