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Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

Tracy A. Cole, Hien Zhao, Timothy J. Collier, Ivette Sandoval, Caryl E. Sortwell, Kathy Steece-Collier, Brian F. Daley, Alix Booms, Jack Lipton, Mackenzie Welch, Melissa Berman, Luke Jandreski, Danielle Graham, Andreas Weihofen, Stephanie Celano, Emily Schulz, Allyson Cole-Strauss, Esteban Luna, Duc Quach, Apoorva Mohan, C. Frank Bennett, Eric E. Swayze, Holly B. Kordasiewicz, Kelvin C. Luk, Katrina L. Paumier
doi: https://doi.org/10.1101/830554
Tracy A. Cole
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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  • For correspondence: tcole@ionisph.com
Hien Zhao
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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Timothy J. Collier
2Michigan State University, Grand Rapids, Michigan, USA.
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Ivette Sandoval
2Michigan State University, Grand Rapids, Michigan, USA.
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Caryl E. Sortwell
2Michigan State University, Grand Rapids, Michigan, USA.
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Kathy Steece-Collier
2Michigan State University, Grand Rapids, Michigan, USA.
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Brian F. Daley
2Michigan State University, Grand Rapids, Michigan, USA.
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Alix Booms
2Michigan State University, Grand Rapids, Michigan, USA.
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Jack Lipton
2Michigan State University, Grand Rapids, Michigan, USA.
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Mackenzie Welch
3Biogen, Cambridge, Massachusetts, USA.
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Melissa Berman
3Biogen, Cambridge, Massachusetts, USA.
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Luke Jandreski
3Biogen, Cambridge, Massachusetts, USA.
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Danielle Graham
3Biogen, Cambridge, Massachusetts, USA.
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Andreas Weihofen
3Biogen, Cambridge, Massachusetts, USA.
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Stephanie Celano
2Michigan State University, Grand Rapids, Michigan, USA.
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Emily Schulz
2Michigan State University, Grand Rapids, Michigan, USA.
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Allyson Cole-Strauss
2Michigan State University, Grand Rapids, Michigan, USA.
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Esteban Luna
4Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
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Duc Quach
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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Apoorva Mohan
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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C. Frank Bennett
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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Eric E. Swayze
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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Holly B. Kordasiewicz
1Ionis Pharmaceuticals, Inc., Carlsbad, California, USA.
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Kelvin C. Luk
4Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
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Katrina L. Paumier
2Michigan State University, Grand Rapids, Michigan, USA.
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Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent pre-formed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the non-human primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that by inhibiting production of aSyn it may be possible to reverse established pathology and thus supports the development of SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.

Summary Antisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinson’s disease patients.

  • Abbreviations

    PD
    Parkinson’s disease
    CNS
    central nervous system
    mRNA
    mature ribonucleic acid
    Snca/SNCA
    alpha synuclein rodent/human gene, respectively
    aSyn
    alpha synuclein protein
    LB
    Lewy body
    LN
    Lewy neurite
    ASO
    antisense oligonucleotide
    PFF
    pre-formed fibril
    CSF
    cerebrospinal fluid
    NHP
    non-human primate
    MSA
    multiple systems atrophy
    DLBD
    Diffuse Lewy body disease
    GD
    Gaucher disease
    PAF
    pure autonomic failure
    TH+
    tyrosine hydroxylase positive
    DA
    dopamine
    SN
    substantia nigra
    IHC
    immunohistochemistry
    pSer129+ aggregates
    phospho serine 129 positive aggregates
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    Posted November 04, 2019.
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    Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease
    Tracy A. Cole, Hien Zhao, Timothy J. Collier, Ivette Sandoval, Caryl E. Sortwell, Kathy Steece-Collier, Brian F. Daley, Alix Booms, Jack Lipton, Mackenzie Welch, Melissa Berman, Luke Jandreski, Danielle Graham, Andreas Weihofen, Stephanie Celano, Emily Schulz, Allyson Cole-Strauss, Esteban Luna, Duc Quach, Apoorva Mohan, C. Frank Bennett, Eric E. Swayze, Holly B. Kordasiewicz, Kelvin C. Luk, Katrina L. Paumier
    bioRxiv 830554; doi: https://doi.org/10.1101/830554
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    Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease
    Tracy A. Cole, Hien Zhao, Timothy J. Collier, Ivette Sandoval, Caryl E. Sortwell, Kathy Steece-Collier, Brian F. Daley, Alix Booms, Jack Lipton, Mackenzie Welch, Melissa Berman, Luke Jandreski, Danielle Graham, Andreas Weihofen, Stephanie Celano, Emily Schulz, Allyson Cole-Strauss, Esteban Luna, Duc Quach, Apoorva Mohan, C. Frank Bennett, Eric E. Swayze, Holly B. Kordasiewicz, Kelvin C. Luk, Katrina L. Paumier
    bioRxiv 830554; doi: https://doi.org/10.1101/830554

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