LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson’s Disease Mouse Model

Zhao, Hien; John, Neena; Delic, Vedad; Ikeda-Lee, Karli; Kim, Aneeza; Weihofen, Andreas; Swayze, Eric E.; Kordasiewicz, Holly; West, Andrew B.; Volpicelli‐Daley, Laura A.

doi:10.1016/j.omtn.2017.08.002

Cited by 176 publications

(170 citation statements)

References 43 publications

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“…To our knowledge, the results presented here are the first observations measuring new protein production of long‐lived protein targets in the CNS after therapeutic intervention. Our approach can be directly applied to multiple RNA‐directed strategies, such as siRNAs 31 and ASOs,32, 33 that target long‐lived proteins in neurodegeneration for clinical trials. Besides its lowered protein production readout, stable isotope labeling could be a powerful tool to examine increased protein production for therapeutic strategies such as gene therapy 34 and splicing ASO treatments 35, 36.…”

Section: Discussionmentioning

confidence: 99%

Protein production is an early biomarker for RNA‐targeted therapies

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Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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ObjectivesClinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA‐targeted therapies.MethodsTransgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule‐associated protein tau (hTau) or superoxide dismutase‐1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6‐leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics.Results ASO treatment lowered hTau mRNA and protein production (measured by 13C6‐leucine‐labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment.InterpretationMeasures of newly generated protein show earlier pharmacodynamics changes for RNA‐lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA‐targeted therapeutics.

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Section: Discussionmentioning

confidence: 99%

Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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“…Furthermore, increasing evidence supports the possibility that nonkinase LRRK2 activity may be involved in the pathogenesis of LRRK2 ‐PD . These issues have encouraged consideration of other approaches, such as the use of LRRK2 antisense oligonucleotides …”

Section: Targets For Disease Modificationmentioning

confidence: 99%

“…85 These issues have encouraged consideration of other approaches, such as the use of LRRK2 antisense oligonucleotides. 87…”

Section: Treatments Directed At Specific Subtypes Of Pd: Lrrk2mentioning

confidence: 99%

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

2018

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The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

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“…It will be critical to understand the level of pathway inhibition required to achieve a therapeutic effect and avoid possible chronic toxic effects. An alternate strategy to reduce LRRK2 activity in the CNS, while bypassing peripheral adverse effects, is the use of antisense oligonucleotides as recently demonstrated in a preclinical report …”

Section: Therapeutic Approaches Targeting the Lrrk2 Pathwaymentioning

confidence: 99%

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

Sardi¹,

2018

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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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LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson’s Disease Mouse Model

Cited by 176 publications

References 43 publications

Protein production is an early biomarker for RNA‐targeted therapies

Protein production is an early biomarker for RNA‐targeted therapies

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

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

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