α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

Cole, Tracy; Zhao, Hien; Collier, Timothy J.; Sandoval, Ivette M.; Sortwell, Caryl E.; Steece‐Collier, Kathy; Daley, Brian F.; Booms, Alix; Lipton, Jack W.; Welch, Mackenzie; Berman, Melissa; Jandreski, Luke; Graham, Danielle; Weihofen, Andreas; Celano, Stephanie L.; Schulz, Emily M.; Cole-Strauss, Allyson; Luna, Esteban; Quach, Duc Trong; Mohan, Apoorva; Bennett, C. Frank; Swayze, Eric E.; Kordasiewicz, Holly; Luk, Kelvin C.; Paumier, Katrina L.

doi:10.1172/jci.insight.135633

Cited by 80 publications

(65 citation statements)

References 93 publications

(140 reference statements)

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“…Cole et al . with Ionis Pharmaceuticals have also tested such an approach and demonstrated efficacy in the non-human primate brain after intrathecal injection [ 83 ]; an AON, ION464, is currently being tested in clinical trials for patients with multiple system atrophy where the aberrant accumulation of α-synuclein is also prominent. Ionis Pharmaceutics have an additional AON in clinical development for PD (ION859) targeting Leucine Rich Repeat Kinase 2 (LRRK2).…”

Section: Targeting Nucleic Acidmentioning

confidence: 99%

RNA-based therapeutics for neurological diseases

Anthony

2022

RNA Biology

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RNA-based therapeutics have entered the mainstream with seemingly limitless possibilities to treat all categories of neurological disease. Here, common RNA-based drug modalities such as antisense oligonucleotides, small interfering RNAs, RNA aptamers, RNA-based vaccines and mRNA drugs are reviewed highlighting their current and potential applications. Rapid progress has been made across rare genetic diseases and neurodegenerative disorders, but safe and effective delivery to the brain remains a significant challenge for many applications. The advent of individualized RNA-based therapies for ultra-rare diseases is discussed against the backdrop of the emergence of this field into more common conditions such as Alzheimer’s disease and ischaemic stroke. There remains significant untapped potential in the use of RNA-based therapeutics for behavioural disorders and tumours of the central nervous system; coupled with the accelerated development expected over the next decade, the true potential of RNA-based therapeutics to transform the therapeutic landscape in neurology remains to be uncovered.

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Section: Targeting Nucleic Acidmentioning

confidence: 99%

RNA-based therapeutics for neurological diseases

Anthony

2022

RNA Biology

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“…Due to the complex ways in which disease risk is influenced by the interaction of genetics and environment, most PD is idiopathic and there are still no treatments to cure PD or slow its progression. Therapies targeting the protein alpha-synuclein, in efforts to reduce its aggregation within dopaminergic neurons, have, however, shown promising therapeutic potential ( Brys et al, 2019 ; Cole et al, 2021 ). Despite the use of alpha-synuclein as a disease modifying target, there is still little known about its functions in a broad range of cell types and how the activity of the protein influences PD risk via such cell types.…”

Section: Introductionmentioning

confidence: 99%

Functions of Intracellular Alpha-Synuclein in Microglia: Implications for Parkinson’s Disease Risk

Booms

Coetzee

2021

Front. Cell. Neurosci.

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Alpha-synuclein accumulation in dopaminergic neurons is one of the primary features of Parkinson’s disease (PD). Despite its toxic properties during PD, alpha-synuclein has some important physiological functions. Although the activity of the protein has been extensively studied in neurons, the protein is also expressed in other cell types including immune cells and glia. Genetic studies show that mutations in synuclein alpha (SNCA), the gene that encodes alpha-synuclein, and alterations in its expression levels are a significant risk factor for PD, which likely impact the functions of a broad range of cell types. The consequences of altered SNCA expression in other cell types is beginning to be explored. Microglia, the primary macrophage population in the Central Nervous System (CNS), for example, are affected by variations in alpha-synuclein levels and functions. Studies suggest that deviations of alpha-synuclein’s normal activity influence hematopoiesis, the process that gives rise to microglia, and microglia’s immune functions. Alpha-synuclein levels also dictate the efficiency of SNARE-mediated vesicle formation, which could influence autophagy and cytokine release in microglia. Starting from the time of conception, these effects could impact one’s risk for developing PD. Further studies are needed to determine the physiological role of alpha-synuclein and how the protein is affected during PD in non-neuronal cells such as microglia. In this review we will discuss the known roles of alpha-synuclein in differentiation, immune responses, and vesicle formation, with insights into how abnormal alpha-synuclein expression and activity are linked to altered functions of microglia during PD.

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“…For in vivo experiments, a statistical power analysis was performed for sample size estimation based on previous data published for the model, 34 based on the presumed biological effect size of the treatment, 20 and based on the effect sizes on the same end-points as observed with antisense oligonucleotides to α-synuclein. 32 Power and group sizes were centred on the lesion size of the loss of dopaminergic neurons in the ipsilateral side of the injection, where an α = 0.05 and power = 0.80 yields a projected sample size of seven capable of resolving 30% effect in the preservation of dopaminergic neurons between treatment and control groups. Samples that did not meet quality control due to tissue staining or sectioning irregularities, abnormalities or suspected perfusion difficulties, were excluded from the final analysis.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of ABT-888 in the amelioration of α-synuclein fibril-induced neurodegeneration

Hastings

Sokratian

Apicco

et al. 2022

Brain Communications

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The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson’s disease. Recent pre-clinical studies suggest poly(ADP-ribose) polymerase-1 activation and the subsequent generation of poly(ADP-ribose) polymer represent key steps in the formation of toxic α-synuclein aggregates and neurodegeneration. Several studies suggest that the inhibition of poly(ADP-ribose) polymerase-1 activity via the poly(ADP-ribose) polymerase-1/2 small molecule inhibitor ABT-888 (Veliparib), a drug in clinical trials for different cancers, may prevent or ameliorate α-synuclein fibril-induced aggregation, inclusion formation and dopaminergic neurodegeneration. Herein, we evaluated the effects of poly(ADP-ribose) polymer on α-synuclein fibrillization in vitro, the effects of ABT-888 on the formation of fibril-seeded α-synuclein inclusions in primary mouse cortical neurons and the effects of an in-diet ABT-888 dosage regimen with the intracranial injection of α-synuclein fibrils into the mouse dorsal striatum. We found that poly(ADP-ribose) polymer minimally but significantly increased the rate of spontaneously formed α-synuclein fibrils in vitro. Machine-learning algorithms that quantitatively assessed α-synuclein inclusion counts in neurons, both in primary cultures and in the brains of fibril-injected mice, did not reveal differences between ABT-888- and vehicle-treated groups. The in-diet administered ABT-888 molecule demonstrated outstanding brain penetration in mice; however, dopaminergic cell loss in the substantia nigra caused by α-synuclein fibril injections in the striatum was similar between ABT-888- and vehicle-treated groups. α-Synuclein fibril-induced loss of dopaminergic fibres in the dorsal striatum was also similar between ABT-888- and vehicle-treated groups. We conclude that additional pre-clinical evaluation of ABT-888 may be warranted to justify further exploration of ABT-888 for disease modification in Lewy body diseases.

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α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

Cited by 80 publications

References 93 publications

RNA-based therapeutics for neurological diseases

RNA-based therapeutics for neurological diseases

Functions of Intracellular Alpha-Synuclein in Microglia: Implications for Parkinson’s Disease Risk

Evaluation of ABT-888 in the amelioration of α-synuclein fibril-induced neurodegeneration

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