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

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

doi:10.1172/jci.insight.135633

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 α-synuclein (aSyn) protein, 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 preformed 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 nonhuman 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; thus, these data support the development of SNCA ASOs as a potential disease-modifying therapy for PD and related synucleinopathies.

Highlights

There is strong genetic evidence implicating the role of α-synuclein protein in the pathogenesis of Parkinson’s disease (PD) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]
Our study demonstrates that antisense oligonucleotides (ASOs)-mediated suppression of Snca prevented and reversed the progression of aSyn-mediated pathology in rodent transmission models of PD, demonstrating the potential of SNCA ASOs as a therapy for PD patients
Central delivery of human SNCA ASOs reduced expression of mRNA and protein throughout the brains of both the humanized mouse and NHPs, demonstrating that human SNCA ASOs are active in regions of the brain susceptible to PD in a larger species

Summary

Introduction

There is strong genetic evidence implicating the role of α-synuclein protein (aSyn) in the pathogenesis of Parkinson’s disease (PD) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. Duplication, triplication, or genetic mutations in the SNCA gene (which produces aSyn protein; e.g., A53T, A30P, E46K, G51D) are linked to autosomal dominant forms of the disease [1, 3, 4, 10, 13, 18]. A toxic gain-of-function of aSyn is established in other synucleinopathies, including multiple-system atrophy (MSA) [21], Diffuse Lewy body disease (DLBD) [22], and Gaucher disease (GD) [23], which collectively affects about 1% of people over 60 years of age. Diagnosed dementia with Lew bodies (DLB) [21] and pure autonomic failure (PAF) [24, 25] exhibit Lewy pathology, suggesting a toxic gain of function of aSyn in DLB and PAF, making aSyn knockdown a potentially viable therapeutic approach for several patient populations

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