Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight.

Matthew Upcott,Kirill D Chaprov,Vladimir L Buchman

doi:10.3390/molecules26237351

Abstract

The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.

Highlights

The pathological aggregation of alpha-synuclein has been implicated in the etiology, pathogenesis and progression of several neurodegenerative diseases, including familial and sporadic forms of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), that have coalesced into a group of alpha-synucleinopathies [1,2]
This study proves that IND-1233ASO has the ability to decrease human alpha-synuclein levels in targeted, PD-relevant brain areas
There is a significant body of evidence suggesting that alpha-synuclein is a contributor to both the pathogenesis and progression of neuropathology in PD

Summary

Introduction

The inhibition of alpha-synuclein aggregation and the spreading of aggregation pathology across the nervous system is considered a suitable target for novel diseasemodifying therapeutics for these diseases. A multistep process of alpha-synuclein aggregation includes nucleation, elongation/fibril growth, secondary nucleation, and, the assembly of mature filaments that, in vivo, form various types of pathological inclusions; these steps were intensively studied in vitro, in cultured cells and in the native nervous system of experimental animals; the results of these studies are summarized and discussed in multiple reviews (for example, see [3,4,5,6,7]). The intermediates of alpha-synuclein aggregation, e.g., oligomers and protofibrils, are believed to be the most important species from the pathology perspective as they exert neurotoxicity and are efficient seeds of further aggregation

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