Towards translational therapies for multiple system atrophy

Https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068324/#!po=4.27928

Towards translational therapies for multiple system atrophy

Daniela Kuzdas-Wood, Nadia Stefanova, [...], and Gregor K. Wenning

Additional article information

Abstract

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Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiopathogenesis manifesting with autonomic failure, parkinsonism, and ataxia in any combination. The underlying neuropathology affects central autonomic, striatonigral and olivopontocerebellar pathways and it is associated with distinctive glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) that contain aggregates of α-synuclein. Current treatment options are very limited and mainly focused on symptomatic relief, whereas disease modifying options are lacking. Despite extensive testing, no neuroprotective drug treatment has been identified up to now; however, a neurorestorative approach utilizing autologous mesenchymal stem cells has shown remarkable beneficial effects in the cerebellar variant of MSA. Here, we review the progress made over the last decade in defining pathogenic targets in MSA and summarize insights gained from candidate disease-modifying interventions that have utilized a variety of well-established preclinical MSA models. We also discuss the current limitations that our field faces and suggest solutions for possible approaches in cause-directed therapies of MSA.

Abbreviations: MSA, multiple system atrophy; MSA-P, parkinsonian variant of MSA; MSA-C, cerebellar variant of MSA; α-Syn, alpha-synuclein; SND, striatonigral degeneration; OPCA, olivopontocerebellar atrophy; GCI, (oligodendro-)glial cytoplasmic inclusions; UMSARS, unified MSA rating scale; wt, wild type; tg, transgenic; PLP, proteolipid protein; MBP, myelin basic protein; CNP, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase; SN, substantia nigra

Keywords: Multiple system atrophy, Striatonigral degeneration, Olivopontocerebellar atrophy, Alpha-synuclein, Neurodegeneration

Conclusion

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Research on MSA has reached the starting point for a new era in attempted disease modification, i.e., the planning of multicenter intervention trials; these should be based on evidence of target engagement in MSA models. Many preclinical and clinical studies have been performed in the past decade, searching for treatment agents that engage selective targets, as delineated in available disease models. To date, none of the clinical trials have produced the results we had hoped for based on the evidence gathered from pre-clinical studies. This is consistent with the failure of interventional therapies for other neurodegenerative disorders such as Parkinson's disease, Huntington's disease or motor neuron disease. In the future, patients need to be recruited in early disease stages and this will likely imply the use of imaging and wet biomarkers. Combination of PET and MR imaging might increase the diagnostic accuracy, however, to date there are few published data to support this. Further, evidence of target engagement for a given investigational compound will require functional imaging tools such as α-Syn PET ligands. To patients, their family members, basic science researchers and clinical practitioners, the quest for developing suitable treatment options for MSA patients continues to be fueled by the paucity of effective symptomatic therapy and the overwhelming absence of any disease-modifying intervention for this invariably fatal disorder. At the present, pre-clinical studies have identified α-Syn metabolism-directed compounds, including active or passive immunization against it, and systemic stem cell infusion as candidate therapies for the next generation of clinical trials. Undoubtedly, the execution of such trials will inform the development of therapies in the closely related disorder of typical PD, and vice versa since MSA and PD both have aggregates of misfolded α-Syn as major hallmark and share similarities in their pattern of neurodegeneration (Fellner et al., 2011; Fellner and Stefanova, 2012; McCann et al., 2014).

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