Skip to main content

Advertisement

SpringerLink
Log in

Recent Advances in Clinical Trials in Multiple System Atrophy

  • Review
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design.

Recent Findings

Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions.

Summary

The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Poewe W, Stankovic I, Halliday G, Meissner WG, Wenning GK, Pellecchia MT, Seppi K, Palma J-A, Kaufmann H. Multiple system atrophy. Nat Rev Dis Primers. 2022;8:1–21.

    Google Scholar 

  2. Cykowski MD, Coon EA, Powell SZ, Jenkins SM, Benarroch EE, Low PA, Schmeichel AM, Parisi JE. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain. 2015;138:2293–309.

    PubMed  PubMed Central  Google Scholar 

  3. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. The Lancet Neurology. 2013;12:264–74.

    PubMed  PubMed Central  Google Scholar 

  4. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM-Y. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in non-transgenic mice. Science. 2012;338:949–53.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wong YC, Krainc D. α-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23:1–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M. The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol. 1997;93:585–91.

    CAS  PubMed  Google Scholar 

  7. Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain. 2004;127:2657–71.

    PubMed  Google Scholar 

  8. Peng C, Gathagan RJ, Covell DJ, et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature. 2018;557:558–63.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. • Shahnawaz M, Mukherjee A, Pritzkow S, et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature. 2020;578:273–7. This article explores the accuracy of a seed amplification assay to detect different patterns of alpha-synuclein aggregation between MSA and PD patients. They combined different methods to compare these patterns and observed distinct conformational strains of alpha-synuclein between MSA and PD

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. • Schweighauser M, Shi Y, Tarutani A, et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020;585:464–9. Using cryo-electron microscopy, the authors observed different structures of alpha-synuclein filaments in MSA and between MSA and DLB patients. This suggests that different alpha-synuclein strains could be related to distinct synucleinopathies

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. •• Wenning GK, Stankovic I, Vignatelli L, et al. The movement disorder society criteria for the diagnosis of multiple system atrophy. Movement Disorders. 2022;37:1131–48. This revision of diagnostic criteria of MSA aims to improve diagnosis accuracy at earlier stages of the disease and describes a new category of clinically established MSA that requires the presence of brain imaging features

    PubMed  PubMed Central  Google Scholar 

  12. Miki Y, Foti SC, Asi YT, Tsushima E, Quinn N, Ling H, Holton JL. Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. Brain. 2019;142:2813–27.

    PubMed  Google Scholar 

  13. Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW. When DLB, PD, and PSP masquerade as MSA. Neurology. 2015;85:404–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Osaki Y, Ben-Shlomo Y, Lees AJ, Wenning GK, Quinn NP. A validation exercise on the new consensus criteria for multiple system atrophy. Mov Disord. 2009;24:2272–6.

    PubMed  Google Scholar 

  15. • Virameteekul S, Revesz T, Jaunmuktane Z, Warner TT, De Pablo-Fernández E. Pathological validation of the MDS criteria for the diagnosis of multiple system atrophy. Movement Disorders. 2023;38:444–52. This article provides evidence of enhanced diagnostic performances of the new diagnostic criteria of MSA and excellent accuracy of the new category of clinically established MSA, even at the early stages of the disease

    PubMed  Google Scholar 

  16. Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord. 2004;19:1391–402.

    PubMed  Google Scholar 

  17. •• Krismer F, Palma J-A, Calandra-Buonaura G, et al. The unified multiple system atrophy rating scale: status, critique, and recommendations. Movement Disorders. 2022;37:2336–41. This review article describes the main limitation of the UMSARS and provides a roadmap to a revised version of the scale. The authors announced the creation of a task force of experts and the preparatory steps for an exhaustive documentation to provide a more comprehensive and patient-centered scale

    PubMed  PubMed Central  Google Scholar 

  18. Krismer F, Seppi K, Jönsson L, et al. Sensitivity to change and patient-centricity of the unified multiple system atrophy rating scale items: a data-driven analysis. Movement Disorders. 2022;37:1425–31.

    PubMed  PubMed Central  Google Scholar 

  19. Potashman M, Brady L, Durham S, et al (2023) Psychometric validation of a modified united multiple system atrophy rating scale (S43.002). In: Wednesday, April 26. Lippincott Williams & Wilkins, p 1958

  20. Potashman M, Huang I, Durham S, et al. Patient concept elicitation interviews: insights into multiple system atrophy (MSA) patient experiences and relevance of a modified united multiple system atrophy rating scale (P8-9.003). In: Tuesday, April 25. Lippincott Williams & Wilkins; 2023. p. 2057.

    Google Scholar 

  21. Palma J-A, Vernetti PM, Perez MA, et al. Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement. Clin Auton Res. 2021;31:157–64.

    PubMed  PubMed Central  Google Scholar 

  22. Foubert-Samier A, Pavy-Le Traon A, Saulnier T, Le-Goff M, Fabbri M, Helmer C, Rascol O, Proust-Lima C, Meissner WG. An item response theory analysis of the unified multiple system atrophy rating scale. Parkinsonism & Related Disorders. 2022;94:40–4.

    Google Scholar 

  23. Foubert-Samier A, Pavy-Le Traon A, Guillet F, Le-Goff M, Helmer C, Tison F, Rascol O, Proust-Lima C, Meissner WG. Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study. Neurobiol Dis. 2020;139:104813.

    PubMed  Google Scholar 

  24. Saulnier T, Philipps V, Meissner WG, Rascol O, Pavy-Le Traon A, Foubert-Samier A, Proust-Lima C. Joint models for the longitudinal analysis of measurement scales in the presence of informative dropout. Methods. 2022;203:142–51.

    CAS  PubMed  Google Scholar 

  25. Péran P, Barbagallo G, Nemmi F, Sierra M, Galitzky M, Traon AP-L, Payoux P, Meissner WG, Rascol O. MRI supervised and unsupervised classification of Parkinson’s disease and multiple system atrophy. Mov Disord. 2018;33:600–8.

    PubMed  Google Scholar 

  26. Chougar L, Faouzi J, Pyatigorskaya N, et al. Automated categorization of Parkinsonian syndromes using magnetic resonance imaging in a clinical setting. Movement Disorders. 2021;36:460–70.

    CAS  PubMed  Google Scholar 

  27. • Smith R, Capotosti F, Schain M, et al. The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases. Nat Commun. 2023;14:6750. This article shows a promising perspective for the use of an alpha-synuclein PET tracer to enhance diagnostic performances. The authors presented a specific biding to strategic brain regions related to MSA pathology and the ability of the tracer to distinguish between MSA patients and healthy controls or other synucleinopathies

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. • Poggiolini I, Gupta V, Lawton M, et al. Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. Brain. 2022;145:584–95. In this article, the authors explored the ability of seed amplification assay to distinguish between synucleinopathies and predict disease conversion of REM-sleep behavior disorder. This highlights the potential use of this method to detect synucleinopathy at prodromal stages

    PubMed  Google Scholar 

  29. Rossi M, Candelise N, Baiardi S, et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 2020;140:49–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chelban V, Nikram E, Perez-Soriano A, et al. Neurofilament light levels predict clinical progression and death in multiple system atrophy. Brain. 2022;145:4398–408.

    PubMed  PubMed Central  Google Scholar 

  31. Singer W, Schmeichel AM, Shahnawaz M, et al. Alpha-synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from Lewy body synucleinopathies. Ann Neurol. 2020;88:503–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting huntingtin expression in patients with Huntington’s disease. New England Journal of Medicine. 2019;380:2307–16.

    CAS  PubMed  Google Scholar 

  33. Wave Life Sciences Provides Update on Phase 1b/2a PRECISION-HD Trials - Wave Life Sciences. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-provides-update-phase-1b2a-precision-hd. Accessed 17 May 2023

  34. Alarcón-Arís D, Recasens A, Galofré M, et al. Selective α-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: potential therapy for Parkinson’s disease. Mol Ther. 2018;26:550–67.

    PubMed  Google Scholar 

  35. Uehara T, Choong C-J, Nakamori M, et al. Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease. Sci Rep. 2019;9:7567.

    ADS  PubMed  PubMed Central  Google Scholar 

  36. Miquel-Rio L, Alarcón-Arís D, Torres-López M, et al. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy. Transl Psychiatry. 2022;12:79.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kallab M, Herrera-Vaquero M, Johannesson M, Eriksson F, Sigvardson J, Poewe W, Wenning GK, Nordström E, Stefanova N. Region-specific effects of immunotherapy with antibodies targeting α-synuclein in a transgenic model of synucleinopathy. Front Neurosci. 2018;12:452.

    PubMed  PubMed Central  Google Scholar 

  38. Schofield DJ, Irving L, Calo L, et al. Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. Neurobiol Dis. 2019;132:104582.

    CAS  PubMed  Google Scholar 

  39. Knecht L, Folke J, Dodel R, Ross JA, Albus A. Alpha-synuclein immunization strategies for synucleinopathies in clinical studies: a biological perspective. Neurotherapeutics. 2022;19:1489–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin. 2010;6:948–52.

    CAS  PubMed  Google Scholar 

  41. Levin J, Maaß S, Schuberth M, et al. Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2019;18:724–35.

    CAS  PubMed  Google Scholar 

  42. Finkelstein DI, Billings JL, Adlard PA, et al. The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. Acta Neuropathol Commun. 2017;5:53.

    PubMed  PubMed Central  Google Scholar 

  43. Levin J, Maaß S, Schuberth M, et al. The PROMESA-protocol: progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach. J Neural Transm. 2016;123:439–45.

    CAS  PubMed  Google Scholar 

  44. Stamler D, Bradbury M, Wong C, Offman E. A phase 1 study of PBT434, a novel small molecule inhibitor of α-synuclein aggregation, in adult and older adult volunteers (4871). Neurology. 2020;94:4871

  45. Devos D, Labreuche J, Rascol O, et al. Trial of deferiprone in Parkinson’s disease. N Engl J Med. 2022;387:2045–55.

    CAS  PubMed  Google Scholar 

  46. Herrera-Vaquero M, Bouquio D, Kallab M, et al. The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy. Biochim Biophys Acta Mol Basis Dis. 2019;1865:165513.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bengoa-Vergniory N, Faggiani E, Ramos-Gonzalez P, et al. CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease. Nat Commun. 2020;11:4885.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bassil F, Fernagut P-O, Bezard E, Pruvost A, Leste-Lasserre T, Hoang QQ, Ringe D, Petsko GA, Meissner WG. Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc Natl Acad Sci U S A. 2016;113:9593–8.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Arotcarena M-L, Bourdenx M, Dutheil N, et al. Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies. JCI Insight. 2019;4(e129719):129719.

    PubMed  Google Scholar 

  50. Mahul-Mellier A-L, Fauvet B, Gysbers A, et al. c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum Mol Genet. 2014;23:2858–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lopez-Cuina M, Guerin PA, Canron M-H, Delamarre A, Dehay B, Bezard E, Meissner WG, Fernagut P-O. Nilotinib fails to prevent synucleinopathy and cell loss in a mouse model of multiple system atrophy. Mov Disord. 2020;35:1163–72.

    CAS  PubMed  Google Scholar 

  52. Inhibikase therapeutics announces FDA has lifted the full clinical hold on IkT-148009 in multiple system atrophy. In: Inhibikase Therapeutics, Inc. 2023 https://www.inhibikase.com/news/press-releases/detail/77/inhibikase-therapeutics-announces-fda-has-lifted-the-full. Accessed 3 Nov 2023

  53. Bassil F, Canron M-H, Vital A, Bezard E, Li Y, Greig NH, Gulyani S, Kapogiannis D, Fernagut P-O, Meissner WG. Insulin resistance and exendin-4 treatment for multiple system atrophy. Brain. 2017;140:1420–36.

    PubMed  PubMed Central  Google Scholar 

  54. Dodel R, Spottke A, Gerhard A, et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord. 2010;25:97–107.

    PubMed  Google Scholar 

  55. Vidal-Martinez G, Segura-Ulate I, Yang B, Diaz-Pacheco V, Barragan JA, De-Leon Esquivel J, Chaparro SA, Vargas-Medrano J, Perez RG. FTY720-Mitoxy reduces synucleinopathy and neuroinflammation, restores behavior and mitochondria function, and increases GDNF expression in Multiple System Atrophy mouse models. Exp Neurol. 2020;325:113120.

    CAS  PubMed  Google Scholar 

  56. Novak P, Williams A, Ravin P, Zurkiya O, Abduljalil A, Novak V. Treatment of multiple system atrophy using intravenous immunoglobulin. BMC Neurol. 2012;12:131.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Mitsui J, Matsukawa T, Uemura Y, et al. High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. eClinicalMedicine. 2023; https://doi.org/10.1016/j.eclinm.2023.101920.

  58. Holmberg B, Johansson J-O, Poewe W, et al. Safety and tolerability of growth hormone therapy in multiple system atrophy: a double-blind, placebo-controlled study. Movement Disorders. 2007;22:1138–44.

    PubMed  Google Scholar 

  59. Mullen JA, Savage AB, Minkwitz MC, Jucaite A, Cselényi Z, Johnström P, Posener J, Kugler A, Wenning G, Kaufmann H, Barone P, Meissner W, Carson R, Kreisl WC, Rabiner EA, Farde L, Poewe W, on behalf of the MSA Study Group. Safety, biomarker effects, and efficacy of the myeloperoxidase inhibitor AZD3241 in patients with multiple system atrophy: a 12-week randomized multicenter PET study (P.6016). Abstracts of the 6th international multiple system atrophy congress. Clin Auton Res 2018;28:137–60.

  60. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19:673–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Cole TA, Zhao H, Collier TJ, et al. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease. JCI Insight. 2021;6(e135633):135633.

    PubMed  Google Scholar 

  62. Boutros SW, Raber J, Unni VK. Effects of alpha-synuclein targeted antisense oligonucleotides on Lewy body-like pathology and behavioral disturbances induced by injections of pre-formed fibrils in the mouse motor cortex. J Parkinsons Dis. 2021;11:1091–115.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang J, Luo S, Zhang J, Yu T, Fu Z, Zheng Y, Xu X, Liu C, Fan M, Zhang Z. Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson’s disease. Neurobiol Dis. 2021;148:105218.

    CAS  PubMed  Google Scholar 

  64. Pavia-Collado R, Cóppola-Segovia V, Miquel-Rio L, et al. Intracerebral administration of a ligand-ASO conjugate selectively reduces α-synuclein accumulation in Monoamine Neurons of Double mutant human A30P*A53T*α-synuclein transgenic mice. Int J Mol Sci. 2021;22:2939.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Abeliovich A, Schmitz Y, Fariñas I, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25:239–52.

    CAS  PubMed  Google Scholar 

  66. Valera E, Spencer B, Fields JA, Trinh I, Adame A, Mante M, Rockenstein E, Desplats P, Masliah E. Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun. 2017;5:2.

    PubMed  PubMed Central  Google Scholar 

  67. Shering C, Pomfret M, Kubiak R, et al. Reducing α-synuclein in human CSF; an evaluation of safety, tolerability, pharmacokinetics and pharmacodynamics of MEDI1341, an α-synuclein-specific antibody, in healthy volunteers and Parkinson’s disease patients (P1-11.007). Neurology. 2023; https://doi.org/10.1212/WNL.0000000000202579.

  68. Fjord-Larsen L, Thougaard A, Wegener KM, Christiansen J, Larsen F, Schrøder-Hansen LM, Kaarde M, Ditlevsen DK. Nonclinical safety evaluation, pharmacokinetics, and target engagement of Lu AF82422, a monoclonal IgG1 antibody against alpha-synuclein in development for treatment of synucleinopathies. MAbs. 13:1994690.

  69. Buur L, Wiedemann J, Larsen F, Ben Alaya-Fourati F, Kallunki P, Ditlevsen D, Sørensen M, Meulien D. The anti-alpha-synuclein antibody Lu AF82422 was safe and well tolerated in a FIH-SAD study in healthy subjects and patients with PD [abstract]. Mov Disord. 2022;37(suppl 2).

  70. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–62.

    CAS  PubMed  Google Scholar 

  71. Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127:861–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Mandler M, Valera E, Rockenstein E, et al. Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener. 2015;10:10.

    PubMed  PubMed Central  Google Scholar 

  73. Mandler M, Rockenstein E, Overk C, et al. Effects of single and combined immunotherapy approach targeting amyloid β protein and α-synuclein in a dementia with Lewy bodies-like model. Alzheimers Dement. 2019;15:1133–48.

    PubMed  PubMed Central  Google Scholar 

  74. Volc D, Poewe W, Kutzelnigg A, et al. Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson’s disease: a randomised, single-blinded, phase 1 trial. Lancet Neurol. 2020;19:591–600.

    CAS  PubMed  Google Scholar 

  75. Poewe W, Volc D, Seppi K, et al. Safety and tolerability of active immunotherapy targeting α-synuclein with PD03A in patients with early Parkinson’s disease: a randomized, placebo-controlled, phase 1 study. J Parkinsons Dis. 2021;11:1079–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Meissner WG, Traon AP-L, Foubert-Samier A, et al. A phase 1 randomized trial of specific active α-synuclein immunotherapies PD01A and PD03A in multiple system atrophy. Movement Disorders. 2020;35:1957–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu HJ, Thijssen E, van Brummelen E, van der Plas JL, Radanovic I, Moerland M, Hsieh E, Groeneveld GJ, Dodart J-C. A randomized first-in-human study with UB-312, a UBITh® α-synuclein peptide vaccine. Mov Disord. 2022;37:1416–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Vaxxinity completes enrollment in part B of UB-312 phase 1 clinical trial for Parkinson’s disease | Vaxxinity. https://ir.vaxxinity.com/news-releases/news-release-details/vaxxinity-completes-enrollment-part-b-ub-312-phase-1-clinical/. Accessed 12 Apr 2023

  79. Ubhi K, Rockenstein E, Mante M, Patrick C, Adame A, Thukral M, Shults C, Masliah E. Rifampicin reduces alpha-synuclein in a transgenic mouse model of multiple system atrophy. Neuroreport. 2008;19:1271–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Low PA, Robertson D, Gilman S, et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014;13:268–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Finkelstein DI, Shukla JJ, Cherny RA, Billings JL, Saleh E, Stefanova N, Barnham KJ, Adlard PA. The compound ATH434 prevents alpha-synuclein toxicity in a murine model of multiple system atrophy. J Parkinsons Dis. 2022;12:105–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Heras-Garvin A, Refolo V, Schmidt C, Malfertheiner K, Wenning GK, Bradbury M, Stamler D, Stefanova N. ATH434 reduces α-synuclein-related neurodegeneration in a murine model of multiple system atrophy. Movement Disorders. 2021;36:2605–14.

    CAS  PubMed  Google Scholar 

  83. Heras-Garvin A, Weckbecker D, Ryazanov S, Leonov A, Griesinger C, Giese A, Wenning GK, Stefanova N. Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Movement Disorders. 2019;34:255–63.

    CAS  PubMed  Google Scholar 

  84. Levin J, Schmidt F, Boehm C, Prix C, Bötzel K, Ryazanov S, Leonov A, Griesinger C, Giese A. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014;127:779–80.

    PubMed  PubMed Central  Google Scholar 

  85. Levin J, Sing N, Melbourne S, et al. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: a randomised, double-blind, placebo-controlled phase 1a trial. eBioMedicine. 2022; https://doi.org/10.1016/j.ebiom.2022.104021.

  86. Levin J, Singh N, Melbourne S, Morgan A, Carroll C, Fietzek U, Ryazanov S, Leonov A, Griesinger CH, Schmidt F, Weckbecker D, Prager K, Matthias T, Giese A. Anle138b-P1-02: a randomised, double-blinded, placebo-controlled phase 1b study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of the oligomer modulator anle138b in Parkinson’s disease [abstract]. Mov Disord. 2023;38(suppl 1).

  87. Lee H-J, Khoshaghideh F, Patel S, Lee S-J. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004;24:1888–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305:1292–5.

    ADS  CAS  PubMed  Google Scholar 

  89. Palma J-A, Martinez J, Millar Vernetti P, et al. mTOR inhibition with sirolimus in multiple system atrophy: a randomized, double-blind, placebo-controlled futility trial and 1-year biomarker longitudinal analysis. Mov Disord. 2022;37:778–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Venezia S, Refolo V, Polissidis A, Stefanis L, Wenning GK, Stefanova N. Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal α-synucleinopathy. Mol Neurodegener. 2017;12:52.

    PubMed  PubMed Central  Google Scholar 

  91. Valera E, Spencer B, Mott J, et al. MicroRNA-101 modulates autophagy and oligodendroglial alpha-synuclein accumulation in multiple system atrophy. Front Mol Neurosci. 2017;10:329.

    PubMed  PubMed Central  Google Scholar 

  92. Spencer B, Valera E, Rockenstein E, Trejo-Morales M, Adame A, Masliah E. A brain-targeted, modified neurosin (kallikrein-6) reduces α-synuclein accumulation in a mouse model of multiple system atrophy. Mol Neurodegener. 2015;10:48.

    PubMed  PubMed Central  Google Scholar 

  93. Kiely AP, Miners JS, Courtney R, Strand C, Love S, Holton JL. Exploring the putative role of kallikrein-6, calpain-1 and cathepsin-D in the proteolytic degradation of α-synuclein in multiple system atrophy. Neuropathol Appl Neurobiol. 2019;45:347–60.

    CAS  PubMed  Google Scholar 

  94. Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study. Brain. 2009;132:156–71.

    PubMed  Google Scholar 

  95. Friess E, Kuempfel T, Modell S, Winkelmann J, Holsboer F, Ising M, Trenkwalder C. Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat Disord. 2006;12:432–7.

    PubMed  Google Scholar 

  96. Rascol O, Cochen de Cock V, Pavy-Le Traon A, et al. Fluoxetine for the symptomatic treatment of multiple system atrophy: the MSA-FLUO trial. Mov Disord. 2021;36:1704–11.

    CAS  PubMed  Google Scholar 

  97. Ubhi K, Inglis C, Mante M, Patrick C, Adame A, Spencer B, Rockenstein E, May V, Winkler J, Masliah E. Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy. Exp Neurol. 2012;234:405–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Meyer M, Lamare F, Asselineau J, et al. Brain 5-HT1A receptor binding in multiple system atrophy: an [18 F]-MPPF PET study. Mov Disord. 2021;36:246–51.

    CAS  PubMed  Google Scholar 

  99. Valera E, Ubhi K, Mante M, Rockenstein E, Masliah E. Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia. 2014;62:317–37.

    PubMed  Google Scholar 

  100. Lee PH, Lee JE, Kim H-S, et al. A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol. 2012;72:32–40.

    PubMed  Google Scholar 

  101. Singer W, Dietz AB, Zeller AD, et al. Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy. Neurology. 2019;93:e77–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Stefanova N, Poewe W, Wenning GK. Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp Neurol. 2008;210:421–7.

    CAS  PubMed  Google Scholar 

  103. Poewe W, Seppi K, Fitzer-Attas CJ, et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 2015;14:145–52.

    CAS  PubMed  Google Scholar 

  104. Park HS, Song YS, Moon BS, Yoo S-E, Lee JM, Chung Y-T, Kim E, Lee BC, Kim SE. Neurorestorative effects of a novel fas-associated factor 1 inhibitor in the MPTP model: an [18F]FE-PE2I positron emission tomography analysis study. Front Pharmacol. 2020;11:953.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shin W, Lim KS, Kim M-K, et al. A first-in-human study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 (FAS-associated factor 1 inhibitor), a drug for Parkinson’s disease, in healthy volunteers. Drug Des Devel Ther. 2019;13:1011–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Tardiff DF, Lucas M, Wrona I, Chang B, Chung CY, Le Bourdonnec B, Rhodes KJ, Scannevin RH. Non-clinical pharmacology of YTX-7739: a clinical stage stearoyl-CoA desaturase inhibitor being developed for Parkinson’s disease. Mol Neurobiol. 2022;59:2171–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Vincent BM, Tardiff DF, Piotrowski JS, et al. Inhibiting stearoyl-CoA desaturase ameliorates α-synuclein cytotoxicity. Cell Rep. 2018;25:2742–2754.e31.

    CAS  PubMed  Google Scholar 

  108. Inc YT (2021) Yumanity Therapeutics’ YTX-7739 achieved target engagement at doses that were generally well tolerated in a phase 1a multiple ascending dose study in healthy volunteers. In: GlobeNewswire News Room. https://www.globenewswire.com/news-release/2021/04/22/2214878/0/en/Yumanity-Therapeutics-YTX-7739-Achieved-Target-Engagement-at-Doses-That-Were-Generally-Well-Tolerated-in-a-Phase-1a-Multiple-Ascending-Dose-Study-in-Healthy-Volunteers.html. Accessed 2 Nov 2023

  109. Vargas-Medrano J, Segura-Ulate I, Yang B, Chinnasamy R, Arterburn JB, Perez RG. FTY720-Mitoxy reduces toxicity associated with MSA-like α-synuclein and oxidative stress by increasing trophic factor expression and myelin protein in OLN-93 oligodendroglia cell cultures. Neuropharmacology. 2019;158:107701.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Sturm E, Fellner L, Krismer F, Poewe W, Wenning GK, Stefanova N. Neuroprotection by epigenetic modulation in a transgenic model of multiple system atrophy. Neurotherapeutics. 2016;13:871–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Ettle B, Kerman BE, Valera E, et al. α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. Acta Neuropathol. 2016;132:59–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med. 2013;369:233–44.

    Google Scholar 

  113. Barca E, Kleiner G, Tang G, et al. Decreased coenzyme Q10 levels in multiple system atrophy cerebellum. Journal of Neuropathology & Experimental Neurology. 2016;75:663–72.

    CAS  Google Scholar 

  114. Compta Y, Giraldo DM, Muñoz E, et al. Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy. Parkinsonism & Related Disorders. 2018;46:16–23.

    Google Scholar 

  115. Schottlaender LV, Bettencourt C, Kiely AP, Chalasani A, Neergheen V, Holton JL, Hargreaves I, Houlden H. Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients. PLOS ONE. 2016;11:e0149557.

    PubMed  PubMed Central  Google Scholar 

  116. Mitsui J, Matsukawa T, Tanaka M, et al. Randomized, double-blind, placebo-controlled phase 1 study to evaluate the safety and pharmacokinetics of high doses of ubiquinol in healthy adults. Neurology and Clinical Neuroscience. 2022;10:14–24.

    CAS  Google Scholar 

  117. Krismer F, Seppi K, Wenning GK, Abler V, Papapetropoulos S, Poewe W. Minimally clinically important decline in the parkinsonian variant of multiple system atrophy. Mov Disord. 2016;31:1577–81.

    PubMed  Google Scholar 

  118. Bassil F, Fernagut P-O, Bezard E, Meissner WG. Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog Neurobiol. 2014;118:1–18.

    CAS  PubMed  Google Scholar 

  119. Lopez-Cuina M, Guérin P, Dutheil N, Martin C, Lasserre TL, Fernagut P-O, Meissner WG, Bezard E. GRK2-targeted knockdown as therapy for multiple system atrophy. Mov Disord. 2023; https://doi.org/10.1002/mds.29422.

  120. Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK. Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov Disord. 2007;22:2196–203.

    PubMed  Google Scholar 

  121. Stefanova N, Georgievska B, Eriksson H, Poewe W, Wenning GK. Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox Res. 2012;21:393–404.

    CAS  PubMed  Google Scholar 

  122. Kaindlstorfer C, Sommer P, Georgievska B, Mather RJ, Kugler AR, Poewe W, Wenning GK, Stefanova N. Failure of neuroprotection despite microglial suppression by delayed-start myeloperoxidase inhibition in a model of advanced multiple system atrophy: clinical implications. Neurotox Res. 2015;28:185–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Jucaite A, Svenningsson P, Rinne JO, et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease. Brain. 2015;138:2687–700.

    PubMed  Google Scholar 

  124. Fukae J, Fujioka S, Yanamoto S, Mori A, Nomi T, Hatano T, Fukuhara K, Ouma S, Hattori N, Tsuboi Y. Serum uric acid level is linked to the disease progression rate in male patients with multiple system atrophy. Clinical Neurology and Neurosurgery. 2017;158:15–9.

    PubMed  Google Scholar 

  125. Yoo HS, Chung SJ, Lee YH, Ye BS, Sohn YH, Kwon H, Lee PH. Urate is closely linked to white matter integrity in multiple system atrophy. Ann Clin Transl Neurol. 2020;7:1029–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Jung Lee J, Han Yoon J, Jin Kim S, et al. Inosine 5’-Monophosphate to Raise Serum Uric Acid Level in Multiple System Atrophy (IMPROVE-MSA study). Clinical Pharmacology & Therapeutics. 2021;109:1274–81.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Univ. Bordeaux, CNRS, IMN, UMR5293, Bordeaux, France

    David Bendetowicz, Alexandra Foubert-Samier & Wassilios G. Meissner

  2. CHU Bordeaux, Service de Neurologie des Maladies Neurodégénératives, IMNc, CRMR AMS, NS-Park/FCRIN Network, Bordeaux, France

    David Bendetowicz, Alexandra Foubert-Samier & Wassilios G. Meissner

  3. MSA French Reference Center, Univ. Hospital Toulouse, Toulouse, France

    Margherita Fabbri, Anne Pavy Le Traon & Olivier Rascol

  4. Univ. Toulouse, CIC-1436, Departments of Clinical Pharmacology and Neurosciences, NeuroToul COEN Center, NS-Park/FCRIN Network, Toulouse University Hospital, Inserm, U1048/1214, Toulouse, France

    Margherita Fabbri, Anne Pavy Le Traon & Olivier Rascol

  5. Univ. Bordeaux, INSERM, BPH, U1219, IPSED, Bordeaux, France

    Federico Sirna, Alexandra Foubert-Samier, Tiphaine Saulnier & Cécile Proust-Lima

  6. Université de Poitiers, Laboratoire de Neurosciences Expérimentales et Cliniques, INSERM UMR-S 1084, Poitiers, France

    Pierre-Olivier Fernagut

  7. Department of Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand

    Wassilios G. Meissner

Authors
  1. David Bendetowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margherita Fabbri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Federico Sirna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pierre-Olivier Fernagut
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexandra Foubert-Samier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tiphaine Saulnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anne Pavy Le Traon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cécile Proust-Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Olivier Rascol
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wassilios G. Meissner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Bendetowicz.

Ethics declarations

Conflict of Interest

M.F. received Grants from MSA Coalition, HORIZON 2022, Honoraria to speak from BIAL, AbbVie, Orkyn, Elivie, LvL médical and consultancies from Bial, Convatec and LvL médicale.

A.F.S. received honoraria from Aguettant Laboratory and Sanofi, grants from the French Rare Disease Foundation, from the French regional health agency (Agence Régionale de Santé de nouvelle Aquitaine), and from France Parkinson association.

W.G.M. reports personal fees from Elsevier, from Biohaven, Lundbeck, Roche, Servier, Alterity, Inhibikase, Teva and Takeda, outside the submitted work; and 1. International Parkinson and movement disorder society (Treasurer and Officer) 2. MSA Coalition (Member research steering committee) 3. Clément Fayat Foundation (Board of directors).

A.P.L. reports honoraria from Biohaven, HAC Pharma and speaker fees from Alnylam, outside the submitted work.

O.R. is advising following compagnies AbbVie, Acorda, Aguettant, Alkahest, AlzProtect, Apopharma, Astrazeneca, Bial, Biogen, Britannia, Buckwang, Cerevel, Clevexel, Contera, GE Healthcare, Handltherapeutic, Ionis, Irlab, Jazz, Kyowa, LGD Nuvamid, Lundbeck, Merck, Merz, MundiPharma, Neuralight, Neuratris, Neuroderm, Novartis, ONO Pharma, Orion Pharma, Parexel, PD Neurotechnology, Pfizer, Polycaps, Prexton, Roche Therapeutics, Sanofi, Scienture, Servier, Sombiotech, Sunovion, Supernus, Synagile, Thelonius Mind, Takeda, Théranexus, Teva, Tools4patient, UCB, Vision 2 voice, Zambon.

C.P.L., D.B., F.S., P.O.F., and T.S. have nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bendetowicz, D., Fabbri, M., Sirna, F. et al. Recent Advances in Clinical Trials in Multiple System Atrophy. Curr Neurol Neurosci Rep 24, 95–112 (2024). https://doi.org/10.1007/s11910-024-01335-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-024-01335-0

Keywords

Search

Navigation