Nhắm mục tiêu α-synuclein bằng PD03 AFFITOPE® và Anle138b cứu vãn bệnh lý thoái hóa thần kinh trong mô hình suy giảm hệ thống đa tiểu: ý nghĩa lâm sàng

Translational Neurodegeneration - 2020
Miguel Lemos1, Serena Venezia1, Violetta Refolo1, Antonio Heras‐Garvin1, Sabine Schmidhuber2, Armin Giese3, Andrei Leonov4, Sergey Ryazanov4, Christian Griesinger5, Gergana Galabova2, Günther Staffler2, Gregor K. Wenning1, Nadia Stefanova1
1Division of Neurobiology, Department of Neurology, Innsbruck Medical University, 6020, Innsbruck, Austria
2AFFiRiS AG, Vienna, Austria
3Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany
4Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
5Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany

Tóm tắt

Tóm tắt Đặt vấn đề Đoàn dạng oligomer α-synuclein bị gập sai đóng vai trò quan trọng trong cơ chế gây bệnh của các bệnh α-synucleinopathy, bao gồm bệnh Parkinson và chứng thoái hóa hệ thống đa tiểu. Sự phát hiện nó song song với việc kích hoạt tế bào viêm microglia và mất neuron ở vùng substantia nigra pars compacta. Trong bài nghiên cứu này, chúng tôi nhằm phân tích hiệu quả điều trị của PD03, một phương pháp miễn dịch AFFITOPE® mới, đơn độc hoặc kết hợp với Anle138b, trong mô hình chuột PLP-α-syn. Phương pháp Các chú chuột PLP-α-syn được điều trị bằng liệu pháp miễn dịch PD03, Anle138b, hoặc sự kết hợp của cả hai. Năm tháng sau khi bắt đầu nghiên cứu, các chú chuột đã trải qua thử nghiệm hành vi và được hy sinh để phân tích bệnh lý thần kinh. Các nhóm điều trị được so sánh với nhóm đối chứng về hiệu suất vận động, mất neuron nigral, kích hoạt microglia và bệnh lý α-synuclein. Kết quả Các chú chuột PLP-α-syn nhận liệu pháp đơn độc PD03 hoặc Anle138b cho thấy sự cải thiện về rối loạn đi lại và bảo tồn các neuron dopaminergic nigral, liên quan đến việc giảm mức độ oligomer α-synuclein và giảm kích hoạt microglia. Liệu pháp kết hợp với Anle138b và PD03 dẫn đến IgG liên kết thấp hơn trong não so với liệu pháp miễn dịch đơn độc với PD03. Kết luận PD03 và Anle138b có thể nhắm mục tiêu chọn lọc vào α-synuclein oligomer, dẫn đến giảm thiểu thoái hóa thần kinh trong mô hình PLP-α-syn. Cả hai phương pháp này đều là những liệu pháp tiềm năng cần được phát triển thêm để điều chỉnh bệnh trong các bệnh α-synucleinopathy.

Từ khóa


Tài liệu tham khảo

Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015;372(3):249–63.

Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and shy-Drager syndrome). J Neurol Sci. 1989;94(1–3):79–100.

Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett. 1998;251(3):205–8.

Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, et al. Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol (Berl). 1998;96(5):445–52.

Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, et al. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A. 2015;112(38):E5308–17.

Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL, et al. Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies. Nature. 2018;557(7706):558–63.

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(15):2196–203.

Refolo V, Bez F, Polissidis A, Kuzdas-Wood D, Sturm E, Kamaratou M, et al. Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies. Acta Neuropathol Commun. 2018;6(1):2.

Stefanova N. Translational therapies for multiple system atrophy: bottlenecks and future directions. Auton Neurosci. 2017;211:7.

O'Hara DM, Kalia SK, Kalia LV. Emerging disease-modifying strategies targeting alpha-synuclein for the treatment of Parkinson's disease. Br J Pharmacol. 2018;175(15):3080–9.

Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol. 2017;298:225–35.

Heras-Garvin A, Weckbecker D, Ryazanov S, Leonov A, Griesinger C, Giese A, et al. Anle138b modulates alpha-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov Disord. 2019;34(2):255–63.

Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, et al. Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 2002;3(6):583–8.

Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, et al. Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol. 2005;166(3):869–76.

Fernagut PO, Meissner WG, Biran M, Fantin M, Bassil F, Franconi JM, et al. Age-related motor dysfunction and neuropathology in a transgenic mouse model of multiple system atrophy. Synapse. 2014;68(3):98–106.

Bassil F, Fernagut PO, Bezard E, Pruvost A, Leste-Lasserre T, Hoang QQ, et al. 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(34):9593–8.

Herrera-Vaquero M, Bouquio D, Kallab M, Biggs K, Nair G, Ochoa J, 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(11):165513.

Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005;46(6):857–68.

Schneeberger A, Mandler M, Mattner F, Schmidt W. Vaccination for Parkinson's disease. Parkinsonism Relat Disord. 2012;18(Suppl 1):S11–3.

Lindstrom V, Ihse E, Fagerqvist T, Bergstrom J, Nordstrom E, Moller C, et al. Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders. Immunotherapy. 2014;6(2):141–53.

Valera E, Spencer B, Masliah E. Immunotherapeutic approaches targeting amyloid-beta, alpha-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics. 2016;13(1):179–89.

Lee JS, Lee SJ. Mechanism of anti-alpha-synuclein immunotherapy. J Mov Disord. 2016;9(1):14–9.

El-Agnaf O, Overk C, Rockenstein E, Mante M, Florio J, Adame A, et al. Differential effects of immunotherapy with antibodies targeting alpha-synuclein oligomers and fibrils in a transgenic model of synucleinopathy. Neurobiol Dis. 2017;104:85–96.

Rockenstein E, Ostroff G, Dikengil F, Rus F, Mante M, Florio J, et al. Combined active humoral and cellular immunization approaches for the treatment of synucleinopathies. J Neurosci. 2018;38(4):1000–14.

Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci. 2004;24(42):9434–40.

Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson's disease. PLoS One. 2010;5(1):e8784.

Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jakala P, et al. The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem. 2001;76(1):87–96.

Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020;1:1. https://doi.org/10.1038/s41586-020-2317-6.

Fleming SM, Ekhator OR, Ghisays V. Assessment of sensorimotor function in mouse models of Parkinson's disease. J Vis Exp. 2013;76:50303.

Levin J, Schmidt F, Boehm C, Prix C, Botzel K, Ryazanov S, et al. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014;127(5):779–80.

Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013;125(6):795–813.

Velayudhan L, Ffytche D, Ballard C, Aarsland D. New therapeutic strategies for Lewy body dementias. Curr Neurol Neurosci Rep. 2017;17(9):68.

Kallab M, Herrera-Vaquero M, Johannesson M, Eriksson F, Sigvardson J, Poewe W, et al. Region-specific effects of immunotherapy with antibodies targeting alpha-synuclein in a transgenic model of synucleinopathy. Front Neurosci. 2018;12:452.

Spencer B, Valera E, Rockenstein E, Overk C, Mante M, Adame A, et al. Anti-alpha-synuclein immunotherapy reduces alpha-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol Commun. 2017;5(1):7.

Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338.

Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci. 2014;34(28):9441–54.

Lindstrom V, Fagerqvist T, Nordstrom E, Eriksson F, Lord A, Tucker S, et al. Immunotherapy targeting alpha-synuclein protofibrils reduced pathology in (Thy-1)-h [A30P] alpha-synuclein mice. Neurobiol Dis. 2014;69:134–43.

Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 2014;127(6):861–79.

Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, Patrick C, 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(1):10.

Volc D, Poewe W, Kutzelnigg A, Lührs P, Thun-Hohenstein C, Schneeberger 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(7):591–600.

Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, et al. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020;578(7794):273–7.

Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia. 2013;61(3):349–60.

Fellner L, Jellinger KA, Wenning GK, Stefanova N. Glial dysfunction in the pathogenesis of alpha-synucleinopathies: emerging concepts. Acta Neuropathol. 2011;121(6):675–93.

Sanchez-Guajardo V, Barnum CJ, Tansey MG, Romero-Ramos M. Neuroimmunological processes in Parkinson's disease and their relation to alpha-synuclein: microglia as the referee between neuronal processes and peripheral immunity. ASN Neuro. 2013;5(2):113–39.

Thông tin
Thông tin xuất bản

Translational Neurodegeneration

Thông tin tác giả