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

Autor: Darren J. Schofield, Lorraine Irving, Laura Calo, Anna Bogstedt, Gareth Rees, Annalisa Nuccitelli, Rajesh Narwal, Marcella Petrone, Jennifer Roberts, Lee Brown, Fiona Cusdin, Bhupinder Dosanjh, Christopher Lloyd, Claire Dobson, Ian Gurrell, Graham Fraser, Mary McFarlane, Edward Rockenstein, Brian Spencer, Eliezer Masliah, Maria Grazia Spillantini, Keith Tan, Andrew Billinton, Tris Vaughan, Iain Chessell, Michael S. Perkinton
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Neurobiology of Disease, Vol 132, Iss , Pp - (2019)
Druh dokumentu: article
ISSN: 1095-953X
34147934
DOI: 10.1016/j.nbd.2019.104582
Popis: There are no approved drug therapies that can prevent or slow the progression of Parkinson's disease (PD). Accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in PD. α-Synuclein is a core component of Lewy bodies and neurites that neuropathologically define PD, suggesting that α-synuclein may be a key causative agent in PD. Recent experimental data suggest that PD progression may arise due to spreading of pathological forms of extracellular α-synuclein throughout the brain via a cellular release, uptake and seeding mechanism. We have developed a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. MEDI1341 binds both monomeric and aggregated forms of α-synuclein. In vitro, MEDI1341 blocks cell-to-cell transmission of pathologically relevant α-synuclein preformed fibrils (pffs). After intravenous injection into rats and cynomolgus monkeys, MEDI1341 rapidly enters the central nervous system and lowers free extracellular α-synuclein levels in the interstitial fluid (ISF) and cerebrospinal fluid (CSF) compartments. Using a novel lentiviral-based in vivo mouse model of α-synuclein spreading in the brain, we show that treatment with MEDI1341 significantly reduces α-synuclein accumulation and propagation along axons. In this same model, we demonstrate that an effector-null version of the antibody was equally as effective as one with effector function. MEDI1341 is now in Phase 1 human clinical trial testing as a novel treatment for α-synucleinopathies including PD with the aim to slow or halt disease progression.
Databáze: Directory of Open Access Journals
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