Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice.
Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (α-synuclein) in the central nervous system (CNS) is an early pathogenic event in Parkinson's disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against α-synuclein as a promising novel treatment strategy. Since large α-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. In support of this, (Thy-1)-h[A30P] α-synuclein transgenic mice with motor dysfunction symptoms were found to display increased levels of α-synuclein protofibrils in the CNS. An α-synuclein protofibril-selective monoclonal antibody (mAb47) was evaluated in this α-synuclein transgenic mouse model. As measured by ELISA, 14month old mice treated for 14weeks with weekly intraperitoneal injections of mAb47 displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. Besides the lower levels of pathogenic α-synuclein demonstrated, a reduction of motor dysfunction in transgenic mice upon peripheral administration of mAb47 was indicated. Thus, immunotherapy with antibodies targeting toxic α-synuclein species holds promise as a future disease-modifying treatment in Parkinson's disease and related disorders.
Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Veronica
V
Lindström
Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Therese
T
Fagerqvist
BioArctic Neuroscience AB, Stockholm, Sweden.
Eva
E
Nordström
BioArctic Neuroscience AB, Stockholm, Sweden.
Fredrik
F
Eriksson
BioArctic Neuroscience AB, Stockholm, Sweden.
Anna
A
Lord
BioArctic Neuroscience AB, Stockholm, Sweden.
Stina
S
Tucker
BioArctic Neuroscience AB, Stockholm, Sweden.
Jessica
J
Andersson
BioArctic Neuroscience AB, Stockholm, Sweden.
Malin
M
Johannesson
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen, Germany.
Heinrich
H
Schell
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen, Germany.
Philipp J
PJ
Kahle
BioArctic Neuroscience AB, Stockholm, Sweden.
Christer
C
Möller
BioArctic Neuroscience AB, Stockholm, Sweden.
Pär
P
Gellerfors
Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Joakim
J
Bergström
Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Lars
L
Lannfelt
Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: martin.ingelsson@pubcare.uu.se.
Martin
M
Ingelsson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D001921:Brain / Q000276:immunology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007274:Injections, Intraperitoneal; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D020734:Parkinsonian Disorders / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; C497604:SNCA protein, human; D051844:alpha-Synuclein
Immunization; Protofibril-selective antibody; α-Synuclein transgenic mice