Immunotherapy targeting alpha-synuclein protofibrils reduced pathology in (Thy-1 )-h[A30P] a-synuclein mice

摘要

Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (a-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 a-synuclein as a promising novel treatment strategy. Since large a-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] a-synuclein transgenic mice with motor dysfunction symptoms were found to display increased levels of a-synuclein protofibrils in the CNS. An a-synuclein protofibril-selective monoclonal antibody (mAb47) was evaluated in this a-synuclein transgenic mouse model. As measured by ELISA, 14 month old mice treated for 14 weeks 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 a-synuclein demonstrated, a reduction of motor dysfunction in transgenic mice upon peripheral administration of mAb47 was indicated. Thus, immunotherapy with antibodies targeting toxic a-synuclein species holds promise as a future disease-modifying treatment in Parkinson's disease and related disorders.