Objective: Progressive accumulation of α-synuclein (α-syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which α-syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing α-syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing antibodies that recognize both monomeric and higher molecular weight α-syn. In this context, the main objective of this study was to investigate the efficacy of immunotherapy with single-chain antibodies (scFVs) against specific conformational forms of α-syn fused to a novel brain penetrating sequence.
Method: We screened various scFVs against α-syn expressed from lentiviral vectors by intracerebral injections in an α-syn tg model. The most effective scFVs were fused to the cell-penetrating peptide penetratin to enhance transport across the blood–brain barrier, and lentiviral vectors were constructed and tested for efficacy following systemic delivery intraperitoneal into α-syn tg mice.
Result: Two scFVs (D5 and 10H) selectively targeted different α-syn oligomers and reduced the accumulation of α-syn and ameliorated functional deficits when delivered late in disease development; however, only one of the antibodies (D5) was also effective when delivered early in disease development. These scFVs were also utilized in an enzyme-linked immunosorbent assay (ELISA) assay to monitor the effects of immunotherapy on α-syn oligomers in brain and plasma.
Interpretation: The design and targeting of antibodies for specific species of α-syn oligomers is crucial for therapeutic immunotherapy and might be of relevance for the treatment of Lewy body disease.
Details
- α-Synuclein Conformational Antibodies Fused to Penetratin Are Effective in Models of Lewy Body Disease
- Spencer, Brian (Author)
- Williams, Stephanie (Author)
- Rockenstein, Edward (Author)
- Valera, Elvira (Author)
- Xin, Wei (Author)
- Mante, Michael (Author)
- Florio, Jazmin (Author)
- Adame, Anthony (Author)
- Masliah, Eliezer (Author)
- Sierks, Michael (Author)
- Ira A. Fulton Schools of Engineering (Contributor)
-
Digital object identifier: 10.1002/acn3.321
-
Identifier TypeInternational standard serial numberIdentifier Value2328-9503
-
The final version of this article, as published in Annals of Clinical and Translational Neurology, can be viewed online at: http://onlinelibrary.wiley.com/wol1/doi/10.1002/acn3.321/abstract
Citation and reuse
Cite this item
This is a suggested citation. Consult the appropriate style guide for specific citation guidelines.
Spencer, B., Williams, S., Rockenstein, E., Valera, E., Xin, W., Mante, M., . . . Sierks, M. R. (2016). α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease. Annals of Clinical and Translational Neurology, 3(8), 588-606. doi:10.1002/acn3.321