α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease.
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.



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.



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.



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.
Department of Neuroscience University of California San Diego California.
Brian
B
Spencer
Department of Chemical Engineering Arizona State University Tempe Arizona.
Stephanie
S
Williams
Department of Neuroscience University of California San Diego California.
Edward
E
Rockenstein
Department of Neuroscience University of California San Diego California.
Elvira
E
Valera
Department of Chemical Engineering Arizona State University Tempe Arizona.
Wei
W
Xin
Department of Neuroscience University of California San Diego California.
Michael
M
Mante
Department of Neuroscience University of California San Diego California.
Jazmin
J
Florio
Department of Neuroscience University of California San Diego California.
Anthony
A
Adame
Department of Neuroscience University of California San Diego California; Department of Pathology University of California San Diego California.
Eliezer
E
Masliah
Department of Chemical Engineering Arizona State University Tempe Arizona.
Michael R
MR
Sierks