Open Accessα ‐synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease
Author(s) -
Spencer Brian,
Williams Stephanie,
Rockenstein Edward,
Valera Elvira,
Xin Wei,
Mante Michael,
Florio Jazmin,
Adame Anthony,
Masliah Eliezer,
Sierks Michael R.
Publication year - 2016
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.321
Subject(s) - antibody , medicine , immunotherapy , parkinson's disease , dementia with lewy bodies , context (archaeology) , neurodegeneration , lewy body , disease , immunology , dementia , immune system , pathology , biology , paleontology
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 (sc FV s) against specific conformational forms of α ‐syn fused to a novel brain penetrating sequence. Method We screened various sc FV s against α ‐syn expressed from lentiviral vectors by intracerebral injections in an α ‐syn tg model. The most effective sc FV s 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 sc FV s (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 sc FV s 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.