ENGINEERED NANOBODIES WITH PROGRAMMABLE TARGET ANTIGEN PROTEOLYSIS (PTAP) FUSIONS REGULATE INTRACELLULAR ALPHA-SYNUCLEIN IN VITRO AND IN VIVO.
Document Type
Article
Abstract
Alpha-synuclein (αSyn) aggregation and the formation of Lewy pathology (LP) is a foundational pathophysiological phenomenon in synucleinopathies. Delivering therapeutic single-chain and single-domain antibodies that bind pathogenic targets can disrupt intracellular aggregation. The fusion of antibody fragments to a negatively-charged proteasomal targeting motif (PEST) creates bifunctional constructs that enhance both solubility and turnover. With sequence-specific point mutations of PEST sequences that modulate proteasomal degradation efficiency, we report the creation of Programmable Target Antigen Proteolysis (PTAP) technology that can provide graded control over the levels of target antigens. We have previously demonstrated our lead anti-αSyn intrabody, VH14-PEST, is capable of reducing the pathological burden of synucleinopathy
Publication Date
3-28-2024
Publication Title
Res Sq
ISSN
2693-5015
PubMed ID
38585932
Digital Object Identifier (DOI)
10.21203/rs.3.rs-4088206/v1
Recommended Citation
Chatterjee, Diptaman; D'Brant, Lianna Y; Hiller, Benjamin M; Marmion, David J; Sandoval, Ivette M; Luk, Kelvin C; Manfredsson, Fredric P; Messer, Anne; Kordower, Jeffrey H; and Butler, David C, "ENGINEERED NANOBODIES WITH PROGRAMMABLE TARGET ANTIGEN PROTEOLYSIS (PTAP) FUSIONS REGULATE INTRACELLULAR ALPHA-SYNUCLEIN IN VITRO AND IN VIVO." (2024). Translational Neuroscience. 2385.
https://scholar.barrowneuro.org/neurobiology/2385