Adeno-Associated Virus 8 Delivers an Immunomodulatory Peptide to Mouse Liver More Efficiently Than to Rat Liver

Authors

Yuqing Wang
Ayrea Hurley
Marco De Giorgi
Mark R Tanner
Rong-Chi Hu
Michael W Pennington
William R Lagor
Christine Beeton

Publication Date

1-1-2023

Journal

PLoS One

DOI

10.1371/journal.pone.0283996

PMID

37040361

PMCID

PMC10089316

PubMedCentral® Posted Date

4-11-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Rats, Mice, Animals, Dependovirus, Peptides, Autoimmune Diseases, Obesity, Liver

Abstract

Targeting the Kv1.3 potassium channel has proven effective in reducing obesity and the severity of animal models of autoimmune disease. Stichodactyla toxin (ShK), isolated from the sea anemone Stichodactyla helianthus, is a potent blocker of Kv1.3. Several of its analogs are some of the most potent and selective blockers of this channel. However, like most biologics, ShK and its analogs require injections for their delivery, and repeated injections reduce patient compliance during the treatment of chronic diseases. We hypothesized that inducing the expression of an ShK analog by hepatocytes would remove the requirement for frequent injections and lead to a sustained level of Kv1.3 blocker in the circulation. To this goal, we tested the ability of Adeno-Associated Virus (AAV)8 vectors to target hepatocytes for expressing the ShK analog, ShK-235 (AAV-ShK-235) in rodents. We designed AAV8 vectors expressing the target transgene, ShK-235, or Enhanced Green fluorescent protein (EGFP). Transduction of mouse livers led to the production of sufficient levels of functional ShK-235 in the serum from AAV-ShK-235 single-injected mice to block Kv1.3 channels. However, AAV-ShK-235 therapy was not effective in reducing high-fat diet-induced obesity in mice. In addition, injection of even high doses of AAV8-ShK-235 to rats resulted in a very low liver transduction efficiency and failed to reduce inflammation in a well-established rat model of delayed-type hypersensitivity. In conclusion, the AAV8-based delivery of ShK-235 was highly effective in inducing the secretion of functional Kv1.3-blocking peptide in mouse, but not rat, hepatocytes yet did not reduce obesity in mice fed a high-fat diet.

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