Reengineered Salivary Glands Are Stable Endogenous Bioreactors for Systemic Gene Therapeutics

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Feb 24

PMID 14978265

Citations 47

Authors

Antonis Voutetakis

Marc R Kok

Changyu Zheng

Ioannis Bossis

Jianghua Wang

Ana P Cotrim

Natanya Marracino

Corinne M Goldsmith

John A Chiorini

Y Peng Loh

Lynnette K Nieman

Bruce J Baum

Affiliations

Soon will be listed here.

Abstract

The use of critical-for-life organs (e.g., liver or lung) for systemic gene therapeutics can lead to serious safety concerns. To circumvent such issues, we have considered salivary glands (SGs) as an alternative gene therapeutics target tissue. Given the high secretory abilities of SGs, we hypothesized that administration of low doses of recombinant adeno-associated virus (AAV) vectors would allow for therapeutic levels of transgene-encoded secretory proteins in the bloodstream. We administered 10(9) particles of an AAV vector encoding human erythropoietin (hEPO) directly to individual mouse submandibular SGs. Serum hEPO reached maximum levels 8-12 weeks after gene delivery and remained relatively stable for 54 weeks (longest time studied). Hematocrit levels were similarly increased. Moreover, these effects proved to be vector dose-dependent, and even a dosage as low as 10(8) particles per animal led to significant increases in hEPO and hematocrit levels. Vector DNA was detected only within the targeted SGs, and levels of AAV copies within SGs were highly correlated with serum hEPO levels (r = 0.98). These results show that SGs appear to be promising targets with potential clinical applicability for systemic gene therapeutics.

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