Lacrimal Gland as a Target Organ for Adenovirus Gene Therapy Encoding Erythropoietin for Dry Eye Induced by Benzalkonium Chloride

Author(s)

Dias, Lara Cristina ^[1] ; Zheng, Changyu ^[2] ; Murashima, Adriana de Andrade Batista ^[1] ; Dias, Ana Carolina ^[1] ; Fantucci, Marina Zilio ^[1] ; Nominato, Luiz Fernando ^[1] ; da Silva, Lilian Eslaine Costa Mendes ^[1] ; Rocha, Eduardo Melani ^[1]

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

^[2] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, Natl Inst Hlth Bethesda, Bethesda, MD - USA

• Document type: Journal article
• Source: CURRENT EYE RESEARCH; v. 46, n. 9, p. 1314-1319, SEP 2 2021.
• Web of Science Citations: 0

Abstract

Purpose: The aims of this work were a) to describe the histology of the lacrimal gland (LG) and cornea induced by an adenovirus (Ad) vector encoding the human erythropoietin (Epo) gene delivered to the LG and b) to evaluate the therapeutic potential of this strategy to prevent benzalkonium chloride (BAK) corneal toxicity. Methods: Structure and function of male Wistar rats LG were compared in the groups: 1) naive control and 2) Ad-hEpo in the right LG (RLG). The protective response against BAK eye drops was compared among the groups 1) naive control, 2) BAK in the right eye, 3) Ad-hEpo RLG + BAK and 4) Ad-hEpo in the right salivary gland (RSG)+BAK. Ad-hEpo groups received an injection of AdLTR2EF1a-hEPO (25 ul, 10(10) particles/ml) in the right LG or SG (positive control). The BAK groups received 0.2% BAK in the right cornea twice a day. The tests applied after 7 days, included tear secretion, hEPO mRNA detection by qRT-PCR, LG and cornea histology, LG ELISA for cytokines and hematocrit. Results: hEPO mRNA was present in the Ad-hEpo RLG and RSG, but not kidney or liver samples (negative controls). TNF-alpha and IL-1 beta increased in the LG exposed to Ad-hEpo compared to naive control (p = .0115 and p = .0397, respectively). BAK reduced tear secretion, but this reduction was prevented by Ad-hEpo RLG+BAK and Ad-hEpo RSG+BAK (p = .017). The corneal epithelia were thinner in the BAK-treated groups independent of Ad-hEpo (p = .0009). Hematocrit increased only in the Ad-hEpo RSG group (p = .01). Conclusions: Ad-hEpo infection of rat LG and SG induces local, but only the SG infection induced systemic changes in rats. Importantly, Ad-hEpo attenuated the BAK-mediated toxic reduction in tear flow. Future studies must consider viral vector tissue tropism, biodistribution and effective therapeutic gene products for ocular surface diseases. (AU)

• FAPESP's process: 14/22451-7 - Sustained drug delivery systems targeting the epithelial tissue
• Grantee: Renata Fonseca Vianna Lopez
• Support Opportunities: Research Projects - Thematic Grants