posted on 2022-12-27, 07:29authored byBo Yi Kim, Changmok Oh, Dongkyu Jeon, Ikhyun Jun, Ho K. Lee, Bo-Rahm Kim, Jinhong Park, Kyoung Yul Seo, Kyeong-A Kim, Dami Lim, Seolhee Lee, Jooyun Lee, Hongchul Yoon, Tae-im Kim, Wan Namkung
Dry eye disease (DED) is one of the most prevalent ocular
diseases
but has limited treatment options. Cystic fibrosis transmembrane conductance
regulator (CFTR), a major chloride channel that stimulates fluid secretion
in the ocular surface, may pave the way for new therapeutic strategies
for DED. Herein, we report the optimization of Cact-3, a potent CFTR
activator with poor solubility, to 16d, a potent CFTR
activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea
and conjunctiva with minimal systemic exposure in rabbit. Topical
ocular instillation of 16d significantly enhanced tear
secretion and improved corneal erosion in a mouse model of DED. In
addition, 16d significantly reduced mRNA expression of
pro-inflammatory cytokines including IL-1β, IL-17, and TNF-α
and MMP2 in cornea and conjunctiva of DED mice.