posted on 2023-11-02, 20:09authored byJiaxin Hu, Xiulong Shen, Mahboubeh Kheirabadi, Matthew D. Streeter, Ziqing Qian, V. Vinod Mootha, David R. Corey
Fuchs’ corneal
endothelial dystrophy (FECD) is a major cause
of vision loss. Corneal transplantation is the only effective curative
treatment, but this surgery has limitations. A pharmacological intervention
would complement surgery and be beneficial for many patients. FECD
is caused by an expanded CUG repeat within intron 2 of the TCF4 RNA. Agents that recognize the expanded repeat can
reverse the splicing defects associated with the disease. Successful
drug development will require diverse strategies for optimizing the
efficacy of anti-CUG oligomers. In this study, we evaluate anti-CUG
morpholinos conjugated to cyclic cell penetrating peptides. The morpholino
domain of the conjugate is complementary to the repeat, while the
peptide has been optimized for import across cell membranes. We show
that morpholino conjugates can enter corneal endothelial cells and
block the CUG RNA foci associated with the disease. These experiments
support morpholino peptide conjugates as an approach for developing
anti-CUG therapies for FECD.