miR 204, miR 211, their anti-miRs, and therapeutic uses of same

Inventors

Wang, Fei • Miller, Sheldon • Zhang, Congxiao • Maminishkis, Arvydas

Assignees

US Department of Health and Human Services

Abstract

Embodiments of the invention provide methods of preventing or treating detrimental epithelial cell proliferation, loss of epithelial cell differentiation, age-related macular degeneration and/or proliferative vitreal retinopathy in an individual comprising administering to an individual in need thereof an effective amount of miR 204, an effective amount of miR 211, or an effective amount of a mixture of miR 204 and miR 211. A further embodiment of the invention provides a method of facilitating the transport of a substance across an epithelium in an individual comprising administrating to an individual an effective amount of anti-miR 204, an effective amount of anti-miR 211, or an effective amount of a mixture of anti-miR 204 and anti-miR 211. Additional embodiments of the invention include pharmaceutical compositions of miR 204 and/or miR 211 and pharmaceutical compositions of anti-miR 204 and/or anti-miR 211.

Core Innovation

The invention provides methods of preventing or treating detrimental epithelial cell proliferation, loss of epithelial cell differentiation, age-related macular degeneration (AMD), and proliferative vitreal retinopathy (PVR) by administering effective amounts of miR 204, miR 211, or mixtures thereof. Additionally, the invention encompasses methods facilitating the transport of substances across epithelia by administering anti-miR 204, anti-miR 211, or mixtures thereof. Pharmaceutical compositions comprising substantially purified miR 204, miR 211, anti-miR 204, and anti-miR 211 are also disclosed.

The problem solved relates to the regulation of epithelial cell functions, particularly the control of proliferation, differentiation, and tight junction integrity in epithelia such as retinal pigment epithelium (RPE). Damage to the RPE, including loss of tight junction integrity and differentiation, contributes to degenerative diseases like AMD and PVR. There is a need for molecules that can modulate miRNA-regulated biological functions to prevent or treat these detrimental conditions as existing treatments are limited.

Administration of miR 204 and/or miR 211 suppresses undesirable epithelial proliferation and supports differentiation, potentially counteracting disease processes involving epithelial dysfunction, such as AMD, PVR, diabetic retinopathy, and glaucoma. Conversely, administration of anti-miR 204 and/or anti-miR 211 decreases transepithelial electrical resistance (TER), thereby increasing epithelial permeability, which can facilitate transport of substances, such as pharmaceuticals, across epithelia. This regulation involves modulation of transcription factors and tight junction proteins, particularly claudin-19, implicating miR 204/211 in maintaining epithelial barrier function and differentiation.

Claims Coverage

The patent contains multiple independent claims focusing on pharmaceutical compositions and methods involving miR 204 and siRNAs or anti-miRs targeting specific genes.

The independent claims cover pharmaceutical compositions that combine miR 204 with siRNAs against key transcription factors (SNAIL1, SNAIL2, SMAD3), signaling molecules (ROCK1, ROCK2, RHOB, PDGFA, PDGFRB), anti-miRs against miR 221/222, or TGFβ receptor antagonists, along with their use in treating detrimental epithelial cell proliferation, differentiation loss, ocular diseases and enhancing epithelial transport. These claims describe the use of miR 204 in combination with other gene modulators for therapeutic applications.

Stated Advantages

Documented Applications