Treatment of angiogenesis-associated diseases using RNA complexes that target ANGPT2 and PDGFB
Inventors
Lee, Dong Ki • Hong, Sun Woo • Lee, Tae Yeon • Lee, Sae-Lo-Oom • Lee, Hanna • Yu, Dayeon • Eom, Ji
Assignees
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Publication Number
US-10519449-B2
Publication Date
2019-12-31
Expiration Date
Abstract
In certain aspects, provided herein are RNA complexes (e.g., asymmetric RNA complexes, such as asiRNAs or cell penetrating asiRNAs) that inhibit ANGPT2 and/or PDGFB expression and are therefore useful for treating angiogenesis-associated diseases, such as cancer, AMD, and DME.
Core Innovation
The invention provides an asymmetric small interfering RNA complex formed with an antisense strand and a sense strand, in which the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end. The antisense strand is 19 nt to 21 nt and is complementary to a PDGFB mRNA sequence, and the sense strand is 16 nt in length and has a nucleotide sequence that is complementary to the antisense strand.
The invention further addresses PDGFB and angiogenesis gene inhibition by using an RNA therapeutic approach in which the asymmetric siRNA is configured for mRNA inhibition and protein expression inhibition. The disclosed therapeutic scope includes cancer, wet age-related macular degeneration (wet AMD), and diabetic macular edema (DME), and it is described as inhibiting PDGFB mRNA expression in a subject.
Composition aspects are described as an RNA complex together with a pharmaceutically acceptable carrier, including delivery to an eye or by parenteral delivery. The document also describes optional chemical modification of the RNA and cell-penetrating designs, including 2′-O-methylated nucleoside, a phosphorothioate bond, and a hydrophobic moiety including a cholesterol moiety, as well as optional combination therapy including an immune checkpoint inhibitor or a chemotherapeutic agent.
Claims Coverage
One independent claim is provided in the partial content. It defines an asymmetric small interfering RNA complex targeted to PDGFB mRNA, with dependent claims refining chemical modification and composition and narrowing use to tumor or eye administration and optional combination therapy.
Blunt-ended asymmetric siRNA complementary to PDGFB mRNA
An asymmetric small interfering RNA complex formed with an antisense strand of 19 nt to 21 nt complementary to a PDGFB mRNA sequence and a sense strand of 16 nt complementary to the antisense strand, wherein the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end.
Asymmetric siRNA complex with chemical modification
The RNA complex includes a chemical modification.
Limited chemical modification types for the RNA complex
The chemical modification is a 2′-O-methylated nucleoside, a phosphorothioate bond, or a hydrophobic moiety.
Cholesterol hydrophobic moiety
The RNA complex includes a hydrophobic moiety specifically a cholesterol moiety.
Pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition includes the RNA complex together with a pharmaceutically acceptable carrier.
Administration to a tumor or to the eye
Administration of the pharmaceutical composition to a tumor or to the eye of a subject.
The claim coverage centers on an asymmetric, blunt-ended siRNA architecture complementary to a PDGFB mRNA target, with refinements allowing 2′-O-methylated nucleoside, phosphorothioate bond, and hydrophobic moieties such as cholesterol, and with composition and use narrowing to formulations including a pharmaceutically acceptable carrier and administration to a tumor or the eye.
Stated Advantages
Inhibition of PDGFB mRNA expression.
Inhibition of protein expression.
Therapeutic applicability to cancer, wet AMD, and DME.
Documented Applications
Treatment scope for cancer.
Therapy for wet age-related macular degeneration (wet AMD).
Therapy for diabetic macular edema (DME).
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