RNA interference in ocular indications
Inventors
Libertine, Lyn • Khvorova, Anastasia • Salomon, William • Kamens, Joanne • Samarsky, Dmitry • Woolf, Tod M. • Cardia, James • PAVCO, PAMELA A.
Assignees
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Publication Number
US-11584933-B2
Publication Date
2023-02-21
Expiration Date
Abstract
The present invention relates to ocular administration of sd-rxRNA and rxRNAori molecules.
Core Innovation
The invention is directed to a method for delivering an sd-rxRNA to an eye of a subject in need thereof by administering the sd-rxRNA in an effective amount to promote RNA interference in the eye. The sd-rxRNA comprises a guide strand and a passenger strand, includes a double stranded region and a single stranded region, and the double stranded region is 8-15 nucleotides long while the single stranded region at the 3′ end of the guide strand is 4-12 nucleotides long.
The sd-rxRNA further includes phosphorothioate modifications in the single stranded region, contains 3 through 12 phosphorothioate modifications in that region, and at least 40% of the nucleotides are modified. The sd-rxRNA is directed against a gene encoding PTGS2 and comprises at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOs: 463-588.
The disclosed examples include sd-rxRNA sequence tables with sense/antisense strands and modified nucleotides targeting multiple genes, including CTGF, TGFβ2, TGFβ1, and VEGF/VEGFRORI, together with measured mRNA expression changes in A549 or Hek293 cells. The examples also define chemical modification encodings such as 2′-Ome, 2′-fluoro, phosphorothioate versus phosphodiester linkages, and cholesterol/TEG-chol conjugates.
Claims Coverage
The provided claim set centers on an eye-delivered sd-rxRNA that promotes RNA interference using a defined guide/passenger architecture with phosphorothioate modification criteria, combined with PTGS2-directed targeting using sequences that include at least 12 contiguous nucleotides from SEQ ID NOs 463-588. The independent claim features present across the inputs are four.
Ocular delivery of self-delivering RNAi sd-rxRNA in effective amount
A method for delivering an sd-rxRNA to an eye of a subject in need thereof by administering the sd-rxRNA in an effective amount to promote RNA interference by the sd-rxRNA in the eye.
Defined guide/passenger ds and ss region architecture
The sd-rxRNA comprises a guide strand and a passenger strand, wherein the sd-rxRNA includes a double stranded region and a single stranded region, wherein the double stranded region is 8-15 nucleotides long, wherein the single stranded region is at the 3′ end of the guide strand and is 4-12 nucleotides long.
Location-specific phosphorothioate modification and overall modified nucleotide percentage
The single stranded region contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 phosphorothioate modifications, and at least 40% of the nucleotides of the sd-rxRNA are modified.
PTGS2 directed sd-rxRNA with contiguous sequence from SEQ ID NOs 463-588
The sd-rxRNA is directed against a gene encoding PTGS2, and the sd-rxRNA comprises at least 12 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 463-588.
Overall, the independent claim focuses on an eye-delivered sd-rxRNA that promotes RNA interference, using a defined guide/passenger structure with a specified ds/ss architecture, high levels of nucleotide modification with location-specific phosphorothioate modifications, and targeting PTGS2 using at least 12 contiguous nucleotides from SEQ ID NOs 463-588.
Stated Advantages
Markedly improved retinal distribution and uptake across all retinal cell layers, including RPE, versus conventional RNAi.
Efficient gene silencing for multiple ocular disorders.
Lack of blood vessel leakage as an in vivo performance/functional safety readout.
Lack of architectural damage as an in vivo performance/functional safety readout.
Lack of impaired retinal function as an in vivo performance/functional safety readout.
Increasing single-stranded polynucleotide stability.
Promoting RISC loading/uptake and improving in vivo functionality.
Reducing off-target effects.
Retention/detection in ocular tissues is described for sd-rxRNA, with comparative evidence versus conventional RNAi indicating decreased signal by 48h for the conventional approach.
Nuclease resistance/stability assessment is described using nuclease resistance metrics and assay readouts.
Supports RNA interference in the eye using sd-rxRNA with defined structural and modification criteria.
Enables targeting of multiple genes and many eye disorders through sd-rxRNA/rxRNAori with target/indication mapping and multi-gene combinations.
Documented Applications
Treatment of an ocular disorder in a subject, including ocular disorders selected from vascular leakage, multiple forms of AMD, diabetic retinopathy conditions, macular edema secondary to retinal vein occlusion, glaucoma, retinopathy of prematurity, fibroproliferative retinal disease, proliferative vitreoretinopathy, epiretinal membranes/vitreomacular adhesions, retinal degenerative disease, retinal vascular occlusive disorders, retinoblastoma, trabeculectomy failure due to scarring, and uveitis.
Delivering an sd-rxRNA to the eye to promote RNA interference directed against PTGS2.
Treatment of an ocular disorder by administering an sd-rxRNA directed against PTGS2 (COX-2) in the eye.
Therapeutic targeting across multiple eye disorders is described, including wet AMD/CNV, DME, PDR, RVO-associated ME, NVG/iris neovascularization, proliferative vitreoretinopathy, dry AMD/GA, cystoid macular edema, retinitis pigmentosa, and glaucoma/uveitis and retinoblastoma.
Multi-gene combinations for ocular disorders are described through co-administration of multiple sd-rxRNA molecules.
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