Liposomal spherical nucleic acid (SNA) constructs presenting antisense oligonucleotides (ASO) for specific knockdown of interleukin 17 receptor mRNA
Inventors
Kang, Richard • MIX, Scott • Kandimalla, Ekambar
Assignees
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Publication Number
US-11866700-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Aspects of the invention relate to antisense oligonucleotides directed to the interleukin 17 receptor (IL-17R), and other targets. Spherical nucleic acid formulations or compositions of antisense oligonucleotides and related methods of treatment are also provided.
Core Innovation
The disclosure provides a multiplex antisense oligonucleotide spherical nucleic acid (mASO-SNA) having a liposome core and an oligonucleotide shell positioned on the exterior of the core. The oligonucleotide shell comprises antisense oligonucleotides 10 to 30 linked nucleosides in length targeted to a first gene and an antisense oligonucleotide 10 to 30 linked nucleosides in length targeted to a second gene, enabling multiplex gene knockdown.
Each antisense oligonucleotide comprises at least two modified nucleosides and includes a molecular species at the 5′ end, 3′ end, or 5′ and 3′ end. The molecular species is a lipid moiety connected to the antisense oligonucleotide by a linker comprising hexaethylene glycol.
The disclosure further supports multiplexed ASO-SNAs for inflammatory gene targeting, including IL-17R/IL-17RA and other inflammatory genes, and describes IL-17RA mRNA knockdown as dose-dependent. The compositions and treatment methods relate to inflammatory disorders including psoriasis, and the document also describes stable self-assembling nanostructures with liposome or solid cores and exterior oligonucleotide shells.
Claims Coverage
The partial claim set includes two independent claims, centered on a multiplex antisense oligonucleotide spherical nucleic acid architecture with a liposome core and exterior oligonucleotide shell, plus lipid-terminated antisense oligonucleotides linked via hexaethylene glycol. The claims identify four inventive features.
Multiplex antisense oligonucleotide spherical nucleic acid with liposome core and exterior oligonucleotide shell
A multiplex antisense oligonucleotide spherical nucleic acid (mASO-SNA) comprising a core having an oligonucleotide shell comprised of an antisense oligonucleotide 10 to 30 linked nucleosides in length targeted to a first gene and an antisense oligonucleotide 10 to 30 linked nucleosides in length targeted to a second gene, wherein the core is a liposome core and the oligonucleotide shell is positioned on the exterior of the core.
Modified nucleosides in each antisense oligonucleotide
Each antisense oligonucleotide comprises at least two modified nucleosides.
Hexaethylene glycol linker connecting lipid molecular species to antisense oligonucleotides
Each antisense oligonucleotide further comprises a molecular species at the 5′ end, 3′ end, or 5′ and 3′ end of the antisense oligonucleotide, wherein the molecular species is a lipid moiety connected to the antisense oligonucleotide by a linker comprising hexaethylene glycol.
Administering an mASO-SNA in an effective amount to treat a disorder
Administering to a subject having a disorder a multiplex antisense oligonucleotide spherical nucleic acid (mASO-SNA) in an effective amount to treat the disorder.
Across the independent claims, the claim coverage centers on an mASO-SNA where multiplex antisense oligonucleotides are arranged as an exterior oligonucleotide shell on a liposome core, with each antisense oligonucleotide containing at least two modified nucleosides and a lipid moiety at a terminus connected through a linker comprising hexaethylene glycol. The treating-method claim additionally requires administering such an mASO-SNA in an effective amount to treat a disorder.
Stated Advantages
Multiplex gene knockdown.
Additive and simultaneous knockdown effects.
IL-17RA mRNA knockdown as dose-dependent.
Stable self-assembling nanostructures.
Documented Applications
Inflammatory gene targeting, including IL-17R/IL-17RA and other inflammatory genes.
Treatment of inflammatory disorders including psoriasis.
Multiplex targeting such as IL-17RA plus TNFα.
Testing and evaluation in cells and skin explants, with readouts including mRNA knockdown and protein expression measures.
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