Particles with RNA cleaving nucleobase polymers and uses for managing inflammatory disorders
Inventors
Salaita, Khalid • Wongtrakool, Cherry • Galior, Kornelia
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-10905710-B2
Publication Date
2021-02-02
Expiration Date
2037-05-24
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Abstract
This disclosure relates to nucleobase polymers useful for degrading GATA-3 mRNA. In certain embodiments, this disclosure relates to nucleobase polymers and nanoparticles conjugated to nucleobase polymers disclosed herein. In certain embodiments, the nucleobase polymers or nanoparticles can be used in methods of managing disorders associated with excessive GATA-3 expression in inflammatory disorders and respiratory disorders such as asthma.
Core Innovation
This disclosure relates to nucleobase polymers useful for degrading GATA-3 mRNA. It includes nucleobase polymers and nanoparticles conjugated to these polymers. The nucleobase polymers or nanoparticles can be used in methods of managing disorders associated with excessive GATA-3 expression in inflammatory and respiratory disorders such as asthma. The nucleobase polymers comprise sequences selected from SEQ ID NO: 1-49, 53-55 or variants thereof, including nucleobase polymers containing an RNA cleaving sequence such as the 10-23 DNAzyme with SEQ ID NO: 51.
The background identifies a problem in managing persistent severe allergic asthma, where existing treatments such as omalizumab have drawbacks including anaphylaxis risk and generation of inactivating antibodies. Allergic asthma involves T-helper 2 (TH2) driven responses that depend on GATA-3 transcription factor overexpression. The disclosure addresses the need to identify improved therapeutic methods to control persistent allergic asthma by targeting GATA-3 mRNA for degradation using nucleobase polymers and nanoparticle conjugates.
Claims Coverage
The claims disclose seven main inventive features focusing on nucleobase polymers, nanoparticles conjugated thereto, compositions, and containers related to RNA cleavage targeting GATA-3 mRNA.
Nucleobase polymer comprising GATA-3 targeting sequences
A nucleobase polymer containing a sequence selected from SEQ ID NO: 1-49, which hybridizes to and cleaves GATA-3 mRNA.
Specific nucleobase polymer sequences
Nucleobase polymers specifically comprising SEQ ID NO: 10, SEQ ID NO: 20, or SEQ ID NO: 30.
Nanoparticles coated with RNA-cleaving nucleobase polymers
Nanoparticles coated with a nucleobase polymer comprising an RNA cleaving sequence and flanking 5′ and 3′ nucleobase sequences that hybridize with SEQ ID NO: 52, wherein the nucleobase polymer sequence is selected from SEQ ID NO: 1-49.
Nanoparticles coated with specific nucleobase polymer sequences
Nanoparticles where the nucleobase polymer is specifically SEQ ID NO: 10, SEQ ID NO: 20, or SEQ ID NO: 30.
Liquid particles comprising the nanoparticles
Liquid particles containing the nanoparticles disclosed, wherein the liquid particle has a diameter between 0.5 microns and 10 microns.
Pharmaceutical compositions comprising the nanoparticles
Pharmaceutical compositions comprising the nanoparticles and a pharmaceutically acceptable excipient, including a pH buffered aqueous salt solution or specific hydrofluoroalkane propellants.
Containers comprising nanoparticles and associated delivery systems
Containers comprising the nanoparticles, which may further include a propellant and be configured with spraying, misting apparatus, mouthpieces, or facemasks suitable for aerosol delivery.
The claims cover nucleobase polymers targeting GATA-3 mRNA, nanoparticles conjugated with these polymers, pharmaceutical compositions containing them, and delivery containers configured for aerosol administration, emphasizing specific sequences and particle size ranges for treating inflammatory disorders like asthma.
Stated Advantages
DNAzyme nanoparticle conjugates (DzNPs) rapidly enter cells, protect DNAzymes against nucleases, and regulate gene expression with minimal off-target effects.
DzNPs do not require transfection agents for cellular uptake, enhancing delivery efficiency and reducing dosage requirements.
DzNP-based targeting of GATA-3 enables significant improvement in airway function with oligonucleotide doses an order of magnitude smaller than soluble DNAzyme treatments.
DzNP administration via nebulization achieves even and distal distribution in lungs, facilitating effective pulmonary delivery.
Documented Applications
Methods for managing inflammatory diseases and respiratory disorders associated with excessive GATA-3 expression, such as asthma and COPD.
Treating chronic inflammatory diseases including atopic dermatitis, psoriasis, ulcerative colitis, bronchitis, emphysema, laryngitis, and cystic fibrosis using nucleobase polymers or nanoparticles.
Formulations of nucleobase polymers or nanoparticles as aerosols, liquids, or micronized powders for pulmonary delivery via nebulizers, inhalers, or other aerosol administering devices.
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