Inflammasome-targeted RNA interference approach to treating kidney injury and disease
Inventors
McDevitt, Michael R. • Scheinberg, David A.
Assignees
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Publication Number
US-12343407-B2
Publication Date
2025-07-01
Expiration Date
Abstract
The present disclosure relates generally to methods for treating, preventing, and/or ameliorating chronic kidney disease (CKD) and/or renal injury in a subject in need thereof. In particular, the methods disclosed herein comprise administering a therapeutically effective amount of a pharmaceutical composition comprising at least one Nlrp3 siRNA non-covalently conjugated to sidewall ammonium-functionalized carbon nanotubes (fCNTs), wherein the at least one Nlrp3 siRNA reduces the expression of NLR pyrin domain-containing protein 3 (NLRP3) in a subject diagnosed with, or at risk for CKD and/or renal injury.
Core Innovation
The invention relates to a pharmaceutical composition comprising a sidewall ammonium-functionalized carbon nanotube (fCNT) and an effective amount of at least one Nlrp3 siRNA that inhibits NLR pyrin domain-containing protein 3 (NLRP3) expression levels or activity in a cell. The at least one Nlrp3 siRNA comprises a sense strand and an antisense strand, and the antisense strand comprises SEQ ID NO:4. The fCNT is non-covalently conjugated to the at least one Nlrp3 siRNA.
The disclosed compositions define the siRNA components by sense/antisense strand design and specific sequence constraints for NLRP3 targeting. In particular, the antisense strand includes a nucleic acid sequence that is complementary to a portion of an NLRP3 nucleic acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2, with an antisense base-pair length range of 20–27. Related design constraints include that at least one composition sense strand comprises SEQ ID NO:3.
The invention further defines the fCNT component as a sidewall ammonium-functionalized carbon nanotube with primary ammonium-bearing moieties represented by Formula I. The Formula I definitions include variable selections for X1 (O, NH, or CH2), X2 (N or CH), and a selected moiety L1 that is selected from alkylene glycol, polyalkylene glycol, —NHC(O)CH(CO2H)—, or a carbon/heteroatom-composed chain or combinations. This fCNT design is used to non-covalently conjugate the Nlrp3 siRNA into a supramolecular complex within a pharmaceutical composition.
Claims Coverage
The independent claims are clm-00001 and clm-00021. Both claims cover a pharmaceutical composition formed by a non-covalent conjugate between a sidewall ammonium-functionalized carbon nanotube (fCNT) and an Nlrp3 siRNA that inhibits NLRP3 expression levels or activity, with claim-specific constraints on which strand contains specified SEQ IDs and which strand design features are required.
Non-covalent conjugate between ammonium-functionalized fCNT and Nlrp3 siRNA
A pharmaceutical composition comprising a sidewall ammonium-functionalized carbon nanotube (fCNT) and an effective amount of at least one Nlrp3 siRNA that inhibits NLRP3 expression levels or activity in a cell, wherein the fCNT is non-covalently conjugated to the at least one Nlrp3 siRNA.
Antisense strand includes SEQ ID NO:4 in Nlrp3 siRNA
The at least one Nlrp3 siRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises SEQ ID NO:4.
Sense strand comprises SEQ ID NO:3 in Nlrp3 siRNA
The at least one Nlrp3 siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises SEQ ID NO:3.
Across both independent claims, the core scope is a pharmaceutical composition containing a sidewall ammonium-functionalized carbon nanotube (fCNT) non-covalently conjugated to an Nlrp3 siRNA that inhibits NLRP3 expression levels or activity in a cell. The key claim-distinguishing feature between the two independent claims is which strand is specified to contain a particular SEQ ID.
Stated Advantages
Inhibits NLRP3 expression levels or activity in a cell.
Documented Applications
Monitoring therapeutic efficacy in a subject with CKD or kidney injury by detecting NLRP3 protein levels after dosing and determining effectiveness when NLRP3 levels are reduced versus pre-dose control levels.
A treatment that leads to reductions in one or more kidney lesion and inflammation markers, including collagen deposits, polysaccharides in interstitial lesions, lymphocyte infiltration into kidney cells, macrophage infiltration into kidney cells, and caspase activation.
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