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Publication Number
US-12234458-B2
Publication Date
2025-02-25
Expiration Date
Abstract
A composition according to an embodiment of the present invention includes nucleic acid molecules which are capable of effectively inhibiting the expression level of connective tissue growth factor (CTGF) and collagen by RNA interference (RNAi), thereby preventing or treating a variety of fibroproliferative diseases due to overexpression of CTGF or collagen.
Core Innovation
The invention relates to a CTGF-inhibiting RNA interference (RNAi)-based pharmaceutical composition that includes a nucleic acid molecule and a porous silica particle. The nucleic acid molecule is selected from siRNA and dsRNA species configured to inhibit connective tissue growth factor (CTGF), and the nucleic acid molecule is loaded on a surface or inside the pores of the porous silica particle.
The nucleic acid molecules are defined by specific sequence sets, including a siRNA comprised of a sense RNA having the sequence of SEQ ID NO: 1 and an antisense RNA having the sequence of SEQ ID NO: 2, and dsRNA species comprised of strands having defined sequences, including SEQ ID NO: 3, SEQ ID NO: 57, and SEQ ID NO: 60, with complementary strands. The porous silica particles have an average pore diameter in the range of 5 to 100 nm and are further characterized by a degradation parameter t, where the absorbance ratio At/Ao becomes 1/2 at t of 24 hours or more.
The composition supports CTGF expression inhibition and sustained CTGF knockdown, including reduced CTGF and collagen expression and outcomes associated with hypertrophic scar and keloid-like results in mouse skin wound models. Documented results indicate high CTGF expression inhibition for the specified complementarity and sequence sets, slow porous silica degradation, and sustained knockdown in vitro, with comparisons to free siRNA and LNP controls and measured release kinetics for the porous silica carrier.
Claims Coverage
The independent claim covers a drug composition defined by specific siRNA/dsRNA sequence selections and a porous silica particle carrier characterized by pore size and a degradation parameter t, with the nucleic acid loaded on the particle surface or inside the pores. Inventive features are supplemented in dependent claims by further constraints on sequence termini, nucleic acid options, and porous silica surface, charge, and functional group properties.
Loaded nucleic acid on porous silica particle
A composition comprising a nucleic acid molecule loaded on a surface or inside the pores of a porous silica particle.
Selected CTGF-inhibiting siRNA and dsRNA species
The nucleic acid molecule comprises at least one selected from siRNA comprised of a sense RNA having the sequence of SEQ ID NO: 1 and an antisense RNA having the sequence of SEQ ID NO: 2, and dsRNA comprised of strands having the sequences of SEQ ID NO: 3, SEQ ID NO: 57, and SEQ ID NO: 60 with complementary strands.
Porous silica pore diameter and degradation parameter t
The porous silica particle has an average pore diameter ranging from 5 to 100 nm and a degradation parameter t such that the absorbance ratio At/Ao becomes 1/2 at t of 24 or more.
Nucleic acid loading location on surface or inside pores
The nucleic acid molecule is loaded on a surface or inside the pores of the porous silica particle.
Overall, the claim coverage centers on a composition where CTGF-inhibiting siRNA/dsRNA sequences, specified by SEQ ID NO sets, are loaded on or within a porous silica particle, and the porous silica is defined by pore size and a degradation parameter t reaching At/Ao = 1/2 at 24 hours or more.
Stated Advantages
High CTGF expression inhibition is reported for specified complementarity and sequence sets.
Slow degradation of the porous silica is reported.
Sustained siCTGF knockdown in vitro is reported.
Reduced CTGF and collagen expression is reported.
Reduced hypertrophic-scar and keloid-like outcomes in mouse skin wound models are reported.
Documented Applications
CTGF inhibition in connection with mouse skin wound models, including reduced hypertrophic-scar and keloid-like outcomes.
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