Methods and compositions for RNAi-based cancer treatment
Inventors
Shemi, Amotz • ZORDE KHVALEVSKY, Elina
Assignees
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Publication Number
US-8889642-B2
Publication Date
2014-11-18
Expiration Date
Abstract
The present invention generally concerns methods and compositions for treating mutated K-ras expressing cancers.
Core Innovation
The invention relates to treating a patient having a solid tumor expressing a mutated K-ras protein using RNA interference (RNAi). The RNAi agent comprises a sense strand and an antisense strand with sequences set forth in A or B (SEQ ID No: 37, 38, 39, and 40), where “o” preceding a residue denotes a 2′-O-Methyl modification of the residue.
In certain embodiments, the method administers a millimeter-scale drug delivery device (DDD) for intratumoral delivery. The DDD comprises a biodegradable polymeric matrix and an RNAi agent incorporated within the biodegradable polymeric matrix.
The disclosed system provides prolonged intratumoral release of defined siRNA duplexes via millimeter-scale biodegradable drug delivery devices (DDD) having controlled diffusion/zero-mode release profiles. The disclosed DDDs are implantable and composed of biodegradable polymeric matrices such as PLGA/PLA/PGA, PEG, and chitosan, with the RNAi agent delivered at defined duplex sequence selections and with optional nucleotide backbone/chemical modifications including 2′-OMe and 2′-F and additional optional conjugations.
Claims Coverage
The provided content includes two independent claims. They cover RNAi treatment of mutated K-ras solid tumors using defined sense/antisense sequences, and millimeter-scale biodegradable DDDs containing chemically modified RNAi for delivery to specified K-ras mutation classes.
Defined mutated K-ras RNAi duplex sequences for treating a solid tumor
Administering a medicament comprising an RNAi agent having a sense strand and an antisense strand, where the sense strand and antisense strand have sequences set forth in A or B (SEQ ID No: 37 with SEQ ID No: 38; or SEQ ID No: 39 with SEQ ID No: 40), wherein “o” preceding a residue denotes a 2′-O-Methyl modification of the residue, thereby treating the patient having the solid tumor expressing the mutated K-ras protein.
Millimeter-scale biodegradable DDD delivering chemically modified RNAi
Administering a millimeter-scale drug delivery device (DDD) comprising a biodegradable polymeric matrix and an RNAi agent incorporated within the biodegradable polymeric matrix, where the RNAi agent is chemically modified with 2′-OMe or 2′-F and comprises a sense strand sequence selected from SEQ ID No: 37 and 39 and an antisense strand sequence selected from SEQ ID No: 38 and 40, as set forth in A or B, thereby treating the patient having the solid tumor expressing mutated K-ras protein wherein the mutation is selected from G12D, G12A, G12S, G12C, G13D, and G13C.
Claim coverage centers on treating mutated K-ras solid tumors with RNAi defined by SEQ ID No: 37–40 and on delivering chemically modified 2′-OMe/2′-F RNAi from a millimeter-scale biodegradable DDD for specified K-ras mutations.
Stated Advantages
Prolonged intratumoral release of defined siRNA duplexes.
Controlled diffusion/zero-mode release profiles.
Documented Applications
Treating a patient having a solid tumor expressing a mutated K-ras protein.
Intratumoral delivery using a millimeter-scale drug delivery device (DDD).
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