Invented by Brian Allen Carr, Vasant R. Jadhav, Denise M. Kenski, David M. Tellers, Aarron T. Willingham, Sirna Therapeutics Inc
The Sirna Therapeutics Inc invention works as followsThe invention concerns compounds, compositions and methods for studying, diagnosing, and treating traits, diseases, and conditions that responds to the modulation or activation of gene expression, activity, and/or modulate gene expression pathways.” The invention relates specifically to small, double-stranded nucleic acids molecules such as siNA molecules (short interfering nucleic acids) that can mediate or that mediate RNA interference against target gene expression.
Background for Short Interfering Nucleic Acid (siNA), Compositions
The following discussion is a discussion on relevant art pertaining RNAi. This discussion is only intended to help you understand the invention. This summary does not imply that any of the below-described work is prior art for the claimed invention.
RNA interference” refers to the process by which sequence-specific post-transcriptional genes are silenced in animals via short interferingRNAs (siRNAs). The same process is found in plants (Heifetz and colleagues, International PCT Publication Number. Post-transcriptional gene suppression or RNA silencing is commonly known as “quelling in fungi” (WO 99/61631). The process of post-transcriptional gene silencing is thought to be an evolutionarily-conserved cellular defense mechanism used to prevent the expression of foreign genes and is commonly shared by diverse flora and phyla (Fire et al., 1999, Trends genet., 15, 358). This protection against foreign gene expression could have evolved from the production of double-strandedRNAs (dsRNAs), which can be derived from viral infections or random integration of transposon element into host genomes via a cellular response that destroys homologous single strandedRNA or viral genomicsRNA.
The therapeutic potential of RNAi is in its ability to modulate the expression of genes in a sequence-specific manner using a robust, highly conserved endogenous mechanism. The endogenous mechanism is a powerful tool for disease modification, as it offers a much wider range of targets than small molecules and biologics. RNA triggers are less stable than exogenously provided small molecules and biologics, which makes them unsuitable for administration, particularly in biological systems. Innovation has addressed this problem, both through chemical modification of triggers for RNA (see U.S. Ser. No. No. 10/444.853, published as U.S. Patent Application. Publ. No. No. 20040192626), and different delivery methods (see U.S. Ser. No. Patent Appl. No. 11/586.102, published in US US-.S. Patent Appl. Publ. No. No. There is still a need to develop additional RNA triggers in order to increase the number of compounds and compositions available for RNAi based therapies, especially those that are compatible with various delivery systems or routes of administration.
The invention solves the problem of not having a sufficient number of compounds and compositions available for RNAi based therapies that are compatible with various delivery modalities or routes of administration, by providing chemically modified siNA molecules.
The present invention provides compounds and compositions that are useful for modulating gene expression and treating diseases or conditions that could respond to such modulation through RNA interference. The present invention consists of chemically modified siNA molecules with any one of the following formulas: A, B C D E F G H I J K L M N O P or other formulas as described in the claims and description. These siNA molecules can be used as RNAi based compositions and therapeutic compounds.
These and other aspects will become apparent from the detailed description of the invention and the attached figures. It is also contemplated to implement any method or component described in this document with respect of any other method, composition or combination described herein.
Additionally patents, applications for patents and other documents have been cited throughout the description to describe and set forth more specifically various aspects of this innovation. All references are hereby incorporated into this document in their entirety, including drawings.
Terms and definitions
The following terms and definitions are used as part of the application.
As used in the specification and claims appended, the singular form?a? ?an,? The words?an?,? Include plural referents, unless the context clearly dictates otherwise. For example, a reference to “a cell” includes combining two or more cells, and the like. “A cell” includes two or more cells and similar combinations.
If not otherwise stated, “Any concentration ranges, percentage ranges, ratio ranges or integer ranges” are to be understood as including the value of each integer within the range recited, and, when appropriate, any fractions (such a tenth, one hundredth, etc.) of the integer.
?About? “?About? As used in this document, a reference to a particular number is generally understood to include any numbers that fall between a range of 5 percent (greater or less) in either direction. This applies unless the context makes it clear otherwise (except when such number exceeds 100% of its possible value). When ranges are mentioned, the endpoints of the range are also included unless stated otherwise or the context makes it clear.
The term “abasic” as used herein refers to its meaning as it is generally accepted in the art. As used in this document, the term ‘abasic’ refers to what is commonly accepted as its meaning. The term is used to describe sugar moieties that lack a nucleobase, or have a hydrogen atom or other non nucleobase chemical group in place of the nucleobase. See, for example, Adamic et. al., U.S. Pat. No. 5,998,203. “In one embodiment, the abasic moiety is a sugar containing ribose or deoxyribose.
The term “acyclic nucleotide” as used herein refers to its meaning as it is generally accepted in the art. As used in this document, the term is understood to mean what it means as accepted by the industry. The term is used to refer to any nucleotide that has an acyclic sugar. For example, if any of the carbon/carbon or oxygen/carbon bonds are absent or combined from the nucleotide.
The term “alkyl” as used herein refers to its meaning as it is generally accepted in the art. As used herein, the term ‘alkyl’ is understood to mean its meaning as it is commonly accepted in this art. The term is used to refer to saturated or unsaturated hydrocarbons, which include straight-chain and branched chain, alkenyls, alkynyls, and cyclics, but not aromatics. Alkyl can also be used to refer to heterocyclic non-aromatic groups. The alkyl group should have between 1 and 12 carbons. It is more preferred that it be a lower alkyl with 1 to 7 or 1 to 4 carbons. Alkyl groups can be substituted, or left unsubstituted. The substituted group is preferred to be hydroxyl or halogen.
The phrase “agents that interfer with cell cycle checkpoints” refers to compounds that inhibit protein kinases, which transduce cell cycle signal. The term “agents that interfere with cell cycle checkpoints” refers to compounds which inhibit protein kinases, which transduce cell-cycle checkpoint signals. This then makes the cancer cells more sensitive to DNA damaging agents.
The phrase “agents that interfere (RTKs),” refers to compounds that inhibit RTKs and therefore inhibit mechanisms involved in oncogenesis and tumor progression. “Compounds that inhibit RTKs inhibit mechanisms involved in tumor progression and oncogenesis.
The phrase “androgen receptor modifiers” refers to compounds that interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. The term “androgen receptor modulators” refers to any compounds that inhibit or interfere with the binding of androgens at the receptor.
The term “angiogenesis inhibits” refers to compounds that prevent the formation of new blood vessels, regardless of their mechanism. The term “angiogenesis inhibitors” refers to substances that inhibit the formation and growth of new blood vessels regardless of their mechanism.
The term “?aryl” as used herein refers to its meaning as it is generally accepted in the art. As used in this document, the term ‘aryl’ is understood to mean its general meaning. The term is used to describe an aromatic group with at least one ring that has a conjugated system of pi electrons. This includes carbocyclic, heterocyclic, and biaryl rings, which may be substituted. “The preferred substitute(s) for aryl groups include halogen, trihalomethyl (SH), OH, cyano C1 to C4 alkyls, C2 to C4 alkenyls, and C2-C4 akynyls, as well as NR1R2 group, where R1 is independently H or C1 to C4 alkyl.
The term “alkylaryl” as used herein refers to its meaning as it is generally accepted in the art. As used in this document, the term ‘alkylaryl’ refers to what is commonly accepted as its meaning. The term is used to describe an alkyl (as above described) that has been covalently attached to an aryl (as above described). The carbocyclic aryl group is a group where the ring atoms of the aromatic ring consist only of carbon atoms. Carbon atoms can be substituted. Heterocyclic groups have 1 to 3 heteroatoms in their aromatic rings, and the rest of the ring is carbon. Examples of heteroatoms that are suitable include oxygen, nitrogen, sulfur and nitrogen. Examples of heterocyclic groups with such heteroatoms, which can be substituted, include furanyls, thienyls, pyridyls, pyrrolyls, N-lower aryl pyrrolos, pyrimidyls, pyrazinyls, imidazolyls and the like. The alkyl groups should be C1-C4.
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