The patent's assignee for patent number 8642751 is miRagen Therapeutics (
News editors obtained the following quote from the background information supplied by the inventors: "MicroRNAs (miRs) have been implicated in a number of biological processes including regulation and maintenance of cardiac function (see,
"miRNA function may be targeted therapeutically by antisense polynucleotides or by polynucleotides that mimic miRNA function ('miRNA mimetic'). However, targeting miRNAs therapeutically with oligonucleotide-based agents poses several challenges, including RNA-binding affinity and specificity, efficiency of cellular uptake, and nuclease resistance. For example, when polynucleotides are introduced into intact cells they are attacked and degraded by nucleases leading to a loss of activity. While polynucleotide analogues have been prepared in an attempt to avoid their degradation, e.g. by means of 2' substitutions (
"Oligonucleotide chemistry patterns or motifs for miRNA inhibitors have the potential to improve the delivery, stability, potency, specificity, and/or toxicity profile of the inhibitors, and such are needed for effectively targeting miRNA function in a therapeutic context."
As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "The invention provides chemically modified oligonucleotides capable of inhibiting the expression (e.g., abundance) of miR-208 family miRNAs, including miR-208a, miR-208b, and/or miR-499. The invention further provides pharmaceutical compositions comprising the oligonucleotides, and methods of treating patients having conditions or disorders relating to, or involving, a miR-208 family miRNA. Such conditions include various cardiovascular conditions. In various embodiments, the oligonucleotides provide advantages in one or more of potency, efficiency of delivery, target specificity, toxicity, and/or stability.
"In one aspect, the invention provides a chemically-modified oligonucleotide capable of reducing the expression or abundance of miR-208 family miRNAs. The activity or potency of the oligonucleotides may be determined in vitro and/or in vivo. For example, the oligonucleotide may significantly inhibit (e.g., about 50% inhibition) the activity of a miR-208 family miRNA (as determined in the dual luciferase assay) at a concentration of about 50 nM or less, or in other embodiments, 40 nM or less, 20 nM or less, or 10 nM or less. Alternatively, or in addition, the activity of the oligonucleotide may be determined in a suitable mouse or rat model, or non-human primate model, such as those described herein, where inhibition (e.g., by at least 50%) of a miR-208 family miRNA is observed at a dose of 50 mg/kg or less, such as 25 mg/kg or less, 10 mg/kg or less, or 5 mg/kg or less. In these embodiments, the oligonucleotide may be dosed subcutaneously or intravenously (and as described herein), and may be formulated in an aqueous preparation (e.g., saline).
"The nucleotide sequence of the oligonucleotide is substantially complementary to a nucleotide sequence of human miR-208a or miR-208b (or corresponding pre- or pri-miRNA), and contains a mixture of locked and non-locked nucleotides. For example, the oligonucleotide may contain at least three, at least five, or at least seven, locked nucleotides, and at least one non-locked nucleotide. Generally, the length of the oligonucleotide and number and position of locked nucleotides is such that the oligonucleotide reduces miR-208a, miR-208b, and/or miR-499 activity at an oligonucleotide concentration of about 50 nM or less in an in vitro luciferase assay, or at a dose of 50 mg/kg or less in a suitable rat or mouse model or non-human primate model as described herein. In exemplary embodiments, the locked nucleotides have a 2' to 4' methylene bridge.
"The oligonucleotide may comprise, consist essentially of, or consist of, a full length or truncated miR-208a, miR-208b, or miR-499 antisense sequence. In these embodiments, the oligonucleotide is from about 6 to 22 nucleotides in length, or is from about 10 to 18 nucleotides in length, or is about 11 to about 16 nucleotides in length. The oligonucleotide in some embodiments is about 14, 15, 16, or 17 nucleotides in length. The oligonucleotide may comprise the nucleotide sequence of 5'-TGCTCGTCTTA-3' (SEQ ID NO:1) or may comprise the nucleotide sequence of 5'-TGTTCGTCTTA-3' (SEQ ID NO:2). In particular embodiments, the oligonucleotide comprises, consists essentially of, or consists of the nucleotide sequence 5'-CTTTTTGCTCGTCTTA-3' (SEQ ID NO:3) or 5'-CCTTTTGTTCGTCTTA-3' (SEQ ID NO:4).
"The oligonucleotide may contain at least about 3, at least about 5, or at least about 7 locked nucleotides, or at least 9 locked nucleotides, but in various embodiments is not fully comprised of locked nucleotides. Generally, the number and position of locked nucleotides is such that the oligonucleotide reduces or inhibits miR-208a, miR-208b, and/or miR-499 activity at high potency. In certain embodiments, the oligonucleotide does not contain a stretch of nucleotides with more than four, or more than three, or more than two, contiguous non-locked nucleotides. In exemplary embodiments, the oligonucleotide has exactly 9 locked nucleotides and 7 non-locked nucleotides. For example, the pattern of locked nucleotides may be such that at least positions 1, 6, 10, 13, and 15 are locked nucleotides. In certain embodiments, at least positions 1, 5, 10, and 16 are locked nucleotides. In certain embodiments, positions 1, 5, 6, 8, 10, 11, 13, 15, and 16 are locked nucleotides, and the remaining positions are non-locked nucleotides. In other embodiments, positions 1, 3, 4, 5, 6, 8, 10, 13, 15, and 16 are locked nucleotides, with the remaining positions being non-locked nucleotides. In still other embodiments, positions 1, 4, 5, 7, 9, 10, 12, 14, and 16 are locked nucleotides, with remaining positions being non-locked nucleotides. These patterns of locked nucleotides may be employed, in certain embodiments, using the nucleotide sequence of SEQ ID NO:3 or SEQ ID NO:4, or variant thereof described herein. Where the inhibitor consists of, or consists essentially of, the nucleotide sequence of SEQ ID NO:3 or SEQ ID NO:4, the oligonucleotide may contain all locked nucleotides.
"For non-locked nucleotides, the nucleotide may contain a 2' modification with respect to a 2' hydroxyl. In some embodiments the 2' modification may be independently selected from O-alkyl (which may be substituted), halo, and deoxy (H).
"The oligonucleotide may also contain one or more phosphorothioate linkages. For example, the oligonucleotide may be fully phosphorothioate-linked or may contain about half or 3/4 phosphorothioate linkages.
"Exemplary oligonucleotide inhibitors are shown in Table 1.
"In another aspect, the invention provides pharmaceutical compositions and formulations comprising the oligonucleotides of the invention, which may involve incorporation of the oligonucleotide within a variety of macromolecular assemblies, micelle, or liposome compositions for cellular delivery. In certain embodiments, the oligonucleotides are formulated for conventional intravenous, subcutaneous, or intramuscular dosing. Such formulations may be conventional aqueous preparations, such as formulation in saline. In certain embodiments, the compositions are suitable or formulated for intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection, or by direct injection into target tissue (e.g., cardiac tissue).
"In still other aspects, the invention provides a method for delivering oligonucleotides and the pharmaceutical compositions to mammalian cells either in vitro or ex vivo, e.g., for treating, ameliorating, or preventing the progression of a condition in a mammalian patient. The method may comprise administering the oligonucleotide or composition comprising the same to a mammalian patient or population of target cells. The patient may have a condition associated with, mediated by, or resulting from, miR-208 family expression. Such conditions include, for example, cardiac hypertrophy, myocardial infarction, heart failure (e.g., congestive heart failure), vascular damage, restenosis, or pathologic cardiac fibrosis. Thus, the invention provides a use of the modified oligonucleotides and compositions of the invention for treating such conditions, and for the preparation of medicaments for such treatments.
"Other aspects and embodiments of the invention will be apparent from the following detailed description of the invention."
For additional information on this patent, see:
Keywords for this news article include: Antisense Technology, Biotechnology, Cardiology, Heart Disease, Heart Failure, Bioengineering, miRagen Therapeutics, Cardiovascular Diseases.
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