Tokyo Medical and Dental University

Osaka University

The University of Tokyo

Kazutaka Nishina

Takanori Yokota

Hidehiro Mizusawa

Satoshi Obika

Kazunori Kataoka

Nobuhiro Nishiyama

Takehiko Ishii

Kanjiro Miyata

Yasutaka Anraku

Kotaro Yoshioka

Yu Matsumoto

Toshinori Unno

Yu Fukusato

Akihiro Mizoguchi

Hiroya Kuwahara

Takeshi Wada

Masahiro Murakami

Takenori Shimo

A method of reducing the level of a transcription product in a cell comprising contacting with the cell a composition comprising a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand hybridizes to the transcription product and comprises (a) a region consisting of at least 4 consecutive nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, (b) one or more nucleotide analogs located on 5' terminal side of the region, (c) one or more nucleotide analogs located on 3′ terminal side of the region and (d) a total number of nucleotides and nucleotide analogs ranging from 8 to 35 nucleotides and (ii) the second nucleic acid strand comprises (a) nucleotides and optionally nucleotide analogs and (b) at least 4 consecutive RNA nucleotides.

Chimeric double-stranded nucleic acid

A method of reducing the level of a transcription product in a cell comprising contacting with the cell a composition comprising a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand hybridizes to the transcription product and comprises (a) a region consisting of at least 4 consecutive nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, (b) one or more nucleotide analogs located on 5' terminal side of the region, (c) one or more nucleotide analogs located on 3&#x2032; terminal side of the region and (d) a total number of nucleotides and nucleotide analogs ranging from 8 to 35 nucleotides and (ii) the second nucleic acid strand comprises (a) nucleotides and optionally nucleotide analogs and (b) at least 4 consecutive RNA nucleotides.

Disclosed are double-stranded nucleic acid agents that can deliver a therapeutic oligonucleotide within a biological sample, and methods for using the same. In one embodiment, the double-stranded nucleic acid agent comprises a first strand comprising a first RNA region, and a second strand comprising a first DNA region, wherein said first RNA region and said first DNA region are hybridized as a RNA/DNA heteroduplex. Said first strand further comprises a nucleic acid therapeutic oligonucleotide region that is capable of being cleaved from at least one nucleotide in said first RNA region. Methods for using the double-stranded nucleic acid agents include methods for delivering the therapeutic oligonucleotide as a single strand by cleaving it from at least a portion of the first RNA region. The methods further include delivering the double-stranded nucleic acid agent and thus the therapeutic oligonucleotide to a target site within the body of a treatment subject.

Double-stranded agents for delivering therapeutic oligonucleotides

The present invention provides a vesicle, a conjugate, a composition comprising the vesicle or the conjugate, for use in delivering a drug to the brain, and a method for administering the same. The composition of the present invention is a composition for administration to a subject according to a dosing regimen, comprising a carrier for drug delivery, wherein the dosing regimen comprises administering the composition to a subject who has been fasted or caused to have hypoglycemia and inducing an increase in blood glucose level in the subject, and the carrier is modified at the outer surface thereof with a GLUT1 ligand.

Carrier for use in delivering drug, conjugate, composition comprising same, and method for administrating same

Chimeric single-stranded polynucleotides and double-stranded antisense agents useful for modifying the expression of a target gene by means of an antisense effect are disclosed. The chimeric single-stranded antisense polynucleotide and double-stranded antisense agents comprise a central nucleotide region flanked by a first 5'-wing region and a first 3&#x2032;-wing region of modified nucleotides, which are themselves flanked by a second 5&#x2032;-wing region and/or a second 3&#x2032;-wing region of nucleotides that have a low affinity for proteins and/or that have higher resistance to DNase or RNase than a natural DNA or RNA and are missing in a cell when the chimeric polynucleotide delivered. The double-stranded antisense agent further comprises a complementary strand annealed to the antisense strand. The polynucleotide can be used to modify RNA transcription levels, miRNA activity, or protein levels in cells.

Chimeric single-stranded antisense polynucleotides and double-stranded antisense agent

Disclosed are double-stranded antisense nucleic acid complexes that can efficiently alter the processing of RNA in a cell via an antisense effect, and methods for using the same. One method comprises contacting with the cell a double-stranded nucleic acid complex comprising: a first nucleic acid strand annealed to a second nucleic acid strand, wherein: the first nucleic acid strand comprises (i) nucleotides independently selected from natural DNA nucleotides, modified DNA nucleotides, and nucleotide analogs, (ii) no regions that have 4 or more consecutive natural DNA nucleotides, (iii) the total number of natural DNA nucleotides, modified DNA nucleotides, and nucleotide analogs in the first nucleic acid strand is from 8 to 100, and (iv) the first nucleic acid strand is capable of hybridizing to RNA inside of the cell; and the second nucleic acid strand comprises nucleotides independently selected from natural RNA nucleotides, modified RNA nucleotides, and nucleotide analogs.

Double-stranded antisense nucleic acid with exon-skipping effect

The present invention aims to provide a pharmaceutical composition for transcolonic absorption capable of delivering a physiologically active substance (in particular, a water-soluble physiologically active substance of high molecular weight) having an intracellular site of action into specific tissue cells with high specificity, noninvasively by a means of administration other than injection. The pharmaceutical composition for transcolonic absorption of the present invention is characterized by comprising at least the following (a) and (b); (a) a physiologically active substance having an intracellular site of action and bound with an introduction substance into lipoprotein, and (b) a compound having an action of enhancing large intestinal mucosal epithelial permeability of the physiologically active substance.

Pharmaceutical composition for transcolonic absorption

The object of present invention is to provide a system that can deliver in vivo nucleic acids such as an siRNA for suppressing a target gene expression in vivo more safely and efficiently, and to provide an expression-suppressing agent and a pharmaceutical composition utilizing the system. An introduction substance into chylomiclon, particularly nucleic acids to which an alpha-tocopherol is bound for suppressing a target gene expression, can be delivered more safely and efficiently into hepatic cells in vivo by administering the nucleic aids under the condition where the production of chylomicron is induced in the body. Alternatively, alpha-tocopherol-bound nucleic acids are mixed with extracted chylomiclon, and then they are administered. Consequently, a target gene expression is suppressed, thereby a disease caused by an elevated expression of the target gene can be treated more safely and efficiently.

Growing community of inventors

Tokyo, Japan

Kazutaka Nishina