US20120252869A1 - Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) - Google Patents

Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) Download PDF

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US20120252869A1
US20120252869A1 US13/386,057 US201013386057A US2012252869A1 US 20120252869 A1 US20120252869 A1 US 20120252869A1 US 201013386057 A US201013386057 A US 201013386057A US 2012252869 A1 US2012252869 A1 US 2012252869A1
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sirtuin
sirt
oligonucleotide
antisense
disease
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Joseph Collard
Olga Khorkova Sherman
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Curna Inc
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Opko Curna LLC
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Priority claimed from PCT/US2009/066445 external-priority patent/WO2010065662A2/fr
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Priority to US13/386,057 priority Critical patent/US20120252869A1/en
Assigned to OPKO CURNA, LLC reassignment OPKO CURNA, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KHORKOVA SHERMAN, OLGA, COLLARD, JOSEPH
Assigned to CURNA, INC. reassignment CURNA, INC. CERT OF MERGER - NAME CHANGE Assignors: OPKO CURNA, LLC
Publication of US20120252869A1 publication Critical patent/US20120252869A1/en
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Definitions

  • Percent complementarity of an antisense compound with a region of a tIrget nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PoweiBLAST programs known in the art. Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman ( Adv. Appl. Math., (1981)2, 482-489).
  • Glutamate dehydrogenase (GDII), another mitochondrial protein involved in energy production, is deacetylated by SIRT3. GDH can also be ADP-ribosylated by SIRT4 in turn to decrease its enzyme activity. This indicates that SIRT3 could play an important role in cell metabolism. SIRT3 has also been shown to be involved in selective apoptosis pathways and cell growth control. SIRT3 and SIRT4, but not SIRT5, have been implicated in the NAD+ salvage pathway that regulates the NAT+ level relating to cell survival. In addition, variability in the hSIRT3 gene has been linked to human longevity.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant
  • Antisense oligonucleotides of the invention may be incorporated into microemulsions, which generally are thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9).
  • surfactant emulsifier
  • co-surfactant co-surfactant
  • an oil phase and a water phase are necessary.
  • solubilizers include, but are not limited to, the following: hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, available commercially as Transcutol.sup.RTM) and diethylene glycol monoethyl ether oleate (available commercially as Soficutol.sup.RTM); polyethylene castor oil derivatives such as polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, etc.; polyethylene glycol, particularly lower molecular weight polyethylene glycols such as PEG 300 and PEG 400, and polyethylene glycol derivatives such as PEG-8 caprylic/capric glycerides (available commercially as Labrasol.sup.RTM); alkyl methyl sulfoxides such as DMSO; pyrrolidones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers can also act as absorption enhancers. A single solubilizer may
  • oligonucleotides comprise nucleic acid sequences set forth as SEQ ID NOS: 15 to 94 including antisense sequences which are identified and expanded, using for example, PCR, hybridization etc. These oligonucleotides can comprise one or more modified nucleotides, shorter or longer fragments, modified bonds and the like. Examples of modified bonds or internucleotide linkages comprise phosphorothioate, phosphorodithioate or the like. In another embodiment, the nucleotides comprise a phosphorus derivative.
  • the oligonucleotides are complementary to or bind to nucleic acid sequences of a Sirtuin (SIRT) natural antisense, set forth as SEQ ID NO: 5 to 14 and modulate expression and/or function of a Sirtuin (SIRT) molecule.
  • SIRT Sirtuin
  • antisense compounds comprise sequences set forth as SEQ ID NOS: 15 to 94.
  • These oligonucleotides can comprise one or more modified nucleotides, shorter or longer fragments, modified bonds and the like.
  • the antisense compounds of the invention have antisense portions of 10 to 50 nucleotides in length.
  • the oligonucleotides are 15 nucleotides in length.
  • the oligomeric compounds of the present invention also include variants in which a different base is present at one or more of the nucleotide positions in the compound.
  • variants may be produced which contain thymidine, guanosine or cytidine at this position. This may be done at any of the positions of the antisense or dsRNA compounds. These compounds are then tested using the methods described herein to determine their ability to inhibit expression of a target nucleic acid.
  • a chimeric oligonucleotide comprises at least one region modified to increase target binding affinity, and, usually, a region that acts as a substrate for RNAse H.
  • Affinity of an oligonucleotide for its target is routinely determined by measuring the Tm of an oligonucleotide/target pair, which is the temperature at which the oligonucleotide and target dissociate; dissociation is detected spectrophotometrically. The higher the Tm, the greater is the affinity of the oligonucleotide for the target.
  • SIRT1, SIRT3 and SIRT6 proteins and mRNA expression can be assayed using methods known to those of skill in the art and described elsewhere herein.
  • immunoassays such as the ELISA can be used to measure protein levels.
  • Sirtuin (SIRT) antibodies for ELISAs are available commercially, e.g., from R&D Systems (Minneapolis, Minn.), Abeam, Cambridge, Mass.
  • compositions of the present invention may also include surfactants.
  • surfactants used in drug products, formulations and in emulsions is well known in the art. Surfactants and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein by reference.
  • HepG2 cells from ATCC were grown in growth media (MEM/EBSS (Hyclone cat#SH30024, or Mediatech cat #MT-10-010-CV) +10% FBS (Mediatech cat# MT35-011-CV)+penicillin/streptomycin (Mediatech cat# MT30-002-CI)) at 37° C. and 5% CO2.
  • MEM/EBSS Hyclone cat#SH30024, or Mediatech cat #MT-10-010-CV
  • FBS Mediatech cat# MT35-011-CV
  • penicillin/streptomycin Mediatech cat# MT30-002-CI
  • the animals were housed individually prior to surgery and postoperatively until sacrifice.
  • the primate building in which the individual cages were situated were illuminated entirely by ambient light, which at 17 degrees north latitude approximates a 12 hr:12 hr light-dark cycle as recommended in the U.S. D.H.H.S guidelines.
  • the RxGen primate building was completely ventilated to the outside. Additional air movement was assured by ceiling fans to maintain a constant target temperature of 23-35° C., as is typical of St. Kitts throughout the year. Twenty-four hour extremes of temperature and relative humidity (which also will not be controlled) were measured daily. During the study, the cages were cleaned at regular intervals.
  • the animals were assigned to 2 treatment groups, comprised of 4 monkeys in each group. Specific animal identification numbers were provided to each monkey according to the facility numbering system. This system uniquely identifies each monkey by a letter followed by a three digit number, e.g. Y032.
  • RNAlater Qiagen

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