WO2010003420A2 - Traitement du psoriasis et de maladies apparentées par modulation de miarn - Google Patents

Traitement du psoriasis et de maladies apparentées par modulation de miarn Download PDF

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WO2010003420A2
WO2010003420A2 PCT/DK2009/050131 DK2009050131W WO2010003420A2 WO 2010003420 A2 WO2010003420 A2 WO 2010003420A2 DK 2009050131 W DK2009050131 W DK 2009050131W WO 2010003420 A2 WO2010003420 A2 WO 2010003420A2
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seq
nucleic acids
mirna
psoriasis
nucleic acid
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PCT/DK2009/050131
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WO2010003420A3 (fr
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John Robert Zibert
Lone Skov
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Gentofte Hospital
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Publication of WO2010003420A3 publication Critical patent/WO2010003420A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C12N2310/113—Antisense targeting other non-coding nucleic acids, e.g. antagomirs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C12N2310/141—MicroRNAs, miRNAs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/10—Applications; Uses in screening processes
    • C12N2320/11—Applications; Uses in screening processes for the determination of target sites, i.e. of active nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2330/00—Production
    • C12N2330/10—Production naturally occurring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2330/00—Production
    • C12N2330/30—Production chemically synthesised
    • C12N2330/31—Libraries, arrays

Definitions

  • the present invention is directed to the identification of a deregulated microRNA profile in psoriasis such as psoriasis vulgaris, and the modulation of these deregulated miRNA species for the treatment of psoriasis and other related diseases. Further, the invention relates to the identification of new microRNA - mRNA target interactions relevant for psoriasis and related diseases.
  • Psoriasis is a chronic inflammatory skin disease affecting 1 -3% of the Caucasian population with a substantial negative impact on the patient's quality of life.
  • Psoriasis is a disease which causes red scaly patches on the skin. The scaly patches are areas of inflammation and excessive cell proliferation leading to a silvery-white appearance. Plaques frequently occur on the skin of the elbows and knees, but can affect any area including the scalp and genitals.
  • Psoriasis can manifest in a variety of forms. Variants include psoriasis vulgaris, pustular psoriasis, and guttate psoriasis (as detailed later). Psoriasis is hypothesized to be immune-mediated.
  • the disorder is a chronic recurring condition which varies in severity from minor localised patches to complete body coverage. Fingernails and toenails are frequently affected (psoriatic nail dystrophy) - and can be seen as an isolated finding. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Ten to fifteen percent of people with psoriasis have psoriatic arthritis.
  • psoriasis The cause of psoriasis is not known, but it is believed to have a genetic component. Several factors are thought to aggravate psoriasis. These include stress, drugs, excessive alcohol consumption, and smoking. Individuals with psoriasis may suffer from depression and loss of self-esteem. As such, quality of life is an important factor in evaluating the severity of the disease. There are many treatments available but because of its chronic recurrent nature psoriasis remains a challenge to treat.
  • a diagnosis of psoriasis is usually clinically based on the appearance of the skin, with no special blood tests or diagnostic procedures for psoriasis. Sometimes a skin biopsy may be needed to rule out other disorders and to confirm the diagnosis. Skin from a biopsy will show parakeratose, epidermal hyperplasi, increased angiogenesis in dermis and infiltration by mononuclear cells if positive for psoriasis. Another sign of psoriasis is that when the plaques are scraped, one can see pinpoint bleeding from the skin below (Auspitz's sign).
  • Psoriasis is a lifelong condition. There is currently no cure but various treatments can help to control the symptoms. Many of the most effective agents used to treat severe psoriasis carry an increased risk of significant morbidity including skin cancers, lymphoma and liver disease. However, the majority of patients with psoriasis suffer of minor localized patches, particularly on the elbows and knees, which can be treated with topical medication. Psoriasis does get worse over time but it is not possible to predict who will go on to develop extensive psoriasis or those in whom the disease may appear to vanish. Individuals will often experience flares and remissions throughout their lives. Controlling the signs and symptoms typically requires lifelong therapy.
  • Step 1 medicines are applied to the skin (topical treatment).
  • step 2 uses light treatments (phototherapy).
  • step 3 involves taking medicines by mouth or injection that treat the whole immune system (called systemic therapy). Treatments modes are detailed later.
  • the present invention addresses this issue by providing new therapeutic targets for the treatment of psoriasis and related diseases.
  • nucleic acid is a biopolymeric macromolecule composed of chains of monomeric nucleotides. In biochemistry these molecules carry genetic information or form structures within cells.
  • the most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
  • Each nucleotide consists of three components: a nitrogenous heterocyclic base (the nucleobase component), which is either a purine or a pyrimidine; a pentose sugar (backbone residues); and a phosphate group
  • a nucleoside consists of a nucleobase (often simply referred to as a base) and a sugar residue in the absence of a phosphate linker.
  • Nucleic acid types differ in the structure of the sugar in their nucleotides - DNA contains 2- deoxyriboses while RNA contains ribose (where the only difference is the presence of a hydroxyl group).
  • the nitrogenous bases found in the two nucleic acid types are different: adenine, cytosine, and guanine are found in both RNA and DNA, while thymine only occurs in DNA and uracil only occurs in RNA.
  • Nucleobases are complementary, and when forming base pairs, must always join accordingly: cytosine-guanine, adenine-thymine (adenine-uracil when RNA).
  • the strength of the interaction between cytosine and guanine is stronger than between adenine and thymine because the former pair has three hydrogen bonds joining them while the latter pair has only two.
  • Nucleic acids are usually either single-stranded or double-stranded, though structures with three or more strands can form.
  • a double-stranded nucleic acid consists of two single-stranded nucleic acids held together by hydrogen bonds, such as in the DNA double helix.
  • RNA is usually single-stranded, but any given strand may fold back upon itself to form secondary structure as in tRNA and rRNA.
  • the sugars and phosphates in nucleic acids are connected to each other in an alternating chain, linked by shared oxygens, forming a phosphodiester bond.
  • the carbons to which the phosphate groups attach are the 3' end and the 5' end carbons of the sugar. This gives nucleic acids polarity.
  • the bases extend from a glycosidic linkage to the 1 ' carbon of the pentose sugar ring. Bases are joined through N-1 of pyrimidines and N-9 of purines to 1 ' carbon of ribose through N- ⁇ glycosyl bond.
  • a heteroduplex is a double-stranded (duplex) molecule of nucleic acid originated through the genetic recombination of single complementary strands derived from different sources, such as from different homologous chromosomes or even from different organisms.
  • One such example is the heteroduplex DNA strand formed in hybridization processes, usually for biochemistry-based phylogenetical analyses.
  • Another example is the heteroduplexes formed when non-natural analogs of nucleic acids are used to bind with nucleic acids; these heteroduplexes result from performing antisense techniques using single-stranded peptide nucleic acid, 2'-O-methyl phosphorothioate or Morpholino oligos to bind with RNA (detailed later).
  • MicroRNAs are single-stranded RNA molecules of about 19-25 nucleotides in length, which regulate gene expression. miRNAs are either expressed from non- protein-coding transcripts or mostly expressed from protein coding transcripts. They are processed from primary transcripts known as pri-miRNA to shorter stem-loop structures called pre-miRNA and finally to functional mature miRNA. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to inhibit gene expression. This may occur by preventing mRNA translation or increasing mRNA turnover/degradation. MicroRNAs were reviewed in Bartel (Cell 2004 Jan 23; 1 16(2): 281 -97).
  • miRNAs are much longer than the processed mature miRNA molecule; miRNAs are first transcribed as primary transcripts or pri-miRNA with a cap and poly-A tail by RNA polymerase Il and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus. This processing is performed in animals by a protein complex known as the Microprocessor complex, consisting of the ribonuclease III Drosha and the double-stranded RNA binding protein Pasha.
  • Microprocessor complex consisting of the ribonuclease III Drosha and the double-stranded RNA binding protein Pasha.
  • RNA-induced silencing complex R ⁇ SC
  • miRNP RNA-like ribonucleoprotein particle
  • RNA molecules When Dicer cleaves the pre-miRNA stem-loop, two complementary short RNA molecules are formed, but only one is integrated into the RISC complex.
  • This strand is known as the guide strand and is selected by the argonaute protein, the catalytically active RNase in the RISC complex, on the basis of the stability of the 5' end.
  • the remaining strand known as the anti-guide or passenger strand, is degraded as a RISC complex substrate.
  • miRNAs After integration into the active RISC complex, miRNAs base pair with their complementary mRNA molecules. This may induce mRNA degradation by argonaute proteins, the catalytically active members of the RISC complex, or it may inhibit mRNA translation into proteins without mRNA degradation.
  • miRNAs The function of miRNAs appears to be mainly in gene regulation.
  • an miRNA is (partly) complementary to a part of one or more mRNAs.
  • Animal miRNAs are usually complementary to a site in the 3' UTR. The annealing of the miRNA to the mRNA then inhibits protein translation, and sometimes facilitates cleavage of the mRNA (depending on the degree of complementarity). In such cases, the formation of the double-stranded RNA through the binding of the miRNA to mRNA inhibits the mRNA transcript through a process similar to RNA interference (RNAi). Further, miRNAs may regulate gene expression post-transcriptionally at the level of translational inhibition at P-bodies.
  • RNAi RNA interference
  • miRNAs are regions within the cytoplasm consisting of many enzymes involved in mRNA turnover; P bodies are likely the site of miRNA action, as miRNA-targeted mRNAs are recruited to P bodies and degraded or sequestered from the translational machinery. In other cases it is believed that the miRNA complex blocks the protein translation machinery or otherwise prevents protein translation without causing the mRNA to be degraded. miRNAs may also target methylation of genomic sites which correspond to targeted mRNAs. miRNAs function in association with a complement of proteins collectively termed the miRNP (miRNA ribonucleoprotein complex).
  • miRNP miRNA ribonucleoprotein complex
  • Patent application US 2007/0281314 (Benson) relates to a method of detecting miRNA from the skin of e.g. psoriasis patients by tape stripping and analysis of miRNA expression. This may be used to diagnose disease and to predict response to treatment. Benson discloses that miRNAs including mir-15b, -34a and 214 can be detected in such a way, but no comparison with healthy or uninvolved skin is made.
  • Patent application US 2006/01 15455 (Reed et al) relates to the use of RNAi agents to prevent or treat psoriasis, by depleting unspecified transcriptionally active genetic regions related to psoriasis. There is no mentioning of miRNA.
  • Patent application US 2007/0265220 is directed to compositions and methods for selectively reducing the expression of a gene product from a desired target gene in a cell, as well as for treating diseases caused by the expression of the gene. More particularly, the invention is directed to compositions that contain double stranded RNA ("dsRNA”), and methods for preparing them, that are capable of reducing the expression of target genes in eukaryotic cells.
  • dsRNA double stranded RNA
  • the RNA duplex may be used to treat diseases such as psoriasis.
  • the present invention relates to the identification of a deregulated subset of miRNAs in psoriasis, and the modulation of said miRNAs for treatment of psoriasis and related diseases.
  • the present invention relates to a nucleic acid capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences.
  • the present invention relates to a nucleic acid capable of hybridizing to and/or inhibiting the pri-miRNA or pre-miRNA comprising the mature miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 .
  • the nucleic acid capable of hybridizing to an miRNA sequence according to the present invention comprises one or more nucleobases, one or more backbone residues and one or more internucleoside linkers.
  • said nucleic acid is selected from the group consisting of antisense oligonucleotides (ASO), small inhibitory RNAs (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • ASO antisense oligonucleotides
  • siRNA small inhibitory RNAs
  • shRNA short hairpin RNA
  • miRNA microRNA
  • the present invention also relates to the chemical modification of said nucleic acid so as to improve resistance to degradation in vivo or in vitro, improve stability, increase affinity for target, optimize solubility properties in vivo or in vitro and render the nucleotide sequence more suitable as a therapeutic agent.
  • nucleobases are modified; in another embodiment, one or more backbone residues are modified; in a further embodiment, one or more internucleoside linkers of the nucleic acid according to the present invention are modified.
  • the nucleic acids according to the present invention may be modified with one or more of said chemical modifications simultaneously.
  • the present invention also relates to the conjugation of the nucleic acid.
  • the nucleic acid according to the present invention may be conjugated with one or more of said conjugates simultaneously.
  • the nucleic acid capable of hybridizing to an miRNA sequence according to the present invention inhibits said miRNA sequence.
  • the present invention is directed in another aspect to a method for producing the nucleic acid capable of hybridising to the miRNAs according to the present invention, said method comprising the steps of providing a vector encoding said nucleic acid and expressing said vector either in vitro, or in vivo in a suitable host organism, thereby producing the nucleic acid.
  • the present invention relates to a vector encoding a nucleic acid having a nucleotide sequence capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182.
  • the present invention is directed in a further aspect to a method for reducing the levels of endogenous miRNA, said method comprising the introduction of the nucleic acid and/or the vector according to the present invention into a cell in an amount sufficient to reduce the levels of said miRNA.
  • the present invention relates to an isolated recombinant or transgenic host cell comprising the nucleic acid and/or the vector according to the present invention.
  • the invention also relates to a method for generating a recombinant or transgenic host cell, said method comprising the steps of providing a vector encoding a nucleic acid according to the present invention, introducing said vector into said recombinant or transgenic host cell and optionally also transcribing said nucleic acid in said recombinant or transgenic host cell, thereby generating a recombinant or transgenic host cell producing said nucleic acid.
  • hybridisation complex comprising the nucleic acid according to the present invention hybridized to a complement sequence, wherein the nucleic acid binds to the complement sequence under stringent conditions.
  • the present invention thus relates to a hybridisation complex wherein the nucleic acid hybridizes to an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182.
  • the present invention relates to an isolated recombinant or transgenic host cell comprising the hybridisation complex according to the present invention.
  • the invention also relates to a method for generating a recombinant or transgenic host cell, said method comprising the steps of providing a vector encoding a nucleic acid according to the present invention, introducing said vector into said recombinant or transgenic host cell, and transcribing said nucleic acid in said recombinant or transgenic host cell, thereby generating a recombinant or transgenic host cell comprising the hybridisation complex according to the present invention.
  • the invention relates to a transgenic, mammalian organism comprising the recombinant or transgenic host cell according to the present invention.
  • the invention further relates to a composition comprising one or more nucleic acids or a vector encoding said one or more nucleic acids according to any the present invention.
  • the composition may be in combination with a physiologically acceptable carrier.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids or a vector encoding said one or more nucleic acids according to any the present invention.
  • the pharmaceutical composition may be in combination with a pharmaceutically acceptable carrier.
  • composition according to the present invention further comprising the combination with one or more additional bioactive agent(s) used to treat psoriasis for medical use.
  • Said one or more bioactive agent(s) may used for topical, systemic or phototherapeutic treatment of psoriasis.
  • composition according to the present invention further comprises the combination with one or more additional bioactive agent(s) used to treat inflammatory diseases, skin diseases, Immune diseases, hyperproliferative diseases and angiogenic diseases for medical use.
  • the present invention is directed in another aspect to a method for administering one or more nucleic acids or a vector encoding said one or more nucleic acids according to the present invention to an individual in need thereof.
  • the present invention also relates to a kit-of-parts comprising one or more nucleic acids or a vector encoding said one or more nucleic acids according to the present invention, or one or the compositions according to the present invention, and at least one additional component.
  • the present invention relates to a method for identifying binding partners for an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, said method comprising the steps of extracting the miRNA and isolating said binding partners.
  • Said binding partners may comprise one or more agonists or antagonists.
  • nucleic acid or a vector encoding said nucleic acid according to the present invention, or one or the compositions according to the present invention, for use as a medicament there is also provided a nucleic acid or a vector encoding said nucleic acid according to the present invention, or one or the compositions according to the present invention, for use as a medicament.
  • the present invention relates to a method for treatment of an individual in need thereof with one or more nucleic acids or a vector encoding said one or more nucleic acids according to the present invention, or one of the compositions according to the present invention, or the agonists or antagonists according to the present invention.
  • the diseases that may be treated according to the present invention comprises psoriasis such as psoriasis vulgaris, inflammatory diseases, skin diseases, immune diseases, autoimmune diseases, hyperproliferative diseases and angiogenic diseases.
  • psoriasis such as psoriasis vulgaris, inflammatory diseases, skin diseases, immune diseases, autoimmune diseases, hyperproliferative diseases and angiogenic diseases.
  • the present invention further discloses a method for treatment of psoriasis comprising the steps of providing one or more nucleic acids capable of hybridizing to a miRNA which is up-regulated in psoriasis, and administering said one or more nucleic acids to an individual in need thereof.
  • Bioactive agent i. e., biologically active substance/agent
  • biologically active substance/agent is any agent, drug, compound, composition of matter or mixture which provides some pharmacologic, often beneficial, effect that can be demonstrated in-vivo or in vitro.
  • this term further includes any physiologically or pharmacologically active substance that produces a localized or systemic effect in an individual.
  • bioactive agents include, but are not limited to, agents comprising or consisting of an oligosaccharide, agents comprising or consisting of a polysaccharide, agents comprising or consisting of an optionally glycosylated peptide, agents comprising or consisting of an optionally glycosylated polypeptide, agents comprising or consisting of a nucleic acid, agents comprising or consisting of an oligonucleotide, agents comprising or consisting of a polynucleotide, agents comprising or consisting of a lipid, agents comprising or consisting of a fatty acid, agents comprising or consisting of a fatty acid ester and agents comprising or consisting of secondary metabolites. It may be used either prophylactically, therapeutically, in connection with treatment of an individual, such as a human or any other animal.
  • drug includes biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body.
  • treating refer equally to curative therapy, prophylactic or preventative therapy and ameliorating or palliative therapy.
  • the term includes an approach for obtaining beneficial or desired physiological results, which may be established clinically.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) condition, delay or slowing of progression or worsening of condition/symptoms, amelioration or palliation of the condition or symptoms, and remission (whether partial or total), whether detectable or undetectable.
  • the term "palliation”, and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering compositions of the present invention.
  • a “treatment effect” or “therapeutic effect” is manifested if there is a change in the condition being treated, as measured by the criteria constituting the definition of the terms “treating” and “treatment.”
  • There is a “change” in the condition being treated if there is at least 5% improvement, preferably 10% improvement, more preferably at least 25%, even more preferably at least 50%, such as at least 75%, and most preferably at least 100% improvement.
  • the change can be based on improvements in the severity of the treated condition in an individual, or on a difference in the frequency of improved conditions in populations of individuals with and without treatment with the bioactive agent, or with the bioactive agent in combination with a pharmaceutical composition of the present invention.
  • “Pharmacologically effective amount”, “pharmaceutically effective amount” or “physiologically effective amount” of a “bioactive agent” is the amount of an active agent present in a pharmaceutical composition as described herein that is needed to provide a desired level of active agent in the bloodstream or at the site of action in an individual (e.g. the lungs, the gastric system, the colorectal system, prostate, etc.) to be treated to give an anticipated physiological response when such composition is administered. The precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e.
  • an "effective amount" of a bioactive agent can be administered in one administration, or through multiple administrations of an amount that total an effective amount, preferably within a 24-hour period. It can be determined using standard clinical procedures for determining appropriate amounts and timing of administration. It is understood that the "effective amount” can be the result of empirical and/or individualized (case-by-case) determination on the part of the treating health care professional and/or individual.
  • enhancing and “improving” a beneficial effect, and variations thereof, as used herein, refers to the therapeutic effect of the bioactive agent against placebo, or an increase in the therapeutic effect of a state-of-the-art medical treatment above that normally obtained when a pharmaceutical composition is administered without the bioactive agent of this invention.
  • An increase in the therapeutic effects is manifested when there is an acceleration and/or increase in intensity and/or extent of the therapeutic effects obtained as a result of administering the bioactive agent(s). It also includes extension of the longevity of therapeutic benefits.
  • the enhancing effect preferably, but not necessarily, results in treatment of acute symptoms for which the pharmaceutical composition alone is not effective or is less effective therapeutically. Enhancement is achieved when there is at least a 5% increase in the therapeutic effects, such as at least 10% increase in the therapeutic effects when a bioactive agent of the present invention is co-administered with a pharmaceutical composition compared with administration of the pharmaceutical composition alone.
  • the increase is at least 25%, more preferably at least 50%, even more preferably at least 75%, most preferably at least 100%.
  • Co-administering or “co-administration” of bioactive agent(s), or bioactive agents and state-of-the-art medicaments, as used herein, refers to the administration of one or more bioactive agents of the present invention, or administration of one or more bioactive agents of the present invention and a state-of-the-art pharmaceutical composition within a certain time period.
  • the time period is preferably less than 72 hours, such as 48 hours, for example less than 24 hours, such as less than 12 hours, for example less than 6 hours, such as less than 3 hours.
  • these terms also mean that the bioactive agent and a therapeutic composition can be administered together.
  • Individual refers to vertebrates, particular members of the mammalian species, preferably primates including humans, and includes but is not limited to cattle, horses, pigs, sheep, mink, dogs, cats, mice, guinea pigs, rabbits, rats, horses and camels.
  • an "individual in need thereof” refers to an individual who may benefit from the present invention.
  • said individual in need thereof is a diseased individual, wherein said disease may be psoriasis.
  • the term "Kit of parts" as used in the present invention provides the nucleic acid according to the present invention and a second bioactive agent for administration in combination.
  • the combined active substances may be used for simultaneous, sequential or separate administration.
  • any of the herein- mentioned medicaments and bioactive agents are administered in pharmaceutically effective amounts, i.e. an administration involving a total amount of each active component of the medicament or pharmaceutical composition or method that is sufficient to show a meaningful patient benefit.
  • the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. It is preferred that the kit may for example contain the active compounds in dosage forms for administration.
  • a dosage form contains a sufficient amount of one or more of the active compound(s) such that a desirable effect can be obtained when administered to a subject.
  • the medical packaging comprises an amount of dosage units corresponding to the relevant dosage regimen.
  • the medical packaging comprises a pharmaceutical composition comprising the compounds as defined above or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers, vehicles and/or excipients.
  • the medical packaging may be in any suitable form - for example for enteral (via the digestive tract) or parenteral (routes other than the digestive tract) administration.
  • the packaging is in the form of a cartridge, such as a cartridge for an injection pen, the injection pen being such as an injection pen known from insulin treatment.
  • the kit-of-parts contains instructions indicating the use of the dosage form to achieve a desirable affect and the amount of dosage form to be taken over a specified time period.
  • the medical packaging comprises instructions for administering the pharmaceutical composition. It is envisaged that at least one (such as 2 or 3) additional medicament(s) acting on hemostasis or on treatment on the underlying cause of hemostasis or risk hereof, and at least one (such as 2 or 3) polypeptide according to the present invention may be used for the manufacture of any of the "kit of parts" described herein for administration to an individual in need thereof.
  • natural nucleotide refers to any of the four deoxyribonucleotides, dA, dG, dT, and dC (constituents of DNA), and the four ribonucleotides, A, G, U, and C (constituents of RNA) are the natural nucleotides.
  • Each natural nucleotide comprises or essentially consists of a sugar moiety (ribose or deoxyribose), a phosphate moiety, and a natural/standard base moiety.
  • Natural nucleotides bind to complementary nucleotides according to well-known rules of base pairing (Watson and Crick), where adenine (A) pairs with thymine (T) or uracil (U); and where guanine (G) pairs with cytosine (C), wherein corresponding base-pairs are part of complementary, anti-parallel nucleotide strands.
  • the base pairing results in a specific hybridization between predetermined and complementary nucleotides.
  • the base pairing is the basis by which enzymes are able to catalyze the synthesis of an oligonucleotide complementary to the template oligonucleotide.
  • building blocks (normally the triphosphates of ribo or deoxyribo derivatives of A, T, U, C, or G) are directed by a template oligonucleotide to form a complementary oligonucleotide with the correct, complementary sequence.
  • the recognition of an oligonucleotide sequence by its complementary sequence is mediated by corresponding and interacting bases forming base pairs.
  • the specific interactions leading to base pairing are governed by the size of the bases and the pattern of hydrogen bond donors and acceptors of the bases.
  • a six membered ring (a pyrimidine in natural oligonucleotides) is juxtaposed to a ring system composed of a fused, six membered ring and a five membered ring (a purine in natural oligonucleotides), with a middle hydrogen bond linking two ring atoms, and hydrogen bonds on either side joining functional groups appended to each of the rings, with donor groups paired with acceptor groups.
  • nucleic acid or “nucleic acid molecule” refers to polynucleotides, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), oligonucleotides, fragments generated by the polymerase chain reaction (PCR), and fragments generated by any of ligation, scission, endonuclease action, and exonuclease action.
  • Nucleic acid molecules can be composed of monomers that are naturally-occurring nucleotides (such as DNA and RNA), or analogs of naturally-occurring nucleotides (e.g. alpha- enantiomeric forms of naturally-occurring nucleotides), or a combination of both.
  • Modified nucleotides can have alterations in sugar moieties and/or in pyrimidine or purine base moieties.
  • Sugar modifications include, for example, replacement of one or more hydroxyl groups with halogens, alkyl groups, amines, and azido groups, or sugars can be functionalized as ethers or esters.
  • the entire sugar moiety can be replaced with sterically and electronically similar structures, such as aza-sugars and carbocyclic sugar analogs.
  • modifications in a base moiety include alkylated purines and pyrimidines, acylated purines or pyrimidines, or other well-known heterocyclic substitutes.
  • Nucleic acid monomers can be linked by phosphodiester bonds or analogs of such linkages.
  • nucleic acid molecule also includes e.g. so-called “peptide nucleic acids,” which comprise naturally-occurring or modified nucleic acid bases attached to a polyamide backbone. Nucleic acids can be either single stranded or double stranded.
  • 'nucleic acid' is meant to comprise antisense oligonucleotides (ASO), small inhibitory RNAs (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • ASO antisense oligonucleotides
  • siRNA small inhibitory RNAs
  • shRNA short hairpin RNA
  • miRNA microRNA
  • complement of a nucleic acid molecule refers to a nucleic acid molecule having a complementary nucleotide sequence and reverse orientation as compared to a reference nucleotide sequence. For example, the sequence 5' ATGCACGGG 3' is complementary to 5' CCCGTGCAT 3'.
  • an "isolated nucleic acid molecule” is a nucleic acid molecule that is not integrated in the genomic DNA of an organism.
  • a DNA molecule that encodes a growth factor that has been separated from the genomic DNA of a cell is an isolated DNA molecule.
  • Another example of an isolated nucleic acid molecule is a chemically- synthesized nucleic acid molecule that is not integrated in the genome of an organism.
  • a nucleic acid molecule that has been isolated from a particular species is smaller than the complete DNA molecule of a chromosome from that species.
  • nucleic acid molecule construct is a nucleic acid molecule, either single- or double- stranded, that has been modified through human intervention to contain segments of nucleic acid combined and juxtaposed in an arrangement not existing in nature.
  • Linear DNA denotes non-circular DNA molecules having free 5' and 3' ends. Linear DNA can be prepared from closed circular DNA molecules, such as plasmids, by enzymatic digestion or physical disruption.
  • Codon DNA is a single-stranded DNA molecule that is formed from an mRNA template by the enzyme reverse transcriptase. Typically, a primer complementary to portions of mRNA is employed for the initiation of reverse transcription.
  • cDNA refers to a double- stranded DNA molecule consisting of such a single-stranded DNA molecule and its complementary DNA strand.
  • cDNA also refers to a clone of a cDNA molecule synthesized from an RNA template.
  • a “promoter” is a nucleotide sequence that directs the transcription of a structural gene. Typically, a promoter is located in the 5' non-coding region of a gene, proximal to the transcriptional start site of a structural gene. Sequence elements within promoters that function in the initiation of transcription are often characterized by consensus nucleotide sequences. If a promoter is an inducible promoter, then the rate of transcription increases in response to an inducing agent. In contrast, the rate of transcription is not regulated by an inducing agent if the promoter is a constitutive promoter. Repressible promoters are also known.
  • a “regulatory element” is a nucleotide sequence that modulates the activity of a promoter.
  • a regulatory element may contain a nucleotide sequence that binds with cellular factors enabling transcription exclusively or preferentially in particular cells, tissues, or organelles. These types of regulatory elements are normally associated with genes that are expressed in a "cell-specific,” “tissue-specific,” or “organelle-specific” manner.
  • An “enhancer” is a type of regulatory element that can increase the efficiency of transcription, regardless of the distance or orientation of the enhancer relative to the start site of transcription.
  • Heterologous DNA refers to a DNA molecule, or a population of DNA molecules, that does not exist naturally within a given host cell.
  • DNA molecules heterologous to a particular host cell may contain DNA derived from the host cell species (i.e., endogenous DNA) so long as that host DNA is combined with non-host DNA (i.e., exogenous DNA).
  • a DNA molecule containing a non-host DNA segment encoding a polypeptide operably linked to a host DNA segment comprising a transcription promoter is considered to be a heterologous DNA molecule.
  • a heterologous DNA molecule can comprise an endogenous gene operably linked with an exogenous promoter.
  • a DNA molecule comprising a gene derived from a wild-type cell is considered to be heterologous DNA if that DNA molecule is introduced into a mutant cell that lacks the wild-type gene.
  • polypeptide is a polymer of amino acid residues preferably joined exclusively by peptide bonds, whether produced naturally or synthetically.
  • a polypeptide produced by expression of a non-host DNA molecule is a "heterologous" peptide or polypeptide.
  • the term "polypeptide” as used herein covers proteins, peptides and polypeptides, wherein said proteins, peptides or polypeptides may or may not have been post-translationally modified. Post-translational modification may for example be phosphorylation, methylation and glucosylation.
  • a "cloning vector” is a nucleic acid molecule, such as a plasmid, cosmid, or bacteriophage that has the capability of replicating autonomously in a host cell.
  • Cloning vectors typically contain one or a small number of restriction endonuclease recognition sites that allow insertion of a nucleic acid molecule in a determinable fashion without loss of an essential biological function of the vector, as well as nucleotide sequences encoding a marker gene that is suitable for use in the identification and selection of cells transformed with the cloning vector.
  • Marker genes typically include genes that provide tetracycline or ampicillin resistance.
  • an “expression vector” is a nucleic acid molecule encoding a gene that is expressed in a host cell.
  • an expression vector comprises a transcription promoter, a gene, and a transcription terminator. Gene expression is usually placed under the control of a promoter, and such a gene is said to be “operably linked to” the promoter.
  • a regulatory element and a core promoter are operably linked if the regulatory element modulates the activity of the core promoter.
  • Simpler vectors called “transcription vectors” are only capable of being transcribed but not translated: they can be replicated in a target cell but not expressed, unlike expression vectors. Transcription vectors are used to amplify their insert.
  • a “recombinant host” is a cell that contains a heterologous nucleic acid molecule, such as a cloning vector or expression vector.
  • expression refers to the biosynthesis of a gene or a gene product.
  • 'Deregulated' means that the expression of a gene or a gene product is altered from its normal baseline levels; comprising both up- and down-regulated.
  • To "hybridize” means annealing nucleic acid strands from different sources; that is, to form base pairs between complementary regions of two strands of DNA that were not originally paired.
  • hybridization under stringent conditions means that after washing for 1 h with 1 times SSC and 0.1% SDS at 50 degree C, preferably at 55 degree C, more preferably at 62 degree C and most preferably at 68 degree C, particularly for 1 h in 0.2 times SSC and 0.1% SDS at 50 degree C, preferably at 55 degree C, more preferably at 62 degree C and most preferably at 68 degree C, a positive hybridization signal is observed.
  • a nucleic acid having a nucleotide sequence which hybridizes under physiological conditions with the miRNA sequence of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, or a nucleotide sequence corresponding thereto in the scope of the degeneracy of the genetic code is encompassed by the present invention.
  • an "antisense oligonucleotide” is defined as having a sequence complementary to a 'sense' strand. In double-stranded DNA, the non-coding strand is antisense; the antisense DNA strand serves as the template for mRNA synthesis ('sense' strand that serves for translation into protein). The mRNA sense strand or an miRNA sequence may hybridise with an ASO.
  • An "anti-miRNA oligonucleotide” (AMO) or anti-miR is an ASO complementary to an miRNA sequence, designed to interfere with miRNA function. The terms may be used interchangeably herein.
  • Oligonucleotide is a short segment of RNA or DNA. Although they can be formed by cleavage of longer segments, they are more commonly synthesized by polymerizing individual nucleotide precursors. The length of the oligonucleotide is usually denoted by 'mer'; a fragment of 25 bases would be called a 25-mer.
  • the term oligonucleotide comprises oligonucleotides of both natural and/or non-natural nucleotides, including any combination thereof. The natural and/or non-natural nucleotides may be linked by natural phosphodiester bonds or by non-natural bonds. Oligonucleotide is used interchancably with polynucleotide.
  • a stretch of "Complete homology” is defined as a match of pairing nucleotides along the sequence of the interacting nucleotides; in natural occurring RNA the pairing of A with U and G with C.
  • a mismatch occurs when one or more nucleotides in one of the double strands in a nucleic acid molecule is without complementary nucleotides in the same position on the other strand. Also called incomplete base-pairing.
  • a “complex” as used herein is an miRNA molecule according to the present invention hybridized or otherwise attached to another molecule such as e.g. an antisense oligonucleotide molecule.
  • the term “homolog to SEQ ID NO:1" refers to a nucleic acid with a sequence similarity to SEQ ID NO:1 , in that it is a nucleic acid comprising or consisting of SEQ ID NO:1 or a fragment hereof. The percent similarity between the nucleotide sequence of the nucleic acid and its homolog is at or above 70%.
  • Transfection describes the introduction of foreign material into eukaryotic cells.
  • the term 'transfection' for non-viral methods is most often used in reference to mammalian cells, while the term 'transformation' is preferred to describe non-viral DNA transfer in bacteria and non-animal eukaryotic cells such as fungi, algae and plants. Both chemical and physical methods may be employed to transfect cells.
  • FIG. 1 The 44 miRNAs profile distinguished lesional psoriasis(PP) from non-lesional psoriasis (PN).
  • A An unsupervised two-way hierarchical cluster analysis of individual PP compared to PN was carried out with a distance measure of 1 -Pearssons correlation coefficient with centroid linkage and a p-value threshold of 0.05 for significant sample clusters and significant gene clusters ordered by peaking time. For patient PP4 the non-lesional psoriasis reference is a duplicate of PN3.
  • B A supervised linear discriminate analysis (LDA) was performed based on the 44 miRNAs gene algorithm.
  • the reference was the mean of PPue-
  • the values were calculated using 2 ⁇ ct (unknown samples being target miRNAs for PP, PN or NN and controls being the endogene controls either U6 or 5S rRNA for PP, PN or NN). Data was transformed using logarithmic base 2. Individual measurements are indicated with black dots and average with scale bars.
  • FIG. 3 Gene ontology functional analysis of the miRNA profile. From the 44 miRNAs information on biological function and disease relation was retrieved using Ingenuity Pathway Analysis. Nineteen genes were identified as being involved in biological functions or disease relations (p ⁇ 0.005). These 19 miRNAs are marked in Table 3. Numbers of focus genes, central for the biological network, are mentioned in brackets.
  • Figure 4 Changes in mRNA levels in PP and PN. From four randomly selected patients of the original cohort of 15 patients the mRNA expression levels were analyzed by mRNA microarray.
  • A Hierarchical unsupervised 2-way clustering was performed. The analysis clearly separated PP from PN in two distinct clusters (p ⁇ 0.005) based on 1 1 15 probe sets corresponding 945 genes.
  • B An unsupervised principal component analysis (PCA) was built based on differences rather than similarities; this analysis confirmed the cluster analysis. Dark-grey indicates PP and light-grey represents PN.
  • PCA principal component analysis
  • FIG. 5 Comparative miRNA and mRNA gene ontology analysis.
  • A The 42 miRNAs being up-regulated and the 2 miRNAs being down-regulated were uploaded to miRBase Targets Version 5 using the Miranda algorithm (13) to find predicted mRNA targets; this resulted in 14133 predicted target genes for the 42 up-regulated miRNAs and 1752 predicted target genes for the 2 down-regulated miRNAs. The genes were compared to the 945 genes found deregulated in psoriasis lesions.
  • the miRNAs likely to affect the 460 mRNAs being down-regulated was accounting 258 mRNAs, of which 171 genes were directly correlated to relevant functions and diseases.
  • C The miRNAs likely to affect the 485 mRNAs being down-regulated was accounting 278 mRNAs, of which 74 genes were directly correlated to relevant functions and diseases. Numbers of focus genes, central for the biological network, are mentioned in brackets.
  • FIG. 6 Unsupervised principal component analysis of miRNAs separated psoriatic skin (PP) from healthy skin (NN). Unsupervised principal component analysis was performed using dCHIP, separating samples based on all 579 miRNAs expressed in psoriatic and non-involved psoriatic skin compared with healthy skin. Dots with an inner ridge represents healthy skin (NN), regular grey dots represents either psoriatic skin (PP) in panel (a) or non-involved psoriatic skin (PN) in panel (b).
  • Figure 8 Unsupervised principal component analysis separated mRNA deregulated in psoriatic skin. mRNA data was filtered by specific variation across samples, 1350 genes were obtained, followed by an unsupervised principal component analysis using dChip separating psoriatic skin from non-involved psoriatic skin and healthy skin. Dots with an inner ridge represent healthy skin samples (NN), regular grey dots represent psoriatic skin samples (PP) and dots with a scalloped edge represent non-involved psoriatic skin samples (PN).
  • NN healthy skin samples
  • PP psoriatic skin samples
  • PN non-involved psoriatic skin samples
  • FIG. 9 Predicted targets for psoriasis. Using four prediction algorithms (PicTar, TargetScan, microRNA.org and MiRanda), target interaction among the up-regulated miRNAs and the 10 most down-regulated mRNAs in psoriatic skin was found. To gain further insight in the predicted hybridizations the miRNA and mRNA sequences were uploaded to RNAhybrid. miR-199a-3p was likely to target Pleiotrophin (PTN) (a), miR- 221 and miR-222 was likely to target the tissue inhibitor of metalloproteinase 3 (TIMP3) (b,c).
  • PPN Pleiotrophin
  • TBN3 tissue inhibitor of metalloproteinase 3
  • RNA folding plots in upper panels (generated in RNAhybrid), of the miRNA-mRNA target interactions and the minimum free energy (mfe) of the hybridization. A simplified alignment is shown in the lower panel.
  • Figure 10 microRNA-target interactions. Predicted target interactions of miRNAs of potential relevance for psoriasis and related diseases are shown.
  • BAD Bcl-2 antagonist of cell death
  • MMPs matrix metalloproteases
  • RA retinoic acid
  • TNF-alpha tumor becorsis factor alpha
  • PTN pleiotrophin
  • SHIP2 SH2 domain- containing inositol-5'-phosphatase 2
  • PDCD4 programmeed cell death 4
  • TPM1 tropomyosin 1 , alpha
  • RTN4 reticulon 4
  • RECK Reversion-inducing cysteine-rich protein with Kazal motifs
  • TIMP3 tissue inhibitor of metalloproteinase 3
  • NFIB nuclear factor I/B
  • STAT3 signal transducer and activator of transcription 3
  • PLZF Zinc finger and BTB domain-containing protein 16
  • FIG. 1 Venn analysis of deregulated mRNA genes. A Venn analysis was performed comparing mRNA genes that were either up-regulated (a) or down-regulated (b) in the comparison of PP with NN, PP with PN and PN with NN.
  • the present invention interestingly discloses a deregulated specific subset of miRNA species in psoriasis.
  • the deregulated miRNAs identified in the present invention thus provides interesting and potential targets for the treatment of psoriasis and related diseases.
  • the inhibition of upregulated or overexpressed miRNAs can be achieved via administering one or more inhibitory nucleic acids capable of hybridising to and/or inhibiting said overexpressed miRNA(s).
  • inhibitory nucleic acids capable of hybridising to and/or inhibiting said overexpressed miRNA(s).
  • ASO antisense oligonucleotides
  • siRNA siRNA
  • shRNA shRNA
  • miRNA or others as described herein below
  • KO 'knockout
  • These may be administered directly or expressed from a plasmid, and may be chemically modified, such as LNA modified.
  • the down- regulated miRNAs identified herein may be reintroduced by ectopic expression of said miRNAs, or direct administration of a pharmaceutically effective amount of an miRNA, or a precursor or analogue thereof.
  • Approach A PP vs. PN
  • biopsy samples were taken from patients with psoriasis vulgaris; one biopsy was taken from a psoriasis plaque (PP) and the level of miRNA was compared to that of psoriasis normal or symptomless skin (PN, non-involved skin from same patient).
  • PP psoriasis plaque
  • PN non-involved skin from same patient. This was achieved by taking 4mm punch biopsies of each condition, isolating total RNA, performing a non-coding RNA Expression Profiling using the miRCURYTM LNA Array (Exiqon, Vedbaek Denmark) and analysing these extensively using available bioinformatics tools (See Example 1 for details).
  • PP vs. PN may characterize the pathogenesis of psoriasis and possibly other related diseases, thus defining a disease profile for psoriasis and providing promising targets for the treatment of this and possibly other related diseases.
  • one or more miRNA sequences selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29
  • one or more miRNAs selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:10, SEQ ID NO
  • one or more miRNAs selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 and SEQ ID NO:83 are significantly down-regulated in psoriasis (PP) as compared to PN.
  • a fragment of an miRNA sequence is meant to comprise part of the full sequence, wherein the disclosed full miRNA sequence is at least 1 , such as 2, for example 3, such as 4, for example 5, such as 6, for example 7, such as 8, for example 9, such as 10, for example 1 1 , such as 12, for example 13, such as 14, for example 15, such as 16, for example 17, such as 18, for example 19, such as 20, for example 21 , such as 22 nucleotide(s) shorter than the sequences disclosed in Table 1 , wherein the total length of the miRNA sequence is at least 5 nucleotides, such as at least 6, for example 7, such as 8, for example 9, such as at least 10 nucleotides.
  • a variant of an miRNA sequence is meant to comprise the full length sequence, wherein the nucleotides of the disclosed full miRNA sequence is substituted on at most 1 , such as 2, for example 3, such as 4, for example 5, such as 6, for example 7, such as 8, for example 9, such as 10, for example 1 1 , such as 12, for example 13, such as 14, for example 15, such as 16, for example 17, such as 18, for example 19, such as 20 position(s) of the sequences disclosed in Table 1 .
  • biopsy samples were taken from patients with psoriasis vulgaris; and the level of miRNA was compared to that of healthy, normal donor skin (NN). This was achieved by taking 4mm punch biopsies of each condition, isolating total RNA, performing a non-coding RNA Expression Profiling using the miRCURYTM LNA Array (Exiqon, Vedbaek Denmark) and analysing these extensively using available bioinformatics tools (See Example 2 for details).
  • PP vs. NN may characterize the pathogenesis of psoriasis and possibly other related diseases, thus defining a disease profile for psoriasis and providing promising targets for the treatment of this and possibly other related diseases.
  • psoriasis psoriasis
  • one or more miRNA sequences selected from the group consisting of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 10, SEQ ID NO:1 1 1 , SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1
  • one or more miRNAs selected from the group consisting of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 10, SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123,
  • one or more miRNAs selected from the group consisting of SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182 are significantly down-regulated in psoriasis (PP) as compared to NN.
  • PP psoriasis
  • a fragment of an miRNA sequence is meant to comprise part of the full sequence, wherein the disclosed full miRNA sequence is at least 1 , such as 2, for example 3, such as 4, for example 5, such as 6, for example 7, such as 8, for example 9, such as 10, for example 1 1 , such as 12, for example 13, such as 14, for example 15, such as 16, for example 17, such as 18, for example 19, such as 20, for example 21 , such as 22 nucleotide(s) shorter than the sequences disclosed in Table 2, wherein the total length of the miRNA sequence is at least 5 nucleotides, such as at least 6, for example 7, such as 8, for example 9, such as at least 10 nucleotides.
  • a variant of an miRNA sequence is meant to comprise the full length sequence, wherein the nucleotides of the disclosed full miRNA sequence is substituted on at most 1 , such as 2, for example 3, such as 4, for example 5, such as 6, for example 7, such as 8, for example 9, such as 10, for example 1 1 , such as 12, for example 13, such as 14, for example 15, such as 16, for example 17, such as 18, for example 19, such as 20 position(s) of the sequences disclosed in Table 2.
  • miRNAs that are deregulated in PN versus NN are listed in Table 6 below (see Example 2).
  • 10 miRNAs are deregulated in PN versus NN; 9 of which are up- regulated and 1 of which is down-regulated. Comparing the genes found deregulated in PP versus NN and PN versus NN reveals 4 miRNAs that are deregulated in both conditions (i.e. in both PP and PN compared to NN): SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 131 and SEQ ID NO: 133.
  • PP psoriasis
  • PN psoriasis normal
  • one or more miRNA sequences selected from the group consisting of SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 131 and SEQ ID NO: 133 are significantly de-regulated in both PP and PN as compared to NN.
  • one or more miRNAs selected from the group consisting of SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 131 and SEQ ID NO: 133 are significantly up-regulated in both PP and PN as compared to NN.
  • the present invention relates to a method for inhibiting one or more miRNAs selected from the group consisting of SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 131 and SEQ ID NO: 133. In one particular embodiment, the present invention relates to a method for inhibiting one or more miRNAs selected from the group consisting of SEQ ID NO: 99, SEQ ID NO: 131 and SEQ ID NO: 133.
  • the production of mature miRNA via processing of pri- and pre-miRNA by various enzymes and complexes is a pathway that may be targeted in a number of ways.
  • the mature, processed, cytoplasmic miRNA is subject to targeted inhibition by the methods disclosed below.
  • the nucleic pri-miRNA; a RNA polymerase II- dependent transcript with the mature miRNA as one arm of a hairpin structure is subject to targeted inhibition by the methods disclosed below.
  • the pre-miRNA cleaved from pri-miRNA in the nucleus and exported to the cytoplasm, still comprising the mature miRNA as one arm of a hairpin structure, is subject to targeted inhibition by the methods disclosed below.
  • the mature miRNA is targeted.
  • Said method may comprise administering a nucleic acid capable of hybridising to said miRNA.
  • the present invention relates to a method for reducing the expression of one or more miRNAs selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:32,
  • the present invention relates to a method for reducing the expression of one or more miRNAs selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO:73,
  • the present invention relates to a method for reducing the expression of one or more miRNAs selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16,
  • Targeted degradation of the pri-miRNA transcript in the nucleus may be feasible with a RNaseH-based antisense oligonucleotide (ASO), and could be advantageous for inhibiting the production of multiple miRNAs from a polycistronic pri-miRNA transcript.
  • ASO RNaseH-based antisense oligonucleotide
  • siRNAs are thought ineffective in targeting pri-miRNAs due to the cytoplasmic location of the RISC complex containing the siRNA.
  • Targeted degradation of the pre-miRNA hairpin transcript may be feasible, should an inhibitory oligonucleotide be able to invade and bind to the hairpin structure.
  • Targeting the loop of the hairpin with a RNaseH-based ASO or a siRNA may be possible and prove effective.
  • Inhibitory nucleic acids having a nucleotide sequences that target and inhibit miRNAs comprises antisense oligonucleotides (ASO), siRNA, shRNA, miRNA or others as described herein below. Inhibitory nucleic acids may collectively be denoted 'knockout (KO) probes'. These may be delivered directly as single-stranded (ASO) or double- stranded (siRNA) oligonucleotides, or expressed from vectors in manners known to the person skilled in the art.
  • a nucleic acid according to the present invention is capable of hybridizing to a miRNA sequence, wherein said miRNA sequence is complementary to the nucleic acid sequence.
  • said nucleic acid hybridizes to a miRNA according to the present invention, and thereby inhibits said miRNA.
  • Inhibition as used herein is meant to comprise a subsequent degradation of the target miRNA, or an interference with cellular processes by binding to the target miRNA sequence thus blocking sterically the function of said miRNA.
  • antisense oligonucleotides are used as inhibitory nucleic acids to target the miRNAs of the present invention. Inhibition of miRNA using synthetic ASOs in disease states is reviewed in Esau (Methods 2008 Jan; 44(1 ): 55-60) and Weiler et al. (Gene Therapy 2006 Mar;13(6): 496-502), incorporated herein by reference.
  • Antisense molecules are single-stranded oligonucleotides that interact with complementary strands of nucleic acids, modifying expression of genes.
  • RNA regions within a double strand of DNA code for genes, which are usually instructions specifying the order of amino acids in a protein along with regulatory sequences, splicing sites, non-coding introns and other complicating details.
  • one strand of the DNA serves as a template for the synthesis of a complementary strand of RNA.
  • the template DNA strand is called the transcribed strand with antisense sequence and the mRNA transcript is said to be sense sequence (the complement of antisense).
  • the strand complementary to the antisense sequence is called non-transcribed strand and has the same sense sequence as the mRNA transcript (though T bases in DNA are substituted with U bases in RNA).
  • Enzyme-dependent antisense includes forms dependent on RNase H activity to degrade target mRNA, including single-stranded DNA, RNA, and phosphorothioate antisense.
  • the R1 plasmid hok/sok system is an example of mRNA antisense regulation process, through enzymatic degradation of the resulting RNA duplex.
  • Double stranded RNA acts as enzyme-dependent antisense through the RNAi/siRNA pathway, involving target mRNA recognition through sense-antisense strand pairing followed by target mRNA degradation by the RNA-induced silencing complex (RISC).
  • RISC RNA-induced silencing complex
  • Steric blocking antisense interferes with gene expression or other mRNA-dependent cellular processes by binding to a target sequence of mRNA and getting in the way of other processes.
  • Steric blocking antisense includes 2'-0 alkyl (usually in chimeras with RNase-H dependent antisense), peptide nucleic acid (PNA), locked nucleic acid (LNA) and Morpholino antisense.
  • Antisense nucleic acid molecules have been used experimentally to bind to mRNA and prevent expression of specific genes.
  • Antisense therapies are currently in development; in the USA, the Food and Drug Administration (FDA) has approved a phosphorothioate antisense oligonucleotide, fomivirsen (Vitravene), for human therapeutic use.
  • FDA Food and Drug Administration
  • the KO probes according to the present invention may in one embodiment be produced under GMP guidelines by the methods employed by Cure Vac (http://www.curevac.de).
  • Chemical modification of the ASO can be beneficial for improving hybridization affinity for the target miRNA, improving resistance to nuclease degradation and improving activation of RNaseH or other proteins involved in the terminating mechanism. Alteration of the binding properties of ASOs in order to delay plasma clearance and promote uptake into tissues is necessary for in vivo delivery, and can be achieved through chemical modification or conjugation to carrier moieties (as detailed herein later).
  • small interfering RNA are used as inhibitory nucleic acids to target the miRNAs of the present invention.
  • siRNA sometimes also known as short interfering RNA or silencing RNA, are a class of 20-25 nucleotide-long double-stranded RNA molecules that play a variety of roles in biology. Most notably, siRNA is involved in the RNA interference (RNAi) pathway where the siRNA interferes with the expression of a specific gene. In addition to their role in the RNAi pathway, siRNAs also act in RNAi-related pathways, e.g. as an antiviral mechanism or in shaping the chromatin structure of a genome; the complexity of these pathways is only now being elucidated.
  • RNAi RNA interference
  • siRNAs have a well defined structure: a short (usually 21 -nt) double-strand of RNA (dsRNA) with 2-nucleotide 3' overhangs on either end. Each strand has a 5' phosphate group and a 3' hydroxyl (-OH) group.
  • Dicer an enzyme that converts either long dsRNAs or small hairpin RNAs (shRNA) into siRNAs.
  • SiRNAs can also be exogenously (artificially) introduced into cells by various transfection methods to bring about the specific knockdown of a gene of interest. Essentially any gene of which the sequence is known can thus be targeted based on sequence complementarity with an appropriately tailored siRNA. This has made siRNAs an important tool for gene function and drug target validation studies in the post-genomic era.
  • RNA polymerase III promoter e.g. U6 or H1
  • snRNAs small nuclear RNAs
  • siRNA transcript is then processed by Dicer.
  • the RNAi pathway has been evaluated for therapeutic use in a phase I trial on age-related macular degeneration, and was generally well-tolerated with suitable pharmacokinetic properties. It has been shown, that siRNA against the loop region of a pre-miRNA specifically down-regulated the corresponding miRNA (Lee et al., J Biol Chem 2005 Apr 29; 280(17): 16635-41 ).
  • microRNA is used as inhibitory nucleic acids to target the miRNAs of the present invention. miRNAs were described in greater detail above.
  • inhibition of up-regulated or overexpressed miRNAs in disease states is achieved via one or more inhibitory nucleic acids capable of hybridising to and/or inhibiting said overexpressed miRNA(s).
  • Such nucleic acids may be antisense oligonucleotides (ASO), siRNA, shRNA, miRNA or others as described herein above, and may also collectively be denoted 'knockout (KO) probes'.
  • compositions such as a pharmaceutical composition, comprising one or more inhibitory nucleic acids capable of hybridizing to an miRNA sequence as identified herein, that may be administered to an individual in need thereof.
  • the inhibitory nucleic acid in one aspect relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID
  • the present invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO:73, SEQ ID NO:
  • the present invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98, SEQ ID NO:100,
  • the invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO
  • the present invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO:73, SEQ ID NO:
  • the present invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78 and SEQ ID NO:79, or fragments or variants of any of the aforementioned miRNA sequences.
  • the invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 10, SEQ ID NO:1 1 1 , SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:
  • the present invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:1 10, SEQ ID NO:1 18, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:124, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:146, SEQ ID NO:157, SEQ ID NO:165, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:171 , SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179 and SEQ ID NO:180, or fragments or variants of any of the aforementioned miRNA sequences.
  • the present invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 16, SEQ ID NO:136, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:147, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:155, SEQ ID NO:156 and SEQ ID NO:163, or fragments or variants of any of the aforementioned miRNA sequences.
  • the invention relates to a nucleic acid capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182.
  • the invention relates to a nucleic acid capable of hybridizing to a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, wherein said nucleic acid is an antisense oligonucleotide capable of inhibiting said miRNA sequence, wherein said antisense oligonucleotide may be chemically modified.
  • a nucleic acid hybridized to a miRNA sequence according to the present invention may in one embodiment inhibit the function of said miRNA sequence, such as by degradation of said miRNA or inhibition of the function of said miRNA.
  • said nucleic acid is an antisense oligonucleotide capable of inhibiting said miRNA sequence, wherein said antisense oligonucleotide may be chemically modified.
  • said nucleic acid is an LNA anti- miR capable of inhibiting said miRNA sequence.
  • said nucleic acid is an siRNA capable of inhibiting said miRNA sequence, wherein said siRNA may be chemically modified.
  • One aspect of the invention relates to the use of a nucleic acid capable of hybridizing to a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, wherein said nucleic acid is capable of inhibiting said miRNA sequence, and wherein said nucleic acid is used for the treatment of a medical condition in an individual in need thereof.
  • said individual may have psoriasis or any other condition as specified herein below.
  • An aspect of the invention thus relates to the use of a nucleic acid capable of inhibiting an miRNA sequence, and wherein said nucleic acid is used for the treatment of a medical condition in an individual in need thereof.
  • said individual may have psoriasis or any other condition as specified herein below.
  • the hybridisation complex of a nucleic acid hybridized to a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences is an object of the present invention.
  • said hybridisation complex comprises a nucleic acid hybridized to a miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO:73, SEQ ID NO
  • said hybridisation complex comprises a nucleic acid hybridized to a miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:1
  • the invention describes a nucleic acid capable of inhibiting a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182.
  • the nucleic acid has a nucleotide sequence with complete homology in at least 12, such as 13, for example 14, such as 15, for example 16, such as 17, for example 18, such as 19, for example 20, such as 21 , for example 22, such as 23, for example 24 consequtive nucleotides to an miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences.
  • the nucleic acid has a nucleotide sequence with complete homology except from maximum 3 mismatches, such as 2 mismatches, for example 1 mismatch to an miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences.
  • the nucleic acid according to the present invention has a total length of 6, such as 7, for example 8, such as 9, for example 10, such as 1 1 , for example 12, such as 13, for example 14, such as 15, for example 16, such as 17, for example 18, such as 19, for example 20, such as 21 , for example 22, such as 23, for example 24 successive nucleotides.
  • the pri-miRNA comprising the mature miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences, in one embodiment may be targeted by the nucleic acids according to the present invention.
  • the pre-miRNA comprising the mature miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences in one embodiment may be targeted by the nucleic acids according to the present invention.
  • two or more nucleic acids that each target a different miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:5, SEQ
  • At least two, such as three, for example four, such as five, for example six, such as seven, for example eight, such as nine, for example ten nucleic acids that each target a different miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 may be used to inhibit at least two, such as three, for example four, such as five, for example six, such as seven, for example eight, such as nine, for example ten of said miRNA sequences simultaneously.
  • nucleic acids such as 3 nucleic acids, for example 4 nucleic acids, such as 5 nucleic acids, for example 6 nucleic acids, such as 7 nucleic acids, for example 8 nucleic acids, such as 9 nucleic acids, for example 10 nucleic acids, such as 1 1 nucleic acids, for example 12 nucleic acids, such as 13 nucleic acids, for example 14 nucleic acids, such as 15 nucleic acids, for example 16 nucleic acids, such as 17 nucleic acids, for example 18 nucleic acids, such as 19 nucleic acids, for example 20 nucleic acids, such as 21 nucleic acids, for example 22 nucleic acids, such as 23 nucleic acids, for example 24 nucleic acids, such as 25 nucleic acids, for example 26 nucleic acids, such as 27 nucleic acids, for example 28 nucleic acids, such as 29 nucleic acids, for example 30 nucleic acids, such as 31 nucleic acids, for example 32 nucleic acids, such
  • the miRNA sequences that are targeted by two or more nucleic acids of the present invention are selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO:73, SEQ
  • the miRNA sequences that are targeted by two or more nucleic acids of the present invention are selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO
  • nucleic acids of the present invention Whilst it is possible for the nucleic acids of the present invention to be administered as the raw chemical, it is preferred to present them in the form of a composition or pharmaceutical formulation. Accordingly, the present invention further provides a composition for medicinal application, which may comprise one or more nucleic acids of the present invention and optionally a pharmacologically and/or pharmaceutically acceptable carrier therefore.
  • Pharmaceutical compositions containing one or more nucleic acids of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa.
  • composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:
  • composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ
  • composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98,
  • the invention relates to a composition
  • a composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 ,
  • the composition according to the present invention comprises one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO
  • the composition according to the present invention comprises one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78 and SEQ ID NO:79, or fragments or variants of any of the aforementioned miRNA sequences.
  • the invention relates to a composition
  • a composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID
  • the composition according to the present invention comprises one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:1 10, SEQ ID NO:1 18, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:124, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:146, SEQ ID NO:157, SEQ ID NO:165, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:171 , SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179 and SEQ ID NO:180, or fragments or variants of any of the aforementioned miRNA sequences.
  • the composition according to the present invention comprises one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 16, SEQ ID NO:136, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:147, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:163, or fragments or variants of any of the aforementioned miRNA sequences.
  • compositions comprising at least two nucleic acids capable of hybridizing to an miRNA sequence, wherein one of said at least two nucleic acids hybridizes to an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO
  • composition according to the present invention in one embodiment comprises 1 nucleic acid, such as 2 nucleic acids, for example 3 nucleic acids, such as 4 nucleic acids, for example 5 nucleic acids, such as 6 nucleic acids, for example 7 nucleic acids, such as 8 nucleic acids, for example 9 nucleic acids, such as 10 nucleic acids.
  • composition according to the present invention in one embodiment comprises less than 50 nucleic acids, such as less than 45 nucleic acids, for example less than 40 nucleic acids, such as less than 35 nucleic acids, for example less than 30 nucleic acids, such as less than 25 nucleic acids, for example less than 20 nucleic acids, such as less than 15 nucleic acids, for example less than 10 nucleic acids, such as less than 8 nucleic acids, for example less than 6 nucleic acids, such as less than 4 nucleic acids, for example less than 2 nucleic acids.
  • nucleic acids such as less than 45 nucleic acids, for example less than 40 nucleic acids, such as less than 35 nucleic acids, for example less than 30 nucleic acids, such as less than 25 nucleic acids, for example less than 20 nucleic acids, such as less than 15 nucleic acids, for example less than 10 nucleic acids, such as less than 8 nucleic acids, for example less than 6 nucleic acids, such as less than 4 nucleic acids,
  • composition according to the present invention in one embodiment comprises at least 1 nucleic acid, such as at least 2 nucleic acids, for example at least 3 nucleic acids, such as at least 4 nucleic acids, for example at least 5 nucleic acids, such as at least 6 nucleic acids, for example at least 8 nucleic acids, such as at least 10 nucleic acids, for example at least 12 nucleic acids, such as at least 14 nucleic acids, for example at least 16 nucleic acids, such as at least 18 nucleic acids, for example at least 20 nucleic acids.
  • nucleic acid such as at least 2 nucleic acids, for example at least 3 nucleic acids, such as at least 4 nucleic acids, for example at least 5 nucleic acids, such as at least 6 nucleic acids, for example at least 8 nucleic acids, such as at least 10 nucleic acids, for example at least 12 nucleic acids, such as at least 14 nucleic acids, for example at least 16 nucleic acids, such as at least 18 nucleic acids,
  • the present invention also relates to a composition
  • a composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, in combination with a physiologically acceptable carrier.
  • compositions as disclosed herein may in one embodiment be formulated in combination with a physiologically acceptable carrier.
  • any composition as disclosed herein may be a pharmaceutical composition.
  • a pharmaceutical composition may be formulated in combination with a pharmaceutically acceptable carrier.
  • composition or pharmaceutical composition according to the present invention may also comprise additional substances such as skin penetration enhancers (see below for examples), carriers, vehicles and/or humectants.
  • compositions for preparing a pharmaceutical composition are well-known in the art, whereby the nucleic acids are combined with a pharmaceutically acceptable carrier (or vehicle).
  • a pharmaceutically acceptable carrier or vehicle.
  • Such compositions will contain an effective amount of the bioactive agent together with a suitable amount of carrier in order to prepare pharmaceutically acceptable compositions suitable for administration to a human or animal in need thereof.
  • Pharmaceutically acceptable carriers may be prepared from a wide range of materials. Without being limited thereto, such materials include diluents, binders and adhesives, excipients, lubricants, humectants (e. g., glycerol and propylene glycol), disintegrants, colorants, bulking agents, stabilizers, preservatives, and miscellaneous materials such as buffers and absorbents in order to prepare a particular pharmaceutical composition.
  • diluents binders and adhesives
  • excipients e. g., glycerol and propylene glycol
  • humectants e. g., glycerol and propylene glycol
  • disintegrants e. g., glycerol and propylene glycol
  • colorants e. glycerol and propylene glycol
  • bulking agents e.g., glycerol and propylene glycol
  • stabilizers e. g
  • the invention relates to a composition
  • a composition comprising a nucleic acid capable of hybridizing to a miRNA sequence, wherein said nucleic acid is an antisense oligonucleotide capable of inhibiting said miRNA sequence, wherein said antisense oligonucleotide may be chemically modified.
  • the invention in another embodiment relates to a composition
  • a composition comprising a nucleic acid capable of hybridizing to a miRNA sequence, wherein said nucleic acid is an LNA anti- miR capable of inhibiting said miRNA sequence.
  • the invention relates to a composition
  • a composition comprising a nucleic acid capable of hybridizing to a miRNA sequence, wherein said nucleic acid is an siRNA capable of inhibiting said miRNA sequence.
  • One aspect of the invention relates to the use of a composition
  • a composition comprising a nucleic acid capable of hybridizing to a miRNA sequence, wherein said nucleic acid is capable of inhibiting said miRNA sequence, and wherein said nucleic acid is used for the treatment of a medical condition in an individual in need thereof.
  • said individual may have psoriasis or any other condition as specified herein below.
  • the invention relates to a composition
  • a composition comprising two or more, such as two, for example three, such as four, for example five, such as six, for example seven, such as eight, for example nine, such as ten different nucleic acids that each target the same miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182.
  • the invention relates to a composition
  • a composition comprising a maximum of 44 nucleic acids each targeting a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:88, such as a maximum of 40 nucleic acids, for example a maximum of 35 nucleic acids, such as a maximum of 30 nucleic acids, for example a maximum of 25 nucleic acids, such as a maximum of 20 nucleic acids, for example a maximum of 15 nucleic acids, such as a maximum of 10 nucleic acids, for example a maximum of 9 nucleic acids, such as a maximum of 8 nucleic acids, for example a maximum of 7 nucleic acids, such as a maximum of 6 nucleic acids, for example a maximum of 5 nucleic acids, such as a maximum of 4 nucleic acids, for example a maximum of 3 nucleic acids, such as a maximum of 2 nucleic acids, for example a maximum of 1 nucleic acid each targeting a miRNA sequence selected from the group
  • the invention relates to a composition
  • a composition comprising a maximum of 47 nucleic acids each targeting a miRNA sequence selected from the group consisting of SEQ ID NO:89 to SEQ ID NO:182, such as a maximum of 40 nucleic acids, for example a maximum of 35 nucleic acids, such as a maximum of 30 nucleic acids, for example a maximum of 25 nucleic acids, such as a maximum of 20 nucleic acids, for example a maximum of 15 nucleic acids, such as a maximum of 10 nucleic acids, for example a maximum of 9 nucleic acids, such as a maximum of 8 nucleic acids, for example a maximum of 7 nucleic acids, such as a maximum of 6 nucleic acids, for example a maximum of 5 nucleic acids, such as a maximum of 4 nucleic acids, for example a maximum of 3 nucleic acids, such as a maximum of 2 nucleic acids, for example a maximum of 1 nucleic acid each targeting a miRNA sequence selected from the group
  • the composition does not comprise a nucleic acid targeting miR- 203 (i.e. SEQ ID NO:122 sense and SEQ ID NO:169 antisense sequence).
  • the composition does not comprise a nucleic acid targeting a miRNA selected from the group of SEQ ID NO:5, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:21 , SEQ ID NO:49, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:65, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:101 , SEQ ID NO:106, SEQ ID NO:1 12, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 17, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:124, SEQ ID NO:126, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO
  • composition for use as a medicament for use as a medicament
  • the pharmaceutical composition according to the present invention may be used therapeutically to treat existing disease (curative treatment), protectively to prevent disease (prophylaxis), or to reduce the severity and/or duration of disease by palliative treatment (ameliorating treatment).
  • the present invention in one embodiment relates to one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences, for use as a medicament.
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, for use as a medicament.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 ,
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 10, SEQ ID NO:1 1 1 , SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:1 10, SEQ ID NO:1 18, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:124, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:146, SEQ ID NO:157, SEQ ID NO:165, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:171 , SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179 and SEQ ID NO:180, or fragments or variants of any of the aforementioned miRNA sequences, for use as a medicament.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 16, SEQ ID NO:136, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:147, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:155, SEQ ID NO:156 and SEQ ID NO:163, or fragments or variants of any of the aforementioned miRNA sequences, for use as a medicament.
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, for use as a medicament for the treatment of a disease such as psoriasis or any other inflammatory disease, skin disease, immune disease, autoimmune disease, hyperproliferative disease or angiogenic disease.
  • a disease such as psoriasis or any other inflammatory disease, skin disease, immune disease, autoimmune disease, hyperproliferative disease or angiogenic disease.
  • the pharmaceutical composition for use as a medicament for the treatment of a disease comprises a nucleic acid capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:
  • the pharmaceutical composition for use as a medicament for the treatment of a disease comprises a nucleic acid capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising nucleic acids capable of hybridizing to and/or inhibiting an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, in combination with a pharmaceutically acceptable carrier and one or more additional bioactive agent(s) for medical use.
  • Said additional bioactive agent(s) for medical use may be those used for the treatment of diseases such as psoriasis or any other inflammatory disease, skin disease, immune disease, autoimmune disease, hyperproliferative disease or angiogenic disease.
  • the present invention also relates to a method for identifying binding partners for the miRNA sequences selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, said method comprising the steps of extracting said miRNA and isolating said binding partners.
  • the present invention also relates to a method for treatment of an individual in need thereof with the binding partners described above such as agonists or antagonists of an miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences.
  • the present invention relates to a kit-of-parts comprising the nucleic acids capable of hybridizing to a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, or one or the compositions described above, and at least one additional component.
  • a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, or one or the compositions described above, and at least one additional component.
  • nucleic acids or inhibitory nucleic acids of the present invention comprising antisense oligonucleotides (ASO), siRNA, shRNA, miRNA or others as described herein, may further be chemically modified. Chemical modifications act to improve resistance to degradation in vivo or in vitro, improve stability, increase affinity for target RNA, optimize solubility properties in vivo or in vitro and render the nucleic acids more suitable as a therapeutic agent e.g. by reducing in vivo toxicity.
  • ASO antisense oligonucleotides
  • the chemical modifications of the inhibitory nucleic acids ASO, siRNA, shRNA or miRNA may comprise modifications to the nucleobases, the backbone residues or the internucleoside linkers of said nucleotide sequences.
  • Modifications to one or more nucleobases of the nucleic acids ASO, siRNA, shRNA or miRNA may comprise one or more inosine base or 4-hydroxy-N-acetylprolinol substitution(s).
  • Modifications to one or more backbone residues of the nucleic acids ASO, siRNA, shRNA or miRNA may comprise one or more of the following: 2' sugar modifications such as 2'-O-methyl (2'-OMe), 2'-0-methoxyethyl (2'-MOE), 2'-0-methoxyethoxy, 2'- Fluoro (2'-F), 2'-AIIyI, 2'-0-[2-(methylamino)-2-oxoethyl], 2'-O-(N-methylcarbamate); 4' sugar modifications including 4'-thio, 4'-CH 2 -O-2'-bridge, 4-(CH 2 ) 2 -O-2'-bridge; Locked Nucleic Acid (LNA); Peptide Nucleic Acid (PNA); Intercalating nucleic acid (INA); Twisted intercalating nucleic acid (TINA); Hexitol nucleic acids (HNA); arabinonucleic acid (ANA); cyclohexane nucleic
  • RNA Aptamers regulated with antidotes on the subject of the specific RNA aptamer (ref. Oney S, Oligonucleotides. 2007 Fall;17(3):265-74.) or any combinations thereof.
  • Modifications to one or more internucleoside linkers of the nucleic acids ASO, siRNA, shRNA or miRNA may comprise one or more of the following: Phosphorothioate, phosphoramidate, phosphorodiamidate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate and phosphoranilidate, or any combinations thereof.
  • a Locked Nucleic Acid is a modified RNA nucleotide.
  • the ribose moiety of an LNA nucleotide is modified with an extra bridge connecting the 2' and 4' carbons (O2',C4'-methylene bridge).
  • the bridge "locks" the ribose in the 3'-endo structural conformation, which is often found in the A-form of DNA or RNA.
  • LNA nucleotides can be mixed with DNA or RNA bases in the nucleic acid whenever desired. Such oligomers are commercially available.
  • the locked ribose conformation enhances base stacking and backbone pre-organization.
  • PNA Peptide Nucleic Acid
  • DNA and RNA have a deoxyribose and ribose sugar backbone, respectively, whereas PNA's backbone is composed of repeating N-(2-aminoethyl)-glycine units linked by peptide bonds.
  • the various purine and pyrimidine bases are linked to the backbone by methylene carbonyl bonds.
  • PNAs are depicted like peptides, with the N- terminus at the first (left) position and the C-terminus at the right.
  • Intercalating nucleic acid is a modified nucleic acid analogue comprised of normal deoxyribonucleotides covalently linked to hydrophobic insertions.
  • INA has high affinity for complementary DNA with stabilization of up to 1 1 degrees for each modification.
  • INA has a higher specificity for a fully matched target over mismatched targets than normal DNA. Utilizing that INAs have higher affinity for DNA makes it possible to use shorter probes and thereby enhance specificity even further.
  • INA is a DNA selective oligonucleotide analogue, with a unique ability to discriminate between DNA and RNA. Even though INAs have high affinities for complementary DNA, it has a lower affinity for a complementary sequence of complementary INAs. Twisted intercalating nucleic acids are denoted TINA.
  • Hexitol nucleic acids are oligonucleotides built up from natural nucleobases and a phosphorylated 1 ,5-anhydrohexitol backbone. Molecular associations between HNA and RNA are more stable than between HNA and DNA and between natural nucleic acids (dsDNA, dsRNA, DNA/RNA).
  • Other synthetically modified oligonucleotides comprise ANA (arabinonucleic acid), CNA (cyclohexane nucleic acids), CeNA (cyclohexenylnucleic acid) and TNA (threosyl nucleic acid).
  • Morpholinos are synthetic molecules which are the product of a redesign of the natural nucleic acid structure. Structurally, the difference between Morpholinos and DNA or RNA is that while Morpholinos have standard nucleobases, those bases are bound to 6-membered morpholine rings instead of deoxyribose/ribose rings and non-ionic phosphorodiamidate intersubunit linkages replace anionic phosphodiester linkages. Morpholinos are sometimes referred to as PMO (phosphorodiamidate morpholino oligonucleotide). The 6-membered morpholine ring has the chemical formula O(CH 2 CH 2 ) 2 NH.
  • Gap-mers are RNA-DNA-RNA chimeric oligonucleotide probes, where windows or 'gaps' of DNA are inserted into an otherwise normal or modified RNA oligonucleotide. This modification increases oligonucleotide stability in vivo and the avidity of the interaction of the probe with the target, so that shorter probes can be used effectively.
  • a Mix-mer is a combination of LNA and DNA.
  • nucleic acids comprising antisense oligonucleotides (ASO), siRNA, shRNA, miRNA or others described herein, may further be conjugated (i.e. attached) to chemical substituents (i.e. conjugates).
  • Functional amines, sugars or peptides may be covalently attached to said nucleotide sequences.
  • Non-limiting examples of conjugates include Cholesterol; Nuclear export signals (NES) and Nuclear localisation signals (NLS); Artificial amphiphilic tvhelical and ⁇ -sheet peptides; Cell- penetrating peptides (CPPs, short polycationic sequences that facilitate cellular uptake) such as Antennapedia (Ant), Tat and chloroquine; Peptides that target the KO probe to specific in vivo locations; and Thermo-responsive polymers (e.g. poly(/V- isopropylacrylamide).
  • nucleic acids comprising antisense oligonucleotides (ASO), siRNA, shRNA, miRNA or others described herein may be chemically modified and comprise a conjugate simultaneously.
  • the miRNA inhibitory agent of the present invention such as the nucleic acids comprising antisense oligonucleotides, siRNA, shRNA, miRNA or others, may be administered directly as short oligonucleotides that hybridize directly to and/or inhibits a miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences.
  • nucleic acids capable of hybridizing to and/or inhibiting a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences may further be complexed with an agent that promotes cellular transfection such as cationic lipids, calcium phosphate, DEAE-dextran, polyethylenimine, polybrene-DMSO, or a combination thereof.
  • an agent that promotes cellular transfection such as cationic lipids, calcium phosphate, DEAE-dextran, polyethylenimine, polybrene-DMSO, or a combination thereof.
  • the present invention also relates to a method for delivering the nucleic acids capable of hybridizing to and/or inhibiting a miRNA sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences, by employing a procedure that promotes cellular transfection such as Electroporation, Iontophoresis, Sonoporation, Thermal poration, Magnetofection, Lipofection, Ultrasound, Tape stripping, Abrasives, Jet injection, Gene guns and Microneedles.
  • a procedure that promotes cellular transfection such as Electroporation, Iontophoresis, Sonoporation, Thermal poration, Magnetofection, Lipofection, Ultrasound, Tape stripping, Abrasives, Jet injection, Gene guns and Microneedles.
  • Lipofection is a technique used to inject genetic material into a cell by means of liposomes, which are vesicles that can easily merge with the cell membrane since they are both made of a phospholipid bilayer.
  • Small unilamellar liposomes containing cationic lipids interact spontaneously with DNA to form lipid-DNA complexes with entrapment of the DNA.
  • the cationic lipids facilitate fusion of the liposome complex with the plasma membrane of target cells, resulting in cellular uptake of the DNA.
  • Liposomes can be composed of naturally-derived phospholipids with mixed lipid chains, or of pure surfactant components.
  • Liposomes can be modified to encapsulate and express both antigens and immunomodulatory agents (immunoliposomes) allowing targeted delivery of e.g. oligonucleotides, by a technique reffered to as antibody-mediated targeting (Brignole C, Cancer Lett. 2005 Oct 18;228(1 -2):181 -6).
  • immunomodulatory agents e.g. oligonucleotides
  • Electroporation is a significant increase in the electrical conductivity and permeability of the cell plasma membrane caused by an externally applied electrical field. It is usually used in molecular biology as a way of introducing some substance into a cell by transfection (physical). Pores are formed when the voltage across a plasma membrane exceeds its dielectric strength. If the strength of the applied electrical field and/or duration of exposure to it are properly chosen, the pores formed by the electrical pulse reseal after a short period of time, during which extracellular compounds have a chance to enter into the cell.
  • the nucleic acids comprising antisense oligonucleotides, siRNA, shRNA, miRNA or others that hybridize to and/or inhibits an miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182 or fragments or variants of any of the aforementioned miRNA sequences may in one embodiment be expressed from a vector.
  • the vector used for expressing the nucleic acids according to the present invention may be selected from the group consisting of: viral vectors (retroviral and adenoviral) or non-viral vectors (plasmid, cosmid, bacteriophage).
  • the invention thus in one embodiment relates to a vector comprising a nucleic acid capable of hybridizing to and/or inhibiting an miRNA selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31
  • the invention relates to a vector comprising a nucleic acid capable of hybridizing to and/or inhibiting an miRNA selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID NO:58, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71
  • the invention relates to a vector comprising a nucleic acid capable of hybridizing to and/or inhibiting an miRNA selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:72, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:98
  • the invention further relates to an isolated recombinant or transgenic host cell comprising a vector encoding a nucleic acid capable of hybridizing to and/or inhibiting an miRNA selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, S
  • the invention also relates to a method for generating a recombinant or transgenic host cell, said method comprising the steps of providing a vector encoding a nucleic acid capable of hybridizing to and/or inhibiting an miRNA selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:182, or fragments or variants of any of the aforementioned miRNA sequences, introducing said vector into said recombinant or transgenic host cell and optionally also expressing said vector in said recombinant or transgenic host cell, thereby generating a recombinant or transgenic host cell producing said nucleic acid.
  • the present invention relates to a transgenic, mammalian organism comprising the host cell described above.
  • the transgenic, mammalian organism comprising the recombinant or transgenic host cell according to the present invention is non-human.
  • the transgenic host cell may be selected from the group consisting of a mammalian, plant, bacterial, yeast or fungal host cell. Ectopic expression of a down-regulated mi RNA
  • the present invention relates to a method for increasing the amount and/or activity of one or more miRNAs selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182.
  • the invention relates to the re-introduction or ectopic expression of an miRNA that is down-regulated in psoriasis as identified herein, as selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182.
  • Administration of down-regulated miRNAs may be achieved via administering one or more of said down-regulated miRNA(s) directly or via a vector expressing said miRNA(s).
  • a lentiviral vector comprising a cassette for the constitutive expression of an miRNA (miR-223) to NB4 cells are disclosed in Fazi et al. (Cell 2005 Dec 2; 123(5): 819-31 ), incorporated herein by reference.
  • the pharmaceutical composition for use in treatment of an individual in need thereof comprises one or more miRNAs, or a vector expressing said miRNAs, directed at re-introducing a down-regulated miRNA as selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182.
  • the invention also relates to a vector comprising a nucleic acid encoding SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 or SEQ ID NO:182 or variants or fragments thereof, said nucleotide sequence being optionally operably linked to regulatory sequences controlling the expression of said nucleotide sequence in a suitable host cell.
  • the invention further relates to an isolated recombinant or transgenic host cell comprising a miRNA sequence or a vector comprising said miRNA sequence selected from the group of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 or SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182 or variants or fragments thereof.
  • the invention also relates to a method for generating a recombinant or transgenic host cell, said method comprising the steps of providing a vector encoding SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83 SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 or SEQ ID NO:182 or variants of fragments thereof, introducing said vector into said recombinant or transgenic host cell and optionally also expressing said vector in said recombinant or transgenic host cell, thereby generating a recombinant or transgenic host cell producing said miRNA sequences.
  • the present invention relates to a transgenic, non-human mammalian organism comprising the host cell described above.
  • the transgenic host cell may be selected from the group consisting of a mammalian, plant, bacterial, yeast or fungal host cell.
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a miRNA selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a vector encoding a miRNA selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182.
  • the present invention in one embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a miRNA selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182., or fragments or variants of any of the aforementioned miRNA sequences, for use as a medicament.
  • It is an aspect of the present invention to provide a method for treatment of psoriasis comprising the steps of providing one or more miRNAs selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182, and administering said one or more miRNAs to an individual in need thereof.
  • said method comprises the administration of said miRNA to an individual in a pharmaceutically effective amount.
  • said miRNA is expressed from a vector. In another embodiment, said miRNA is administered directly or as a precursor or analogue thereof.
  • the present invention is used to treat a diseased organism.
  • a diseased organism below is disclosed a non-limiting list of the multitude of patient groups that are likely to benefit from treatment such as in the prophylaxis, cure and amelioration of disease or symptoms.
  • the present invention may be used therapeutically to treat existing disease, protectively to prevent disease, or to reduce the severity and/or duration of disease.
  • nucleic acids capable of modulating the expression of one or more up-regulated miRNA(s), or the administration of a down-regulated miRNA, according to the present invention in the form of a pharmaceutical composition will likely be used for the following medical conditions.
  • the list is non-limiting in that other conditions might prove treatable with pharmaceutical compositions comprising the nucleotide sequences according to the present invention.
  • Psoriasis was introduced in the "Technical Background of the lnvention"-section above.
  • Psoriasis is a complex disease, the pathogenesis of which includes several characteristic changes of the skin. These include hyperproliferation (acanthosis or thickening of viable cell layer, hyperplasia of epidermal cells resulting in rete ridges, hyperkeratosis which is a thickening of cornified layer and parakeratosis with munro micro abscesses); granular layer loss, angiogenesis (an increase in dermal blood vessel size and number, elongated to the upper plexus) and mixed leukocyte infiltrate.
  • hyperproliferation acanthosis or thickening of viable cell layer, hyperplasia of epidermal cells resulting in rete ridges, hyperkeratosis which is a thickening of cornified layer and parakeratosis with munro micro abscesses
  • granular layer loss angiogenesis (an increase
  • 'psoriasis' covers both psoriasis and psoriatic arthritis.
  • psoriasis The symptoms of psoriasis can manifest in a variety of forms. Variants include plaque, pustular, guttate and flexural psoriasis.
  • Psoriasis vulgaris (Plaque psoriasis) is the most common form of psoriasis. It affects 80 to 90% of people with psoriasis. Plaque psoriasis typically appears as raised areas of inflamed skin covered with silvery white scaly skin.
  • Flexural psoriasis (inverse psoriasis) appears as smooth inflamed patches of skin. It occurs in skin folds, particularly around the genitals (between the thigh and groin), the armpits, under an overweight stomach (pannus), and under the breasts (inframammary fold). It is aggravated by friction and sweat, and is vulnerable to fungal infections.
  • Guttate psoriasis is characterized by numerous small oval (teardrop-shaped) spots. These numerous spots of psoriasis appear over large areas of the body, such as the trunk, limbs, and scalp. Guttate psoriasis is often associated with streptococcal throat infection.
  • Pustular psoriasis appears as vesicles that are filled with non-infectious pus (pustules). The skin under and surrounding pustules is red and tender. Pustular psoriasis can be localised, commonly to the hands and feet (palmoplanar pustulosis), or generalised with widespread patches occurring randomly on any part of the body. Nail psoriasis produces a variety of changes in the appearance of finger and toe nails. These changes include discolouring under the nail plate, pitting of the nails, lines going across the nails, thickening of the skin under the nail, and the loosening (onycholysis) and crumbling of the nail. Psoriatic arthritis involves joint and connective tissue inflammation.
  • Psoriatic arthritis can affect any joint but is most common in the joints of the fingers and toes. This can result in a sausage-shaped swelling of the fingers and toes known as dactylitis. Psoriatic arthritis can also affect the hips, knees and spine (spondylitis). About 10-15% of people who have psoriasis also have psoriatic arthritis. Erythrodermic psoriasis involves the widespread inflammation and exfoliation of the skin over most of the body surface. It may be accompanied by severe itching, swelling and pain. It is often the result of an exacerbation of unstable plaque psoriasis, particularly following the abrupt withdrawal of systemic treatment. This form of psoriasis can be fatal, as the extreme inflammation and exfoliation disrupt the body's ability to regulate temperature and for the skin to perform barrier functions.
  • Psoriasis is currently treated in steps based on the severity of the disease, size of the areas involved, type of psoriasis, and the patient's response to initial treatments. Treatments include medicines that are applied to the skin (topical treatment), light treatments (phototherapy) and taking medicines by mouth or injection (systemic therapy).
  • Affected skin can become resistant to treatment over time, especially when topical corticosteroids are used. Also, a treatment that works very well in one person may have little effect in another. Thus, doctors often use a trial-and-error approach to find a treatment that works, and they may switch treatments periodically (for example, every 12 to 24 months) if a treatment does not work or if adverse reactions occur.
  • Treatments applied directly to the skin may improve its condition. Doctors find that some patients respond well to ointment or cream forms of corticosteroids, vitamin D3, retinoids, coal tar, or anthralin. Bath solutions and moisturizers may be soothing, but they are seldom strong enough to improve the condition of the skin. Therefore, they usually are combined with stronger remedies. • Corticosteroids. These drugs reduce inflammation and the turnover of skin cells, and suppress the immune system. Available in different strengths, topical corticosteroids (cortisone) are usually applied to the skin twice a day. Short- term treatment is often effective in improving, but not completely eliminating, psoriasis.
  • High-potency corticosteroids may also be prescribed for plaques that don't improve with other treatment, particularly those on the hands or feet.
  • medium-potency corticosteroids may be prescribed for the broader skin areas of the torso or limbs. Low-potency preparations are used on delicate skin areas.
  • Low-potency corticosteorids comprise desonide (Desowen), aclometasone dipropionate (Aclovate); hydrocortisone agents (Cortizone, Cortaid, etc.;
  • Medium-potency corticosteorids comprise triamcinolone acetonide (Kenalog), hydrocortisone valerate (Westcort), fluticasone propionate (Cutivate), halcinonide (Halog), mometasone furoate (Elocon);
  • High-potency corticosteorids comprise halobetasol propionate (Ultravate), clobetasol propionate (Temovate), diflorasone diacetate (Psorcon), betamethasone dipropionate (Diprolene), clobetasole propionate
  • Calcipotriene This drug is a synthetic form of vitamin D3 that can be applied to the skin. Applying calcipotriene ointment (for example, Dovonex) twice a day controls the speed of turnover of skin cells. Calcipotriene can irritate the skin and is therefore not recommended for use on the face or genitals. It is sometimes combined with topical corticosteroids to reduce irritation. Use of more than 100 grams of calcipotriene per week may raise the amount of calcium in the body to unhealthy levels.
  • calcipotriene ointment for example, Dovonex
  • Topical retinoids are synthetic forms of vitamin A.
  • the retinoid tazarotene (Tazorac) is available as a gel or cream that is applied to the skin. If used alone, this preparation does not act as quickly as topical corticosteroids, but it does not cause thinning of the skin or other side effects associated with steroids. However, it can irritate the skin, particularly in skin folds and the normal skin surrounding a patch of psoriasis. It is less irritating and sometimes more effective when combined with a corticosteroid.
  • Coal tar Preparations containing coal tar (gels and ointments) may be applied directly to the skin, added (as a liquid) to the bath, or used on the scalp as a shampoo. Coal tar products are available in different strengths, and many do not require a prescription. Coal tar is less effective than corticosteroids and many other treatments and, therefore, is sometimes combined with ultraviolet B
  • Coal tar preparations include Estar gel, Balnetar, MG271 , Neutrogena T/Gel, DHS Tar. • Anthralin. Anthralin (Anthra-Derm, Drithocreme, Dritho-Scalp, Miconal) reduces the increase in skin cells and inflammation. Doctors sometimes prescribe a 15- to 30-minute application of anthralin ointment, cream, or paste once each day to treat chronic psoriasis lesions.
  • anthralin must be washed off the skin to prevent irritation. This treatment often fails to adequately improve the skin, and it stains skin, bathtub, sink, and clothing brown or purple. In addition, the risk of skin irritation makes anthralin unsuitable for acute or actively inflamed eruptions.
  • Salicylic acid This peeling agent, which is available in many forms such as ointments, creams, gels, and shampoos, can be applied to reduce scaling of the skin or scalp. Often, it is more effective when combined with topical corticosteroids, anthralin, or coal tar.
  • Calcineurin inhibitors are only approved for the treatment of atopic dermatitis, but studies have shown them to be effective at times in the treatment of psoriasis as well. Calcineurin inhibitors are thought to disrupt the activation of T cells, which in turn reduces inflammation. Calcineurin inhibitors are not recommended for long-term or continuous use because of a potential increased risk of skin cancer and lymphoma.
  • Tacrolimus is a macrolid also known as FK-506 and fukimycin (Protopic, Prograf and Adragraf).
  • Pimecrolimus is a macrolactam (Elidel). • Bath solutions.
  • People with psoriasis may find that adding oil when bathing, then applying a moisturizer, soothes their skin. Also, individuals can remove scales and reduce itching by soaking for 15 minutes in water containing a coal tar solution, oiled oatmeal, Epsom salts, or Dead Sea salts.
  • moisturizers When applied regularly over a long period, moisturizers have a soothing effect. Preparations that are thick and greasy usually work best because they seal water in the skin, reducing scaling and itching.
  • occlusive corticosteroid tape for chronically excoriated lesions of psoriasis, and intralesional triamcinolone injections for very localized, refractory lesions.
  • Substances such as Aloe vera, Jojoba, Zinc pyrithione, Capsaicin, Apple cider vinegar, Emu oil, Evening primrose oil, Oats,
  • Tea tree oil and others are frequently used to moisturize, soothe, remove scale or relieve itching. The effectiveness of some of these products is not known.
  • Natural ultraviolet light from the sun and controlled delivery of artificial ultraviolet light are used in treating psoriasis.
  • UV light Much of sunlight is composed of bands of different wavelengths of ultraviolet (UV) light. When absorbed into the skin, UV light suppresses the process leading to disease, causing activated T cells in the skin to die. This process reduces inflammation and slows the turnover of skin cells that causes scaling. Daily, short, non-burning exposure to sunlight clears or improves psoriasis in many people. Therefore, exposing affected skin to sunlight is one initial treatment for the disease.
  • UV light ultraviolet
  • UVB Ultraviolet B
  • UVB is light with a short wavelength that is absorbed in the skin's epidermis.
  • An artificial source can be used to treat mild and moderate psoriasis.
  • Some physicians will start treating patients with UVB instead of topical agents.
  • a UVB phototherapy called broadband UVB, can be used for a few small lesions, to treat widespread psoriasis, or for lesions that resist topical treatment. This type of phototherapy is normally given in a doctor's office by using a light panel or light box. Some patients use UVB light boxes at home under a doctor's guidance.
  • UVB emits the part of the ultraviolet light spectrum band that is most helpful for psoriasis.
  • Narrowband UVB treatment is superior to broadband UVB, but it is less effective than PUVA treatment (see next paragraph). It is gaining in popularity because it does help and is more convenient than PUVA.
  • patients may require several treatments of narrowband UVB spaced close together to improve their skin. Once the skin has shown improvement, a maintenance treatment once each week may be all that is necessary. However, narrowband UVB treatment is not without risk. It can cause more severe and longer lasting burns than broadband treatment.
  • Psoralen and ultraviolet A phototherapy This treatment combines oral or topical administration of a medicine called psoralen with exposure to ultraviolet A (UVA) light.
  • UVA has a long wavelength that penetrates deeper into the skin than UVB.
  • Psoralen makes the skin more sensitive to this light.
  • PUVA is normally used when more than 10 percent of the skin is affected or when the disease interferes with a person's occupation (for example, when a teacher's face or a salesperson's hands are involved).
  • PUVA treatment taken two to three times a week clears psoriasis more consistently and in fewer treatments. However, it is associated with more short-term side effects, including nausea, headache, fatigue, burning, and itching.
  • UVB phototherapy for example, may be combined with retinoids and other treatments.
  • One combined therapy program referred to as the Ingram regime, involves a coal tar bath, UVB phototherapy, and application of an anthralin-salicylic acid paste that is left on the skin for 6 to 24 hours.
  • the Goeckerman treatment combines coal tar ointment with UVB phototherapy.
  • PUVA can be combined with some oral medications (such as retinoids) to increase its effectiveness.
  • oral medications such as retinoids
  • the FDA has also approved a special type of laser, an excimer laser, as a phototherapy device to treat mild-to-moderate psoriasis. These lasers can deliver a much more controlled beam of light to small areas of the affected skin.
  • methotrexate Like cyclosporine, methotrexate (Rheumatrex) slows cell turnover by suppressing the immune system. Patients taking methotrexate must be closely monitored because it can cause liver damage and/or decrease the production of red and white blood cells, and platelets. As a precaution, doctors do not prescribe the drug for people who have had liver disease or anemia.
  • Another example is Sulfasalazine, Azathioprine and Leflunomide.
  • Retinoids A retinoid, such as acitretin (Soriatane) and isotretinoin (Accutane), is a compound with vitamin A-like properties that may be prescribed for severe cases of psoriasis that do not respond to other therapies. Most patients experience a recurrence of psoriasis after these products are discontinued.
  • Cyclosporine Taken orally, cyclosporine (Neoral, Sandimmune) acts by suppressing the immune system to slow the rapid turnover of skin cells. It may provide quick relief of symptoms, but the improvement stops when treatment is discontinued. The best candidates for this therapy are those with severe psoriasis who have not responded to, or cannot tolerate, other systemic therapies.
  • Cyclosporine may impair kidney function or cause high blood pressure (hypertension). Therefore, patients must be carefully monitored. Also, cyclosporine is not recommended for patients who have a weak immune system or those who have had skin cancers as a result of
  • 6-Thioguanine This drug is nearly as effective as methotrexate and cyclosporine. It has fewer side effects, but there is a greater likelihood of anemia.
  • Hydroxyurea (Hydrea). Compared with methotrexate and cyclosporine, hydroxyurea is somewhat less effective. It is sometimes combined with PUVA or UVB treatments. Possible side effects include anemia and a decrease in white blood cells and platelets. • Biologic Response Modifiers. Recently, attention has been given to a group of drugs called 'biologies', which are made from proteins produced by living cells instead of chemicals. They interfere with specific immune system processes which cause the overproduction of skin cells and inflammation. Some examples are alefacept (Amevive), etanercept (Enbrel), efalizumab (Raptiva), adalimumab (Humira), infliximab (Remicade).
  • a new natural systemic option, XP-828L, for mild to moderate psoriasis relief has been developed by a Canadian life science and technology company. This oral product with clinically proven efficacy and safety is extracted through a patented process from whey and has immuno-modulatory effects. • Antibiotics. These medications are not indicated in routine treatment of psoriasis. However, antibiotics may be employed when an infection, such as that caused by the bacteria Streptococcus, triggers an outbreak of psoriasis, as in certain cases of guttate psoriasis.
  • Combination Therapy There are many approaches for treating psoriasis. Combining various topical, light, and systemic treatments often permits lower doses of each and can result in increased effectiveness. Therefore, doctors are paying more attention to combination therapy. Future drugs for treatment of psoriasis
  • PSORS psoriasis susceptibility loci
  • MHC major histocompatability complex
  • Psoriasis has an inflammatory component, and thus in one embodiment may be regarded as belonging to the group of inflammatory diseases.
  • Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body. Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues.
  • a cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue.
  • Prolonged inflammation known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
  • Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underlie a variety of human diseases.
  • the immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation.
  • Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischaemic heart disease.
  • a large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise deregulates the normal function and expression of that protein.
  • inflammatory diseases selected from the group consisting of Asthma, Autoimmune diseases (see below), Chronic Inflammation, Chronic prostatitis, Glumerulonephritis, Hypersensitives (including type 1 (immediate, or atopic, or anaphylactic) comprising Allergic asthma, Allergic conjunctivitis, Allergic rhinitis (hay fever), Anaphylaxis, Angioedema, Urticaria (hives), Eosinophilia, and response to Penicillin and Cephalosporin; Type 2 (antibody-dependent) comprising Autoimmune hemolytic anemia, Goodpasture's syndrome, Pemphigus, Pernicious anemia (if autoimmune), Psoriasis, Psoriasis Arthritis, Immune thrombocytopenia, Transfusion reactions, Hashimoto's thyroiditis, Graves disease, Myastenia gravis, Rheumatic fever, Hemolytic disease of the newborn and Acute transplant rejection
  • Symptoms of leprosy Symptoms of tuberculosis, Mantoux test, Coeliac disease and Chronic transplant rejection
  • Inflammatory bowel diseases including Crohn's disease, Ulcerative colitis, Collagenous collitis, Lymphocytic collitis, Ischaemic collitis, Diversion collitis, Behcet's syndrome, Infective collitis and Indeterminate collitis
  • Myopathies including dermatomyositis, polymyositis, and inclusion body myositis
  • Pelvic inflammatory disease Reperfusion Injury, Rheumatoid arthritis, Transplant rejection and Vasculitis
  • Skin or dermatoloaical diseases including Crohn's disease, Ulcerative colitis, Collagenous collitis, Lymphocytic collitis, Ischaemic collitis, Diversion collitis, Behcet's syndrome, Infective collitis and Indeterminate collitis
  • Myopathies including dermatomyositis, polymyositis, and inclusion body myos
  • Psoriasis is a pathological condition of the skin, and thus in one embodiment may be regarded as belonging to the group of skin or dermatological diseases.
  • Skin is the largest organ of the integumentary system made up of multiple layers of epithelial tissues that guard underlying muscles and organs (the integumentary system is the external covering of the body, comprising the skin, hair, scales, nails, sweat glands and their products (sweat and mucus)).
  • skin plays the most important role in protecting the body against pathogens. Its other main functions are insulation and temperature regulation, sensation, and synthesis of vitamin D and the protection of vitamin B folates. Severely damaged skin will try to heal by forming scar tissue, often giving rise to discoloration and depigmentation of the skin.
  • the branch concerned with the skin is called dermatology.
  • the skin is subject to constant attack from without, and so can be afflicted by numerous ailments.
  • skin diseases selected from the group consisting of disorders of inflammation and differentiation, vesicular and bullous disorders, disorders of epidermal appendages, epidermal and appendageal tumors, disorders of melanocytes, inflammatory and neoplastic disorders of dermis and subcutis, disorders of mucocutaneous integument, cutaneous changes due to altred reactivity, skin changes due to mechanical and physical factors, skin changes due to drugs, skin changes due to nutritional, metabolic and heritable disorders, skin changes due to systemic diseases as hematologic diseases, renal disorders, cardiovascular, pulmonary, endocrine or rheumatologic disorders, skin disorders due to bacterial, fungal, viral infection or infestations , may be subject to treatment according to the present invention.
  • Skin diseases that may be treatable according to the present invention comprise those arasing from the above conditions, with specific subtypes of skin diseases or skin manifestations. All skin diseases as listed in Fitzpatrick's Dermatology in General Medicine (sixth edition, McGraw-Hill) are understood to be comprised in treatable skin conditions, and are incorporated herein by reference. Immune diseases
  • Psoriasis has a deregulated immune component possibly with an autoimmune component, and thus in one embodiment may be regarded as belonging to the group of diseases.
  • An immune system is a collection of mechanisms within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function properly. Detection is complicated as pathogens adapt and evolve new ways to successfully infect the host organism.
  • the adaptation process creates immunological memories and allows even more effective protection during future encounters with these pathogens.
  • This process of acquired immunity is the basis of vaccination.
  • Disorders in the immune system can cause disease. These are disorders caused by abnormal or absent immunologic mechanisms, whether humoral, cell-mediated, or both.
  • Immunodeficiency diseases occur when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an infection, such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV.
  • AIDS acquired immune deficiency syndrome
  • autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were foreign organisms.
  • Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as 'self, which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease.
  • Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.
  • immune diseases selected from the group consisting of Acute disseminated encephalomyelitis (ADEM), Addison's disease, Agammaglobulinemia, Allergies, Alopecia universalis, Anaphylaxis, Ankylosing spondylitis, Antiphospholipid Syndrome, Aplastic anemia, Asthma, Ataxia- Telangiectasia, Autoimmune Diseases, Autoimmune haemolytic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Behcet's disease, Celiac/Coeliac disease, Chagas' disease, Crohn's disease, Chronic fatique syndrome, Chronic Granulomatous Disease, Common Variable Immunodeficiency, Diabetes mellitus type 1 , DiGeorge Syndrome, Dysautonomia, Electrosensitivity, Endometriosis, Familial Mediterranean Fever, Gestational pemphigoid, Goodpasture's syndrome, Graft vs Host Disease,
  • ADAM Acute dis
  • Psoriasis is a condition of the skin which has a hyperproliferative component, and thus in one embodiment may be regarded as belonging to the group of hyperproliferative diseases.
  • hyperproliferative diseases are neoplastic diseases or cancer.
  • Cancer is a group of diseases in which cells are aggressive (grow and divide without respect to normal limits), invasive (invade and destroy adjacent tissues), and sometimes metastatic (spread to other locations in the body). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited in their growth and do not invade or metastasize (although some benign tumor types are capable of becoming malignant or may be detrimental due to occupancy of space e.g. in the cranium). Cancer may affect people at all ages, but risk for the more common varieties tends to increase with age.
  • neoplastic diseases selected from the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Anal Cancer, Astrocytoma (e.g.
  • Uterine Cancer Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma (such as Childhood Visual Pathway and Hypothalamic Glioma), Waldenstrom's Macroglobulinemia and Wilms' Tumor, may be subject to treatment according to the present invention.
  • Visual Pathway and Hypothalamic Glioma such as Childhood Visual Pathway and Hypothalamic Glioma
  • Waldenstrom's Macroglobulinemia and Wilms' Tumor may be subject to treatment according to the present invention.
  • MPDs myeloproliferative diseases
  • CML Chronic Myelogenous Leukemia
  • PV Polycythemia Vera
  • ET Essential Thrombocytosis
  • MF Myelofibrosis
  • lymphoproliferative disorders refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in patients who have compromised immune systems. They are sometimes equated with "immunoproliferative disorders", but technically Lymphoproliferative disorders are a subset of immunoproliferative disorders, along with hypergammaglobulinemia and paraproteinemias.
  • LPDs selected from the group consisting of acute lymphoblastic leukemia, lymphomas, chronic lymphocytic leukemia and multiple myeloma along with hypergammaglobulinemia types 1 to 5 and paraproteinemia, may be subject to treatment according to the present invention.
  • hyperproliferative diseases are hyperplasia or hyperplastic disorders, which is a general term referring to the proliferation of cells within an organ or tissue beyond that which is ordinarily seen in e.g. constantly dividing cells.
  • Hyperplasia may result in the gross enlargement of an organ, the formation of a benign tumor, or may be visible only under a microscope. Hyperplasia is considered to be a physiological response to a specific stimulus, and the cells of a hyperplastic growth remain subject to normal regulatory control mechanisms. This stands in contrast to neoplasia (the process underlying cancer and some benign tumors), in which genetically abnormal cells proliferate in a non-physiological manner which is unresponsive to normal stimuli.
  • hyperplasia disorders selected from the group consisting of Benign prostatic hyperplasia, Compensatory liver hyperplasia, Congenital adrenal hyperplasia, Endometrial hyperplasia, Focal epithelial hyperplasia, Hyperplasia of the breast, Menetrier disease and Sebaceous hyperplasia, may be subject to treatment according to the present invention.
  • Psoriasis is a condition of the skin which has an angiogenetic component, and thus in one embodiment may be regarded as belonging to the group of angiogenic diseases.
  • Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels.
  • Angiogenesis is a normal process in growth and development, as well as in wound healing. However, this is also a fundamental step in the transition of tumors from a dormant state to a malignant state.
  • angiogenic conditions selected from the group consisting of Macular degeneration, Psoriasis and Solid cancers may be subject to treatment according to the present invention. A list of cancers was provided above ('hyperproliferative diseases').
  • said up-regulated miRNA is selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34,
  • said one or more nucleic acids comprises 1 nucleic acid, such as 2 nucleic acids, for example 3 nucleic acids, such as 4 nucleic acids, for example 5 nucleic acids, such as 6 nucleic acids, for example 7 nucleic acids, such as 8 nucleic acids, for example 9 nucleic acids, such as 10 nucleic acids.
  • said one or more nucleic acids comprises less than 50 nucleic acids, such as less than 45 nucleic acids, for example less than 40 nucleic acids, such as less than 35 nucleic acids, for example less than 30 nucleic acids, such as less than 25 nucleic acids, for example less than 20 nucleic acids, such as less than 15 nucleic acids, for example less than 10 nucleic acids, such as less than 8 nucleic acids, for example less than 6 nucleic acids, such as less than 4 nucleic acids, for example less than 2 nucleic acids.
  • said one or more nucleic acids comprises at least 1 nucleic acid, such as at least 2 nucleic acids, for example at least 3 nucleic acids, such as at least 4 nucleic acids, for example at least 5 nucleic acids, such as at least 6 nucleic acids, for example at least 8 nucleic acids, such as at least 10 nucleic acids, for example at least 12 nucleic acids, such as at least 14 nucleic acids, for example at least 16 nucleic acids, such as at least 18 nucleic acids, for example at least 20 nucleic acids.
  • It is a further aspect of the present invention to provide a method for treatment of psoriasis comprising the steps of providing one or more nucleic acids capable of hybridizing to a miRNA which is up-regulated in psoriasis, and administering said one or more nucleic acids to an individual in need thereof, wherein said up-regulated miRNA is selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51 , SEQ ID
  • It is a further aspect of the present invention to provide a method for treatment of psoriasis comprising the steps of providing one or more nucleic acids capable of hybridizing to a miRNA which is up-regulated in psoriasis, and administering said one or more nucleic acids to an individual in need thereof, wherein said up-regulated miRNA is selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:16, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67,
  • It is a further aspect of the present invention to provide a method for treatment of psoriasis comprising the steps of providing at least two nucleic acids capable of hybridizing to a miRNA which is up-regulated in psoriasis, and administering said one or more nucleic acids to an individual in need thereof, wherein at least one of said up-regulated miRNA is selected from the group consisting of SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:14, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:51
  • It is another aspect to provide a method for treatment of psoriasis comprising the steps of providing one or more nucleic acids capable of hybridizing to a miRNA which is up- regulated in psoriasis, and administering said one or more nucleic acids to an individual in need thereof, further comprising the steps of providing one or more miRNAs selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:81 , SEQ ID NO:83, SEQ ID NO:1 1 1 , SEQ ID NO:1 19, SEQ ID NO:128, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:158, SEQ ID NO:166, SEQ ID NO:175, SEQ ID NO:181 and SEQ ID NO:182, and administering said one or more miRNAs to an individual in need thereof.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective amount of a composition of the present invention.
  • Topical administration includes epicutaneous (application onto the skin), inhalational, eye drops (ocular, onto the conjunctiva), ear drops, intranasal route, rectal and vaginal.
  • Enteral administration is any form of administration that involves any part of the gastrointestinal tract and includes oral administration (by mouth e.g. tablets, capsules or drops), intrarectal (e.g. suppository or enema) administration besides by gastric or duodenal feeding tube.
  • oral administration by mouth e.g. tablets, capsules or drops
  • intrarectal e.g. suppository or enema
  • gastric or duodenal feeding tube e.g. suppository or enema
  • Parenteral delivery by injection or infusion are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, and include intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), subcutaneous (under the skin), intraosseous infusion (into the bone marrow), intradermal, (into the skin itself), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane, e.g.
  • Sublingual administration is also a form of parenteral administration, whereby drugs diffuse into the bloodstream through the mucosal tissue under the tongue.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, emulsion, gel, lotion, paste, aerosols, or other forms known in the art.
  • Topical formulations that enhance skin hydration, penetration, or both are preferred.
  • a dermal (or skin) patch or dressing is used as a means of locally delivering the pharmaceutical composition or formulation of the present invention to the skin.
  • This is a medicated adhesive patch (or plaster) that is placed on the skin to deliver a specific dose of medication via the skin, providing a controlled release of the medicament to the patient.
  • the medicament of the patch must often be combined with skin penetration enhancer substances (see below).
  • the patch may be occlusive or non-occlusive.
  • Occlusive dressings such as vapor-impenetrable plastic films (e. g., polyvinylidine, polyethylene) enhance absorption or skin penetration principally through increased hydration of the stratum corneum, a result of swelling of the corneocytes, and uptake of water into the intercellular corridors.
  • Hydrocolloid patches may also be used to enhance skin penetration. Multiple patches may be applied at frequent intervals or constantly over a period of time.
  • the effective dosage of active ingredient employed may vary depending on the particular composition employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the nucleic acids of the composition of the present invention is administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1 .0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams.
  • the total daily dose will generally be from about 1 milligram to about 350 milligrams.
  • the dosage for an adult human may be as low as 0.1 mg.
  • the dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.
  • Oral administration will usually be carried out using tablets.
  • Examples of doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 250 mg.
  • Other oral forms can also have the same dosages (e.g. capsules).
  • the composition according to the present invention is given in an effective amount to an individual in need there of.
  • the amount of nucleic acids of the composition according to the present invention in one embodiment is in the range of from about 0.01 milligram per kg body weight per dose to about 20 milligram per kg body weight per dose, such as from about 0.02 milligram per kg body weight per dose to about 18 milligram per kg body weight per dose, for example from about 0.04 milligram per kg body weight per dose to about 16 milligram per kg body weight per dose, such as from about 0.06 milligram per kg body weight per dose to about 14 milligram per kg body weight per dose, for example from about 0.08 milligram per kg body weight per dose to about 12 milligram per kg body weight per dose, such as from about 0.1 milligram per kg body weight per dose to about 10 milligram per kg body weight per dose, such as from about 0.2 milligram per kg body weight per dose to about 10 milligram per kg body weight per dose, for example from about 0.3 milligram per kg body weight per
  • Skin is composed of three primary layers: the epidermis, which provides waterproofing and serves as a barrier to infection; the dermis, which serves as a location for the appendages of skin; and the hypodermis (subcutaneous adipose layer).
  • Epidermis is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface and is made up of stratified squamous epithelium with an underlying basal lamina.
  • the outermost epidermis consists of stratified squamous epithelium with an underlying connective tissue section, or dermis, and a hypodermis, or basement membrane.
  • the epidermis contains no blood vessels, and cells in the deepest layers are nourished by diffusion from blood capillaries extending to the upper layers of the dermis.
  • the main type of cells which make up the epidermis are keratinocytes, with melanocytes and Langerhans cells also present.
  • the epidermis can be further subdivided into the following strata (beginning with the outermost layer): corneum, lucidum (only in palms of hands and bottoms of feet), granulosum, spinosum, basale. Cells are formed through mitosis at the basal layer. The daughter cells, (see cell division) move up the strata changing shape and composition as they die due to isolation from their blood source.
  • the cytoplasm is released and the protein keratin is inserted. They eventually reach the corneum and slough off (desquamation). This process is called keratinization and takes place within about 27 days. This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection.
  • the dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain.
  • the dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels.
  • the blood vessels in the dermis provide nourishment and waste removal to its own cells as well as the Stratum basale of the epidermis.
  • the dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region. Skin penetration enhancement
  • the pharmaceutical composition of the present invention is delivered via the skin (see above for modes of delivery).
  • the skin provides a physical barrier to the harmful effects of the external environment. In so doing, it also interferes with the absorption of topical therapeutic drugs.
  • the affected skin areas subject to treatment constitute an imperfect skin barrier thus allowing for the increased penetration of pharmaceutical compositions through the outer skin layers, as compared to unaffected, healthy skin. Still, drug delivery is likely enhanced by the use of skin penetrating enhancers (or percutaneous penetration enhancement).
  • Enhancement technologies include three basic variants: Physical, chemical, and combinations of physical and chemical enhancement.
  • Physical enhancement of absorption of drug molecules through skin includes: Iontophoresis, Electroporation, Sonoporation, Thermal poration, Ultrasound, Tape stripping, Abrasives, Jet injection, Gene guns and Microneedles.
  • Chemical enhancers include: Organic solvents, Fatty acids and Alcohols, Detergents and surfactants and Proprietary chemical enhancers.
  • Four major mechanisms by which such enhancers can enhance drug absorption include Extraction of intercellular lipids and dilations between cornified cells permitting percutaneous passage of polar substances; Increase in partitioning into the skin; Increase in the fluidity of stratum corneum lipids and reduction in diffusional resistance; and Increase in thermodynamic activity in vehicles.
  • a skin penetration enhancer to the pharmaceutical composition of the present invention is envisioned to further enhance the penetration of the nucleic acids of the present invention into the skin.
  • a skin penetration enhancer to further enhance the penetration of the nucleic acids of the present invention into the skin.
  • the addition of a skin penetrating enhancer to the pharmaceutical composition according to the present invention is selected from the group consisting of Fatty acids (saturated or unsaturated) such as Linoleic acid, Linolenic acid, Oleic acid, Myristic acid (also called tetradecanoic acid); Amines such as polyoxyalkyleneamine D 400; Amides; Polyethylene glycol (PEG); Alcohols such as Ethanol and propylene glycol (PG); Pirotiodecane (HPE-101 ); diethylene glycol monoethyl ether (DGME); Glyceryl monoethyl ether; Monoglycerides (or monoacylglycerol, a glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule through an ester linkage); Polyglycosylated glycerides; lsopropyl myristate (an ester of fatty acid and alcohol); Dodecan
  • Cyclodextrins 1 -Dodecylaza cycloheptan-2-one (Azone®) and other caprolactams; Cyclopentadecalactone (CPE-215®); Alkyl-2-(N;N-disubstituted amino)-alkanoate ester (NexAct®); 2-(n-nonyl)-1 ,3-dioxolane (SEPA0009®); other SEPA ('soft enhancement of percutaneous absorption') compounds (MacroChem); MZL (Meyer ZaII Laboratories) Exorex lotion (Emzaloid delivery system); MZL Anthru-Derm; Voltaren Emulgel
  • the physical and chemical skin penetration enhancement may also be applied directly to the skin prior to application of the pharmaceutical composition according to of the present invention, simultaneously with application of the pharmaceutical composition according to of the present invention, or after application of the pharmaceutical composition according to of the present invention.
  • miRNAs interact with mRNA targets, as described in the above.
  • the targets and functions of plant miRNAs are relatively easy to identify due to the near-perfect complementarity.
  • the incomplete target complementarity typical of animal miRNAs implies a huge regulatory potential, but also presents a challenge for target identification.
  • a number of algorithms have been developed for predicting animal miRNA targets. While these models are supported as a basis for identifying many well- conserved miRNA targets, studies suggest that G-U or mismatches can be well tolerated, and that a conserved match does not guarantee mRNA repression.
  • the algorithms may represent only a subset of functional target sites, and additional factors are involved in further defining target specificity.
  • miRNA:target duplexes may be predicted by softwares such as PicTar, TargetScan, MicroRNA.org and the MiRanda algorithm.
  • Such mRNA targets may be candidates for future direct therapeutic targeting of said mRNAs in the treatment of psoriasis.
  • microRNA expression profile and the mRNA expression profile were identified in active psoriatic skin compared with healthy skin, as described in Example 2 below. In total, 42 microRNAs were up-regulated and 5 microRNAs were down- regulated in PP versus NN. 8 of these microRNAs (miR-17, -20a, -21 , -29a, -29c, -205, -221 and -222) were found likely to have mRNA targets in psoriatic skin.
  • microRNAs interacts with and inhibits their mRNA targets.
  • the effect of the inhibitory nucleic acids capable of inhibiting the microRNAs as detailed herein above is in one embodiment to inhibit the miRNAs that are up-regulated in a condition such as psoriasis.
  • Inhibition of miRNAs according to the present invention in turn causes a relief of the inhibitory or repressive effect of said miRNAs on their mRNA targets.
  • the correlation between miRNAs and some potential mRNA targets is illustrated in figure 10.
  • the present invention relates to the relief of the inhibitory effect on a mRNA by a miRNA associated with psoriasis by use of a nucleic acid capable of inhibiting said miRNA as detailed herein above.
  • the inhibition of miR-21 by a nucleic acid will cause an increase in the level of active TIMP3 and thus a de-repression of the downstream targets of TIMP3.
  • the inhibition of miR-21 by a nucleic acid will cause an increase in the level of acitive RECK and thus a de-repression of the downstream targets of RECK.
  • the inhibition of miR-21 by a nucleic acid will cause an increase in the level of acitive PDCD4and thus a de-repression of the downstream targets of PDCD4.
  • the inhibition of miR-21 by a nucleic acid will cause an increase in the level of acitive TPM1 and thus a de-repression of the downstream targets of TPM 1.
  • the inhibition of miR-21 by a nucleic acid will cause an increase in the level of acitive NFIB and thus a de-repression of the downstream targets of NFIB.
  • the inhibition of miR-21 by a nucleic acid will cause an increase in the level of acitive RTN4 and thus a de-repression of the downstream targets of RTN4.
  • the inhibition of miR-29a by a nucleic acid will cause an increase in the level of acitive p85-alpha and thus a de-repression of the downstream targets of p85-alpha.
  • the inhibition of miR-29c by a nucleic acid will cause an increase in the level of acitive p85-alpha and thus a de-repression of the downstream targets of p85-alpha.
  • the inhibition of miR-205 by a nucleic acid will cause an increase in the level of acitive SHIP2 and thus a de-repression of the downstream targets of SHIP2.
  • the inhibition of miR-221 by a nucleic acid will cause an increase in the level of acitive p57 and thus a de-repression of the downstream targets of p57.
  • the inhibition of miR-221 by a nucleic acid will cause an increase in the level of acitive c-kit and thus a de-repression of the downstream targets of c-kit.
  • the inhibition of miR-222 by a nucleic acid will cause an increase in the level of acitive p57 and thus a de-repression of the downstream targets of p57.
  • the inhibition of miR-222 by a nucleic acid will cause an increase in the level of acitive c-kit and thus a de-repression of the downstream targets of c-kit.
  • PP psoriatic skin
  • PN non-involved psoriatic skin
  • RNA purification and analysis From each patient skin biopsies were taken from involved psoriasis skin (PP) and non-involved psoriasis skin lesions (PN), one skin biopsy was obtained from each of the healthy subjects (NN); using a liquid nitrogen spray to inhibit RNA degradation. Total RNA was purified and quality analyzed. Further details can be found in S/ Methods.
  • miRNA microarray hybridization and normalization miRNA from fifteen patients (PP and PN) were analyzed using the miRNA analysis platform miRCURYTM LNA Array (v.8.1 ) (Exiqon, Vedbaek, Denmark). All miRNA microarray data reported is described in accordance with MIAME guidelines. Further details can be found in SI Methods.
  • mRNA microarray hybridization mRNA from four patients (PP and PN) were analyzed using the Affymetrix GeneChip ® Human Genome U133A 2.0 Array platform (Affymetrix, Santa Clara, CA, USA). Further details are found in SI Methods. miRNA and mRNA bioinformatics analysis and statistics. All data were imported, pre- processed and analyzed in DNA-Chip Analyzer 2007 (http://www.dchip.org) (15). All statistics was accessed in Significance Analysis of Microarray (SAM) (1 ). The deregulated miRNAs profile was analysed in Ingenuity IPA version 6.0 (Redwood City, CA, USA) to find possible biological, functional and disease relations. Further details are found in SI Methods.
  • Bioinformatics for target prediction by gene ontology Predicted targets for the deregulated miRNAs was found in miRBase targets version v5 using the miRanda algorithm (13). All predicted miRNA targets were compared to the mRNA profile using a Venn diagram generator (http://www.pangloss.com/seidel/Protocols/venn.cgi). The possible affected mRNA genes by the miRNA profile were analysed in Ingenuity IPA version 6.0 (Redwood City, CA, USA) to obtain relevant biological, functional and disease relations. Further details are found in SI Methods.
  • RNA samples were grinded with a pistil in a mortar containing liquid nitrogen. The tissue powder was immediately transferred without thawing to 10 volumes of ice cold Lysis/Binding Buffer (Applied Biosystems, UK) and homogenized with a rotor stator (IKA, Homogenizer, T8 U LTRA-TU RRAX). Total RNA, including small RNA species was then isolated using the m/ ⁇ /anaTM miRNA Isolation Kit (Applied Biosystems, UK) following the manufacturers instructions.
  • RNA integrity index RIN
  • Hy3TM/Hy5TM labeling kit and hybridized on the miRCURYTM LNA Array (v.8.1 ) following the manufacturers instructions at the miRNA core facility at Exiqon, Vedbaek, Denmark.
  • a Tecan HS4800 hybridization station was used (Tecan, Austria) and the slides were scanned by a ScanArray 4000 XL scanner (Packard Biochip Technologies, USA). Image analysis was carried out using the ImaGene 6.1.0 software (BioDiscovery, Inc., USA).
  • the array contains capture probes targeting 544 probes which cover 75% of the miRNAs present in Homo sapiens (544 of 722 in miRBase ver.
  • Intensity extraction by background correction was carried out globally across the array and subtracted from the foreground intensities of each probe spot. Exclusion of probes were carried out if a probe spot was with no intensity; negative (signal intensity ⁇ background); blank spot ((signal - background) / (standard deviation of pixel intensities over the local background region) ⁇ 1 ); inadequate spot (unsaturated spot or spot morphology not optimal). All miRNA-probes were probed in a tetra-plicate on the array, 3 out of 4 probes had to be present in order to be included in the further analysis.
  • the ratio of PP/PN was calculated and logarithmic base 2 transformed. If the ratio was more than 2 fold change, and had a present call ratio in minimum 10 out of 15 samples of either lesional or non-lesional psoriasis it was included.
  • RNA samples were isolated in accordance to the previously mentioned protocol.
  • q-RT-PCR of miRNAs was carried out for miR-148a, miR-203 and miR-331 -3p by miRCURYTM LNA microRNA PCR system (Exiqon, Vedbaek, Denmark) and for miR-203, miR-484 and miR-486-5p by TaqMan® MicroRNA Assays (Applied Biosystems, Rotterdam, Netherlands) as described by the manufacturers.
  • miRCURYTM LNA microRNA PCR system 5 ng of template RNA was reverse transcribed using miRCURYTM LNA First-strand cDNA synthesis kit and miRNA-specific reverse primer.
  • the specific miRNA cDNA template (4.0 ⁇ l) was then introduced into the 20 ⁇ l PCR reactions with miRCURYTM LNA miRNA primer sets (including specific forward and reverse miRNA primers) together with the miRCURYTM LNA SYBR ® Green master mix.
  • the samples were loaded on 96-well plates and analyzed in the Stratagene Mx 3000P QPCR system (AH diagnostics, Aarhus, Denmark) at 95 °C for 10 min, followed by 40 cycles of 95 9 C for 10s and 60 9 C for 20s.
  • Target gene expression was normalized between different samples to 5S rRNA expression.
  • RNA microarray hybridization 5 ng of template RNA was reverse transcribed using the TaqMan MicroRNA Reverse Transcription Kit and miRNA-specific 3' stem-loop primers. The specific cDNA (1.33 ⁇ l) was then introduced into the 20 ⁇ l PCR reactions with TaqMan MicroRNA Assay (including specific forward and reverse miRNA primers) together with the TaqMan Universal PCR Master Mix with no AmpErase UNG. The samples were loaded on 96-well plates and analyzed in Stratagene Mx 3000P QPCR system (AH diagnostics, Aarhus, Denmark) at 95°C for 10 min, followed by 40 cycles of 95°C for 15s and 60 °C for 60s. Target gene expression was normalized between different samples to RNU6B expression. mRNA microarray hybridization.
  • RNA was obtained and amplified using Affymetrix Two-Cycle Eukaryotic Target Labeling kit.
  • the two-cycle labeling procedure included two successive rounds of T7-based in vitro transcription incorporating biotin rNTPs in the second round reaction.
  • One hundred ng total RNA was used in the first-round synthesis of double- stranded cDNA, followed by amplification with MEGAscript T7 kit (Ambion, UK) using an unlabeled ribonucleotide mix.
  • the unlabeled cRNA was reverse transcribed to generate the second-round double-stranded cDNA template followed by amplification with biotinylated nucleotide analog/ribonucleotide mix in the second in vitro transcription reaction (BioArrayTM High Yield RNA Transcript Labeling Kit; Enzo Diagnostics, Farmingdale, NY, USA).
  • BioArrayTM High Yield RNA Transcript Labeling Kit BioArrayTM High Yield RNA Transcript Labeling Kit; Enzo Diagnostics, Farmingdale, NY, USA.
  • the quality of the resulting biotin-labeled cRNA was confirmed with Agilent ® 2100 bioanalyzer.
  • An aliquot (20 ⁇ g) of cRNA was fragmented at 94 °C for 35 min. After heat and ion-mediated fragmentation by hydrolysis at 94 0 C for 35 min in fragmentation buffer (40 mM Tris, 30 mM MgOAc,
  • Affymetrix GeneChip ® Human Genome U133A 2.0 Array which is a single array with 18,400 transcripts and variants, including 14,500 well-characterized human genes (Affymetrix, Santa Clara, CA, USA).
  • the arrays were washed and stained with phycoerythrin conjugated streptavidin using the Affymetrix Fluidics Station ® 400, and the arrays were scanned in the Affymetrix GeneArray ® scanner to generate fluorescent images, as described in the Affymetrix GeneChip protocol.
  • the raw probe intensities were stored in electronic files (in .DAT and .CEL formats) using the Affymetrix Microarray Suite 5.0 software.
  • the hybridization, washing, staining and scanning of the arrays were carried out at the Affymetrix core facility at the Microarray Center at the National University Hospital, Copenhagen, Denmark.
  • the eel image files were imported, pre-processed and analyzed in DNA- Chip Analyzer 2007 (http://www.dchip.org) (15).
  • the array files were normalized using the non-linear invariant set normalization method, choosing the array with PP1 as baseline (with a median probe intensity of 266). Quality measures of the arrays were analyzed by observing normalization curves (MA-plots) and none of the arrays were critical.
  • model-based gene expression indexes MBEI
  • gene expression modeling was calculated using the PM (perfect match only) method. To determine differentially expressed genes in PP compared to PN the ration was calculated and logarithmic base 2 transformed. We selected genes having a fold change of more than 1 .5 and with a false discovery rate of null and p ⁇ 0.05 using SAM (I ).
  • each miR was uploaded to miRBase targets version v5 (based on Ensembl 46 and microRNA registry release 10.0.)-
  • miRanda algorithm 13
  • Potential binding sites for a given miRNA in genomic sequences was identified. This algorithm aligns the 5' end of the miRNA (seed region) and if more than one base is not complementary to a target site it is not included as target. Furthermore, the target sites are passed through the Vienna RNA folding routines in order to estimate their thermodynamic stability. All predicted miRNA target genes were then compared to the mRNA profile using a Venn diagram generator (http://www.pangloss.com/seidel/Protocols/venn.cgi). Subsequently, the possible affected genes by the miRNA profile were uploaded to Ingenuity IPA version 6.0 (Redwood City, CA, USA) to obtain relevant biological, functional and disease relations.
  • a straight hierarchical cluster was built dividing PP from PN (p ⁇ 0.001 ) (Fig. 1 A).
  • the data could be trained to identify unlabeled samples from the cohort correct in accord to their biopsy of origin (either PP or PN) (Fig. 1 B). This finding supports that the identified miRNA characterized a distinct miRNA profile for the involved psoriasis skin.
  • Validation of the found results from the miRNA microarray platform was performed with four randomly selected miRNAs from the miRNA profile (Fig. 2A).
  • RNA from three additional patients and on two different q-RT-PCR platforms based on either LNA primers or TaqMan stem-loop primers were performed with RNA from three additional patients and on two different q-RT-PCR platforms based on either LNA primers or TaqMan stem-loop primers.
  • the pattern of q-RT-PCR expression average values did confirm the average values seen on the microarray expression platform (Fig.2A).
  • the normalized expression levels were more than twice as high on the miRNA microarray compared to q-RT-PCR expression levels from the two platforms indicating a higher sensitivity in detecting miRNA probes on the miRNA microarray platform.
  • Recently published data on miR-203 (2, 3) was evaluated in our data set.
  • Table 3 Examples of the 44 miRNAs in the profile with chromosomal locus and psoriasis relations. 1 The miRNA has been reported to be function and disease related. Comparing PP with PN in the miRNA microarray, miR-203 was in average 1.5 fold change up-regulated, comparing the additional three PP with their corresponding PN in the TaqMan based q-RT-PCR platform miR-203 was in average 1.6 fold change up- regulated and in the LNA based q-RT-PCR platform in average 1.3 fold change up- regulated.
  • miRNA profile identified is related to disease relevant chromosomal loci and genes.
  • miRNA-182/183 on chromosome 7q32.2 Three up-regulated distinct miRNA psoriasis clusters were identified by miRBase (Table 4); miRNA-182/183 on chromosome 7q32.2; miRNA-338-5p/657 on chromosome 17q25.3 and miRNA-518b/526b on chromosome 19q13.42.
  • mRNA profile identifying possible miRNA targets mRNA isolated from four randomly chosen patients from the original cohort (matched PP and PN biopsies) were analyzed on mRNA microarray (including 14,500 well- characterized human mRNA genes).
  • a distinct mRNA profile based on ratios of PP and PN having a significant (p ⁇ 0.005) fold change higher than 1.5 was generated from 1 1 15 probe sets (945 genes), with 570 probe sets being up-regulated (485 genes) and 545 probe sets being down-regulated (460 genes).
  • a hierarchical cluster was built based on the 1 1 15 probe algorithm of individually PP or PN samples separating the samples in either PP or PN clusters (Fig. 4A), confirmed by a principal component analysis (Fig.4B).
  • up-regulated miRNA was reflected by key mediators found on the mRNA microarray. Up-regulated on mRNA levels in psoriasis lesions was: miRNA transcription (TAF13 RNA pol Il (p ⁇ 0.05)), miRNA processing (Diceri (p ⁇ 0.05)) and miRNA RNA-induced silencing complex (AGO2 and PIWIL1 ) (data not shown).
  • the 44 miRNAs were individually submitted to miRBase targets version v5 using the miRanda algorithm (13). Each miRNA, in total 15886 genes were identified as predicted targets, whereas 14133 gene targets were found for the 42 up-regulated miRNAs and 1753 gene targets for the 2 down -regulated miRNAs. The potential targets were then analysed in a comparative analysis of computational predicted miRNA targets correspond with the actual mRNA profile observed in situ (Fig.5A). This identified 278 predicted target genes being up-regulated and 258 predicted genes being down- regulated in PP (Fig. 5A).
  • the 278 up-regulated targets and 258 down-regulated targets were analyzed for relevant biological, functional and disease relations.
  • the main focus of deregulation in specific gene hubs were tropomyosin, actin, insulin, LEPR, LEP, VEGF and P38 MAPK (data not shown).
  • 258 down-regulated genes 257 genes could be influenced by the 42 up-regulated miRNAs and 1 gene of the 2 down-regulated miRNAs (Fig.5A). This one gene is the chemokine CCL5 a key mediator in inflammatory processes of psoriasis (14) and closely related to the TNF signalling pathway.
  • the inventors disclose the miRNA and mRNA expression in involved (psoriatic skin; PP) and non-involved (non-involved psoriatic skin; PN) psoriatic skin compared with healthy skin (NN). Further, we aimed to associate previously experimentally validated miRNA-mRNA target interactions with our miRNA and mRNA expression data. Finally, we aimed to predict new potential miRNA targets among the most significant down-regulated mRNAs in psoriasis.
  • microRNAs A specific microRNA expression profile was identified in active psoriatic skin compared with healthy skin: 42 microRNAs were up-regulated and 5 microRNAs were down- regulated, of which 8 microRNAs (miR-17, -20a, -21 , -29a, -29c, -205, -221 and -222) were found likely to have mRNA targets in psoriatic skin.
  • the identified target mRNAs were involved in cellular growth, proliferation, apoptosis and degradation of the extracellular matrix.
  • Our data indicate novel associations for microRNAs in chronic inflammatory skin diseases.
  • Table 6 Overview of the psoriasis non-involved skin miRNA profile alienated in mir-families. Genes in italics were down-regulated.
  • miRNAs were up-regulated in both PP and PN compared with NN, miR-22 (fold change in PP 2.3 and PN 1.4), miR-24-1 (fold change in PP 1.5 and PN 1.4), miR-498 (fold change in PP 1.5 and PN 1 .7), and miR-551 a (fold change in PP 1.4 and PN 1 .98).
  • miRNA profile from psoriatic skin three polycistronic gene clusters were identified, miR-17/20a, miR-24-1/27b and miR-221/222, as being genes expressed from the same primary miRNA transcript (pri-miRNA), with an inter-miRNA distance of respectively 0.4, 0.5 and 0.7 kb (Griffiths-Jones et al., 2005).
  • pri-miRNA primary miRNA transcript
  • miR-24-1/27b and miR-221/222 were grouped closely in the hierarchical clustering analysis indicating a similar expression pattern for each gene cluster and confirming that they are expressed from the same pri-miRNA.
  • MiRNA families have a similar mature miRNA structure and similar target functions (Griffiths-Jones et al., 2005).
  • miR-203 was up-regulated in PP, confirming previously published data by Sonkoly et al., 2007.
  • PDCD4 Increase cell growth (Frankel e(a/., 2008) 202730 S at -2 17 -3 94 - 202731 at -2 23 -4 31
  • TPM 1 Increase cell growth (Zhu e( a/ , 2007) 210986_s_at -3 22 -5 80 -2 50 -4 85 210987_x_at -2 86 -6 17 -2 40 -4 96 206116 s at -2 71 -5 15 -2 47 -5 56
  • NFIB m ⁇ r-21 targets the nuclear factor I/B, which in its (Fujita ef at, 2008) 213029 at -2 39 -5 23 -2 00 -3 75 protein form binds the m ⁇ R-21 promoter as a 209289 at -2 23 -4 38 -1 96 -3 46 negative regulator 209290 s at -2 28 -4 31 -1 98 -3 72 213032 at -2 57 -4 76 -2 07 -4 08
  • RTN4 Regulate neural apoptosis (Yang et a/., 2009) 214629 x at -1 38 -3 06 -1 31 -2 61 211509_s_at -1 46 -3 32 -1 33 -3 05 ⁇ > 210968 s at -1 51 -2 99 -1 37 -2 76 00 miR-29a/29c
  • P85-alpha Upregulate p53, leading to increased cell growth (Park et al., 2009) 212240 s at -2 20 -3 61 -2 18 -3 61 212249 at -2 81 -4 76 -2 51 -4 63 miR-205
  • SHIP2 Decrease apoptosis (Yu et al , 2008) 201598 s at -2 09 -4 97 -1 61 -2 63 miR-221/222
  • P57 Regulate cell proliferation (Med ⁇ a ef a/ , 2008) 213182 x at -2 69 -3 58 -2 98 -4 62 213348 at -2 00 -3 97 -2 63 -6 27 216894_x_at -2 57 -4 05 -3 10 -5 79 219534 x at -2 47 -4 40 -3 11 -6 48 c-kit Enhance proliferation (Felicetti et at, 2008) 205051 s at -1 95 -3 65
  • the most prevalent chromosome cluster in the mRNA profile in psoriatic skin compared with healthy skin was the locus 6p21 , known as PSORS1 , a cluster encoding human leukocyte antigen (HLA) associations (Elder et al., 1994).
  • PSORS1 human leukocyte antigen
  • the 1q21 locus also known as the epidermal differentiation complex, late cornified envelope gene cluster or PSORS4 (Hardas et al., 1996), encodes stratum corneum proteins of the cornified envelope that have important functions in epidermal terminal differentiation (Hoffjan and Stemmler, 2007).
  • miR-142-3p/-5p, -146a/b and miR-155 were up-regulated in psoriatic skin. These are all miRNAs that have been related to immune function and may therefore be involved in psoriasis.
  • the mir-142 family (miR-142-3p/142-5p) is up- regulated in mice during antigen-induced T cell proliferation (Wu et al., 2007).
  • the mir- 146 family (miR-146a/146b-5p) is induced in monocytes exposed to microbial components and proinflammatory cytokines and found primarily in CD68+ macrophages, CD3+ T cells and CD79a+ B cells (Taganov et al., 2006).
  • the mir-146 family is expressed in the synovial tissue of the inflammatory disorder rheumatoid arthritis and act as anti-apoptotic by suppressing NF- ⁇ B. Moreover the mir-146 expression is induced by IL1 -beta and TNF-alpha treatment (Nakasa et al., 2008). TNF-alpha has also been shown to stimulate miR-155 upregulation by stimulating synovial fibroblasts (Stanczyk et al., 2008), and a positive feedback loop has been reported for miR-155 promoting the TNF-alpha production (Thai et al., 2007).
  • miR-155 An immunologic role of miR-155 is documented in monocytes (Taganov et al, 2006), and in regulating elements of the adaptive immune response by antigen presentation (Vigorito et al, 2007).
  • IL1 -beta and TNF-alpha stimulate psoriasis by amplifying Th-17 cells (reviewed in (Nickoloff et al., 2007)), thereby an immunological role of miR-146a/b and miR-155 in psoriasis could be evident.
  • Keratinocyte hyperproliferation in psoriasis is linked to negative regulation of cell growth and anti-apoptosis (Wrone-Smith et al., 1995).
  • miR-29a/c, -221 , - 222, -21 , -27a/b, -205 and -199-3p were up-regulated in psoriatic skin. These are all miRNA that have been shown to be involved in regulating cell growth and apoptosis in psoriasis.
  • the tumor suppressor p53 ⁇ TP53 is activated by the mir-29 family, which directly suppresses the p53 negative regulators p85 alpha and the GTPase CDC42 (Park et al., 2009).
  • p53 In psoriasis, p53 is present in the basal layer of epidermis, which can result in the hyperproliferative condition in psoriasis (Tadini et al., 1989). We found that p85 alpha was significantly down-regulated and likely to be linked to the presence of p53 in psoriasis.
  • the cell cycle regulator p57/kip2 (P57) causing cell cycle arrest, is targeted by miR-221/222, increasing cellular proliferation (Medina et al., 2008).
  • the c-KIT receptor in melanomas is a target of miR-221/222, leading to enhanced proliferation (Felicetti et al., 2008).
  • P57 and c-Klt mRNA were down-regulated, implicating a potential role of miR-221/222 in epidermal hyperproliferation.
  • the transcription factor promyelocytic leukemia zinc finger protein (PLZF) has been shown to suppress the miR-221/222 expression by binding to a putative regulatory region of miR-221/222 (Felicetti et al., 2008).
  • PLZF has been reported to negatively control the miR-146a expression (Labbaye et al., 2008).
  • miR-21 is positively regulated by the signal transducer and activator of transcription 3 (Stat3) in malignant myeloma cells (Loffler et ai, 2007) and negatively regulated by the nuclear factor I/B (NFIB) by binding to the miR-21 promoter (Fujita et al., 2008).
  • Stat3 signal transducer and activator of transcription 3
  • NFIB nuclear factor I/B
  • NFIB downregulation of NFIB
  • Akt and phosphorylated BAD levels are increased, the level of apoptosis decreases.
  • the lipid phosphatase SHIP2 regulating Akt and phosphorylated BAD is a target of miR-205 in stratified squamous epithelia cells (Yu et al, 2008).
  • SHIP2 mRNA was down-regulated in psoriasis, which may be related to the concomitant upregulation of miR-205.
  • the dermal extracellular matrix in psoriasis is composed of a degraded architecture that allows epidermal proliferation in to the dermis (reviewed in (lizuka et al., 2004)).
  • Activated matrix metalloproteases are involved in the degradation of the extracellular matrix (Ravi et al., 2007).
  • MMPs can be controlled by tissue inhibitor of metalloprotease-3 (TIMP3) and the reversion-inducing-cysteine-rich protein (RECK) (Gabriely et al., 2008).
  • TIMP3 tissue inhibitor of metalloprotease-3
  • RECK reversion-inducing-cysteine-rich protein
  • miR-21 targets TIMP3 and RECK leading to activation of MMPs promoting cancer cells to be invasive (Gabriely et a/., 2008).
  • TIMP3 and RECKmRNA were significantly down- regulated in psoriatic skin
  • MMP1 and MMP9 mRNA were significantly up- regulated in psoriatic compared with healthy skin and non-involved psoriatic skin.
  • miR-221/222 putatively targets TIMP3 mRNA (Figure 9). This could explain why TIMP3 is so dramatically down -regulated in psoriasis, leading to high levels of matrix metalloproteinases.
  • MiR-21 , miR-221 and miR-222 could therefore contribute to the degraded dermal architecture of psoriatic skin.
  • the reticulon 4 (RTN4) is a gene that act as a potent neurite outgrowth inhibitor and also acts as a regulator of apoptosis (reviewed by (Watari and Yutsudo, 2003)). It is suggested that miR-21 targets RTN4 in cancer cell lines (Yang et al., 2009). We found that this miRNA-mRNA target interaction could occur in psoriasis, indirectly supporting that the role of neuropeptides released from nerve fibers could contribute to the development of psoriasis (reviewed by (Saraceno et al., 2006)).
  • RNA quality was assessed using an Agilent RNA 6000 Nano Assay on an Agilent 2100 Bioanalyzer (Agilent Technologies, Naerum, Denmark) accepting only an RNA integrity number (RIN) of more than 7.5, which was the case for all samples.
  • the slides were scanned by a ScanArray 4000 XL scanner (Packard Biochip Technologies, PerkinElmer Life and Analytical Science, Massachusetts USA) and image analysis was carried out using the ImaGene 6.1 .0 software (BioDiscovery, El Segundo, CA, USA). The intensity of each spot was included for the statistical analysis if the probe-spot intensity exceeded the local background by a factor of 2 or more. All miRNA-probes were spotted in a tetraplicate on the array, 3 of 4 probes had to be present to be included in the statistical analysis. Data were imported to dChip (DNA-Chip Analyzer 2008; www.dchip.org (Li and Wong, 2001 )) and quantile normalized.
  • Statistically deregulated miRNAs were identified (q ⁇ 0.05) using Significance Analysis of Microarray (SAM) (Tusher et al., 2001 ) accepting a global false discovery rate of less than 0.05. Unsupervised Principal Component Analysis (PCA) was performed using dCHIP. All miRNA microarray data reported were described in accordance with MIAME guidelines and were deposited at EMBL-EBI.
  • SAM Significance Analysis of Microarray
  • PCA Unsupervised Principal Component Analysis
  • the analysis of miR-203 was assed by TaqMan® MicroRNA Assays (Applied Biosystems, Rotterdam, Netherlands) following the manufacturer's instructions. Briefly 5 ng of template RNA was reverse transcribed using the TaqMan MicroRNA Reverse Transcription Kit and miRNA-specific 3 ' stem-loop primers. The specific cDNA (1.33 ⁇ l) was then introduced into the 20 ⁇ l PCR reactions with TaqMan MicroRNA Assay (including specific forward and reverse miRNA primers) together with the TaqMan Universal PCR Master Mix with no AmpErase UNG.
  • the samples were loaded on 96-well plates and analyzed in the Stratagene Mx 3000P QPCR system (AH diagnostics, Aarhus, Denmark) at 95 9 C for 10 min, followed by 40 cycles of 95°C for 15s and 60 °C for 60s.
  • Target gene expression was normalized to the RNU6B expression for each sample. The significance was calculated by unpaired t-tests (SPSS, Chicago, IL).
  • RNA from four healthy subjects and four patients including PP and PNs were analyzed using the Affymetrix GeneChip ® Human Genome U133A 2.0 Array platform (Affymetrix, Santa Clara, CA, USA).
  • the RNA was amplified using the Affymetrix Two- Cycle Eukaryotic Target Labeling kit.
  • the two-cycle labeling procedure included two successive rounds of T7-based in vitro transcription incorporating biotin rNTPs in the second round reaction.
  • One hundred ng of total RNA was used in the first-round synthesis of double-stranded cDNA, followed by amplification with MEGAscript T7 kit (Ambion, UK) using an unlabeled ribonucleotide mix.
  • the unlabeled cRNA was reverse transcribed to generate the second-round double-stranded cDNA template followed by amplification with biotinylated nucleotide analog/ribonucleotide mix in the second in vitro transcription reaction (BioArrayTM High Yield RNA Transcript Labeling Kit; Enzo Diagnostics, Farmingdale, NY, USA).
  • BioArrayTM High Yield RNA Transcript Labeling Kit BioArrayTM High Yield RNA Transcript Labeling Kit; Enzo Diagnostics, Farmingdale, NY, USA.
  • the quality of the resulting biotin-labeled cRNA was confirmed with Agilent ® 2100 bioanalyzer. An aliquot (20 ⁇ g) of cRNA was fragmented at 94 °C for 35 min.
  • Affymetrix GeneChip ® Human Genome U133A 2.0 Array which is a single array with 18,400 transcripts and variants, including 14,500 well-characterized human genes (Affymetrix, Santa Clara, CA, USA).
  • the arrays were washed and stained with phycoerythrin conjugated streptavidin using the Affymetrix Fluidics Station ® 400 and were scanned in the
  • Affymetrix GeneArray ® scanner to generate fluorescent images, as described in the Affymetrix GeneChip protocol. After scanning chips, the raw probe intensities were stored in electronic files (in .DAT and .CEL formats) using the Affymetrix Microarray Suite 5.0 software. The CEL image files (Affymetrix) were imported, pre-processed and analyzed in dChip 2008. The array files were quantile normalized with PN7 as baseline (with a median probe intensity of 278). Normalization curves were visually inspected and none of the arrays was critical. To interpret the probe signal, model-based gene expression indexes (MBEI) were calculated using the PM/MM (perfect match/ miss match) method.
  • MBEI model-based gene expression indexes
  • the data were filtered accepting only probes that had a variation across samples between 0.5 ⁇ Standard deviation / mean ⁇ 1000, a presence call of 20% in the arrays, and differed between samples (PP, PN or NN) of 100 or more to account for probes that were near background level.
  • the data were Iog2 transformed and imported to SAM identifying deregulated mRNAs (q ⁇ 0.05) by accepting a global false discovery rate of less than 0.05.
  • Predicted targets for deregulated miRNAs From the 10 most down-regulated mRNAs in psoriatic skin we uploaded each gene to four miRNA target prediction programs TargetScan 5.0 (Friedman et al., 2009), Pictar (LaII et al., 2006), MiRanda (Griffiths-Jones et al., 2008) and microRNA.org (Betel et ai, 2008). Predicted targets were compared with the deregulated miRNAs in psoriatic skin.
  • RNAhybrid (Kruger and Rehmsmeier, 2006) accepting hybridization conditions with: a helix constraint of nucleotide position 2-8 in the 5 ' seed region of each miRNA binding to the 3 ' UTR of the target mRNA (Lewis et al., 2005), and a minimum free energy of -21 kcal/mol.
  • SEQ ID NO:10 SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ
  • SEQ ID NO:85 SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108,
  • SEQ ID NO:1 1 1 SEQ ID NO:1
  • SEQ ID NO:1 12 SEQ ID NO:1 13
  • SEQ ID NO:1 14 SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:120,
  • SEQ ID NO:131 SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, SEQ ID NO:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166
  • SEQ ID NO:1 12 SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID
  • SEQ ID NO:134 SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156,
  • nucleic acid according to any of items 1 to 3, wherein the nucleic acid comprises one or more nucleobases, one or more backbone residues and one or more internucleoside linkers.
  • nucleic acid according to item 4 wherein said nucleic acid is selected from the group consisting of antisense oligonucleotides (ASO), small inhibitory RNAs (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • ASO antisense oligonucleotides
  • siRNA small inhibitory RNAs
  • shRNA short hairpin RNA
  • miRNA microRNA
  • nucleic acid according to any of items 1 to 5, wherein one or more nucleic acid residues are modified so as to improve resistance to degradation in vivo or in vitro, improve stability, increase affinity for target, optimize solubility properties in vivo or in vitro and render the nucleotide sequence more suitable as a therapeutic agent.
  • nucleic acid according to item 6, wherein one or more modified nucleobases is selected from inosine or 4-hydroxy-N-acetylprolinol substitution(s).
  • nucleic acid according to item 6, wherein one or more modified backbone residues are selected from the group consisting of 2' sugar modifications comprising 2'-O-methyl (2'-OMe), 2'-0-methoxyethyl (2'-MOE), 2'-O- methoxyethoxy, 2'-Fluoro (2'-F), 2'-AIIyI, 2'-0-[2-(methylamino)-2-oxoethyl], 2'- O-(N-methylcarbamate); 4' sugar modifications including 4'-thio, 4'-CH 2 -O-2'- bridge, 4-(CH 2 ) 2 -O-2'-bridge; Morpholino; Locked Nucleic Acid (LNA); Peptide Nucleic Acid (PNA); Intercalating nucleic acid (INA); Twisted intercalating nucleic acid (TINA); Hexitol nucleic acids (HNA); arabinonucleic acid (ANA); cyclohexane nucleic acids
  • nucleic acid according to item 4 wherein one or more internucleoside linkers are selected from the group consisting of phosphorothioate, phosphoramidate, phosphorodiamidate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate and phosphoranilidate linkers.
  • nucleic acid according to item 4 wherein the nucleic acid is conjugated with functional amines, sugars or peptides as selected from the group consisting of Cholesterol; Nuclear export signals (NES) and Nuclear localisation signals (NLS); Artificial amphiphilic alpha-helical and beta-sheet peptides; Cell- penetrating peptides (CPPs) such as Antennapedia (Ant), Tat and chloroquine; Peptides that target the nucleotide to specific in vivo locations; and Thermo- responsive polymers (e.g. poly( ⁇ /-isopropylacrylamide) among others.
  • Thermo- responsive polymers e.g. poly( ⁇ /-isopropylacrylamide
  • nucleic acid according to any of items 1 to 1 1 , wherein said nucleic acid has complete homology corresponding to at least 12, such as 13, for example
  • SEQ ID NO:1 SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:
  • SEQ ID NO:1 10 SEQ ID NO:1 1 1 , SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID
  • nucleic acid according to any of items 1 to 12, wherein said nucleic acid has complete homology except for a maximum of 3 mismatches, such as 2 mismatches, for example 1 mismatch to an miRNA selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID
  • SEQ ID NO:40 SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51 , SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:40, SEQ ID NO:41 , SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50
  • SEQ ID NO:1 14 SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:
  • nucleic acid according to any of items 1 to 13, wherein said nucleic acid has a total length at least 6, such as 7, for example 8, such as 9, for example
  • nucleotides such as 1 1 , for example 12, such as 13, for example 14, such as 15, for example 16, such as 17, for example 18, such as 19, for example 20, such as 21 , for example 22, such as 23, for example 24 successive nucleotides.
  • nucleic acid according to any of items 1 to 14, wherein the nucleic acid inhibits the miRNA sequence.
  • SEQ ID NO:3 SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:
  • nucleic acid comprised in said vector is operably linked to regulatory sequences controlling the transcription of said nucleic acid in a suitable host cell.
  • a method for reducing the levels of endogenous miRNA comprising the introduction of the nucleic acid according to any of items 1 to 15 and/or the vector according to items 16 to 19 into a cell in an amount sufficient to reduce the levels of said miRNA.
  • An isolated recombinant or transgenic host cell comprising the nucleic acid according to any of items 1 to 15 and/or the vector according to items 16 to 19.
  • a method for generating a recombinant or transgenic host cell comprising the steps of providing a vector encoding a nucleic acid according to any of items 1 to 15, introducing said vector into said recombinant or transgenic host cell and optionally also transcribing said nucleic acid in said recombinant or transgenic host cell, thereby generating a recombinant or transgenic host cell producing said nucleic acid.
  • a transgenic, mammalian organism comprising the host cell according to item 21.
  • transgenic, mammalian organism wherein said mammalian host cell is an animal cell selected from the group consisting of a Blastomere cell, an Egg cell, an Embryonic stem cell, an Erythrocyte, a Fibroblast, a Hepatocyte, a Keratinocyte, a Myoblast, a Myotube, a Neuron, an animal cell selected from the group consisting of a Blastomere cell, an Egg cell, an Embryonic stem cell, an Erythrocyte, a Fibroblast, a Hepatocyte, a Keratinocyte, a Myoblast, a Myotube, a Neuron, an animal cell selected from the group consisting of a Blastomere cell, an Egg cell, an Embryonic stem cell, an Erythrocyte, a Fibroblast, a Hepatocyte, a Keratinocyte, a Myoblast, a Myotube, a Neuron, an animal cell selected from the group consisting of a Blastomere cell
  • Oocyte an Osteoblast, an Osteoclast, a Sperm cell, a B-cell, a T-CeII, clones and subclones of T-cells, a Zygote, immortalised cells and tumor cells.
  • a method for generating a transgenic, mammalian host cell comprising the steps of providing a vector encoding a nucleic acid according to any of items 1 to 15, introducing said vector into said transgenic, mammalian host cell and optionally also transcribing said nucleic acid in said transgenic, mammalian host cell, thereby generating a transgenic, mammalian host cell producing said nucleic acid.
  • a recombinant bacterial host cell comprising the nucleic acid according to any of items 1 to 15 and/or the vector according to items 16 to 19.
  • a method for generating a recombinant bacterial host cell comprising the steps of providing a vector encoding a nucleic acid according to any of items 1 to 15, introducing said vector into said bacterial host cell and optionally also transcribing said nucleic acid in said bacterial host cell, thereby generating a recombinant bacterial host cell producing said nucleic acid.
  • a recombinant yeast host cell comprising the nucleic acid according to any of items 1 to 15 and/or the vector according to items 16 to 19. 31.
  • a method for generating a recombinant yeast host cell comprising the steps of providing a vector encoding a nucleic acid according to any of items 1 to 15, introducing said vector into said yeast host cell and optionally also transcribing said nucleic acid in said yeast host cell, thereby generating a recombinant yeast host cell producing said nucleic acid.
  • a recombinant fungal host cell comprising the nucleic acid according to any of items 1 to 15 and/or the vector according to items 16 to 19.
  • a method for generating a recombinant fungal host cell comprising the steps of providing a vector encoding a nucleic acid according to any of items 1 to 15, introducing said vector into said fungal host cell and optionally also transcribing said nucleic acid in said fungal host cell, thereby generating a recombinant fungal host cell producing said nucleic acid.
  • a hybridisation complex comprising the nucleic acid according to any of items 1 to 15 hybridized to a complement sequence, wherein the nucleic acid binds to the complement sequence under stringent conditions.
  • hybridisation complex according to item 36, wherein the nucleic acid hybridizes to an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:
  • SEQ ID NO:1 10 SEQ ID NO:1 1 1 , SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:1 17, SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:
  • a method for generating a recombinant or transgenic host cell comprising the steps of providing a vector encoding a nucleic acid according to any of items 1 to 15, introducing said vector into said recombinant or transgenic host cell, and transcribing said nucleic acid in said recombinant or transgenic host cell, thereby generating a recombinant or transgenic host cell comprising the hybridisation complex according to items 37 to 38.
  • a transgenic, mammalian organism comprising the host cell according to item 38.
  • a composition comprising one or more nucleic acids according to any of items 1 to 15 or a vector encoding said one or more nucleic acids according to any of items 16 to 19.
  • composition according to item 41 in combination with a physiologically acceptable carrier.
  • a pharmaceutical composition comprising one or more nucleic acids according to any of items 1 to 15 or a vector encoding said one or more nucleic acids according to any of items 16 to 19.
  • composition according to item 43 in combination with a pharmaceutically acceptable carrier.
  • composition according to item 43 in combination with a skin penetration enhancer selected from the group consisting of Fatty acids (saturated or unsaturated) such as Linoleic acid, Linolenic acid, Oleic acid,
  • Myristic acid also called tetradecanoic acid
  • Amines such as polyoxyalkyleneamine D 400; Amides; Polyethylene glycol (PEG); Alcohols such as Ethanol and propylene glycol (PG); Pirotiodecane (HPE-101 ); diethylene glycol monoethyl ether (DGME); Glyceryl monoethyl ether; Monoglycerides (or monoacylglycerol, a glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule through an ester linkage); Polyglycosylated glycerides; lsopropyl myristate (an ester of fatty acid and alcohol); Dodecanol (or Lauryl alcohol, a fatty alcohol); N-Octanol (a fatty alcohol); Terpenes; Terpinol (An oil substance obtained by the action of acids on terpin); Menthol; D-Limonene (a hydro
  • Alkyl N,N-distributed-amino acetates Dimethyl acetamide; Dimethyl formamide; Dimethyl sulfoxide; Decylmethylsulfoxide; Alkyl sulfoxide; Phosphine oxide; Benzlyalkonium; Benzylalkonium chloride polymers; Silicone based polymers; Liposomes; Cyclodextrins; 1 -Dodecylaza cycloheptan-2-one (Azone®) and other caprolactams; Cyclopentadecalactone (CPE-215®); Alkyl-2-(N;N- disubstituted amino)-alkanoate ester (NexAct®); 2-(n-nonyl)-1 ,3-dioxolane (SEPA0009®); other SEPA ('soft enhancement of percutaneous absorption') compounds (MacroChem); MZL (Meyer ZaII Laboratories) Exorex lotion (Emzaloid delivery system
  • composition according to items 41 to 46 further comprising the combination with one or more additional bioactive agent(s) used to treat psoriasis for medical use.
  • composition according to item 47 wherein the one or more bioactive agent(s) is used for topical, systemic or phototherapeutic treatment of psoriasis.
  • composition according to item 48 wherein the one or more bioactive agent(s) is selected from the group consisting of Corticosteroids such as desonide (Desowen), aclometasone dipropionate (Aclovate); hydrocortisone agents (Cortizone, Cortaid, triamcinolone acetonide (Kenalog), hydrocortisone valerate (Westcort), fluticasone propionate (Cutivate), halcinonide (Halog), mometasone furoate (Elocon), halobetasol propionate (Ultravate), clobetasol propionate (Temovate), diflorasone diacetate (Psorcon), betamethasone dipropionate (Diprolene), clobetasole propionate (Cormax); Calcipotriene
  • Corticosteroids such as desonide (Desowen), aclometasone dipropionate (Aclovate
  • Adragraf) and pimecrolimus (Elidel); Azathioprine; Triamcinolone; Moisturizers; Bath solutions containing for example oil, oiled oatmeal, Epsom salts, or Dead Sea salts; Aloe vera; Jojoba; Zinc pyrithione; Capsaicin; Apple cider vinegar; Emu oil; Evening primrose oil; Oats; and Tea tree oil.
  • composition according to item 48 wherein the one or more bioactive agent(s) is selected from the group consisting of cyclosporine (Neoral, Sandimmune); methotrexate (Rheumatrex); Azathioprine; Sulfasalazine; Leflunomide; acitretin (Soriatane, an oral retinoid); 6-Thioguanine, Hydroxyurea (Hydrea); alefacept (Amevive); etanercept (Enbrel); ustekinumab; XP-828L; efalizumab (Raptiva); adalimumab (Humira); infliximab (Remicade); isotretinoin (Accutane); Mycophenolate mofetil (CellCept); and Antibiotics.
  • cyclosporine Neoral, Sandimmune
  • methotrexate Rheumatrex
  • Azathioprine Sulfa
  • composition according to item 48 wherein the one or more bioactive agent(s) is selected from the group consisting of Sunlight, UVA (ultraviolet A) phototherapy, UVB (ultraviolet B) phototherapy, PUVA (Psoralen and ultraviolet A phototherapy) and an excimer laser.
  • composition according to items 41 to 46 further comprising the combination with one or more additional bioactive agent(s) used to treat inflammatory diseases, skin diseases, Immune diseases, hyperproliferative diseases and angiogenic diseases for medical use.
  • 53. A method for administering one or more nucleic acids according to any of items 1 to 15 or a vector encoding said one or more nucleic acids according to any of items 16 to 19 to an individual in need thereof.
  • nucleic acid being further complexed with a cationic lipid, calcium phosphate, DEAE-dextran, polyethylenimine, polybrene-DMSO, or a combination thereof.
  • kit-of-parts comprising one or more nucleic acids according to any of items 1 to 15, or a vector encoding said one or more nucleic acids according to any of items 16 to 19, or one or the compositions according to any of items 41 to 46, and at least one additional component to be administered simultaneously, sequentially or separately.
  • kit-of-parts according to item 56 further comprising an instruction pamphlet of desirable administration and dosis regiment.
  • kit-of-parts according to item 56, wherein at least one or more said additional component(s) are bioactive agent(s) used to treat psoriasis.
  • kit-of-parts according to item 58 wherein at least one or more said additional component(s) are bioactive agent(s) selected from the groups cited in items 45, 49 and 50.
  • kits-of-parts according to item 56, wherein the additional component is selected from one or more additional bioactive agent(s) used to treat inflammatory diseases, skin diseases, Immune diseases, hyperproliferative diseases and angiogenic diseases.
  • additional component is selected from one or more additional bioactive agent(s) used to treat inflammatory diseases, skin diseases, Immune diseases, hyperproliferative diseases and angiogenic diseases.
  • 61. A method for identifying binding partners for an miRNA sequence selected from the group consisting of SEQ ID NO:1 , SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1 1 , SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID
  • SEQ ID NO:44 SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51 , SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51 , SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54,
  • SEQ ID NO:94 SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:1 10, SEQ ID NO:1 1 1 , SEQ ID NO:1 12, SEQ ID NO:1 13, SEQ ID NO:1 14, SEQ ID NO:1 15, SEQ ID NO:1 16, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:
  • SEQ ID NO:1 17 SEQ ID NO:1 18, SEQ ID NO:1 19, SEQ ID NO:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139,
  • binding partner comprise one or more agonists or antagonists.
  • a method for treatment of psoriasis comprising administration of the composition according to items 41 to 46 to an individual in need thereof.
  • composition according to items 41 to 46 for the manufacture of a medicament for therapeutic applications targeted at treating psoriasis.
  • 71. The composition according to items 41 to 46 for treatment of psoriasis.
  • a pharmaceutical composition for treating psoriasis comprising the composition according to items 41 to 46.
  • a method for treatment of Inflammatory Diseases comprising administration of the composition according to items 41 to 46 to an individual in need thereof.
  • Inflammatory Diseases is selected from the group consisting of Asthma; Autoimmune diseases; Chronic Inflammation; Chronic prostatitis; Glumerulonephritis; Hypersensitives (including type 1 (immediate, or atopic, or anaphylactic) comprising Allergic asthma, Allergic conjunctivitis, Allergic rhinitis (hay fever), Anaphylaxis, Angioedema, Urticaria (hives), Eosinophilia, and response to Penicillin and
  • Type 2 (antibody-dependent) comprising Autoimmune hemolytic anemia, Goodpasture's syndrome, Pemphigus, Pernicious anemia (if autoimmune), Psoriasis, Psoriasis Arthritis, Immune thrombocytopenia, Transfusion reactions, Hashimoto's thyroiditis, Graves disease, Myastenia gravis, Rheumatic fever, Hemolytic disease of the newborn and Acute transplant rejection; Type 3 (immune complex) comprising Rheumatoid arthritis, Immune complex glumerulonephritis, Serum sickness, Subacute, bacterial endocarditis, Symptoms of malaria, Systemic lupus erythematosus (SLE), Arthus reaction, Farmer's lung and Polyarteritis nodosa; Type 4 (cell-mediated or delayed-type hypersensitivity DTH) comprising Contact dermatitis, Atopic dermatitis (eczema), Temporal arteritis
  • composition according to items 41 to 46 for the manufacture of a medicament for therapeutic applications targeted at the Inflammatory Diseases selected from the group consisting of Asthma; Autoimmune diseases; Chronic
  • Inflammation Chronic prostatitis; Glumerulonephritis; Hypersensitives (including type 1 (immediate, or atopic, or anaphylactic) comprising Allergic asthma, Allergic conjunctivitis, Allergic rhinitis (hay fever), Anaphylaxis, Angioedema, Urticaria (hives), Eosinophilia, and response to Penicillin and Cephalosporin; Type 2 (antibody-dependent) comprising Autoimmune hemolytic anemia, Goodpasture's syndrome, Pemphigus, Pernicious anemia (if autoimmune), Psoriasis, Psoriasis Arthritis, Immune thrombocytopenia, Transfusion reactions, Hashimoto's thyroiditis, Graves disease, Myastenia gravis, Rheumatic fever, Hemolytic disease of the newborn and Acute transplant rejection; Type 3 (immune complex) comprising Rheumatoid arthritis,
  • composition according to items 41 to 46 for treatment of Inflammatory diseases selected from the group consisting of: Asthma; Autoimmune diseases; Chronic Inflammation; Chronic prostatitis; Glumerulonephritis; Hypersensitives (including type 1 (immediate, or atopic, or anaphylactic) comprising Allergic asthma, Allergic conjunctivitis, Allergic rhinitis (hay fever), Anaphylaxis, Angioedema, Urticaria (hives), Eosinophilia, and response to Penicillin and Cephalosporin; Type 2 (antibody-dependent) comprising Autoimmune hemolytic anemia, Goodpasture's syndrome, Pemphigus, Pernicious anemia (if autoimmune), Psoriasis, Psoriasis Arthritis, Immune thrombocytopenia, Transfusion reactions, Hashimoto's thyroiditis, Graves disease, Myastenia gravis, Rheumatic fever, Hemolytic disease of the newborn
  • a pharmaceutical composition for treating Inflammatory Diseases selected from the group consisting of Asthma; Autoimmune diseases; Chronic Inflammation;
  • Type 3 (immune complex) comprising Rheumatoid arthritis, Immune complex glumerulonephritis, Serum sickness, Subacute, bacterial endocarditis, Symptoms of malaria, Systemic lupus erythematosus (SLE), Arthus reaction, Farmer's lung and Polyarteritis nodosa; Type 4 (cell-mediated or delayed-type hypersensitivity DTH) comprising Contact dermatitis, Atopic dermatitis (eczema), Temporal arteritis, Symptoms of leprosy, Symptoms of tuberculosis,
  • Mantoux test Coeliac disease and Chronic transplant rejection
  • Inflammatory bowel diseases including Crohn's disease, Ulcerative colitis, Collagenous collitis, Lymphocytic collitis, lschaemic collitis, Diversion collitis, Behcet's syndrome, Infective collitis and Indeterminate collitis
  • Myopathies including dermatomyositis, polymyositis, and inclusion body myositis
  • Pelvic inflammatory disease Reperfusion Injury
  • Rheumatoid arthritis Transplant rejection and Vasculitis, comprising the composition according to items 41 to 46.
  • a method for treatment of Skin Diseases comprising administration of the composition according to items 41 to 46 to an individual in need thereof.
  • said Skin Diseases is selected from the group consisting of disorders of inflammation and differentiation, vesicular and bullous disorders, disorders of epidermal appendages, epidermal and appendageal tumors, disorders of melanocytes, inflammatory and neoplastic disorders of dermis and subcutis, disorders of mucocutaneous integument, cutaneous changes due to altred reactivity, skin changes due to mechanical and physical factors, skin changes due to drugs, skin changes due to nutritional, metabolic and heritable disorders, skin changes due to systemic diseases as hematologic diseases, renal disorders, cardiovascular, pulmonary, endocrine or rheumatologic disorders, skin disorders due to bacterial, fungal, viral infection or infestations.
  • composition according to items 41 to 46 for the manufacture of a medicament for therapeutic applications targeted at the Skin Diseases selected from the group consisting of disorders of inflammation and differentiation, vesicular and bullous disorders, disorders of epidermal appendages, epidermal and appendageal tumors, disorders of melanocytes, inflammatory and neoplastic disorders of dermis and subcutis, disorders of mucocutaneous integument, cutaneous changes due to altred reactivity, skin changes due to mechanical and physical factors, skin changes due to drugs, skin changes due to nutritional, metabolic and heritable disorders, skin changes due to systemic diseases as hematologic diseases, renal disorders, cardiovascular, pulmonary, endocrine or rheumatologic disorders, skin disorders due to bacterial, fungal, viral infection or infestations.
  • composition according to items 41 to 46 for treatment of Skin Diseases selected from the group consisting of disorders of inflammation and differentiation, vesicular and bullous disorders, disorders of epidermal appendages, epidermal and appendageal tumors, disorders of melanocytes, inflammatory and neoplastic disorders of dermis and subcutis, disorders of mucocutaneous integument, cutaneous changes due to altred reactivity, skin changes due to mechanical and physical factors, skin changes due to drugs, skin changes due to nutritional, metabolic and heritable disorders, skin changes due to systemic diseases as hematologic diseases, renal disorders, cardiovascular, pulmonary, endocrine or rheumatologic disorders, skin disorders due to bacterial, fungal, viral infection or infestations.
  • a pharmaceutical composition for treating Skin Diseases selected from the group consisting of disorders of inflammation and differentiation, vesicular and bullous disorders, disorders of epidermal appendages, epidermal and appendageal tumors, disorders of melanocytes, inflammatory and neoplastic disorders of dermis and subcutis, disorders of mucocutaneous integument, cutaneous changes due to altred reactivity, skin changes due to mechanical and physical factors, skin changes due to drugs, skin changes due to nutritional, metabolic and heritable disorders, skin changes due to systemic diseases as hematologic diseases, renal disorders, cardiovascular, pulmonary, endocrine or rheumatologic disorders, skin disorders due to bacterial, fungal, viral infection or infestations, comprising the composition according to items 41 to 46.
  • a method for treatment of Immune Diseases comprising administration of the composition according to items 41 to 46 to an individual in need thereof.
  • Immune Diseases is selected from the group consisting of Acute disseminated encephalomyelitis (ADEM), Addison's disease, Agammaglobulinemia, Allergies, Alopecia universalis,
  • ADAM Acute disseminated encephalomyelitis
  • Addison's disease Agammaglobulinemia
  • Allergies Alopecia universalis
  • Anaphylaxis Ankylosing spondylitis, Antiphospholipid Syndrome, Aplastic anemia, Asthma, Ataxia-Telangiectasia, Autoimmune Diseases, Autoimmune haemolytic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Behcet's disease, Celiac/Coeliac disease, Chagas' disease, Crohn's disease, Chronic fatique syndrome, Chronic Granulomatous Disease, Common Variable
  • IgA Deficiency Idiopathic thrombocytopenic purpura, IgG Subclass Deficiency, Immune Complex Diseases, Immune System Diseases, Immunologic Deficiency Syndromes, Intestinal cystitis, Kawasaki's disease, Lambert-Eaton Myasthenic Syndrome, Lyme disease, Lymphoproliferative Disorders, Mixed connective tissue disease, Morphea, Multiple Chemical Sensitivity, Multiple sclerosis (MS), Myasthenia gravis, Narcolepsy, Neuromyotonia, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroiditis, Pemphigus, Pernecious anemia, Polymyositis, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Purpura, Rheumatoid arthritis (RA), Reiter's syndrome, Samter's Syndrome, Sarcoidosis, Schizophrenia, Schoenlein-
  • composition according to items 41 to 46 for the manufacture of a medicament for therapeutic applications targeted at Immune Diseases selected from the group consisting of Acute disseminated encephalomyelitis (ADEM), Addison's disease, Agammaglobulinemia, Allergies, Alopecia universalis, Anaphylaxis, Ankylosing spondylitis, Antiphospholipid Syndrome, Aplastic anemia, Asthma, Ataxia-Telangiectasia, Autoimmune Diseases, Autoimmune haemolytic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Behcet's disease, Celiac/Coeliac disease, Chagas' disease, Crohn's disease, Chronic fatique syndrome, Chronic Granulomatous Disease, Common Variable Immunodeficiency, Diabetes mellitus type 1 , DiGeorge Syndrome, Dysautonomia, Electrosensitivity, Endometriosis, Familial Mediterranean Fever, Gestational pemphi
  • ADAM Acute
  • GBS Guillain-Barre syndrome
  • Hashimoto's disease Hidradenitis suppurativa
  • HIV Infections Hyper-lgM syndrome, Hypersensitivity, IgA Deficiency, Idiopathic thrombocytopenic purpura, IgG Subclass Deficiency, Immune Complex Diseases, Immune System Diseases, Immunologic Deficiency Syndromes, Intestinal cystitis, Kawasaki's disease, Lambert-Eaton
  • Myasthenic Syndrome Lyme disease, Lymphoproliferative Disorders, Mixed connective tissue disease, Morphea, Multiple Chemical Sensitivity, Multiple sclerosis (MS), Myasthenia gravis, Narcolepsy, Neuromyotonia, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroiditis, Pemphigus, Pernecious anemia, Polymyositis, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Purpura, Rheumatoid arthritis (RA), Reiter's syndrome, Samter's Syndrome, Sarcoidosis, Schizophrenia, Schoenlein-Henoch, Scleroderma, Selective IgA deficiency, Severe Combined Immunodeficiency (SCID), Sick Building Syndrome, Sjogren's Syndrome, Systemic lupus erythromatosus (SLE), Takayasu's arteriti
  • composition according to items 41 to 46 for treatment of Immune Diseases selected from the group consisting of Acute disseminated encephalomyelitis
  • ADAM Addison's disease
  • Agammaglobulinemia Allergies, Alopecia universalis
  • Anaphylaxis Ankylosing spondylitis
  • Antiphospholipid Syndrome Aplastic anemia, Asthma, Ataxia-Telangiectasia
  • Autoimmune Diseases Autoimmune haemolytic anemia
  • Autoimmune hepatitis Autoimmune Oophoritis
  • Behcet's disease Celiac/Coeliac disease, Chagas' disease, Crohn's disease, Chronic fatique syndrome, Chronic Granulomatous Disease, Common Variable Immunodeficiency, Diabetes mellitus type 1 , DiGeorge Syndrome, Dysautonomia
  • Electrosensitivity, Endometriosis Familial Mediterranean Fever, Gestational pemphigoid, Goodpasture's syndrome, Graft vs Host Disease, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease,
  • Hidradenitis suppurativa HIV Infections, Hyper-lgM syndrome, Hypersensitivity, IgA Deficiency, Idiopathic thrombocytopenic purpura, IgG Subclass Deficiency, Immune Complex Diseases, Immune System Diseases, Immunologic Deficiency Syndromes, Intestinal cystitis, Kawasaki's disease, Lambert-Eaton Myasthenic Syndrome, Lyme disease, Lymphoproliferative Disorders, Mixed connective tissue disease, Morphea, Multiple Chemical Sensitivity, Multiple sclerosis (MS), Myasthenia gravis, Narcolepsy, Neuromyotonia, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroiditis, Pemphigus, Pernecious anemia, Polymyositis, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Purpura, Rheumatoid arthritis (RA), Reit
  • a pharmaceutical composition for treating Immune Diseases selected from the group consisting of Acute disseminated encephalomyelitis (ADEM), Addison's disease, Agammaglobulinemia, Allergies, Alopecia universalis, Anaphylaxis, Ankylosing spondylitis, Antiphospholipid Syndrome, Aplastic anemia, Asthma, Ataxia-Telangiectasia, Autoimmune Diseases, Autoimmune haemolytic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Behcet's disease, Celiac/Coeliac disease, Chagas' disease, Crohn's disease, Chronic fatique syndrome, Chronic Granulomatous Disease, Common Variable
  • IgA Deficiency Idiopathic thrombocytopenic purpura, IgG Subclass Deficiency, Immune Complex Diseases, Immune System Diseases, Immunologic Deficiency Syndromes, Intestinal cystitis, Kawasaki's disease, Lambert-Eaton Myasthenic Syndrome, Lyme disease, Lymphoproliferative Disorders, Mixed connective tissue disease, Morphea, Multiple Chemical Sensitivity, Multiple sclerosis (MS), Myasthenia gravis, Narcolepsy, Neuromyotonia, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroiditis, Pemphigus, Pernecious anemia, Polymyositis, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Purpura, Rheumatoid arthritis (RA), Reiter's syndrome, Samter's Syndrome, Sarcoidosis, Schizophrenia, Schoenlein-
  • a method for treatment of Hyperproliferative Diseases comprising administration of the composition according to items 41 to 46 to an individual in need thereof.
  • Hyperproliferative Diseases is selected from the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Anal Cancer, Astrocytoma (e.g.
  • Chronic Lymphocytic Leukemia Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Cutaneous T-CeII Lymphoma, Endometrial Cancer, Ependymoma (such as Childhood Ependymoma), Esophageal Cancer, Ewing's Family of Tumors, Essential Thrombocytosis, Extracranial Germ Cell Tumor (such as Childhood Extracranial Germ Cell
  • Tumor Extragonadal Germ Cell Tumor
  • Eye Cancer Intraocular Melanoma or Retinoblastoma
  • Gallbladder Cancer Gastric (Stomach) Cancer
  • Gastrointestinal Carcinoid Tumor Gestational Trophoblastic Tumor
  • Glioma Hairy Cell Leukemia
  • Head and Neck Cancer Hepatocellular (Liver) Cancer
  • Hodgkin's Lymphoma Hypergammaglobulinemia types 1 to 5
  • Hypothalamic and Visual Pathway Glioma such as Childhood Hypothalamic and Visual Pathway Glioma
  • Intraocular Melanoma Islet Cell Carcinoma (Endocrine Pancreas)
  • Kaposi's Sarcoma Kidney (Renal Cell) Cancer
  • Laryngeal Cancer Lip and Oral Cavity Cancer
  • Lung Cancer Non- Small Cell or Small Cell
  • Lymphoma such as AIDS-Related Lymphoma
  • Burkitt's Lymphoma Cutaneous T-CeII Lymphoma, Non-Hodgkin's Lymphoma), Macroglobulinemia (such as Waldenstrom's Macroglobulinemia), Malignant Fibrous Histiocytoma of Bone/ Osteosarcoma, Malignant Melanoma, Medulloblastoma (such as Childhood Medulloblastoma), Melanoma, Merkel Cell Carcinoma, Mesothelioma (such as Adult Malignant Mesothelioma or childhood
  • T-CeII Lymphoma Cutaneous T-CeII Lymphoma, Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (such as Gestational Trophoblastic Tumor), Urethral Cancer, Endometrial Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma (such as Childhood Visual
  • composition according to items 41 to 46 for the manufacture of a medicament for therapeutic applications targeted at the Hyperproliferative Diseases selected from the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Anal Cancer, Astrocytoma (e.g.
  • Extracranial Germ Cell Tumor Extracranial Germ Cell Tumor
  • Extragonadal Germ Cell Tumor Extragonadal Germ Cell Tumor
  • Eye Cancer Intraocular Melanoma or Retinoblastoma
  • Gallbladder Cancer Gastric (Stomach) Cancer
  • Gastrointestinal Carcinoid Tumor Gestational Trophoblastic Tumor
  • Glioma Hairy Cell Leukemia
  • Head and Neck Cancer Hepatocellular (Liver) Cancer
  • Hodgkin's Lymphoma Hypergammaglobulinemia types 1 to 5
  • Hypothalamic and Visual Pathway Glioma such as Childhood Hypothalamic and Visual Pathway Glioma
  • Intraocular Melanoma Islet Cell Carcinoma (Endocrine Pancreas)
  • Kaposi's Sarcoma Kidney (Renal Cell) Cancer
  • Laryngeal Cancer Lip and Oral Cavity Cancer
  • Lung Cancer Non-Small Cell or Small Cell
  • Lymphoma such as AIDS-Related Lymphoma
  • Burkitt's Lymphoma Cutaneous T-CeII Lymphoma, Non-Hodgkin's Lymphoma), Macroglobulinemia (such as Waldenstrom's Macroglobulinemia), Malignant Fibrous Histiocytoma of Bone/ Osteosarcoma, Malignant Melanoma, Medulloblastoma (such as Childhood Medulloblastoma), Melanoma, Merkel Cell Carcinoma, Mesothelioma (such as Adult Malignant Mesothelioma or childhood
  • Nasopharyngeal Cancer such as Childhood Nasopharyngeal Cancer
  • Neuroblastoma such as Childhood Nasopharyngeal Cancer
  • Oropharyngeal Cancer Osteosarcoma/ Malignant Fibrous Histiocytoma of Bone
  • Ovarian Cancer such as Childhood Ovarian Cancer
  • Ovarian Epithelial Cancer Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Paranasal
  • Sinus and Nasal Cavity Cancer Paraproteinemia, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastoma, Polycythemia Vera, Prostate Cancer, Psoriasis, Renal Pelvis and Ureter Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma (such as Childhood Rhabdomyosarcoma), Salivary Gland Cancer, Adult-onset soft tissue Sarcoma, Soft Tissue Sarcoma (such as Childhood Soft Tissue Sarcoma), Uterine Sarcoma, Sezary Syndrome, Skin Cancer (such as non-Melanoma skin cancer), Merkel Cell Skin Carcinoma, Small Intestine Cancer, Supratentorial Primitive Neuroectodermal Tumors (such as occurring in Childhood),
  • T-CeII Lymphoma Cutaneous T-CeII Lymphoma, Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (such as Gestational Trophoblastic Tumor), Urethral Cancer, Endometrial Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma (such as Childhood Visual
  • composition according to items 41 to 46 for treatment of Hyperproliferative Diseases selected from the group consisting of Acute
  • Lymphoblastic Leukemia Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Anal Cancer, Astrocytoma (e.g. Childhood Cerebellar or Childhood Cerebral), Basal Cell Carcinoma, Extrahepatic Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Male Breast Cancer, Bronchial Adenomas/ Carcinoids, Burkitt's
  • Lymphoma Carcinoid Tumor, Carcinoma of Unknown Primary, Primary Central Nervous System Lymphoma, Cerebral Astrocytoma/ Malignant Glioma, Cervical Cancer, Childhood Cancers, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Cutaneous T-CeII Lymphoma, Endometrial Cancer, Ependymoma (such as
  • Tumor Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Hodgkin's Lymphoma, Hypergammaglobulinemia types 1 to 5, Hypopharyngeal Cancer, Hypothalamic and Visual Pathway Glioma (such as Childhood Hypothalamic and Visual Pathway Glioma), Intraocular Melanoma, Islet Cell Carcinoma (Endocrine Pancreas), Kaposi's Sarcoma, Kidney (Renal Cell) Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Lung Cancer (Non-Small Cell or Small Cell), Lymphoma (such as AIDS-Related Lymphoma, Burkitt's Lymphoma, Cutaneous T-CeII Lymphoma, Non-Hodgkin's Lymphoma), Macroglobulinemia (such as Waldenstrom's Macroglobulinemia), Malignant Fibrous Histio
  • Medulloblastoma such as Childhood Medulloblastoma
  • Melanoma Merkel Cell Carcinoma
  • Mesothelioma such as Adult Malignant Mesothelioma or childhood Mesothelioma
  • Metastatic Squamous Neck Cancer with Occult Primary Multiple Endocrine Neoplasia Syndrome (such as occurring in childhood), Multiple Myeloma/ Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic
  • Myelodysplastic/ Myeloproliferative Diseases Myeloma (such as Multiple Myeloma), Myelofibrosis, Chronic myeloproliferative disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer (such as Childhood Nasopharyngeal Cancer), Neuroblastoma, Oropharyngeal Cancer, Osteosarcoma/ Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Childhood Ovarian Cancer), Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Paranasal Sinus and Nasal Cavity Cancer, Paraproteinemia, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastoma,
  • Polycythemia Vera Prostate Cancer, Psoriasis, Renal Pelvis and Ureter Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma (such as Childhood Rhabdomyosarcoma), Salivary Gland Cancer, Adult-onset soft tissue Sarcoma, Soft Tissue Sarcoma (such as Childhood Soft Tissue Sarcoma), Uterine Sarcoma, Sezary Syndrome, Skin Cancer (such as non-Melanoma skin cancer), Merkel Cell Skin Carcinoma, Small Intestine Cancer, Supratentorial Primitive Neuroectodermal Tumors (such as occurring in Childhood), Cutaneous T-CeII Lymphoma, Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (such as Gestational Trophoblastic Tumor),
  • Urethral Cancer Endometrial Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma (such as Childhood Visual Pathway and Hypothalamic Glioma), Waldenstrom's Macroglobulinemia and Wilms' Tumor. .
  • a pharmaceutical composition for treating Hyperproliferative Diseases selected from the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Anal Cancer, Astrocytoma (e.g. Childhood Cerebellar or Childhood Cerebral), Basal Cell Carcinoma, Extrahepatic Bile Duct Cancer, Bladder Cancer, Bone Cancer,
  • Brain Stem Glioma Brain Tumor, Breast Cancer, Male Breast Cancer, Bronchial Adenomas/ Carcinoids, Burkitt's Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Primary Central Nervous System Lymphoma, Cerebral Astrocytoma/ Malignant Glioma, Cervical Cancer, Childhood Cancers, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic
  • Retinoblastoma Gallbladder Cancer
  • Gastric (Stomach) Cancer Gastrointestinal Carcinoid Tumor
  • Gestational Trophoblastic Tumor Gastrointestinal Carcinoid Tumor
  • Glioma Hairy Cell Leukemia, Head and Neck Cancer
  • Hodgkin's Lymphoma Hypergammaglobulinemia types 1 to 5
  • Hypopharyngeal Cancer Hypothalamic and Visual Pathway Glioma (such as Childhood
  • Lymphoma such as AIDS-Related Lymphoma, Burkitt's Lymphoma, Cutaneous T-CeII Lymphoma, Non-Hodgkin's Lymphoma
  • Macroglobulinemia such as Waldenstrom's Macroglobulinemia
  • Malignant Fibrous Histiocytoma of Bone/ Osteosarcoma Malignant Melanoma
  • Medulloblastoma such as Childhood Medulloblastoma
  • Melanoma Merkel Cell Carcinoma
  • Mesothelioma such as Adult Malignant Mesothelioma or childhood Mesothelioma
  • Metastatic Squamous Neck Cancer with Occult Primary such as Waldenstrom's Macroglobulinemia
  • Soft Tissue Sarcoma such as Childhood Soft Tissue Sarcoma
  • Uterine Sarcoma Sezary Syndrome
  • Skin Cancer such as non-Melanoma skin cancer
  • Merkel Cell Skin Carcinoma Small Intestine Cancer
  • Supratentorial Primitive Neuroectodermal Tumors such as occurring in Childhood
  • Cutaneous T-CeII Lymphoma Testicular Cancer, Thymoma and Thymic
  • Trophoblastic Tumor such as Gestational Trophoblastic Tumor
  • Urethral Cancer Endometrial Uterine Cancer
  • Uterine Sarcoma Vaginal Cancer
  • Visual Pathway and Hypothalamic Glioma such as Childhood Visual Pathway and Hypothalamic Glioma
  • Waldenstrom's Macroglobulinemia Waldenstrom's Macroglobulinemia
  • Wilms' Tumor comprising the composition according to items 41 to 46.
  • a method for treatment of Angiogenic Diseases comprising administration of the composition according to items 41 to 46 to an individual in need thereof.
  • Angiogenic Diseases is selected from the group consisting of Macular degeneration, Psoriasis and Solid cancers.
  • composition according to items 41 to 46 for the manufacture of a medicament for therapeutic applications targeted at the Angiogenic Diseases selected from the group consisting of Macular degeneration, Psoriasis and Solid cancers.
  • composition according to items 41 to 46 for treatment of Angiogenic Diseases selected from the group consisting of Macular degeneration, Psoriasis and Solid cancers.
  • a pharmaceutical composition for treating Angiogenic Diseases selected from the group consisting of Macular degeneration, Psoriasis and Solid cancers, comprising the composition according to items 41 to 46.

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  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne l'identification d'un profil de miARN dérégulés en cas de psoriasis et la modulation de ces espèces de miARN dérégulés pour le traitement du psoriasis et d'autres maladies apparentées. L'invention concerne également l'utilisation d'acides nucléiques 5 inhibiteurs, tels que des oligonucléotides antisens chimiquement modifiés, comme produits pharmaceutiques, par exemple pour le traitement du psoriasis et d'autres maladies apparentées.
PCT/DK2009/050131 2008-06-17 2009-06-17 Traitement du psoriasis et de maladies apparentées par modulation de miarn WO2010003420A2 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017697A1 (fr) * 2009-08-07 2011-02-10 New York University Compositions et méthodes pour traiter des troubles inflammatoires
US8518908B2 (en) 2009-09-10 2013-08-27 University Of Idaho Nucleobase-functionalized conformationally restricted nucleotides and oligonucleotides for targeting of nucleic acids
WO2013155371A1 (fr) * 2012-04-12 2013-10-17 Cornell University Microarn-31 comme agent diagnostique, pronostique et thérapeutique du cancer
US20130331290A1 (en) * 2011-01-28 2013-12-12 Febit Holding Gmbh Complex mirna sets as novel biomarkers for lung diseases
US8716258B2 (en) 2010-06-04 2014-05-06 The Board Of Regents, The University Of Texas System Regulation of metabolism by miR-378
US9879222B2 (en) 2007-12-14 2018-01-30 Mofa Group Llc Gender-specific separation of sperm cells and embryos
US9885082B2 (en) 2011-07-19 2018-02-06 University Of Idaho Embodiments of a probe and method for targeting nucleic acids
JP2020054336A (ja) * 2018-07-24 2020-04-09 チャン グァン メモリアル ホスピタル，カオシュン 乾癬性関節炎の診断及び治療
CN111956632A (zh) * 2020-09-27 2020-11-20 上海市同仁医院 一种抗肿瘤的组合物及其应用
WO2024124315A1 (fr) * 2022-12-16 2024-06-20 Mirscience Therapeutics Servicos De Pesquisa E Desenvolvimento Ltda. Analogues oligonucléotidiques antisens de mir-29 et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006047454A2 (fr) * 2004-10-21 2006-05-04 Rutgers, The State University Of New Jersey Optimisation rationnelle des sondes utilisees pour la detection des micro arn
US20060185027A1 (en) * 2004-12-23 2006-08-17 David Bartel Systems and methods for identifying miRNA targets and for altering miRNA and target expression
WO2007095387A2 (fr) * 2006-02-17 2007-08-23 Dharmacon, Inc. Compositions et procédés permettant l'inhibition de silençage de gènes par l'interférence arn

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7683036B2 (en) * 2003-07-31 2010-03-23 Regulus Therapeutics Inc. Oligomeric compounds and compositions for use in modulation of small non-coding RNAs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006047454A2 (fr) * 2004-10-21 2006-05-04 Rutgers, The State University Of New Jersey Optimisation rationnelle des sondes utilisees pour la detection des micro arn
US20060185027A1 (en) * 2004-12-23 2006-08-17 David Bartel Systems and methods for identifying miRNA targets and for altering miRNA and target expression
WO2007095387A2 (fr) * 2006-02-17 2007-08-23 Dharmacon, Inc. Compositions et procédés permettant l'inhibition de silençage de gènes par l'interférence arn

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
DATABASE EMBL [Online] 9 October 2007 (2007-10-09), "Sequence 40 from Patent WO2007073737." XP002544438 retrieved from EBI accession no. EMBL:CS692048 Database accession no. CS692048 *
DATABASE Geneseq [Online] 14 June 2007 (2007-06-14), "LNA probe rno-miR129*/LNA used to detect conserved vertebrate miRNAs." XP002544437 retrieved from EBI accession no. GSN:AFO07994 Database accession no. AFO07994 *
DATABASE Geneseq [Online] 21 September 2006 (2006-09-21), "Mouse probe for miRNA #80." XP002544439 retrieved from EBI accession no. GSN:AEJ22146 Database accession no. AEJ22146 *
DATABASE Geneseq [Online] 21 September 2006 (2006-09-21), "Rat probe for miRNA #29." XP002544440 retrieved from EBI accession no. GSN:AEJ22489 Database accession no. AEJ22489 *
DATABASE Geneseq [Online] 5 May 2005 (2005-05-05), "Antisense oligonucleotide targeting a human miRNA, ISIS344342." XP002544432 retrieved from EBI accession no. GSN:ADX04670 Database accession no. ADX04670 -& WO 2005/013901 A (ISIS PHARMACEUTICALS INC [US]; ESAU CHRISTINE [US]; LOLLO BRIDGET [US]) 17 February 2005 (2005-02-17) *
KIM JOHN ET AL: "Identification of many microRNAs that copurify with polyribosomes in mammalian neurons." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 6 JAN 2004, vol. 101, no. 1, 6 January 2004 (2004-01-06), pages 360-365, XP002544430 ISSN: 0027-8424 *
SONKOLY E ET AL: "MicroRNAs: novel regulators in skin inflammation" CLINICAL AND EXPERIMENTAL DERMATOLOGY, BLACKWELL SCIENTIFIC PUBLICATIONS, OXFORD, GB, vol. 33, no. 3, 1 May 2008 (2008-05-01), pages 312-315, XP002511185 ISSN: 0307-6938 *
SONKOLY ENIKÖ ET AL: "MicroRNAs: novel regulators involved in the pathogenesis of Psoriasis?" PLOS ONE, PUBLIC LIBRARY OF SCIENCE, SAN FRANCISCO, CA, US, vol. 2, no. 7, 1 July 2007 (2007-07-01), pages e610-1, XP002511184 ISSN: 1932-6203 *
TILI ESMERINA ET AL: "Expression and function of micro-RNAs in immune cells during normal or disease state." INTERNATIONAL JOURNAL OF MEDICAL SCIENCES 2008, vol. 5, no. 2, 2008, pages 73-79, XP002544431 ISSN: 1449-1907 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9879222B2 (en) 2007-12-14 2018-01-30 Mofa Group Llc Gender-specific separation of sperm cells and embryos
WO2011017697A1 (fr) * 2009-08-07 2011-02-10 New York University Compositions et méthodes pour traiter des troubles inflammatoires
US8518908B2 (en) 2009-09-10 2013-08-27 University Of Idaho Nucleobase-functionalized conformationally restricted nucleotides and oligonucleotides for targeting of nucleic acids
US8912318B2 (en) 2009-09-10 2014-12-16 University Of Idaho Nucleobase-functionalized conformationally restricted nucleotides and oligonucleotides for targeting nucleic acids
US8716258B2 (en) 2010-06-04 2014-05-06 The Board Of Regents, The University Of Texas System Regulation of metabolism by miR-378
US20130331290A1 (en) * 2011-01-28 2013-12-12 Febit Holding Gmbh Complex mirna sets as novel biomarkers for lung diseases
US9885082B2 (en) 2011-07-19 2018-02-06 University Of Idaho Embodiments of a probe and method for targeting nucleic acids
WO2013155371A1 (fr) * 2012-04-12 2013-10-17 Cornell University Microarn-31 comme agent diagnostique, pronostique et thérapeutique du cancer
JP2020054336A (ja) * 2018-07-24 2020-04-09 チャン グァン メモリアル ホスピタル，カオシュン 乾癬性関節炎の診断及び治療
CN111956632A (zh) * 2020-09-27 2020-11-20 上海市同仁医院 一种抗肿瘤的组合物及其应用
CN111956632B (zh) * 2020-09-27 2022-10-18 上海市同仁医院 一种抗肿瘤的组合物及其应用
WO2024124315A1 (fr) * 2022-12-16 2024-06-20 Mirscience Therapeutics Servicos De Pesquisa E Desenvolvimento Ltda. Analogues oligonucléotidiques antisens de mir-29 et leurs utilisations

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