Treatment of hepatocyte growth factor (HGF) related diseases by inhibition of natural antisense transcript to HGF

#The present application claims the priority of U.S. provisional patent application No. 61/289,647 filed Dec. 23, 2009 which is incorporated herein by reference in its entirety.

#Embodiments of the invention comprise oligonucleotides modulating expression and/or function of HGF and associated molecules.

#DNA-RNA and RNA-RNA hybridization are important to many aspects of nucleic acid function including DNA replication, transcription, and translation. Hybridization is also central to a variety of technologies that either detect a particular nucleic acid or alter its expression. Antisense nucleotides, for example, disrupt gene expression by hybridizing to target RNA, thereby interfering with RNA splicing, transcription, translation, and replication. Antisense DNA has the added feature that DNA-RNA hybrids serve as a substrate for digestion by ribonuclease H, an activity that is present in most cell types. Antisense molecules can be delivered into cells, as is the case for oligodeoxynucleotides (ODNs), or they can be expressed from endogenous genes as RNA molecules. The FDA recently approved an antisense drug, VITRAVENE™ (for treatment of cytomegalovirus retinitis), reflecting that antisense has therapeutic utility.

#FIG. 1 is a graph of real time PCR results showing the fold change+standard deviation in HGF mRNA after treatment of CHP212 cells with phosphorothioate oligonucleotides introduced using Lipofectamine 2000, as compared to control. Real time PCR results show that the levels of HGF mRNA in CHP212 cells are significantly increased 48 h after treatment with one of the oligos designed to HGF antisense. Bars denoted as CUR-0679, CUR-0680, CUR-0673 to CUR-0678 correspond to samples treated with SEQ ID NOS: 5 to 12 respectively.

#Sequence Listing Description—SEQ ID NO: 1: Homo sapiens hepatocyte growth factor (hepapoietin A; scatter factor) (HGF), transcript variant 5, mRNA. (NCBI Accession No.: NM—001010934); SEQ ID NO: 2: Natural HGF antisense sequence Hs.677861; SEQ ID NO: 3: Natural HGF antisense sequence AL546825; SEQ ID NO: 4: Natural HGF antisense sequence BX356413; SEQ ID NOs: 5 to 12: Antisense oligonucleotides. * indicates phosphothioate bond.

#Several aspects of the invention are described below with reference to example applications for illustration. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or with other methods. The present invention is not limited by the ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention.

#All genes, gene names, and gene products disclosed herein are intended to correspond to homologs from any species for which the compositions and methods disclosed herein are applicable. Thus, the terms include, but are not limited to genes and gene products from humans and mice. It is understood that when a gene or gene product from a particular species is disclosed, this disclosure is intended to be exemplary only, and is not to be interpreted as a limitation unless the context in which it appears clearly indicates. Thus, for example, for the genes disclosed herein, which in some embodiments relate to mammalian nucleic acid and amino acid sequences are intended to encompass homologous and/or orthologous genes and gene products from other animals including, but not limited to other mammals, fish, amphibians, reptiles, and birds. In an embodiment, the genes or nucleic acid sequences are human.