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G- 1200 W Mirna Treatment GD VT 1000 & 5 800 -C E 600 =5 5 400 Q) © 200 Patent Application Publication Jul US 20090175827A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2009/0175827A1 Byrom et al. (43) Pub. Date: Jul. 9, 2009 (54) MIR-16 REGULATED GENES AND (30) Foreign Application Priority Data PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION Dec. 10, 2007 (US) ....................... PCT/US07/87038 (76) Inventors: Mike W. Byrom, Austin, TX (US); Publication Classification Lubna Patrawala, Austin, TX (51) Int. Cl. (US); Charles D. Johnson, Austin, A61 K 35/76 (2006.01) TX (US); David Brown, Austin, TX CI2N 5/06 (2006.01) (US); Andreas G. Bader, Austin, A61 K. 3 1/7088 (2006.01) TX (US) CI2O I/68 (2006.01) Correspondence Address: A6IP 3 I/00 (2006.01) Fullbright & Jaworski L.L.P. A61R 31/7/05 (2006.01) 600 Congress Avenue, Suite 2400 A61 K. 3 1/7 II (2006.01) Austin, TX 78701 (US) (52) U.S. Cl. ............... 424/93.2; 435/375; 514/44; 435/6 (21) Appl. No.: 11/967,663 (57) ABSTRACT (22) Filed: Dec. 31, 2007 The present invention concerns methods and compositions for identifying genes or genetic pathways modulated by miR Related U.S. Application Data 16, using miR-16 to modulate a gene or gene pathway, using (60) Provisional application No. 60/882,758, filed on Dec. this profile in assessing the condition of a patient and/or 29, 2006. treating the patient with an appropriate miRNA. 1400 g- 1200 W miRNA treatment GD VT 1000 & 5 800 -C E 600 =5 5 400 Q) © 200 Patent Application Publication Jul. 9, 2009 Sheet 1 of 2 US 2009/0175827 A1 i i . g — : ; uOI!ele]]|Old 9% Patent Application Publication Jul. 9, 2009 Sheet 2 of 2 US 2009/0175827 A1 # : C O C O O CD O Cº) O O C C CO CO ~f CN § - i 90 x] Jequnu IIeo US 2009/0175827 A1 Jul. 9, 2009 MIR-16 REGULATED GENES AND Others have evaluated the expression patterns of large num PATHWAYS AS TARGETS FOR bers of miRNAs in multiple human cancers and observed THERAPEUTIC INTERVENTION differential expression of almost all miRNAs across numer ous cancer types (Lu et al., 2005). Most studies link miRNAs to cancer only by indirect evidence. However, He et al. (2005) [0001] This application claims priority to U.S. provisional has provided more direct evidence that miRNAs may contrib application No. 60/882,758 filed Dec. 29, 2006 and PCT ute directly to causing cancer by forcing the over-expression application PCT/U.S.07/87038, filed Dec. 10, 2007, both of of six miRNAs in mice that resulted in a significant increase which are incorporated herein by reference in their entirety. in B cell lymphomas. [0002] This application is related to U.S. patent application [0009] Others have shown that miR-16 is down-regulated Ser. No. 11/141,707 filed May 31, 2005 and Ser. No. 1 1/273, in B-cells from patients with chronic lymphocytic leukemia 640 filed Nov. 14, 2005, each of which is incorporated herein (Calin et al., 2002). Reduced expression of these miRNAs in by reference in their entirety. B cell lymphomas results in overexpression of a miR-16 target gene, BCL2, and subsequent inhibition of apoptosis by BACKGROUND OF THE INVENTION the BCL2 gene product. Reduced expression of miR-16 I. Field of the Invention results in uncontrolled cellular proliferation and B cell malig [0004] The present invention relates to the fields of molecu nancy (reviewed in Calin and Croce, 2006). Together these lar biology and medicine. More specifically, the invention data suggest that miR-16-1 appears to function as a tumor relates to methods and compositions for the treatment of suppressor in human B cells. diseases or conditions that are affected by miR-16 microR [0010] The inventors previously demonstrated that hsa NAs, microRNA expression, and genes and cellular pathways miR-16 is involved with the regulation of numerous cell directly and indirectly modulated by such. activities that represent intervention points for cancertherapy and for therapy of other diseases and disorders (U.S. patent II. Background application Ser. No. 11/141,707 filed May 31, 2005 and Ser. No. 11/273,640 filed Nov. 14, 2005). Expression of miR-16 [0005] In 2001, several groups used a cloning method to was reduced in lung tumors from numerous lung cancer isolate and identify a large group of “microRNAs” (miRNAs) patients when compared to its expression in normal adjacent from C. elegans, Drosophila, and humans (Lagos-Quintana et lung tissues from the same patients. The inventors observed al., 2001; Lau et al., 2001; Lee and Ambros, 2001). Several increased expression of miR-16 in breast and prostate tumors hundreds of miRNAs have been identified in plants and ani as compared to expression in adjacent normal cells from the mals—including humans—which do not appear to have same cancer patients. In human foreskin fibroblasts, hsa endogenous siRNAs. Thus, while similar to siRNAs, miR miR-16 activated the hi?ert gene that encodes the catalytic NAs are distinct. domain of telomerase. Over 90% of human cancer samples [0006] miRNAs thus far observed have been approximately have active telomerase (reviewed in Dong et al., 2005). Hsa 21-22 nucleotides in length and they arise from longer pre miR-16 also induces cells to enter the S phase of the cell cycle cursors, which are transcribed from non-protein-encoding and decreases the proliferation of lung cancer cells (A549 and genes. See review of Carrington et al (2003). The precursors HTB-57 lung carcinoma cells), prostate cancer cells (22Rv1), form structures that fold back on themselves in self-comple and human basal cell carcinomas (TE354T). Anti-miR inhibi mentary regions; they are then processed by the nuclease tors of hsa-miR-16 increased the proliferation of non-malig Dicer in animals or DCL1 in plants. miRNA molecules inter nant human breast epithelial cells and basal cell carcinoma rupt translation through precise or imprecise base-pairing cells (TE354T). In addition, the inventors previously with their targets. observed that hsa-miR-16 is up-regulated in patients with [0007] Many miRNAs are conserved among diverse organ prion disease and Alzheimer’s disease when compared to isms, and this has led to the suggestion that miRNAs are patients without those diseases. As is the case for cancer involved in essential biological processes throughout the life therapy, genes and pathways that are altered by expression of span of an organism (Esquela-Kerscher and Slack, 2006). In hsa-miR-16 represent targets for therapeutic intervention in particular, miRNAs have been implicated in regulating cell the treatment of certain diseases like Alzheimer’s Disease and growth, and cell and tissue differentiation; cellular processes prion diseases, in which hsa-miR-16 likely plays a role. In that are associated with the development of cancer. For animals, most miRNAs are thought to interact with target instance, lin-4 and miR-16 both regulate passage from one genes through imprecise base pairing within the 3' untrans larval state to another during C. elegans development (Am lated regions of their gene targets. Regulation of target genes bros, 2001). mir-14 and bantam are Drosophila miRNAs that by miRNAs is thought to occur primarily by translation inhi regulate cell death, apparently by regulating the expression of bition, but mRNA instability may also be a mechanism (Rein genes involved in apoptosis (Brennecke et al., 2003, Xu et al., hartet al., 2000; Bagga et al., 2005). Bioinformatics analyses 2003). suggest that any given miRNA may bind to and alter the [0008] Research on miRNAs is increasing as scientists are expression of up to several hundred different genes. In addi beginning to appreciate the broad role that these molecules tion, a single gene may be regulated by several miRNAs. play in the regulation of eukaryotic gene expression. In par Thus, each miRNA may regulate a complex interaction ticular, several recent studies have shown that expression among genes, gene pathways, and gene networks. Mis-regu levels of numerous miRNAs are associated with various can lation or alteration of these regulatory pathways and net cers (reviewed in Esquela-Kerscher and Slack, 2006). works, involving miRNAs, are likely to contribute to the Reduced expression of two miRNAs correlates strongly with development of disorders and diseases such as cancer. chronic lymphocytic leukemia in humans, providing a pos Although bioinformatics tools are helpful in predicting sible link between miRNAs and cancer (Calin et al., 2002). miRNA binding targets, all have limitations. Because of the US 2009/0175827 A1 Jul. 9, 2009 imperfect complementarity with their target binding sites, it is one or more protein encoded by one or more gene associated difficult to accurately predict miRNA targets with bioinfor with a pathway. In still a further aspect, a subject or patient matics tools alone. Furthermore, the complicated interactive may be selected based on aberrations in miRNA expression, regulatory networks among miRNAs and target genes make it or biologic and/or physiologic pathway(s). A subject may be difficult to accurately predict which genes will actually be assessed for sensitivity, resistance, and/or efficacy of a mis-regulated in response to a given miRNA. therapy or treatment regime based on the evaluation and/or [0011] Correcting gene expression errors by manipulating analysis of miRNA or mRNA expression or lack thereof. A miRNA expression or by repairing miRNA mis-regulation subject may be evaluated for amenability to certain therapy represent promising methods to repair genetic disorders and prior to, during, or after administration of one ortherapy to a cure diseases like cancer. A current, disabling limitation of subjector patient. Typically, evaluation or assessment may be this approach is that, as mentioned above, the details of the done by analysis of miRNA and/or mRNA, as well as com regulatory pathways and networks that are affected by any bination of other assessment methods that include but are not given miRNA remain largely unknown.
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