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(12) Patent Application Publication (10) Pub. No.: US 2007/0286856A1 Brown Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0286856A1 Brown Et Al US 20070286856A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0286856A1 BrOWn et al. (43) Pub. Date: Dec. 13, 2007 (54) MODULATION OF HYALURONAN (30) Foreign Application Priority Data SYNTHESIS AND DEGRADATION IN THE TREATMENT OF DISEASE Oct. 10, 2003 (AU)...................................... 200390.5551 Dec. 1, 2003 (AU).................................... 20033906658 (75) Inventors: Tracey Jean Brown, Flemington (AU); Publication Classification Gary Russell Brownlee, East Burwood (51) Int. Cl. (AU) A6IR 48/00 (2006.01) A 6LX 39/395 (2006.01) A6IP 43/00 (2006.01) Correspondence Address: C7H 2L/04 (2006.01) SEED INTELLECTUAL PROPERTY LAW C07K 6/18 (2006.01) GROUP PLLC (52) U.S. Cl. ............... 424/133.1; 424/130.1; 424/142.1; 701 FIFTHAVE 514/44; 530/387.1: 530/387.3; SUTES4OO 530/388.1; 530/389.1; 536/22.1; SEATTLE, WA 98104 (US) 536/23.2:536/24.5 (57) ABSTRACT (73) Assignee: ALCHEMIA ONCOLOGY LIMITED, The present invention provides compositions and methods Eight Mile Plains (AU) for modulating the expression of Hyaluronan (HA). In particular, this invention relates to compounds, which (21) Appl. No.: 10/574,903 hybridize with nucleic acid molecules encoding hyaluronan synthase (HAS), particularly HAS isoforms HAS1, HAS2 and HAS3. These compounds may range in size from (22) PCT Filed: Oct. 11, 2004 oligonucleotides to full length sequences. Such compounds (86). PCT No.: PCT/AUO4/O1383 are exemplified to modulate proliferation, such as cancer and inflammatory disorders, such as arthritis. It will be under S 371(c)(1), stood, however, that the compounds can be used for any (2), (4) Date: Feb. 28, 2007 other condition in which HA is involved. Patent Application Publication Dec. 13, 2007 Sheet 1 of 18 US 2007/0286856A1 FIGURE 1 4. Patent Application Publication Dec. 13, 2007 Sheet 2 of 18 US 2007/0286856A1 FIGURE 2 4.O Panel A 3 30 -a- ASHAS2 -H Parental ?aL 100 kDa 3. 20 5 40 kDa C 15 kDa O 10 y SS O L -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 KAV PANEL B 18O i 6 O 2 O O Parental Mock ASHAS2 Patent Application Publication Dec. 13, 2007 Sheet 3 of 18 US 2007/0286856A1 FIGURE3 18 16 ... O parental 14 -V- mock 10 2 Patent Application Publication Dec. 13, 2007 Sheet 4 of 18 US 2007/0286856A1 FIGURE 4 500000 400000 300000 200000 1OOOOO O. mock IOm ASHAS2 O O 24 48 72 96 120 144 Time (h) Patent Application Publication Dec. 13, 2007 Sheet 5 of 18 US 2007/0286856 A1 FIGURE 5 PANEL. A Time (h) 40 PANEL B 2O ASHAS2 O O 4 8 12 16 20 24 28 32 36 Time (h) 3D O PANELC O 4 8 12 16 2D 24, 28 32 36 Time (h) Patent Application Publication Dec. 13, 2007 Sheet 6 of 18 US 2007/0286856A1 FIGURE 6 120 1 100 R 33 g 80 - is 60 22 E 40 89Š 20 Parental Mock ASHAS2 Patent Application Publication Dec. 13, 2007 Sheet 7 of 18 US 2007/0286856A1 FIGURE 7 1400 1200 --- Parental - A - Mock 1000 -o- ASHAS2 a 800 is 600 D 400 200 H 10 O 80 60 40 20 Parental to Mock ASHAS2 Patent Application Publication Dec. 13, 2007 Sheet 8 of 18 US 2007/0286856 A1 FIGURE 8 o15 R. 1. 25 20 Patent Application Publication Dec. 13, 2007 Sheet 9 of 18 US 2007/0286856A1 FIGURE 9 120 10O 20 O S 120 100 20 Breast cancer Cell lines Patent Application Publication Dec. 13, 2007 Sheet 10 of 18 US 2007/0286856 A1 FIGURE 10 140 120 1CO 80 40 20 Parental Mock ASHAS2 Patent Application Publication Dec. 13, 2007 Sheet 11 of 18 US 2007/0286856 A1 FIGURE 11 18O 1111 O Parental Mock ASHAS2 Patent Application Publication Dec. 13, 2007 Sheet 12 of 18 US 2007/0286856 A1 FIGURE 12 Patent Application Publication Dec. 13, 2007 Sheet 13 of 18 US 2007/0286856 A1 FIGURE 13 2 O 24 48 72 96 120 144 Time (hours) Patent Application Publication Dec. 13, 2007 Sheet 14 of 18 US 2007/0286856 A1 FIGURE 14 10000 kDa 100 kDa 800 kDa | y 0.2 0.4 0.6 0.8 1.0 1.2 Kav Patent Application Publication Dec. 13, 2007 Sheet 15 of 18 US 2007/0286856 A1 FIGURE 15 500000 A 400000 E E 300000 200000 9 ( OOOOO O 24, 48 72 96 120 144 Time (h) 100 24.68OOOO IAO 4, 8 12 16 20 24 28 32 36 time (h) 100 406 4 8 12 16 20 24 28 32 36 me 234.OoO 10sey: 4, 8 12 16 20 24 28 32 36 Time (h) Patent Application Publication Dec. 13, 2007 Sheet 16 of 18 US 2007/0286856 A1 FIGURE 16 120 2 100 () ) g 80 E E 60 55 40 Os N 20 O Parental Mock ASHAS2 Patent Application Publication Dec. 13, 2007 Sheet 17 of 18 US 2007/0286856 A1 FIGURE 17 1400 A 1200 5 1000 MN 800 O SOO O-O-SR 400 -(Af e MTV 200 O A O a-a-a-o. O 2 4. 6 8 10 12 Weeks 100 af 2 10 B E 1 SS 0.1 ss O.01 o s O.OO1 Threshold O 0.00001 s 1.0x100 Patent Application Publication Dec. 13, 2007 Sheet 18 of 18 US 2007/0286856 A1 FIGURE 18 100 10 1 0.1 O.O1 O.001 Threshold O.OOO 0.00001 O.OOOOO1 1.0x10-07 125 B 100 75 50 25 O O 50 100 150 200 Days elapsed following intracardiac US 2007/0286856 A1 Dec. 13, 2007 MODULATION OF HYALURONAN SYNTHESIS another with respect to temporal and differential expression AND DEGRADATION IN THE TREATMENT OF during different physiological processes and disease states. DISEASE 0009. In work leading up to the present invention, it was observed that HAS and HYAL are differentially expressed BACKGROUND OF THE INVENTION under various physiological conditions. In particular, they 0001) 1. Field of the Invention were up-regulated during disease conditions such as an inflammatory condition or cancer. HAS, and in particular, 0002 The present invention relates generally to the HAS1, 2 and/or 3 and HYAL1, 2 and/or 3 represent useful modulation of hyaluronan (HA) synthesis and degradation. drug targets. More particularly, the present invention provides composi tions and methods for modulating the expression of genetic SUMMARY OF THE INVENTION material encoding HA synthase (HAS) and other enzymes or receptors primarily involved in hyaluronan metabolism; or 0010 Throughout the specification, unless the context modulating the proteins that synthesise or degrade hyaluro requires otherwise, the word “comprise', or variations such nan including HAS function or activity. The compositions as “comprises' or “comprising, will be understood to imply include or comprise nucleic acid molecules and interactive the inclusion of a stated element or integer or group of molecules Such as antibodies and Small molecule inhibitors elements or integers but not to the exclusion of any other and HAS substrate analogs. The present invention further element or integer or group of elements or integers. contemplates modulation of cellular proliferation, useful in the prophylaxis and/or treatment of inflammatory disorders 0011) Nucleotide and amino acid sequences are referred including hyperproliferative conditions. Such as but not to by a sequence identifier number (SEQID NO:). The SEQ limited to, cancer and psoriasis ID NOs: correspond numerically to the sequence identifiers <400>1 (SEQ ID NO:1), <400>2 (SEQ ID NO:2), etc. A 0003 2. Description of the Prior Art Summary of the sequence identifier numbers is provided in 0004 Bibliographic details of the publications referred to Table 1. A sequence listing is provided after the claims. in this specification are also collected at the end of the 0012. The present invention is directed to compounds, description. Such as nucleic acid and nucleic acid-like oligomer com 0005 Reference to any prior art in this specification is pounds or complexes comprising same, which are targeted not, and should not be taken as, an acknowledgment or any to a nucleic acid encoding HAS and/or HYAL a nucleic acid form of Suggestion that this prior art forms part of the molecule required for or which facilitates expression of general knowledge in any country. HAS and/or HYAL-encoding material as well as compounds Such as interactive molecules including antibodies or recom 0006 Inflammatory conditions represent a major caus binant or chimeric or derivative forms thereof or small ative factor in numerous medically significant disorders. molecules which are specific for HAS and/or HYAL and Inflammation can result from a range of stimuli from outside which antagonize HAS and/or HYAL function or activity. or within the body. However, these stimuli trigger cells and The nucleic acid and nucleic acid-like oligomers or com physiological processes within a host environment. Whilst a plexes comprising same, conveniently target to a nucleic Substantial amount of research has been undertaken to acid encoding an isoform of HAS such as HAS1, HAS2 investigate the cellular and cytokine nature of inflammatory and/or HAS3. The nucleic acid and nucleic acid-like oligo processes, less is known about other possible participants in mers or complexes comprising same, conveniently target to inflammation. a nucleic acid encoding an isoform of HYAL Such as HYAL1, HYAL2, HYAL3 and/or PH-20. Preferred interac 0007 One such class of participants is transmembrane tive molecules are antibodies such as monoclonal or poly proteins. Transmembrane proteins are involved in a range of clonal antibodies. Pharmaceutical and other compositions signalling activities and many have enzymic activity.
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