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(12) STANDARD PATENT (11) Application No. AU 2010202722 B2 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2010202722 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2010202722 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Juvenile hemochromatosis gene (HFE2A), expression products and uses thereof (51) International Patent Classification(s) C12Q 1/68 (2006.01) G01N 33/50 (2006.01) C07K 14/47 (2006.01) (21) Application No: 2010202722 (22) Date of Filing: 2010.06.29 (43) Publication Date: 2010.07.15 (43) Publication Journal Date: 2010.07.15 (44) Accepted Journal Date: 2012.12.20 (62) Divisional of: 2004231122 (71) Applicant(s) Xenon Pharmaceuticals, Inc. (72) Inventor(s) Ludwig, Erwin H.;Papanikolaou, George;MacDonald, Marcia L.E.;Samuels, Mark E.;Franchini, Patrick;Kamboj, Rajender K.;Goldberg, Yigal Paul (74) Agent / Attorney Spruson & Ferguson, L 35 St Martins Tower 31 Market St, SYDNEY, NSW, 2000 (56) Related Art WO 2000/073801 WO 2002/051438 GenBank Accession No: BAB26407 JUVENILE HEMOCHROMATOSIS GENE (HFE2A), EXPRESSION PRODUCTS 2010 AND USES THEREOF Jun Abstract 29 5 Polynucleotide and polypeptide sequences for HFE2A, as well as mutations associated with juvenile hemochromatosis, and methods of utilizing these for screening and identification of agents for the treatment of diseases of iron metabolism, including small organic compounds, are disclosed along with methods of treating and/or io ameliorating diseases of iron metabolism, especially in human patients are disclosed. 2010202722 Diagnostic compounds, kits and methods using HFE2A are also described. S&FRef: 739254D1 AUSTRALIA 2010 PATENTS ACT 1990 COMPLETE SPECIFICATION Jun 29 FOR A STANDARD PATENT 2010202722 Name and Address Xenon Pharmaceuticals, Inc., of 3650 Gilmore Way, of Applicant: Burnaby, British Columbia, V5G 4W8, Canada Actual Inventor(s): Erwin H. Ludwig George Papanikolaou Marcia L.E. MacDonald Mark E. Samuels Patrick Franchini Rajender K. Kamboj Yigal Paul Goldberg Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Juvenile hemochromatosis gene (HFE2A), expression products and uses thereof The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(2803893_1) 2010 Jun JUVENILE HEMOCHROMATOSIS GENE (HFE2A), 29 EXPRESSION PRODUCTS AND USES THEREOF 1. This patent application ciaims priority of US provisional applications Serial No. 60/462,867, filed 15 April 2003, Serial No. 2010202722 US/60/488,607, filed 18 July 2003, and Serial No. 60/498,458, filed 28 August 2003, the disclosures of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The present invention relates generally to the field of iron metabolism fO diseases, especially juvenile hemochromatosis, to a gene associated therewith, and to methods of using this gene, including expression products thereof, for the screening and identification of agents useful in the treatment of diseases of iron metabolism, including methods of such treatment. BACKGROUND OF THE INVENTION /S’ At least 4 iron-overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Hemochromatosis type 1 is classic hemochromatosis (sometimes designated “HFE") (see OMIM Number: 235200; Online Mendelian Inheritance in Man, OMIM™. Johns Hopkins University, Baltimore, MD, at www.ncbi.nlm.nih.gov/omim/), an autosomal recessive disorder, which is caused by mutation in a gene designated HFE on chromosome 6p21.3. The medical disorder called juvenile hemochromatosis (sometimes called “JH" or "juvenile haemochromatosis"), is also known as hemochromatosis type 2 ("HFE2”). Hemochromatosis type 3 (HFE3; OMIM 604250), an autosomal 2010 recessive disorder, is caused by mutation in the gene encoding transferrin receptor-2 (TFR2; OMIM 604720), which maps to 7q22. Hemochromatosis Jun type 4 (HFE4; OMIM 606069), an autosomal dominant disorder, is caused by 29 mutation in the SLC11A3 gene (OMIM 604653), which encodes ferroportin 5 and maps to 2q32. In some families juvenile hemochromatosis shows linkage to chromosome 1q21, whereas in others it is caused by mutation in the gene encoding hepcidin antimicrobial peptide, which maps to chromosome 19q13. The two forms of juvenile hemochromatosis (HFE2) are tentatively designated 2010202722 10 HFE2A and HFE2B, respectively. The present invention relates to the genetic basis of HFE2A, the form of JH linked to chromosome 1 q21. Juvenile hemochromatosis (JH) differs from typical hereditary hemochromatosis. While HFE has a prevalent male expression, JH affects both sexes equally. JH involves iron accumulation, which begins early in life 15 and typically causes clinical symptoms before the age of 30 years. JH is a more severe disease than typical hereditary hemochomotosis, with JH showing hypogonadotropic hypogonadism, heart failure, arrhythmias and/or cardiomyopathy as frequent features. If untreated, the disease is lethal because of cardiac and other complications. 20 Identification of 1 q21 as the chromosomal location of HFE2A was first reported in Roetto et al., Am. J.Hum. Genet. 64:1388-1393 (1999) but this locus did not correspond to the chromosomal location of any known gene involved in iron metabolism. The present invention provides identification of the hereditary basis for 25 HFE2A, thereby facilitating development of more potent agents for treating diseases of iron metabolism. Administration of the HFE2A gene or protein itself may be therapeutic. Alternatively, the underlying genetic mutation identifies a novel therapeutic target for treating diseases of iron metabolism. This therapeutic target can be used to identify and discover more effective 30 therapeutic agents. Diagnostic compounds, kits and methods using HFE2A are also included which may be used to diagnose JH as well as to diagnose 2 3 and predict onset and severity of adult hemochromatosis and to distinguish between types of iron metabolism disorders. 2012 BRIEF SUMMARY OF THE INVENTION Nov 5 In a first aspect, the present invention provides an isolated antisense 22 molecule complementary to SEQ ID NO: 2 or 3, wherein said antisense molecule is the complement of the oligonucleotide of SEQ ID NO: 13, 15, 17, 29, 31, 33, 37, 39, 41, 43, 45, 47, 49, 51 or 53, wherein said antisense molecule modulates iron transport, across a cell membrane of a cell that transport iron. 10 In a second aspect, the present invention provides a method for inhibiting 2010202722 hemojuvelin activity in a cell, comprising contacting a cell with an isolated antisense molecule of the first aspect, wherein said antisense molecule inhibits hemojuvelin activity in said cell. In a third aspect, the present invention provides a method for modulating 15 iron transport across the membrane of a cell, comprising contacting a cell with an isolated antisense molecule of the first aspect, wherein said antisense molecule modulates iron transport across said cell. In a fourth aspect, the present invention provides a method for inhibiting hepcidin production in a cell, comprising contacting a cell with an isolated 20 antisense molecule of the first aspect, wherein said antisense molecule inhibits hepcidin production in said cell. In a fifth aspect, the present invention provides an isolated polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein said polypeptide modulates iron transport across a cell membrane of a 25 cell that transports iron. In a sixth aspect, the present invention provides an isolated fragment of SEQ ID NO: 26 or 27, wherein said polypeptide modulates iron transport across a cell membrane of a cell that transports iron. In a seventh aspect, the present invention provides a composition when 30 used for treating a disease of iron metabolism comprising a therapeutically effective amount of the polypeptide of the fifth or sixth aspect in a pharmaceutically acceptable carrier. (6885017) 3a The invention relates to the discovery that juvenile hemochromatosis (hemochromatosis type 2A, or HFE2A), is caused by a mutation in a human gene 2012 found at 1 q22 having, the nucleotide sequence as set out in SEQ ID Nos. 1-9, and/or the corresponding amino acid sequences as set out in SEQ ID Nos. 10-12. Nov 5 The gene and the protein are referred to herein as HFE2A and also as 22 hemojuvelin, these words referring to the gene, the gene product and the protein expressed therefrom, unless the context specifies otherwise. The gene has also been named HFE2, by which is meant the form JH caused by the gene at lq21. This naming protocol is not essential to the invention claimed herein. 10 Described herein is a method for identifying an agent that modulates hemojuvelin, comprising contacting a test compound with hemojuvelin and 2010202722 determining a change in hemojuvelin activity due to the compound, thereby identifying a modulator of the type being sought. The modulator may be a drug­ like small molecule, an antibody, an antisense nucleic acid, a ribozyme or any 15 other compound which changes the activity of the gene or protein. Described herein is a method for identifying an agent that modulates HFE2A gene expression, comprising contacting a test compound with a polynucleotide comprising a HFE2A gene and under conditions promoting expression of said gene (i.e., conditions wherein the polynucleotide is being 20 expressed) and determining a change in expression due to the presence of the test compound. This identifies the test compound as such a modulator. In a preferred embodiment, this change in expression is detected as a change in transcription of the gene, preferably where the gene is a mammalian gene and most preferably where the gene is expressed by a cell. (6885017) 4 Further described herein is a method for identifying an agent that modulates HFE2A gene expression, comprising contacting a test compound with a 2012 reporter gene operably linked to a promoter sequence and determining a change in Nov expression of the reporter gene due to the test compound, thus identifying a 5 modulator of the construct. Preferably, this is modulation of transcription of said 22 reporter gene operably linked to an HFE2A promoter, most preferably a mammalian HFE2A, such as a mouse, rat or human HFE2A promoter.
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