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I WO 2015/019381 Al Fig. 2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2015/019381 Al 12 February 2015 (12.02.2015) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12Q 1/68 (2006.01) G01N 33/68 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/IT20 14/0002 14 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 8 August 2014 (08.08.2014) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: Italian TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every RM2013A000465 8 August 2013 (08.08.2013) IT kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors; and UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicants : SALTINI, Cesare [IT/IT]; Via Valle Delia TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Noce, 10/B, 1-00046 Grottaferrata RM (IT). MARIANI, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, FT, LT, LU, LV, Francesca [IT/IT]; Vicolo delle Lucarie, 37, 1-00138 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Roma (FT). PUXEDDU, Emanno [IT/IT]; Via Damiano TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Chiesa, 4, 1-05100 Terni (IT). AMICOSANTE, Massimo KM, ML, MR, NE, SN, TD, TG). [IT/IT]; Via Laiatico 24, 1-00138 Roma (IT). PEZZUTO, Published: Gabriella [FT/IT]; Via Delia Mola Vecchia, 32, 1-00046 Grottaferrata (IT). — with international search report (Art. 21(3)) (74) Agent: IANNONE, Carlo Luigi; Barzano' & Zanardo — before the expiration of the time limit for amending the Roma S.p.A., Via Piemonte, 26, 1-00187 Roma (IT). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — with sequence listing part of description (Rule 5.2(a)) (54) Title: METHOD FOR IN VITRO DIAGNOSIS OF IDIOPATHIC PULMONARY FIBROSIS B < 150 10 5 ° fi CT IPF HFE- IPF FE+ 00 Fig. 2 © (57) Abstract: The present invention regards a method for the in vitro diagnosis of one form of pulmonary fibrosis characterised by o the presence of variant alleles or polymorphisms of the gene for hereditary hemochromatosis type 1 (HFE), by the abnormal expres sion of the non coding transcript for the "full length" protein of the SLC1 1A1/ NRAMP1 gene in pulmonary alveolar macrophages, and by the quantity of free intracellular iron in pulmonary alveolar macrophages as compared to that of a healthy subject. Moreover, the invention concerns iron chelators for use in the treatment of pulmonary fibrosis characterised by a greater quantity of intracellu lar free iron in alveolar macrophages. METHOD FOR IN VITRO DIAGNOSIS OF IDIOPATHIC PULMONARY FIBROSIS The present invention regards a method for the in vitro diagnosis of idiopathic pulmonary fibrosis. More precisely, the invention regards a method for the in vitro diagnosis of a form of pulmonary fibrosis characterized by altered regulation of intracellular iron and by the consequential exaggerated generation of chelatable iron-dependent oxygen radicals. This is characterized in vitro by the presence of allelic variants of HFE, the gene for Type 1 hereditary hemochromatosis, by the abnormal expression in alveolar macrophages of SLC1 1A1/NRAMP1 gene transcripts, non coding for the full length protein, and by the quantity of intracellular free (chelatable) iron in pulmonary alveolar macrophages as compared to healthy subjects. This form of pulmonary fibrosis is included in the group of idiopathic interstitial pneumonias, preferably Idiopathic pulmonary fibrosis "IPF", not excluding nonspecific interstitial pneumonia or "NSIP", in its cellular (Cellular NSIP) or fibrosing (Fibrosing NSIP) forms, other fibrosing idiopathic interstitial pneumonias, even when associated with other diseases, in particular systemic illnesses. The idiopathic interstitial pneumonias also include cryptogenic organizing pneumonia or "COP", acute interstitial pneumonia or "AIP", respiratory bronchiolitis-associated interstitial lung disease or "RB-ILD", desquamative interstitial pneumonia or "DIP" and lymphocytic interstitial pneumonia or "LIP". Idiopathic pulmonary fibrosis (IPF) [histopathologically characterized by the usual interstitial pneumonia (UIP) pattern] or IPF/UIP differs from the other idiopathic interstitial pneumonias by its rapid progression, with an average survival of 2-4 years, in contrast to the higher mean survival of ten years in patients with NSIP or DIP. The cause and the pathogenetic mechanism of idiopathic pulmonary fibrosis are presently unknown. Idiopathic pulmonary fibrosis is characterized by cell and tissue damage and interstitial inflammation and fibrosis affecting the pulmonary parenchyma: the pulmonary alveoli, the alveolar interstitium (the space between the pulmonary alveolar epithelium and the capillary endothelium), the peri-bronchial and the peri-vascular interstitium, leading to anatomic and functional damage. The diagnosis, in the absence of a specific causal factor and specific biomarkers, is made on the basis of clinical criteria which include: the history, the physical exam, chest radiology, and, when the chest radiological findings are not sufficiently specific, the histopathology of lung tissue. Currently, there are no valid diagnosic tests based on the identification of genes for the susceptibility to the disease nor biomarkers specific for the disease. (An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management Am J Respir Crit Care Med. 201 1 Mar 15;183(6):788-824.). However, clinical studies have shown that the clinical, radiological and pathological criteria described above, used in the diagnosis of IPF/UIP, have low sensitivity and specificity in nonsmoking subjects, and are even less sensitive and specific in subjects with a history of smoking and emphysema (Akira M , Inoue Y, Kitaichi M , Yamamoto S, Arai T, Toyokawa K . Usual interstitial pneumonia and nonspecific interstitial pneumonia with and without concurrent emphysema: thin-section CT findings. Radiology. 2009 Apr;251(1):271-9.). It has been shown that one third of patients with NSIP present with histopatholoigical aspects of UIP in one or more lobes. These patients have a worse prognosis than patients with fibrosing NSIP without histological aspects of UIP. In addition, the observation that patients with NSIP associated with localized aspects of UIP, are 8- 0 years older than patients with NSIP without localized aspects of UIP, suggests a connection - or a progression - from NSIP to IPF/UIP (Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, Jain A , Strawderman RL, Flint A , Lynch JP, Martinez FJ. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001 ;164:1722-7). Is it therefore reasonable to think that patients who present with a radiological picture of pulmonary fibrosis that is not "possible" or not "confident" may in reality develop idiopathic pulmonary fibrosis of the type IPF/UIP. IPF generally presents as a sporadic illness, but there are reported cases of familial aggregations which suggests an important component of genetic susceptibility. Certain genes have been associated with susecpitibility in the familial form of pulmonary fibrosis: in particular the genes that code for surfactant protein C (SFTPC), surfactant protein A (SFTPA2) or telomerase reverse transcriptase (TERT). These observations suggest the existence of genetic factors that may favor the susceptibility to noxious environmental substances, as in the case of tobacco smoke exposure (Lawson WE, Loyd JE, Degryse AL. Genetics in pulmonary fibrosis familial cases provide clues to the pathogenesis of idiopathic pulmonary fibrosis. Am J Med Sci. 201 1 Jun;341(6):439-43). Many studies have demonstrated that in idiopathic pulmonary fibrosis, pulmonary alveolar macrophages produce reactive oxygen species and are cytotoxic to pulmonary epithelial cells. (AM. Cantin, SL. North, GA. Fells, RC. Hubbard, and RG. Crystal Oxidant-mediated Epithelial Cell Injury in Idiopathic Pulmonary Fibrosis. J. Clin. Invest. 1987;79:1665-1673). In the generation of oxygen radicals, in particular the hydroxyl radical which is the most toxic oxygen radical, iron plays an important role. Macrophagaes (i) phagocytize old and damaged red blood cells, thus recovering heme iron, (ii) return iron to the circulation, after binding it to transferrin, rendering it available for hemopoiesis and numerous vital cell processes, (iii) sequester iron in its inactive form in siderosomes, subcellular structures containing iron bound to ferritin, which reduces its toxic potential or (iv) use the iron for the production of oxygen radicals in order to destroy microorganisms. In this regard, it is known that the phagocytosis of mircroorganisms, for example air borne mircroorganisms, determines in the alveolar macrophages the activation of
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