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(12) Patent Application Publication (10) Pub. No.: US 2012/0178642 A1 Salomon Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0178642 A1 Salomon Et Al US 2012O178642A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0178642 A1 Salomon et al. (43) Pub. Date: Jul. 12, 2012 (54) GENE EXPRESSION PROFILES ASSOCATED Related U.S. Application Data WITH CHRONICALLOGRAFT (60) Provisional application No. 61/224.328, filed on Jul.9. NEPHROPATHY 2009, provisional application No. 61/224.317, filed on Jul. 9, 2009. (75) Inventors: Daniel Salomon, San Diego, CA (US); Sunil M. Kurian, Ssan Publication Classification Diego, CA (US); Steven R. Head, (51) Int. Cl. Lakeside, CA (US) C40B 30/04 (2006.01) C40B 40/06 (2006.01) (73) Assignee: The Scripps Research Institute, (52) U.S. Cl. ............................................... 506/9; 506/16 La Jolla, CA (US) (57) ABSTRACT (21) Appl. No.: 13/261,130 By a genome-wide gene analysis of expression profiles of over 50,000 known or putative gene sequences in peripheral (22) PCT Fled: Jul. 9, 2010 blood, the present inventors have identified a consensus set of gene expression-based molecular biomarkers associated with (86) PCT NO.: PCT/US2O10/041598 chronic allograft nephropathy and/or interstitial fibrosis and tubular atrophy CAN/IFTA and subtypes thereof. These S371 (c)(1), genes sets are useful for diagnosis, prognosis, monitoring (2), (4) Date: Mar. 20, 2012 and/or subtyping of CAN/IFTA. Patent Application Publication Jul. 12, 2012 Sheet 1 of 2 US 2012/0178642 A1 Top 50 Mild CAN genes 1.0 ------------- 0.9 ---------- 0.8 -- 0.7 ----- Top 50 Mild CAN genes 0.6 - 0.5 79%. 82% 0.4 82% 79% O.O O.2 0.4 O.6 O.8 1.O FIG. 1 Patent Application Publication Jul. 12, 2012 Sheet 2 of 2 US 2012/0178642 A1 Top 50 ModeratelSevere CAN Genes 'll ----------------------------------- 0.85 / ----- Top 50 Moderate/Severe CAN Genes 0.65 0.45 Banff 2,3 FIG. 2 US 2012/0178642 A1 Jul. 12, 2012 GENE EXPRESSION PROFILES ASSOCATED genes that are differentially expressed at the mRNA level in WITH CHRONICALLOGRAFT kidney biopsies in the presence of CAN/IFTA16.20.21. The NEPHROPATHY limitation of these studies is that they require an invasive transplant biopsy. Others have reported analyzing urine and CROSS-REFERENCE TO RELATED peripheral blood using RT-qPCR or proteomics to identify APPLICATIONS small numbers of potential biomarkers for CAN/IFTA, 0001. The present application is a nonprovisional and though none is validated for clinical use22.23. claims the benefit of U.S. Ser. No. 61/224,328 and 61/224, 317 each filed Jul. 9, 2009, and incorporated by reference in BRIEF SUMMARY OF THE INVENTION its entirety for all purposes. 0006. The invention provides methods of prognosing, diagnosing or monitoring chronic allograft nephropathy and/ STATEMENT AS TO RIGHTS TO INVENTIONS or interstitial fibrosis and tubular atrophy (CAN/IFTA). The MADE UNDER FEDERALLY SPONSORED methods entail (a) determining expression levels in a subject RESEARCH ORDEVELOPMENT of at least 5 genes selected from the genes in Table A, B, C, D, E, F, G, H, I and/or J.; and (b) prognosing diagnosing or 0002 The invention was made in part with funding pro monitoring CAN/IFTA in a subject from the expression lev vided by NIH grant U19A1063603. The US Government has els. Optionally, for each of the at least five genes, step (b) certain rights in the invention. comprises comparing the expression level of the gene in the Subject to one or more reference expression levels of the gene BACKGROUND OF THE INVENTION associated with CAN/IFTA or lack of CAN/IFTA. Option 0003 Kidney transplantation offers a significant improve ally, step (b) further comprises for each of the at least five ment in life expectancy and quality of life for patients with genes assigning the expression level of the gene in the Subject end stage renal disease 1. Unfortunately, a chronic, progres a value or other designation providing an indication whether sive allograft dysfunction of uncertain etiology continues to the subject has or is at risk of CAN/IFTA. Optionally, the be a primary cause of graft loss2.3. There has been some expression level of each of the at least five genes is assigned evolution of terminology for describing the histological basis a value on a normalized scale of values associated with a of this chronic, progressive nephropathy, which is still com range of expression levels in kidney transplant patients with monly referred to as chronic allograft nephropathy (CAN) and without CAN/IFTA. Optionally, the expression level of and more recently as interstitial fibrosis and tubular atrophy each of the at least five genes is assigned a value or other (IFTA)4-6. In current practice CAN refers to a clinical designation providing an indication that the Subject has is at entity of a chronic progressive loss of kidney transplant func risk of CAN/IFTA, lacks and is not at risk of CAN/IFTA, or tion associated with a rising serum creatinine and a falling that the expression level is uninformative. Optionally, step (b) creatinine clearance. In current practice, IFTA refers to the further comprises, combining the values or designations for histological findings based on review of a kidney transplant each of the genes to provide a combined value or designation biopsy. Immunologic factors linked to CAN/IFTA are acute, providing an indication whether the Subject has or is at risk of sub-clinical and CAN/IFTA, HLA mismatching and circulat CAN/IFTA. Optionally, the method is repeated at different ing donor-specific anti-HLA antibodies7.8). Non-immuno times on the Subject. logic factors include hypertension, chronic toxicity of cal 0007. In some methods, the subject is receiving a drug, and cineurin inhibitors, hyperfiltration and diabetes mellitus 9 a change in the combined value or designation over time 12. The unifying mechanism is thought to be a progressive provides an indication of the effectiveness of the drug. cycle of vascular and tissue injury, incomplete repair, com Optionally, the Subject has undergone a kidney transplant pensatory hypertrophy, progressive interstitial fibrosis and within 1-10 years of performing step (a). Optionally, step (a) nephron loss 13. Moreover, increasing evidence is Suggest is performed on a blood sample of the subject. Optionally, the ing that the primary mechanism of CAN/IFTA is a chronic blood sample is a plasma sample. Optionally, step (a) is immunological injury mediated by a combination of T cell performed on at least ten, 20, 40, or 100 genes from Table A, and antibody-mediated immunity, in other words, chronic B, C, D, E, F, G, H, I and/or J. rejection. 0008. Some methods further comprise changing the treat 0004 As early as two years post kidney transplant, proto ment regime of the patient responsive to the prognosing, col biopsies have shown that more than 50% of recipients diagnosing or monitoring step. In some methods, the Subject have mild CAN/IFTA2,15,16 and by 10 years over 50% of has received a drug before performing the methods, and the kidney transplant recipients have severe CAN/IFTA that is change comprises administering an additional drug or admin associated with diminishing graft function2. Traditional istering a higher dose of the same drug. Some methods, fur kidney function measurements like serum creatinine and ther comprise performing an additional procedure, such as a glomerular filtration rates used to predict CAN/IFTA have kidney biopsy, to detect CAN/IFTA or risk thereof if the poor predictive values 17 and a diagnosis requires a trans determining step provides an indication the Subject has or is at plant biopsy 18, 19. Predicting graft outcomes strictly based risk of CANAIFTA. on the kidney biopsy is difficult and this invasive procedure In some methods, the at least five genes are from Table A, B, has significant costs and risks for patients. Thus, there is a C and/or D expression levels are determined at the mRNA pressing medical need to identify minimally invasive biom level. In some methods, the at least five genes are from Tables arkers that are able to identify early stages of CAN/IFTA at a E, F, G, H, I, and/or J and expression levels are determined at time that changes in therapy may alter outcomes. the protein level. In some methods, step (b) is performed by a 0005 Rapidly evolving technologies for genomics have computer. In some methods, the at least five genes are created new opportunities to develop minimally invasive selected from Tables C and D. In some methods, the at least biomarkers. Recent studies, including our own, have reported five genes are selected from Table C. In some methods, the at US 2012/0178642 A1 Jul. 12, 2012 least five genes are selected from Table D. In some methods, reference expression levels of the gene associated with the the at least five genes are selected from Table E and For Hand subtype of CAN/IFTA or lack of CAN/IFTA. Some methods I and expression levels are determined at the protein level. further comprise for each of the at least five genes assigning 0009. The invention further provides an array, comprising the expression level of the gene in the subject a value or other a Support or Supports bearing a plurality of nucleic acid designation providing an indication whether the Subject has probes complementary to a plurality of mRNAs fewer than or is at risk of the subtype of CAN/IFTA. In some methods, 5000 in number, wherein the plurality of mRNAs includes the expression level of each of the at least five genes is mRNAs expressed by at least five genes selected from Tables assigned a value on a normalized scale of values associated A, B, C, D.
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