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(12) Patent Application Publication (10) Pub. No.: US 2016/0244833 A1 POTASHKN Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0244833 A1 POTASHKN Et Al US 20160244833A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0244833 A1 POTASHKN et al. (43) Pub. Date: Aug. 25, 2016 (54) METHODS AND KITS FOR DIAGNOSING, Publication Classification PROGNOSING AND MONITORING PARKINSONS DISEASE (51) Int. Cl. CI2O I/68 (2006.01) (71) Applicant: Rosalind Franklin University of (52) U.S. Cl. Medicine and Science, North Chicago, CPC ........ CI2O I/6883 (2013.01); C12O 2600/158 IL (US) (2013.01); C12O 2600/1 18 (2013.01); C12O 2600/1 12 (2013.01) (72) Inventors: Judith Ann POTASHKIN, North (57) ABSTRACT Chicago, IL (US); Jose Alfredo Network-based meta-analysis of four independent microar SANTIAGO, North Chicago, IL (US) ray studies identified the hepatocyte nuclear factor (HNF4A), a transcription factor associated with gluconeogenesis and (73) Assignee: Rosalind Franklin University of diabetes, as a central regulatory hub gene upregulated in Medicine and Science, North Chicago, blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and IL (US) mRNA translation of insulin, was identified as the most downregulated gene. Using both markers, PD patients were (21) Appl. No.: 14/870,960 classified with 90% sensitivity and 80% specificity. Longitu dinal performance analysis demonstrated that relative abun dance of HNF4A and PTBP1 mRNAssignificantly decreased (22) Filed: Sep. 30, 2015 and increased, respectively, in PD patients during 3 years follow up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin Related U.S. Application Data signaling observed in PD patients. The longitudinally (60) Provisional application No. 62/120,848, filed on Feb. dynamic biomarkers identified in this study may be useful for 25, 2015. monitoring disease-modifying therapies for PD. Patent Application Publication Aug. 25, 2016 Sheet 1 of 8 US 2016/0244833 A1 FIG.1A kicroarrays FIG.1B 888-28 8.iii.38-) --- --- / Gai: (, ^ loss \ 33. tes f 491 N a. * / 8Ex: Meta-analysis ---...--- ---...-- ------------------------------------------------ (Class ki: {arrays 8stwarkaziyst 3: E. GSE 83.38 & C SE2243 {SE8838 8ici:3&f disci.wery & SSE363 Patent Application Publication Aug. 25, 2016 Sheet 2 of 8 US 2016/0244833 A1 FIG.2A & 8:33:3883 x888: 8 x 33888& 8 P.R.R x88&83 ". : ... x38x43 FIG.2B 88.88:3 8823: i.88: 8K88 Patent Application Publication Aug. 25, 2016 Sheet 3 of 8 US 2016/0244833 A1 FIG.3A RO-3E Cirt FIG.3B -8S C-3; of 8 t 5 Patent Application Publication Aug. 25, 2016 Sheet 4 of 8 US 2016/0244833 A1 FIG.4A s s: -0.20 at .308 & 3^ s s . a : { h -NF4A RNA &a. : ; s: : t f ;:t d re. wa-0.32, w ps:0.002 18, . (3 : . 2. d s: “. 33 d . 'ssessessessessessessessesbeeeeeeeeeee,assee,888,888.88,888,888,888,888beeeeeeeeeee,8,888,888,888,888beeeeeeeeeee,deeeeeeeeeeeeeeeeeeeeeee,8,888,888,888,888-88,888,888,888 3 : 3 X 3 : : 8 & 33 23 : : 38 23 3.3 Oer aid Yahir Patent Application Publication Aug. 25, 2016 Sheet 5 of 8 US 2016/0244833 A1 FIG.5 20 si 2 ) 2 2 Patent Application Publication Aug. 25, 2016 Sheet 6 of 8 US 2016/0244833 A1 Figure 6 rxists-stics x 8.8: ". EE20 cespa rar sic26 Pos : (SYN {x i. : x8: ; :. soupescri . or (Mascag arrestsexPegra csx. .* est. ... x 8xx -- 8 (Ygs:{xxY 84.3 « 8x8:8: ... ...:” ......."-----------'''.....*::::... x 8.3: H88 Patent Application Publication Aug. 25, 2016 Sheet 7 of 8 US 2016/0244833 A1 FIG.7A preggiated spicing factors 3888& Rax:- FIG.7B {:}swifeguiated: sspicing actors 38:Eisaki: Patent Application Publication Aug. 25, 2016 Sheet 8 of 8 US 2016/0244833 A1 FIG.8A $0. s ACO2 2 to go to 100% - % Specificity AC:O.82 3{ 38 88 8. Ot 100% - % Specificity FI G. 8 C 8 8 NF4A-3- 4. ACO.90 2 { { i 8. 8 100% - % Specificity US 2016/0244833 A1 Aug. 25, 2016 METHODS AND KITS FOR DIAGNOSING, would to dopamine. An antiviral drug, amantadine, also PROGNOSING AND MONITORING appears to reduce symptoms. In May 2006, the FDA approved PARKINSONS DISEASE rasagiline to be used along with levodopa for patients with advanced PD or as a single-drug treatment for early PD. CROSS REFERENCE 0005. In some cases, surgery may be appropriate if the disease does not respond to drugs. Atherapy called deep brain 0001. This application is related to U.S. provisional patent stimulation (DBS) has now been approved by the U.S. Food application No. 62/120,848, filed Feb. 25, 2015, the disclo and Drug Administration. In DBS, electrodes are implanted sure of which is incorporated by reference herein in its into the brain and connected to a small electrical device called entirety. The sequence listing Submitted herewith is incorpo a pulse generator that can be externally programmed. DBS rated by reference in its entirety. can reduce the need for levodopa and related drugs, which in turn decreases the involuntary movements called dyskinesias STATEMENT REGARDING FEDERALLY that are a common side effect of levodopa. It also helps to SPONSORED RESEARCH alleviate fluctuations of symptoms and to reduce tremors, 0002 This invention was made with U.S. government Sup slowness of movements, and gait problems. DBS requires port by the US Army Medical Research and Materiel Com careful programming of the stimulator device in order to work mand under awards number W81XWH-09-0708 and correctly. W81XWH13-1-0O25. 0006. There is a need in the art for a better understanding of the underlying disease mechanism and methods to facili BACKGROUND OF THE DISCLOSURE tate the discovery of accurate biomarkers and therapeutic 0003 Parkinson's disease (PD; also known as idiopathic targets for Parkinson's disease. or primary parkinsonism, hypokinetic rigid syndrome (HRS), or paralysis agitans) belongs to a group of conditions called SUMMARY OF THE DISCLOSURE motor system disorders, which are the result of the loss of 0007. This disclosure demonstrates that network-based dopamine-producing brain cells. The four primary symptoms meta-analysis of four independent microarray studies pro of PD are tremor, or trembling in hands, arms, legs, jaw, and vides a useful framework to identify candidate biomarkers, face; rigidity, or stiffness of the limbs and trunk; bradykine and that expression of highly ranked genes identified can be sia, or slowness of movement; and postural instability, or used as diagnostic and prognostic biomarkers for PD. impaired balance and coordination. As these symptoms 0008. In one aspect, the disclosure provides a method for become more pronounced, patients may have difficulty walk diagnosing, prognosing or monitoring Parkinson's Disease ing, talking, or completing other simple tasks. PD usually (PD) in a human Subject, comprising: (a) obtaining a blood affects people over the age of 60. Early symptoms of PD are sample from a human Subject Suspected of having PD; (b) Subtle and occur gradually. In some people the disease determining the expression level of at least one gene in the progresses more quickly than in others. As the disease blood sample from the human Subject Suspected of having progresses, the shaking, or tremor, which affects the majority PD, wherein the at least one gene is selected from: HNF4A, of people with PD may begin to interfere with daily activities. THY1, SPEF1, SF3A2, SEMA6B, EN2, RTN3, BCAM, Other symptoms may include depression and other emotional SPATA2L and TPSG1; and (c) comparing the expression changes; difficulty in Swallowing, chewing, and speaking; level of the at least one gene expressed in the blood sample to urinary problems or constipation: skin problems; and sleep the expression level of the at least one gene expressed in a disruptions. There are currently no blood or laboratory tests non-PD, healthy control sample, whereby the increased that have been proven to help in diagnosing sporadic PD. expression level of the at least one gene expressed in the blood Therefore the diagnosis is based on medical history and a sample from the human Subject Suspected of having PD as neurological examination, but the disease can be difficult to compared to the non-PD sample is indicative of PD, thereby diagnose accurately. Doctors may sometimes request brain diagnosing the human Subject as having PD. scans or laboratory tests in order to rule out other diseases. 0009. In another aspect, the disclosure provides a method 0004 At present, there is no cure for PD, but a variety of of treating a human subject for Parkinson's Disease (PD), the medications provide dramatic relief from the symptoms. Usu method comprising: (a) obtaining a diagnosis identifying a ally, affected individuals are given levodopa (L-DOPA: human Subject as having PD, wherein the diagnosis was SINEMETTM, PARCOPATM, ATAMETTM, STALEVOTM, obtained by: (i) obtaining a blood sample from a human MADOPARTM, and PROLOPATM) combined with carbidopa Subject Suspected of having PD; (ii) determining the expres (LODOSYNTM) (products containing a combination of sion level of at least one gene selected from: HNF4A,THY1. levodopa and carbidopa include DUOPAR) and RYTARYR). SPEF1, SF3A2, SEMA6B, EN2, RTN3, BCAM, SPATA2L Carbidopa delays the conversion of levodopa into dopamine and TPSG1; and (iii) comparing the expression level of the at until it reaches the brain. Nerve cells can use levodopa to least one gene expressed in the blood sample to the expression make dopamine and replenish the brain's dwindling Supply. level of the at least one gene expressed in a non-PD, healthy Although levodopa helps at least three-quarters of PD cases, control sample, whereby the increased expression level of the not all symptoms respond equally to the drug. Bradykinesia at least one gene expressed in the blood sample from the and rigidity typically respond best, while tremor may be only human Subject Suspected of having PD as compared to the marginally reduced.
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