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Thai Hun Taiteit Ut La in Tutta Latoare THAI HUN TAITEIT US009970056B2UT LA IN TUTTA LATOARE (12 ) United States Patent ( 10 ) Patent No. : US 9 ,970 , 056 B2 Potashkin et al. ( 45 ) Date of Patent: May 15 , 2018 ( 54 ) METHODS AND KITS FOR DIAGNOSING , Aviles- Olmos , et al. “ Parkinson ' s Disease , Insulin Resistance and PROGNOSING AND MONITORING Novel Agents of Neuroprotection ” , Brain , 2013 , vol. 136 ( Pt 2 ) , pp . PARKINSON ' S DISEASE 37414 -- 384 .. Bassil, et al, “ Insulin , IGF - 1 and GLP - 1 Signaling in Neurodegenerative Disorders : Targets for Disease Modification ? ” , ( 71 ) Applicant: Rosalind Franklin University of Prog Neurobiol , Jul. 2014 , vol. 118 , pp . 1 - 18 . ( Abstract only ) . Medicine and Science , North Chicago , Bonnefond , et al. , “ The Emerging Genetics of Type 2 Diabetes ” , IL (US ) Trends Mol Med , Sep . 2010 , vol. 16 ( 9 ) , pp . 407 -416 . ( Abstract only ) . (72 ) Inventors : Judith Ann Potashkin , North Chicago , Cereda, et al. , “ Diabetes and Risk of Parkinson ' s Disease : A IL (US ) ; Jose Alfredo Santiago , North Systematic Review and Meta - Analysis ” , Diabetes Care, Dec . 2011 , Chicago , IL (US ) vol . 34 , pp . 2614 - 2623 . Cereda , et al. , “ Diabetes and Risk of Parkinson ' s Disease ” , Move ( 73 ) Assignee : Rosalind Franklin University of ment Disorders, 2013 , vol. 28 , pp . 257 - 261 ( Abstract only ) . Medicine and Science , North Chicago , Cereda , et al . , “ Clinical Features of Parkinson ' s Disease When Onset of Diabetes Came First: A Case - Control Study” , Neurology , IL (US ) May 8 , 2012 , vol . 78 ( 19 ), pp . 1507 - 1511 , doi: 10 .1212 /WNL . Ob013e3182553cc9 , Epub Apr. 25 , 2012 . ( Abstract only ) . ( * ) Notice : Subject to any disclaimer , the term of this Chen - Plotkin , et al. , “ Plasma Epidermal Growth Factor Levels patent is extended or adjusted under 35 Predict Cognitive Decline in Parkinson ' s Disease " , Ann Neurol , U . S . C . 154 (b ) by 94 days. Apr. 2011 , vol. 69 ( 4 ), pp . 655 - 663 , doi: 10 . 1002 / ana. 22271 , Epub Nov. 29 , 2010 . ( 21) Appl. No .: 14 /870 , 960 Deas , et al. , “ PINK1 Deficiency in Beta - Cells Increases Basal Insulin Secretion and Improves Glucose Tolerance in Mice ” , Open ( 22 ) Filed : Sep . 30 , 2015 Biol, Apr. 7 , 2014 , vol. 4 , p . 140051, http : / /dx .doi .org / 10 . 1098/ rsob . 140051 . (65 ) Prior Publication Data DiFonzo , et al. , “ A Frequent LRRK2 Gene Mutation Associated with Autosomal Dominant Parkinson ' s Disease ” , Lancet, Jan . 29 , US 2016 / 0244833 A1 Aug . 25, 2016 2005 , vol. 365 ( 9457 ) , pp . 412 -415 . ( Abstract only ) . Related U . S . Application Data Ding , et al. , “ Association of SNCA with Parkinson : Replication in the Harvard NeuroDiscovery Center Biomarker Study ” , Movement ( 60 ) Provisional application No. 62/ 120, 848 , filed on Feb. Disorders, 2011, vol. 26 , pp . 2283 - 2286 . 25, 2015 . Ding, et al. , “ Unrecognized Vitamin D3 Deficiency is Common in Parkinson ' s Disease: Harvard Biomarker Study ” , Neurology, Oct . (51 ) Int. Ci. 22 , 2013 , vol. 81 ( 17 ) , pp . 1531 - 1537 . C120 1 /68 ( 2018 . 01 ) Dunn , et al. , “ Dysregulation of Glucose Metabolism is an Early ( 52 ) U . S . CI. Event in Sporadic Parkinson ' s Disease” , Neurobiology of Aging , CPC . C12Q 1 /6883 (2013 . 01 ) ; C12Q 2600 /158 May 2014 , vol. 35 ( 5 ) , pp . 1111 - 1115 . ( 2013 .01 ) Farrer, et al. , “ LRRK2 Mutations in Parkinson ' s Disease” , Neurol ( 58 ) Field of Classification Search ogy , Sep . 13 , 2005 , vol. 65 ( 5 ), pp . 738 -740 . (Abstract only ) . None (Continued ) See application file for complete search history. Primary Examiner — James S Ketter (74 ) Attorney, Agent, or Firm — McDonnell Boehnen (56 ) References Cited Hulbert & Berghoff LLP U . S . PATENT DOCUMENTS ( 57 ) ABSTRACT 8 , 772 ,468 B2 7 / 2014 Potashkin 8 ,841 ,436 B29 / 2014 Gorodeski et al. Network -based meta -analysis of four independent microar 2005 /0026191 A1 * 2 / 2005 Carman . .. .. .. .. .. CO7K 14 / 47 ray studies identified the hepatocyte nuclear factor 435 / 6 . 16 (HNF4A ) , a transcription factor associated with gluconeo 2011/ 0021600 A1* 1 /2011 Yamada .. .. A61K 31/ 7088 genesis and diabetes , as a central regulatory hub gene 514 / 44 A upregulated in blood of PD patients . In parallel, the poly pyrimidine tract binding protein 1 (PTBP1 ) , involved in the OTHER PUBLICATIONS stabilization and mRNA translation of insulin , was identified as the most downregulated gene . Using both markers , PD Adler , et al. , “ Low Clinical Diagnostic Accuracy of Early vs patients were classified with 90 % sensitivity and 80 % speci Advanced Parkinson ' s Disease : Clinicopathologic Study ” , Neurol ficity . Longitudinal performance analysis demonstrated that ogy , Jul. 29 , 2014 , vol. 83 , pp . 406 - 412 . relative abundance of HNF4A and PTBP1 mRNAs signifi Alieva , et al . , “ Involvement of Endocytosis and Alternative Splicing cantly decreased and increased , respectively , in PD patients in the Formation of the Pathological Process in the Early Stages of during 3 years follow up period . The inverse regulation of Parkinson ' s Disease ” , Biomed Res Int, 2014 , vol. 2014 , Article ID 718732 , doi: 10 . 1155 / 2014 /718732 , Epub Apr. 3 , 2014 . HNF4A and PTBP1 provides a molecular rationale for the Aviles- Olmos , et al . , “ Exenatide and the Treatment of Patients with altered insulin signaling observed in PD patients . The lon Parkinson ' s Disease” , The Journal of Clinical Investigation , 2013 , gitudinally dynamic biomarkers identified in this study may vol. 123 ( 6 ), pp . 2730 - 2736 . be useful for monitoring disease -modifying therapies for Aviles- Olmos , et al. " Motor and Cognitive Advantages Persist 12 PD . Months After Exenatide Exposure in Parkinson ' s Disease ” , Journal of Parkinson ' s Disease , 2014 , vol. 4 , pp . 337 -344 . 12 Claims, 8 Drawing Sheets US 9 , 970 ,056 B2 Page 2 References Cited Molochnikov , et al. , “ A Molecular Signature in Blood Identifies ( 56 ) Early Parkinson ' s Disease ” , Mol Neurodegener , May 31 , 2012 , vol. 7 , p . 26 , doi: 10 . 1186 / 1750 - 1326 - 7 - 26 . OTHER PUBLICATIONS Moroo , et al ., “ Loss of Insulin Receptor Immunoreactivity from the Foltynie , et al. , “ Exenatide as a Potential Treatment for Patients with Substantia Nigra Pars Compacta Neurons in Parkinson ' s Disease ” , Parkinson ' s Disease : First Steps into the Clinic ” , Alzheimer & Acta Neuropathol, 1994 , vol. 87 ( 4 ) , pp . 343 -348 . ( Abstract only ) . Dementia , Feb . 2014 , vol. 10 , pp . S38 - 46 , doi: 10 . 1016 /j . jalz . 2013 . Morris , et, al . , “ Neurodegeneration in an Animal Model of Parkin 12 .005 . son ' s Disease is Exacerbated by a High -Fat Diet ” , Am J Physiol Geng, et al. , “ Alpha -Synuclein Binds the K ( ATP ) Channel at Regul Integr Comp Physiol, Oct . 2010 , vol . 299 ( 4 ) , pp . R1082 1090 , doi: 10 . 1152/ ajpregu . 00449 . 2010 , Epub Aug . 11, 2010 . Insulin - Secretory Granules and Inhibits Secretion ” , Am J Physiol Morris , et al. , “ Insulin Resistance Impairs Nigrostriatal Dopamine Endocrinol Metab , Feb . 2011 , vol. 300 ( 2 ) , pp . E276 - 286 , doi: 10 . Function ” , Exp Neurol , Sep . 2011 , vol. 231 ( 1 ) , pp . 171 - 180 , doi : 10 . 1152/ ajpendo. 00262 . 2010 , Epub Sep . 21, 2010 . 1016 / j . expneurol. 2011 . 06 . 005 . Gilks, et al. , “ A Common LRRK2 Mutation in Idiopathic Parkin Mutez , et al. , “ Transcriptional Profile of Parkinson ' s Blood son ' s Disease ” , Lancet , Jan . 18 , 2005 , vol . 365 (9457 ) , pp . 415 -416 . Mononuclear Cells with LRRK2 Mutation ” , Neurobiol Aging , Oct. ( Abstract only ) . 2011, vol. 32 ( 10 ) , pp . 1839 - 1848 , doi: 10 . 1016 / j. neurobiolaging . Han , et al ., “ Diagnosis of Parkinson ' s Disease Based on Disease 2009. 10 .016 , Epub Jan . 22 , 2010 . ( Abstract only ) . Specific Autoantibody Profiles in Human Sera ” , PloS One , 2012 , Nolan , et al ., “ Parkinson ' s Disease in the Nuclear Age of vol. 7 ( 2 ) , Article ID e32383 , pp . 1 - 6 , doi: 10 . 1371/ journal. pone . Neuroinflammation ” , Trends in Molecular Medicine , Mar. 2013 , 0032383 , Epub Feb . 22 , 2012 . vol. 19 , pp . 187 - 196 , Epub Jan . 11, 2013 . ( Abstract only ) . Harries , et al. , “ The Diabetic Phenotype in HNF4A Mutation Potashkin , et al. , “ Biosignatures for Parkinson ' s Disease and Atypi Carriers is Moderated by the Expression of HNF4A Isoforms from cal Parkinsonian Disorders Patients ” , PloS One , 2012, vol. 7 ( 8 ) , the P1 Promoter During Fetal Development” , Diabetes , Jun . 2008 , Article ID 43595 , pp . 1 - 13 . vol . 57 ( 6 ) , pp . 1745 - 1752 , doi: 10 .2337 / db07 - 1742 , Epub Mar. 20 , Przedborski, “ Inflammation and Parkinson ' s Disease Pathogen 2008 . esis ” , Movement Disorders : Official Journal of the Movement Hegele , et al ., “ Dynamic Protein -Protein Interaction Wiring of the Disorder Society , 2010 , vol . 25 , Suppl 1 , pp . S55 -S57 . Human Spliceosome" , Mol Cell , Feb . 24 , 2012 , vol. 45 ( 4 ) , pp . Puigserver , et al. , “ Insulin - Regulated Hepatic Gluconeogenesis 567 - 580 , doi : 10 . 1016 / j .molcel .2011 . 12 .034 . Through FOXO 1 -PGC - 1alpha Interaction ” , Nature , May 29, 2003 , vol. 423 (6939 ) , pp . 550 -555 , Epub May 18 , 2003 . ( Abstract only ) . Hetz , et al. , “ Targeting the Unfolded Protein Response in Disease ” , Rajput, et al. , “ Accuracy of Parkinson ' s Disease Diagnosis Nat Rev Drug Discov , Sep . 2013 , vol. 12 ( 9 ) , pp . 703 - 719 , doi: 10 . Unchanged in 2 Decades ” , Neurology , 2014 , vol. 85( 5 ) , pp . 386 1038 / nrd3976 . ( Abstract only ) . 387 , Epub Jun . 27
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