WO2019070802A1 - Use of novel biomarkers in the diagnosis, confirmation, and treatment of parkinson's disease - Google Patents

Use of novel biomarkers in the diagnosis, confirmation, and treatment of parkinson's disease Download PDF

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WO2019070802A1
WO2019070802A1 PCT/US2018/054093 US2018054093W WO2019070802A1 WO 2019070802 A1 WO2019070802 A1 WO 2019070802A1 US 2018054093 W US2018054093 W US 2018054093W WO 2019070802 A1 WO2019070802 A1 WO 2019070802A1
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gene
subject
afflicted
expression level
polr2j2
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PCT/US2018/054093
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French (fr)
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David Sulzer
Alessandro Sette
Bjoern Peters
Cecilia LINDESTAM ARLEHAMN
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The Trustees Of Columbia University In The City Of New York
The Research Foundation For Mental Hygiene, Inc.
La Jolla Institute For Allergy And Immunology
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
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    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • G01N2800/28—Neurological disorders
    • G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette

Definitions

  • Parkinson's disease affects about 1 of 250 people older than 40, about 1 of 100 people older than 65, and about 1 of 10 people older than 80.
  • Parkinson's disease may result from abnormal deposits of synuclein (a protein in the brain that helps nerve cells communicate) (Merck Manual) .
  • synuclein a protein in the brain that helps nerve cells communicate
  • Lewy bodies can accumulate in several regions of the brain, particularly in the substantia nigra (deep within the cerebrum) and interfere with brain function (Merck Manual) .
  • Lewy bodies often accumulate in other parts of the brain and nervous system, suggesting that they may be involved in other disorders (Merck Manual) .
  • Lewy bodies In Lewy body dementia, Lewy bodies form throughout the outer layer of the brain (cerebral cortex) . Lewy bodies may also be involved in Alzheimer's disease (Merck Manual).
  • the present invention provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
  • determining the expression level of a gene in the sample iii) determining the expression level of a gene in the sample; iii) identifying the subject as afflicted with or at risk of developing PD if the expression level of the gene is elevated or lowered compared to baseline levels, wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
  • the present invention also provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
  • baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
  • Fig. 1 10 Parkinson's Disease (PD) donors and 10 age-matched healthy controls (HC) were recruited. The figure displays the ages of the members of each cohort.
  • PD Parkinson's Disease
  • HC healthy controls
  • Fig. 2A Sorted CD4 cells from PD and HC donors were analyzed using RNA-seq for expression levels of CD4 and CD8.
  • Fig. 2B Sorted CD8 cells from PD and HC donors were analyzed using RNA-seq for expression levels of CD4 and CD8.
  • Fig. 3 Principle component analysis (PCA) of expression levels in CD4 and CD8 sorted cells.
  • Fig. 4A Comparison of major immune cell subsets in HC vs PD donors.
  • Fig. 4B Comparison of major subsets of CD4 memory cells in HC vs PD donors .
  • Fig. 4C Comparison of major subsets of CD8 memory cells in HC vs PD donors .
  • each group of data points represents either PD data points or HC data points .
  • the PD or HC recited above each group of data points indicates which group of donors the group of data points represents .
  • Fig. 5 DEseq Analysis of HC vs PD donors.
  • Fig. 6Ai and 6Aii Heat map of top 100 genes in CD4 cells in HC vs PD donors .
  • the heat map is color coded so that Red indicates higher relative expression of a given gene and blue indicates lower relative expression.
  • the cohort column displays yellow for HC donors and blue for PD donors. All blue is shown as greyscale, all red is shown as greyscale with a "*" within the greyscale and all yellow is shown with a "+” within the greyscale.
  • the "*" and "+” may be black text or white text depending on the shade of greyscale.
  • Fig. 6B Principle component analysis (PCA) of the expression levels of the top 100 genes in CD4 cells for HC vs PD donors.
  • Fig. 7Ai and 7Aii Heat map of top 100 genes in CD8 cells in HC vs PD donors . The heat map is color coded so that Red indicates higher relative expression of a given gene and blue indicates lower relative expression.
  • the cohort column displays yellow for HC donors and blue for PD donors. All blue is shown as greyscale, all red is shown as greyscale with a "*" within the greyscale and all yellow is shown with a "+” within the greyscale. The "*" and "+” may be black text or white text depending on the shade of greyscale.
  • Fig. 7B Principle component analysis (PCA) of the expression levels of the top 100 genes in CD8 cells for HC vs PD donors.
  • PCA Principle component analysis
  • Fig. 8A PCA analysis of the expression levels of a combined set of the top 100 genes for each of the CD4 and CD8 cells (total of 200 genes) in both CD4 and CD8 cells for HC vs PD donors.
  • Fig. 8B PCA analysis of the expression levels of a combined set of the top 100 genes for each of the CD4 and CD8 cells (total of 200 genes) in CD4 cells for HC vs PD donors.
  • Fig. 8C PCA analysis of the expression levels of a combined set of the top 100 genes for each of the CD4 and CD8 cells (total of 200 genes) in CD8 cells for HC vs PD donors.
  • the present invention provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
  • identifying the subject as afflicted with or at risk of developing PD if the expression level of the gene is elevated or lowered compared to baseline levels, wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
  • the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC28310
  • the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC28310
  • the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2 , URMl, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, SKP2, LOC100131320 , FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687, ADAMTSl, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM
  • the T cells are CD4 cells.
  • the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45,
  • the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEAT1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104,
  • the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2 , URMl, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2, and the expression level of the gene is lowered compared to baseline levels.
  • the T cell is a CD8 cell.
  • the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AM , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20,
  • the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20, Y
  • the gene is one or more of: LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687 , ADAMTSl, FADS2, ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels .
  • the present invention also provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
  • baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
  • the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC28310
  • the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20,
  • the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC28310
  • the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2 , URMl, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2, and the expression level of the gene is lowered compared to baseline levels.
  • the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20,
  • the gene is one or more of: LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687 , ADAMTS1, FADS2, ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FA CF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels .
  • the present invention also provides methods for treating a subject afflicted with Parkinson's disease (PD), comprising administering to the subject a compound that is approved for use in treating subjects afflicted with PD.
  • PD Parkinson's disease
  • the subject is afflicted with cognitive decline, constipation or orthostatic hypotension.
  • the subject is afflicted with cognitive decline, and the cognitive decline is reduced spatial reasoning ability and/or reduced memory ability.
  • the present invention provides methods for treating a subject afflicted with Parkinson's disease (PD), comprising administering an immunosuppressant therapy to the subject.
  • PD Parkinson's disease
  • the present invention also provides methods for prophylactically treating a subject who has been identified as being at risk of developing Parkinson's disease (PD) , comprising administering to the subject an immunosuppressant therapy.
  • PD Parkinson's disease
  • the immunosuppressant therapy comprises administering an effective amount of an immunosuppressive compound to the subject.
  • the immunosuppressive compound is a calcineurin inhibitor, a compound that blocks a chemokine receptor that is expressed by a leukocyte, a glucocorticoid, a mTOR inhibitor, an anti-metabolic compound, a phosphodiesterase-5 inhibitor, an antibody, or a leukocyte function antigen-3 (LFA-3)/Fc fusion protein .
  • the immunosuppressive compound is a calcineurin inhibitor, and the calcineurin inhibitor is cyclosporine or tacrolimus .
  • the calcuneurin inhibitor is cyclosporine.
  • the immunosuppressive compound is a compound that blocks a chemokine receptor that is expressed by a leukocyte.
  • the immunosuppressive compound is approved for use in the treatment of subjects afflicted with human immunodeficiency virus (HIV) .
  • HIV human immunodeficiency virus
  • the immunosuppressive compound is maraviroc.
  • the immunosuppressive compound is a glucocorticoid, and the glucocorticoid is prednisone or prednisolone .
  • the immunosuppressive compound is a mTOR inhibitor, and the mTOR inhibitor is rapamaycin.
  • the immunosuppressive compound is an anti- metabolic compound
  • the anti-metabolic compound is azathioprine, micophenolate or mofetil.
  • the immunosuppressive compound is a phosphodiesterase-5 inhibitor, and the phosphodiesterase-5 inhibitor is sildenafil or paclitaxel.
  • the immunosuppressive compound is a LFA-3/Fc fusion protein
  • the LFA-3/Fc fusion protein is a CD2-directed LFA-3/Fc fusion protein.
  • the CD2-directed LFA-3/Fc fusion protein is alefacept .
  • the T cells in step i) are in a blood sample taken from the subject. In some embodiments, the sample is a blood sample .
  • the subject is a human subject.
  • NINDS Backgrounder According to the National Institute of Neurological disorders and Stroke, there is currently no test that can clearly identify the disease. (NINDS Backgrounder) . Sometimes people with suspected PD are given anti-Parkinson's drugs to see if they respond (NINDS Backgrounder) .
  • NINDS Backgrounder Microscopic brain structures called Lewy bodies, which can be seen only during an autopsy, are regarded as a hallmark of classical PD (NINDS Backgrounder) .
  • Autopsies have uncovered Lewy bodies in a surprising number of older persons without diagnosed PD -- 8% of people over 50, almost 13% of people over 70, and almost 16% of those over 80, according to one study (NINDS Backgrounder) .
  • NINDS Backgrounder a surprising number of older persons without diagnosed PD -- 8% of people over 50, almost 13% of people over 70, and almost 16% of those over 80, according to one study (NINDS Backgrounder) .
  • NINDS Backgrounder some experts believe PD is something of an "iceberg; phenomenon, " lurking undetected in as many as 20 people for each known Parkinson's patient (NINDS Backgrounder). Without wishing to be bound by any scientific theory, a few researchers contend that almost everyone would develop Parkinson's eventually if they lived long enough (NINDS Backgrounder) .
  • the present invention provides methods for identifying subjects afflicted with PD that would previously have remained undetected. Aspects of the present invention enable the detection of PD in presymptomatic stages . Additionally, the present invention provides methods for identifying those who might eventually develop PD.
  • PD has an increased prevalence with age. See, for example, the NINDS Backgrounder; and Van Den Eeden et al., (2003) Incidence of Parkinson's Disease: Variation by Age, Gender, and Race/Ethnicity, Am. J. Epidemiol. 157 (11) : 1015-1022, the entire content of each of which is hereby incorporated herein by reference.
  • PD ranks among the most common late-life neurodegenerative diseases, affecting approximately 1.5% to 2.0% of people aged 60 years and older (Patrick Sweeney, Parkinson's Disease, Cleveland Clinic, available at
  • the peripheral immune response of PD may begin in a subject decades before PD may be diagnosed by a neurologist, and subjects having the peripheral immune response may be identified for earlier therapy using methods of the invention.
  • peripheral symptoms associated with PD including orthostatic hypotension and constipation.
  • the present invention provides methods for diagnosing causes of these symptoms, and be used to identify subjects who may benefit from prophylactic treatment for PD.
  • aspects of the present invention provide a gene useful as a test/biomarker for PD, which could include identifying patients in preclinical stages or in danger of PD, and to measure disease progression and/or response. As described herein, aspects of the invention provide means to detect these biomarkers in patient blood.
  • baseline refers to expression levels of a gene in a subject not afflicted with Parkinson's Disease.
  • a "subject afflicted with" a condition means a subject who was been affirmatively diagnosed to have the condition .
  • treating a subject may comprise substantially reducing, slowing, stopping, preventing or reversing the progression of a disease, particularly a neurological disorder such as PD.
  • treating a subject may comprise substantially reducing, slowing, stopping, preventing or reversing a symptom of a disease. In the most favorable case, reduction is equivalent to prevention.
  • a "symptom" associated with PD includes any clinical or laboratory manifestation associated with PD and is not limited to what the subject can feel or observe.
  • Common symptoms of PD include but are not limited to tremors, muscle stiffness, difficulty maintaining balance, difficulty maintaining posture, bradykinesia, akinesia, rigid limbs, a shuffling gait, and a stooped posture.
  • Other symptoms of PD include but are not limited to depression, personality changes, dementia, sleep disturbances, speech impairments, and sexual difficulties.
  • ⁇ when referring to an amount of a compound administered to a subject for the treatment of a neurological disease refers to the quantity of the compound that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • anticholinergic compounds e.g., trihexyphenidyl, benztropine, amitiriptyline and diphenhydramine
  • antiviral compounds e.g., amantadine
  • beta-blockers e.g., propranolol
  • Non-limiting examples of compounds which may be used in the treatment of PD in embodiments of the invention also include immunosuppressive compounds.
  • an immunosuppressive compound targets an autoimmune component in PD, for example T cell activation or function.
  • approaches for suppressing the immune system, or a component thereof, in embodiments of the subject invention include:
  • Blocking receptors of chemokines such as CCR5 present on cytotoxic T cells. This can be achieved by using anatgonist drugs such as maraviroc. It will be understood that CCR5 is one of the HIV-1 receptors and such drugs have been in use for years to treat HIV patients.
  • glucocorticoid such as prednisone or prednisolone
  • a glucocorticoid such as prednisone or prednisolone
  • MS multiple sclerosis
  • calcineurin inhibitor such as cyclosporine or tacrolimus
  • calcineurin inhibitor such as cyclosporine or tacrolimus
  • calcineurin which blocks phosphatase activity, and thus T cell activation.
  • transplant rejection Administering an inhibitor of mTOR such as rapamaycin, which blocks cell cycle at G1>S phase. Rapamaycin inhibits T cell activation and proliferation. It is used to treat transplant rej ection .
  • a phosphodiesterase-5 inhibitor such as sildenafil or paclitaxel
  • This experiment investigated whether novel biomarkers could be derived from T cells in subjects suffering from Parkinson's Disease (PD) .
  • PD Parkinson's Disease
  • a cohort of PD and healthy control (HC) donors was recruited with the following characteristics: Age-matched 10 PD and 10 HC ( Figure 1), of which 5 PD and 4 HC expressed the DRB1*15:01 HLA allele. This allele has been shown to be associated with PD disease (Sulzer et al . , 2017) .
  • CD4 and CD8 memory T cells from these donors were sorted into two populations (excluding CD45RA + CCR7 + cells) .
  • the staining panel used to stain specific markers is shown in Table 1.
  • PCA Principal Component analysis

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Abstract

The present invention provides methods for assessing whether a subject is at risk of developing Parkinson's disease (PD), diagnosing or confirming whether a subject is afflicted with PD, assessing whether PD has progressed in a subject afflicted with PD, assessing whether PD is developing in a subject who has been identified as being at risk of developing PD, assessing whether a subject afflicted with PD is likely to benefit from a therapy, assessing whether a subject afflicted with PD has benefited from a therapy, treating a subject afflicted with PD, and prophylactically treating a subject who has been identified as being at risk of developing PD. The present invention also provides biomarkers relating to these methods.

Description

USE OF NOVEL BIOMARKERS IN THE DIAGNOSIS, CONFIRMATION, AND
TREATMENT OF PARKINSON' S DISEASE
This application claims priority of U.S. Provisional Application No. 62/567,718, filed October 3, 2017, the content of which is hereby incorporated by reference in its entirety.
Throughout this application, various publications are referenced, including referenced in parenthesis. Full citations for publications referenced in parenthesis may be found listed at the end of the specification immediately preceding the claims. The disclosures of all referenced publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains
Background of Invention
Parkinson's disease (PD) affects about 1 of 250 people older than 40, about 1 of 100 people older than 65, and about 1 of 10 people older than 80. Merck Manual, Parkinson's Disease, last full review/revision August 2007 by David Eidelberg and Michael Pourfar, available at merckmanuals.com/home/brain spinal cord and nerve disorders/movement disorders/parkinsons disease.html (hereinafter "Merck Manual") .
What causes PD is unclear. According to one theory, Parkinson's disease may result from abnormal deposits of synuclein (a protein in the brain that helps nerve cells communicate) (Merck Manual) . These deposits, called Lewy bodies, can accumulate in several regions of the brain, particularly in the substantia nigra (deep within the cerebrum) and interfere with brain function (Merck Manual) . Lewy bodies often accumulate in other parts of the brain and nervous system, suggesting that they may be involved in other disorders (Merck Manual) . In Lewy body dementia, Lewy bodies form throughout the outer layer of the brain (cerebral cortex) . Lewy bodies may also be involved in Alzheimer's disease (Merck Manual).
Improved and novel methods for diagnosing, confirming, providing biomarkers for, and treating PD are needed. Summary of the Invention
The present invention provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
i) obtaining a sample of T cells from the subject;
ii) determining the expression level of a gene in the sample; iii) identifying the subject as afflicted with or at risk of developing PD if the expression level of the gene is elevated or lowered compared to baseline levels, wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
The present invention also provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
i) obtaining a sample of T cells from the subject;
ii) separating the T cells into a pool of CD4 cells and a pool of CD8 cells;
iii) determining the expression level of a first gene in the pool of CD4 cells;
iv) determining the expression level of a second gene that is different from the first gene in the pool of CD8 cells; v) identifying the subject as afflicted with or at risk of developing PD if the expression levels of the first and second genes are independently elevated or lowered compared to baseline levels,
wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
Brief Description of the Drawings
Fig. 1: 10 Parkinson's Disease (PD) donors and 10 age-matched healthy controls (HC) were recruited. The figure displays the ages of the members of each cohort.
Fig. 2A: Sorted CD4 cells from PD and HC donors were analyzed using RNA-seq for expression levels of CD4 and CD8.
Fig. 2B: Sorted CD8 cells from PD and HC donors were analyzed using RNA-seq for expression levels of CD4 and CD8.
Fig. 3: Principle component analysis (PCA) of expression levels in CD4 and CD8 sorted cells. Fig. 4A: Comparison of major immune cell subsets in HC vs PD donors. Fig. 4B: Comparison of major subsets of CD4 memory cells in HC vs PD donors .
Fig. 4C: Comparison of major subsets of CD8 memory cells in HC vs PD donors .
In Fig. 4A-4C, each group of data points represents either PD data points or HC data points . The PD or HC recited above each group of data points indicates which group of donors the group of data points represents . Fig. 5: DEseq Analysis of HC vs PD donors.
Fig. 6Ai and 6Aii : Heat map of top 100 genes in CD4 cells in HC vs PD donors . The heat map is color coded so that Red indicates higher relative expression of a given gene and blue indicates lower relative expression. The cohort column displays yellow for HC donors and blue for PD donors. All blue is shown as greyscale, all red is shown as greyscale with a "*" within the greyscale and all yellow is shown with a "+" within the greyscale. The "*" and "+" may be black text or white text depending on the shade of greyscale.
Fig. 6B: Principle component analysis (PCA) of the expression levels of the top 100 genes in CD4 cells for HC vs PD donors. Fig. 7Ai and 7Aii : Heat map of top 100 genes in CD8 cells in HC vs PD donors . The heat map is color coded so that Red indicates higher relative expression of a given gene and blue indicates lower relative expression. The cohort column displays yellow for HC donors and blue for PD donors. All blue is shown as greyscale, all red is shown as greyscale with a "*" within the greyscale and all yellow is shown with a "+" within the greyscale. The "*" and "+" may be black text or white text depending on the shade of greyscale.
Fig. 7B: Principle component analysis (PCA) of the expression levels of the top 100 genes in CD8 cells for HC vs PD donors.
Fig. 8A: PCA analysis of the expression levels of a combined set of the top 100 genes for each of the CD4 and CD8 cells (total of 200 genes) in both CD4 and CD8 cells for HC vs PD donors.
Fig. 8B: PCA analysis of the expression levels of a combined set of the top 100 genes for each of the CD4 and CD8 cells (total of 200 genes) in CD4 cells for HC vs PD donors.
Fig. 8C: PCA analysis of the expression levels of a combined set of the top 100 genes for each of the CD4 and CD8 cells (total of 200 genes) in CD8 cells for HC vs PD donors.
Detailed Description of the Invention
The present invention provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
i) obtaining a sample comprising a population of T cells from the subject;
ii) determining the expression level of a gene in the population;
iii) identifying the subject as afflicted with or at risk of developing PD if the expression level of the gene is elevated or lowered compared to baseline levels, wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD. In some embodiments, the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5 , MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961 , APEX2, URM1 , GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, SKP2, NRIP3, EMR1 , SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, MTOR, LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOCI 00505687 , ADAMTS1 , FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1. In some embodiments, the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5 , NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AM , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, or MTOR, and the expression level of the gene is elevated compared to baseline levels.
In some embodiments, the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2 , URMl, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, SKP2, LOC100131320 , FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687, ADAMTSl, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2 , C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels.
In some embodiments, the T cells are CD4 cells. In some embodiments, the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5 , MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPA 3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961 , APEX2, URM1 , GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2. In some embodiments, the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEAT1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDDIA, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, or LRP5, and the expression level of the gene is elevated compared to baseline levels.
In some embodiments, the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2 , URMl, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2, and the expression level of the gene is lowered compared to baseline levels.
In some embodiments, the T cell is a CD8 cell.
In some embodiments, the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AM , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, MTOR, LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOCI 00505687 , ADAMTS1 , FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1.
In some embodiments, the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, or MTOR, and the expression level of the gene is elevated compared to baseline levels. In some embodiments, the gene is one or more of: LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687 , ADAMTSl, FADS2, ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels .
The present invention also provides methods for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising
i) obtaining a sample of T cells from the subject; ii) separating the T cells into a pool of CD4 cells and a pool of CD8 cells;
iii) determining the expression level of a first gene in the pool of CD4 cells;
iv) determining the expression level of a second gene that is different from the first gene in the pool of CD8 cells; v) identifying the subject as afflicted with or at risk of developing PD if the expression levels of the first and second genes are independently elevated or lowered compared to baseline levels,
wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
In some embodiments, the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5 , MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPA 3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961 , APEX2, URM1 , GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2.
In some embodiments, the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, MTOR, LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOCI 00505687 , ADAMTS1, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1.
In some embodiments, the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217 , SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4 , OTUD1, SHCBP1, TMEM170A, METTL5 , CEP192, SCG5, PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, or LRP5, and the expression level of the gene is elevated compared to baseline levels.
In some embodiments, the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2 , URMl, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2, and the expression level of the gene is lowered compared to baseline levels.
In some embodiments, the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS6, SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4 , ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, or MTOR, and the expression level of the gene is elevated compared to baseline levels. In some embodiments, the gene is one or more of: LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687 , ADAMTS1, FADS2, ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FA CF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels .
The present invention also provides methods for treating a subject afflicted with Parkinson's disease (PD), comprising administering to the subject a compound that is approved for use in treating subjects afflicted with PD.
In some embodiments, the subject is afflicted with cognitive decline, constipation or orthostatic hypotension.
In some embodiments, the subject is afflicted with cognitive decline, and the cognitive decline is reduced spatial reasoning ability and/or reduced memory ability.
The present invention provides methods for treating a subject afflicted with Parkinson's disease (PD), comprising administering an immunosuppressant therapy to the subject.
The present invention also provides methods for prophylactically treating a subject who has been identified as being at risk of developing Parkinson's disease (PD) , comprising administering to the subject an immunosuppressant therapy.
In some embodiments, the immunosuppressant therapy comprises administering an effective amount of an immunosuppressive compound to the subject.
In some embodiments, the immunosuppressive compound is a calcineurin inhibitor, a compound that blocks a chemokine receptor that is expressed by a leukocyte, a glucocorticoid, a mTOR inhibitor, an anti-metabolic compound, a phosphodiesterase-5 inhibitor, an antibody, or a leukocyte function antigen-3 (LFA-3)/Fc fusion protein . In some embodiments, the immunosuppressive compound is a calcineurin inhibitor, and the calcineurin inhibitor is cyclosporine or tacrolimus .
In some embodiments, the calcuneurin inhibitor is cyclosporine.
In some embodiments, the immunosuppressive compound is a compound that blocks a chemokine receptor that is expressed by a leukocyte.
In some embodiments, the immunosuppressive compound is approved for use in the treatment of subjects afflicted with human immunodeficiency virus (HIV) .
In some embodiments, the immunosuppressive compound is maraviroc.
In some embodiments, the immunosuppressive compound is a glucocorticoid, and the glucocorticoid is prednisone or prednisolone .
In some embodiments, the immunosuppressive compound is a mTOR inhibitor, and the mTOR inhibitor is rapamaycin.
In some embodiments, the immunosuppressive compound is an anti- metabolic compound, and the anti-metabolic compound is azathioprine, micophenolate or mofetil.
In some embodiments, the immunosuppressive compound is a phosphodiesterase-5 inhibitor, and the phosphodiesterase-5 inhibitor is sildenafil or paclitaxel.
In some embodiments, the immunosuppressive compound is a LFA-3/Fc fusion protein, and the LFA-3/Fc fusion protein is a CD2-directed LFA-3/Fc fusion protein.
In some embodiments, the CD2-directed LFA-3/Fc fusion protein is alefacept . In some embodiments, the T cells in step i) are in a blood sample taken from the subject. In some embodiments, the sample is a blood sample .
In some embodiments, the subject is a human subject.
PD is often diagnosed by a neurologist who can evaluate symptoms and their severity. National Institute of Neurological Disorders and Stroke, Parkinson's Disease Backgrounder, available at www.ninds.nih.gov/disorders/parkinsons disease/parkinsons disease ba ckgrounder.htm, last updated October 18, 2004 (hereinafter "NINDS Backgrounder". According to the National Institute of Neurological disorders and Stroke, there is currently no test that can clearly identify the disease. (NINDS Backgrounder) . Sometimes people with suspected PD are given anti-Parkinson's drugs to see if they respond (NINDS Backgrounder) . Other tests, such as brain scans, can help doctors decide if a patient has true PD or some other disorder that resembles it (NINDS Backgrounder) . Microscopic brain structures called Lewy bodies, which can be seen only during an autopsy, are regarded as a hallmark of classical PD (NINDS Backgrounder) . Autopsies have uncovered Lewy bodies in a surprising number of older persons without diagnosed PD -- 8% of people over 50, almost 13% of people over 70, and almost 16% of those over 80, according to one study (NINDS Backgrounder) . As a result, some experts believe PD is something of an "iceberg; phenomenon, " lurking undetected in as many as 20 people for each known Parkinson's patient (NINDS Backgrounder). Without wishing to be bound by any scientific theory, a few researchers contend that almost everyone would develop Parkinson's eventually if they lived long enough (NINDS Backgrounder) .
The present invention provides methods for identifying subjects afflicted with PD that would previously have remained undetected. Aspects of the present invention enable the detection of PD in presymptomatic stages . Additionally, the present invention provides methods for identifying those who might eventually develop PD. PD has an increased prevalence with age. See, for example, the NINDS Backgrounder; and Van Den Eeden et al., (2003) Incidence of Parkinson's Disease: Variation by Age, Gender, and Race/Ethnicity, Am. J. Epidemiol. 157 (11) : 1015-1022, the entire content of each of which is hereby incorporated herein by reference. PD ranks among the most common late-life neurodegenerative diseases, affecting approximately 1.5% to 2.0% of people aged 60 years and older (Patrick Sweeney, Parkinson's Disease, Cleveland Clinic, available at
www . clevelandclinicmeded . com/medicalpubs /diseasemanagement/neurology /parkinsons-disease/ ) . Without wishing to be bound by any scientific theory, the peripheral immune response of PD may begin in a subject decades before PD may be diagnosed by a neurologist, and subjects having the peripheral immune response may be identified for earlier therapy using methods of the invention. There are a number of peripheral symptoms associated with PD including orthostatic hypotension and constipation. The present invention provides methods for diagnosing causes of these symptoms, and be used to identify subjects who may benefit from prophylactic treatment for PD.
Aspects of the present invention provide a gene useful as a test/biomarker for PD, which could include identifying patients in preclinical stages or in danger of PD, and to measure disease progression and/or response. As described herein, aspects of the invention provide means to detect these biomarkers in patient blood.
Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention .
It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, "0.2-5 mg/kg" is a disclosure of 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg etc. up to 5.0 mg/kg . Terms
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs.
As used herein, and unless stated otherwise or required otherwise by context, each of the following terms shall have the definition set forth below.
As used herein, "about" in the context of a numerical value or range means +10% of the numerical value or range recited or claimed, unless the context requires a more limited range.
As used herein, "baseline", as used in connection with expression levels, refers to expression levels of a gene in a subject not afflicted with Parkinson's Disease.
As used herein, a "subject afflicted with" a condition, e.g. PD, means a subject who was been affirmatively diagnosed to have the condition .
It will be understood that by "treating" a subject there are multiple possible outcomes. For instance, treating a subject may comprise substantially reducing, slowing, stopping, preventing or reversing the progression of a disease, particularly a neurological disorder such as PD. Additionally, treating a subject may comprise substantially reducing, slowing, stopping, preventing or reversing a symptom of a disease. In the most favorable case, reduction is equivalent to prevention.
As used herein, a "symptom" associated with PD includes any clinical or laboratory manifestation associated with PD and is not limited to what the subject can feel or observe. Common symptoms of PD include but are not limited to tremors, muscle stiffness, difficulty maintaining balance, difficulty maintaining posture, bradykinesia, akinesia, rigid limbs, a shuffling gait, and a stooped posture. Other symptoms of PD include but are not limited to depression, personality changes, dementia, sleep disturbances, speech impairments, and sexual difficulties.
As used herein, "effective" when referring to an amount of a compound administered to a subject for the treatment of a neurological disease refers to the quantity of the compound that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
Non-limiting examples of compounds which may be used in the treatment of PD in embodiments of the invention include dopamine precursors
(e.g., levodopa and carbidopa) , dopamine agonists (e.g., bromocriptine, pramipexole, ropinirole, apomorphine, and rotigotine) , MAO-B inhibitors (e.g., rasagiline and selegiline), COMT inhibitors
(e.g., entacapone and tolcapone) , anticholinergic compounds (e.g., trihexyphenidyl, benztropine, amitiriptyline and diphenhydramine) antiviral compounds (e.g., amantadine), and beta-blockers (e.g., propranolol) .
Non-limiting examples of compounds which may be used in the treatment of PD in embodiments of the invention also include immunosuppressive compounds. In some embodiments, an immunosuppressive compound targets an autoimmune component in PD, for example T cell activation or function. Non-limiting examples of approaches for suppressing the immune system, or a component thereof, in embodiments of the subject invention include:
1. Blocking receptors of chemokines such as CCR5 present on cytotoxic T cells. This can be achieved by using anatgonist drugs such as maraviroc. It will be understood that CCR5 is one of the HIV-1 receptors and such drugs have been in use for years to treat HIV patients.
2. Administering a glucocorticoid such as prednisone or prednisolone, which are are effective immunosuppressive agents. They inhibit the activation of cytotoxic T cells . Additionally, they cross the blood brain barrier and are used to treat multiple sclerosis (MS).
Administering a calcineurin inhibitor such as cyclosporine or tacrolimus, which are potent immunosuppressive agents. They inhibit calcineurin, which blocks phosphatase activity, and thus T cell activation. They are used to inhibit transplant rejection Administering an inhibitor of mTOR such as rapamaycin, which blocks cell cycle at G1>S phase. Rapamaycin inhibits T cell activation and proliferation. It is used to treat transplant rej ection .
Administering an anti-metabolic drug including azathioprine , micophenolate or mofetil to block killer T cells .
Administeration of antibodies for LFA-3Igl fusion protein, which interferes with T cell activation. This has been used in psoriasis .
Administering a phosphodiesterase-5 inhibitor such as sildenafil or paclitaxel, which have been used in melanoma to lead to cell- mediated T cell immunosupression .
General techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.) . These references in their entireties are hereby incorporated by reference into this application.
All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference. Publications and references cited herein are not admitted to be prior art.
This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as defined in the claims which follow thereafter .
Experimental Details
Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only .
Example 1
This experiment investigated whether novel biomarkers could be derived from T cells in subjects suffering from Parkinson's Disease (PD) .
A cohort of PD and healthy control (HC) donors was recruited with the following characteristics: Age-matched 10 PD and 10 HC (Figure 1), of which 5 PD and 4 HC expressed the DRB1*15:01 HLA allele. This allele has been shown to be associated with PD disease (Sulzer et al . , 2017) . CD4 and CD8 memory T cells from these donors were sorted into two populations (excluding CD45RA+CCR7+ cells) . The staining panel used to stain specific markers is shown in Table 1.
Table 1. Staining Panel
Marker Fluorochrome Clone
CD25 FITC M-A251
CD56 PE CMSSB
CCR7 PerCPCy5.5 G043H7
CD19 PECy7 HIB19
CD4 APCEf780 RPA-T4
LiveDead V500 -
CD45RA Ef450 HI100
CD14 APC 61D3
CD3 AF700 UCHT1
CD8a BV650 RPA-T8
In terms of CD4 and CD8 expression, differences were detected between the two populations, irrespective of whether the donor was from the PD or HC cohorts (Figure 2A and 2B) .
As expected, Principal Component analysis (PCA) could readily discriminate between CD4 and CD8 samples (Figure 3) . However, no differences were found in the frequency of the major cell subsets between PD and HC (Figure 4A-C) .
Gene expression was then analyzed in the CD4 and CD8 samples. Table 2 below lists the comparisons that were conducted. As shown in Figure 5, no transcriptional signature was found that could differentiate PD donors as compared to HC donors when analyzed with DEseq .
Table 2. DEseq Comparisons
Figure imgf000022_0001
However, analysis of the top 100 genes demonstrated significant differences in gene expression between PD and HC in the case of either CD4 (Figure 6A and 6B) or CD8 (Figure 7A and 7B) .
An analysis of the combined set of the top 100 genes for each of CD4 and CD8 cells (a total of 200 genes) was also conducted. Figs. 8A-C display the results of this analysis. References
1. Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin Liebes J, et al . (2017) T cells from patients with Parkinson' disease recognize alpha-synuclein peptides. Nature, 5 6 ( 7660 ): 656 61.

Claims

Claims What is claimed is :
1. A method for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising:
i) obtaining a sample from the subject comprising a population of T cells;
ii) determining the expression level of a gene in the population; and
iii) identifying the subject as afflicted with or at risk of developing PD if the expression level of the gene is elevated or lowered compared to baseline levels, wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
2. The method of claim 1, wherein the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217, SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4, OTUD1, SHCBP1, TMEM17 OA, METTL5 , CEP192, SCG5 , PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5, MYLK, NODI, HEXIM2 , GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2, URM1 , GPX7, WDR83, SUOX, NOG, PUS1, CCDC127, BIK, SKP2, NRIP3, EMR1 , SNN, RPS6KL1, LOCI 00128191 , SNORD36B, SNORD31, HNF1A, LOCI 00506801 , LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2, ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, MTOR, LOC100131320 , FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687 , ADAMTSl, FADS2, ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2 , C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FA CF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2, C7orf49, MRPS16, TMLHE, or HDHD1.
3. The method of claims 1 or 2, wherein the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217, SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4, OTUD1, SHCBP1, TMEM17 OA, METTL5 , CEP192, SCG5 , PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5 , NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2 , SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, or MTOR, and the expression level of the gene is elevated compared to baseline levels .
4. The method of claims 1 or 2, wherein the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961 , APEX2, URM1 , GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, SKP2, LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687 , ADAMTS1 , FADS2, ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2 , C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels .
5. The method of claim 1, wherein the T cells are CD4 cells.
6. The method of claim 5, wherein the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217, SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEAT1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4, OTUD1, SHCBP1, TMEM17 OA, METTL5 , CEP192, SCG5 , PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5, MYLK, NODI, HEXIM2 , GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2, URM1 , GPX7, WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2.
7. The method of claims 5 or 6, wherein the gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217, SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEAT1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4, OTUD1, SHCBP1, TMEM17 OA, METTL5 , CEP192, SCG5 , PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDDIA, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, or LRP5 , and the expression level of the gene is elevated compared to baseline levels .
8. The method of claims 5 or 6, wherein the gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961 , APEX2, URM1 , GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2, and the expression level of the gene is lowered compared to baseline levels .
9. The method of claim 1, wherein the T cell is a CD8 cell.
10. The method of claim 9, wherein the gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AM , PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, MTOR, LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687, ADAMTSl, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2 , C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1.
11. The method of claims 9 or 10, wherein the gene is one or more of: NRIP3, EMR1 , SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2 , SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, or MTOR, and the expression level of the gene is elevated compared to baseline levels.
12. The method of claims 9 or 10, wherein the gene is one or more of: LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOCI 00505687 , ADAMTSl, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2, C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels .
13. A method for assessing whether a subject is afflicted with or at risk of developing Parkinson's disease (PD) comprising:
i) obtaining a sample of T cells from the subject;
ii) separating the T cells into a pool of CD4 cells and a pool of CD8 cells;
iii) determining the expression level of a first gene in the pool of CD4 cells;
iv) determining the expression level of a second gene that is different from the first gene in the pool of CD8 cells; v) identifying the subject as afflicted with or at risk of developing PD if the expression levels of the first and second genes are independently elevated or lowered compared to baseline levels,
wherein the baseline expression level represents the level of expression of the gene in a subject not afflicted with PD.
14. The method of claim 13, wherein the first gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217, SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4, OTUD1, SHCBP1, TMEM17 OA, METTL5 , CEP192, SCG5 , PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, LRP5, MYLK, NODI, HEXIM2 , GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2, URM1 , GPX7, WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2.
15. The method of claims 13 or 14, wherein the second gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOCI 00128191 , SNORD36B, SNORD31, HNF1A, LOC100506801, LOC644656, BTBD19 , PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2 , SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2 , ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, MTOR, LOC100131320, FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687, ADAMTSl, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2 , C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1.
16. The method of any of claims 13-15, wherein the first gene is one or more of: RNF139, KIF20B, SECISBP2, C10orfll8, C6orf72, ATP11C, HNRNPH1, SNORD18A, SNORD27, PFDN4, PTGES3, AP3S1, ZNF770, RIPK2, LOC100507217, SNORD80, SLTM, PFN2, PAPOLA, CTNNAL1, SNORD47, MFF, GPR174, ATAD2B, XPA, BBIP1, NEA 1 , TMEM167A, HSP90AB2P, MAP3K13, ERP44, WDR5B, CPM, CCZ1B, FER, MMS22L, JAZF1, LARP4, CBR4, OTUD1, SHCBP1, TMEM17 OA, METTL5 , CEP192, SCG5 , PRSS12, DCAF16, LYRMl, C14orf45, FAM133B, LYAR, LOC283104, ACER3, C20orfl97, AGBL2 , FNDC9, FNLJ40292, TLR6, CR1, Cllorf63, SNORD58A, ANKDD1A, EPAS1, RRN3P3, SH3D21, ZNF43B, POLR2J2, or LRP5 , and the expression level of the gene is elevated compared to baseline levels .
17. The method of any of claims 13-15, wherein the first gene is one or more of: MYLK, NODI, HEXIM2, GUSB, NBPF14, SLC30A6, FMNL1, CYP2U1, CLDN12, EXOC3L1, ZNF311, DBH, ZNF57, EMR4P, LOC440131, AGPAT3 , FLJ12334, CYP2D7P1, TPRN, S100A11, CTSL1, LOC100129961, APEX2, URM1, GPX7 , WDR83, SUOX, NOG, PUS1, CCDC127, BIK, or SKP2, and the expression level of the gene is lowered compared to baseline levels .
18. The method of any of claims 13-17, wherein the second gene is one or more of: NRIP3, EMR1, SNN, RPS6KL1, LOC100128191, SNORD36B, SNORD31, HNF1A, LOCI 00506801 , LOC644656, BTBD19, PIP5KL1, CCDC114, SCARNA12, NANS, SPAG6 , HIST1H3H, ZFYVE9, HIST1H4A, AMT, PVRL2, SETD9, LILRB3, SNORD78, SNED1, CHKA, GAS 6 , SLC5A6, HEY2, OASL, TSPYL2, SYBU, POLR2J2, BEST1, CCDC84, PER2, YRDC, ACINI, SRRT, RHBDL1, RSAD2, ZC3HAV1, SH2B3, HSBP1L1, ILF3, COL18A1, SLC9A8, PHF20, SLC24A4, OTUD4, ZNF850, METTL20, YWHAE, FRMD4B, NDFIP1, VLDLR, PRKRA, LONP1, ISG20, or MTOR, and the expression level of the gene is elevated compared to baseline levels .
19. The method of any of claims 13-17, wherein the second gene is one or more of: LOC100131320 , FBX021, CCDC81, TRPM2, PRSS57, GMPR, ARHGAP20 , KIAA0889, EIF4EBP1, TMEM119, MGC23284, STXBP6, LOC100505687, ADAMTS1, FADS2 , ZNF501, NUDT7, ZNF619, POLI, FAM21C, ARRDC3, ATF1, TMEM81, APC2 , C14orfll9, ZNF585B, SLC46A3, ZFP90, DIS3L, GALNT7, FANCF, ZNF41, TIGD7, TSEN2, NIF3L1, ACAA2 , C7orf49, MRPS16, TMLHE, or HDHD1, and the expression level of the gene is lowered compared to baseline levels.
20. A method for treating a subject afflicted with Parkinson's disease (PD) , comprising determining whether the subject is afflicted with PD using the methods of any of claims 1-19, and administering to the subject identified to be afflicted with PD a compound that is approved for use in treating subjects afflicted with PD.
21. The method of claim 20, wherein the subject is afflicted with cognitive decline, constipation or orthostatic hypotension.
22. The method of claims 20 or 21, wherein the subject is afflicted with cognitive decline, and the cognitive decline is reduced spatial reasoning ability and/or reduced memory ability.
23. A method for treating a subject afflicted with Parkinson's disease (PD) , comprising determining whether the subject is afflicted with PD using the methods of any of claims 1-19, and administering an immunosuppressant therapy to the subject.
24. A method for prophylactically treating a subject who has been identified as being at risk of developing Parkinson's disease (PD) , comprising determining whether the subject is at risk of developing PD using the methods of any of claims 1-19, and administering to the subject an immunosuppressant therapy.
25. The method of claims 23 or 24, wherein the immunosuppressant therapy comprises administering an effective amount of an immunosuppressive compound to the subject.
26. The method of any of claims 23-25, wherein the immunosuppressive compound is a calcineurin inhibitor, a compound that blocks a chemokine receptor that is expressed by a leukocyte, a glucocorticoid, a mTOR inhibitor, an anti-metabolic compound, a phosphodiesterase-5 inhibitor, an antibody, or a leukocyte function antigen-3 (LFA-3)/Fc fusion protein.
27. The method of any of claims 23-26, wherein the immunosuppressive compound is a calcineurin inhibitor, and the calcineurin inhibitor is cyclosporine or tacrolimus.
28. The method of any of claims 23-27, wherein the calcuneurin inhibitor is cyclosporine.
29. The method of any of claims 23-26, wherein the immunosuppressive compound is a compound that blocks a chemokine receptor that is expressed by a leukocyte.
30. The method of any of claims 23-26, wherein the immunosuppressive compound is approved for use in the treatment of subjects afflicted with human immunodeficiency virus (HIV) .
31. The method of any of claims 23-26, wherein the immunosuppressive compound is maraviroc.
32. The method of any of claims 23-26, wherein the immunosuppressive compound is a glucocorticoid, and the glucocorticoid is prednisone or prednisolone.
33. The method of any of claims 23-26, wherein the immunosuppressive compound is a mTOR inhibitor, and the mTOR inhibitor is rapamaycin.
34. The method of any of claims 23-26, wherein the immunosuppressive compound is an anti-metabolic compound, and the anti-metabolic compound is azathioprine , micophenolate or mofetil.
35. The method of any of claims 23-26, wherein the immunosuppressive compound is a phosphodiesterase-5 inhibitor, and the phosphodiesterase-5 inhibitor is sildenafil or paclitaxel.
36. The method of any of claims 23-26, wherein the immunosuppressive compound is a LFA-3/Fc fusion protein, and the LFA-3/Fc fusion protein is a CD2-directed LFA-3/Fc fusion protein.
37. The method of claim 36, wherein the CD2-directed LFA-3/Fc fusion protein is alefacept.
38. The method of any of claims 1-37, wherein the sample is a blood sample .
39. The method of any of claims 1-38, wherein the subject is a human subj ect .
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