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(12) Patent Application Publication (10) Pub. No.: US 2016/0289762 A1 KOH Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0289762 A1 KOH Et Al US 201602897.62A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0289762 A1 KOH et al. (43) Pub. Date: Oct. 6, 2016 (54) METHODS FOR PROFILIING AND Publication Classification QUANTITATING CELL-FREE RNA (51) Int. Cl. (71) Applicant: The Board of Trustees of the Leland CI2O I/68 (2006.01) Stanford Junior University, Palo Alto, (52) U.S. Cl. CA (US) CPC ....... CI2O 1/6883 (2013.01); C12O 2600/112 (2013.01); C12O 2600/118 (2013.01); C12O (72) Inventors: Lian Chye Winston KOH, Stanford, 2600/158 (2013.01) CA (US); Stephen R. QUAKE, Stanford, CA (US); Hei-Mun Christina FAN, Fremont, CA (US); Wenying (57) ABSTRACT PAN, Stanford, CA (US) The invention generally relates to methods for assessing a (21) Appl. No.: 15/034,746 neurological disorder by characterizing circulating nucleic acids in a blood sample. According to certain embodiments, (22) PCT Filed: Nov. 6, 2014 methods for S. a Nial disorder include (86). PCT No.: PCT/US2O14/064355 obtaining RNA present in a blood sample of a patient Suspected of having a neurological disorder, determining a S 371 (c)(1), level of RNA present in the sample that is specific to brain (2) Date: May 5, 2016 tissue, comparing the sample level of RNA to a reference O O level of RNA specific to brain tissue, determining whether a Related U.S. Application Data difference exists between the sample level and the reference (60) Provisional application No. 61/900,927, filed on Nov. level, and indicating a neurological disorder if a difference 6, 2013. is determined. Patent Applica US 2016/02897.62 A1 Patent Application Publication Oct. 6, 2016 Sheet 2 of 37 US 2016/02897.62 A1 0000|| 000G ?.Od 0000G-0000|- 000G 000G Patent Application Publication US 2016/02897.62 A1 Patent Application Publication Oct. 6, 2016 Sheet 4 of 37 US 2016/02897.62 A1 Patent Application Publication Oct. 6, 2016 Sheet 7 of 37 US 2016/02897.62 A1 Ranking by Significance Gene Name 5 HIST1H4B 6 TREML.1 7 NPTN 8 LSM2 SCGB1C1 NOP10 MFSD1 MALAT1 GDI1 HIST1H1C HIST1H4H CD226 FIG. 4 Patent Application Publication Oct. 6, 2016 Sheet 9 of 37 US 2016/02897.62 A1 SEINE5)Ol=|13)EdSENTISSILHONOI_L\/OI=I_LNEIGII 5DNIHOLVINEILV/Tc||NELL'], TO?|LNOOALITVITO"Z |SEITCHINVSOIHIDEICHSEITISSIL Patent Application Publication Oct. 6, 2016 Sheet 11 of 37 US 2016/02897.62 A1 ºnSSIL IOXOqpeQUDIJOJ 3uueNIInHºu05) ZQUOUJOU,U?AAOJ?ZHR) A. O 9 Patent Application Publication Oct. 6, 2016 Sheet 12 of 37 US 2016/02897.62 A1 ejuºseI,IgJequêu‘KIIULIEJ9XIII-XINILNpubLITS ZVN5) 9IIRIGIÐ (HdHAO 18.L^IXI |OZHOHIA INIAI RIIAdAN IRISJLN IZVO LOSd. ©IGHÈO,LAI CHOHRI Z{{JLVS LVNI«TRICHS ?XIRILITIS Patent Application Publication Oct. 6, 2016 Sheet 13 of 37 US 2016/0289762 A1 FIG. 9A Example of raw qPCR data for fetal brain transcript ZNF238 obtained from subject sample P53 shows the changes across the three trimesters & post-partum. Amplification É Patent Application Publication Oct. 6, 2016 Sheet 14 of 37 US 2016/02897.62 A1 FIG. 9B Example of raw qPCR data for fetal brain transcript ZNF238 obtained from subject sample P53 shows the melting curve of the same experiments of 9A. Melting O.40 0.38 O.36. 0.34 0.32. O3O 0.28 0.26 0.24. 0.22 O20 O. 18. 0.16. 0.14 0.12 O 1 O. O.O8. 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Patent Application Publication Oct. 6, 2016 Sheet 17 of 37 US 2016/02897.62 A1 3. 8) Rico v v CD Patent Application Publication Oct. 6, 2016 Sheet 18 of 37 US 2016/02897.62 A1 ZXTG|GOTW ZEIVS||HSLN INWIZVN9||ZXTG|GOTVO on O efuel picio Patent Application Publication Oct. 6, 2016 Sheet 19 of 37 US 2016/02897.62 A1 (eiti e de Patent Application Publication Oct. 6, 2016 Sheet 20 of 37 US 2016/02897.62 A1 ZXTO XOO & Rei 20 Patent Application Publication Oct. 6, 2016 Sheet 21 of 37 US 2016/0289762 A1 Figure 3. i-eative Caposition of different orga:8 coiiriisitioi towaris piasinia ceilies: transcript 313& ig ire 4, ac{{np}{38iticis of {}rgan citrit::tio towards ce: free transcripton: 3:iig. 3 NA-se: sia: Patent Application Publication Oct. 6, 2016 Sheet 23 of 37 US 2016/0289762 A1 Detecting a Sample level of RNA in a Biological Sample Comparing the Sample Level of RNA to a Reference eve of RNA Determining Whether a Difference Exists Between the Sample Level and the Reference Level Characterizing the Tissue as Abnormal if a Difference is Detected FIG. 16 Patent Application Publication US 2016/02897.62 A1 casa s ? F.G. 17 Patent Application Publication Oct. 6, 2016 Sheet 25 of 37 US 2016/02897.62 A1 Experimental Des gn SSS: &8 grass 8888g: * * : * Sists & Syst &sis: WY & ?r tiss E is firsa S. SSSSSSSSSSSSSSSSSSSSSSSSSSSSS s SSSSSSSSSSSSSSSSSSSSSSSSSSSSS stilized NFS pigeiste %?*** FIG. 18 Patent Application Publication Oct. 6, 2016 Sheet 26 of 37 US 2016/02897.62 A1 Temporal varying Genes FIG. 19 Patent Application Publication Oct. 6, 2016 Sheet 27 of 37 US 2016/0289762 A1 & S. & 83. W S. $8& ::ssssss & S. Patent Application Publication Oct. 6, 2016 Sheet 28 of 37 US 2016/02897.62 A1 % s Ssss & &w8 s |uo?anqunuopmenad Patent Application Publication Oct. 6, 2016 Sheet 29 of 37 US 2016/0289762 A1 S. S Sss XXX SSXX S.& S. S.& Patent Application Publication Oct. 6, 2016 Sheet 30 of 37 US 2016/0289762 A1 Patent Application Publication Oct. 6, 2016 Sheet 31 of 37 US 2016/0289762 A1 | & S. & $& S.$ S.S S & & & S & Patent Application Publication Oct. 6, 2016 Sheet 32 of 37 US 2016/02897.62 A1 ssie Cornpos ::: S. S. × FIG. 25 Patent Application Publication Oct. 6, 2016 Sheet 33 of 37 US 2016/02897.62 A1 Tissue Composition Subject Stject 2 Sigriseasis 2s Hypoala Sas iyiphthalasis : W Sisirisis: 888. Big: iaiti:8isitsis 3% ymphods Boneiaarow 3% &ryggaia 4% 3:3Rivisis is Sotite issues 3% iyiri is 38. 8:33,838. ge3.cxxiii.2% Sutject 3 Subject 4. gags: hygihaiaris & 8:33:31:3 is: lying:3ie 88. Broix:aEpiteia:Ceis 3% 88:38::3% Si:icists 8: Sysius.2% S$38, Sis itytrid 2% S sayings 3% FG. 26 Patent Application Publication Oct. 6, 2016 Sheet 34 of 37 US 2016/0289762 A1 m ississis & & FIG. 27 Patent Application Publication Oct. 6, 2016 Sheet 35 of 37 US 2016/0289762 A1 s S SSss & $8S : WW’ MWSS^^^^^^^^^^^^^^^^^^^W. SS 3.s S. s &SS S 8-X-XX-3---------------x-----------------------------& Patent Application Publication Oct. 6, 2016 Sheet 36 of 37 US 2016/02897.62 A1 SSS Patent Application Publication Oct. 6, 2016 Sheet 37 of 37 US 2016/0289762 A1 100 ,, sysS. sisSaaS s, AUC: O.79. S .. s: ... 0.50 o.75 Faise Fositive Rate FG. 3O US 2016/02897.62 A1 Oct. 6, 2016 METHODS FOR PROFLING AND circulating nucleic acid that are specific to brain tissue. The QUANTITATING CELL-FREE RNA present invention recognizes that abnormal deviations in circulating nucleic acid result from tissue-specific nucleic RELATED APPLICATIONS acid being released into the blood in large amounts as tissue 0001. This application claims the benefit of and priority begins to fail and degrade. By focusing on genes the to U.S. Provisional No. 61/900,927, filed Nov. 6, 2013, and expression of which is highly specific to brain tissue, meth is a continuation-in-part of U.S. Non-Provisional Ser. No. ods of the invention allow one to characterize the extent of 13/752,131, filed Jan. 28, 2013, which claims the benefit of brain degradation based on statistically-significant levels of and priority to U.S. Provisional No. 61/591,642, filed on Jan. circulating brain-specific transcripts; and use that character 27, 2012. The entirety of each foregoing application is ization to diagnose and determine the stage of the neuro incorporated herein by reference. logical disease. Accordingly, methods of the invention allow one to characterize neurological disorders without focusing TECHNICAL FIELD on Small Subset of known biomarkers, but rather focusing on the extent to which nucleic acid is released into blood from 0002 The present invention relates to assessing neuro brain tissue affected by disease. Methods of the invention are logical disorders based on nucleic acid specific to brain particularly useful in diagnosing and determining the stage tissue. of Alzheimer's disease. 0007. In particular embodiments, methods of the inven BACKGROUND tion include obtaining RNA from a blood sample of a patient 0003. Dementia is a catchall term used to characterize Suspected of having a neurological disorder, and determin cognitive declines that interfere with one’s ability to perform ing a level of the sample RNA that originated from brain everyday activities. Signs of dementia include declines in tissue. In certain embodiments, the RNA is converted to the following mental functions: memory, communication cDNA. The level of the sample RNA specific to brain tissue and language, ability to focus and pay attention, reasoning, is then compared to a reference level of RNA that is specific judgment, motor skills, and visual perception. While there to brain tissue. The reference level may be derived from a are several neurological disorders that cause dementia, Subject or patient population having a neurological disorder Alzheimer's disease is the most common, accounting for 60 or from a normal/control Subject or patient population.
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