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( 19 ) United States US 20190242909A1 ( 19) United States ( 12) Patent Application Publication ( 10 ) Pub. No. : US 2019 / 0242909 A1 Narain et al. (43 ) Pub. Date : Aug. 8 , 2019 ( 54 ) COMPOSITIONS AND METHODS FOR CO7K 16 / 18 ( 2006 . 01 ) DIAGNOSIS AND TREATMENT OF A61K 38 / 48 ( 2006 . 01 ) PERVASIVE DEVELOPMENTAL DISORDER A61K 38 / 46 (2006 .01 ) (71 ) Applicant : Berg LLC , Framingham , MA (US ) A61K 38 / 45 ( 2006 .01 ) A61K 38 /44 ( 2006 .01 ) ( 72 ) Inventors : Niven Rajin Narain , Cambridge , MA (52 ) U . S . CI. (US ) ; Paula Patricia Narain , Cambridge , MA (US ) CPC .. GOIN 33 /6896 ( 2013 .01 ) ; C12Q 2600 / 158 ( 2013. 01 ); C12Q 1 /6883 (2013 .01 ) ; CO7K ( 21 ) Appl. No. : 16 /275 , 944 16 / 18 (2013 .01 ) ; A61K 38 /4813 (2013 . 01 ) ; A61K 38 /46 ( 2013 .01 ) ; A61K 38 /45 ( 2013 .01 ) ; (22 ) Filed : Feb . 14 , 2019 A61K 38 /44 ( 2013 .01 ) ; CO7K 2317 / 51 Related U . S . Application Data ( 2013 .01 ) ; GOIN 2500 / 00 ( 2013 .01 ) ; GOIN (63 ) Continuation of application No. 15 /830 , 982 , filed on 2800 / 50 ( 2013. 01 ) ; C12Q 2600/ 178 (2013 . 01 ) ; Dec . 4 , 2017 , now abandoned , which is a continuation C12Q 2600 /136 ( 2013 .01 ) ; GOIN 2333 /70546 of application No. 15 / 493 , 383 , filed on Apr. 21 , 2017 , ( 2013 .01 ) ; GOIN 2800 / 56 ( 2013 .01 ) ; GOIN now abandoned , which is a continuation of applica 2800 /52 ( 2013 .01 ) ; GOIN 2800/ 2821 tion No. 15 /265 , 174 , filed on Sep . 14 , 2016 , now abandoned , which is a continuation of application No . ( 2013. 01 ) ; GOIN 2800 /2814 (2013 .01 ) ; GOIN 14 / 383 ,450 , filed on Sep . 5 , 2014 , now abandoned , 2333 / 8121 (2013 .01 ) ; GOIN 2333 / 705 filed as application No . PCT/ US2013 / 029201 on Mar. ( 2013 .01 ) ; GOIN 2333/ 47 ( 2013 .01 ) ; GOIN 5 , 2013 . 2333 / 9643 ( 2013 .01 ) ; GOIN 2333/ 948 (60 ) Provisional application No . 61 /606 , 935, filed on Mar . ( 2013 . 01 ) ; GOIN 2333/ 914 (2013 . 01 ) ; GOIN 5 , 2012 . 2333/ 902 (2013 . 01) ; A61K 38 /1709 (2013 . 01) Publication Classification ( 57 ) ABSTRACT (51 ) Int. CI. Methods for treatment and diagnosis of pervasive develop GOIN 33 /68 ( 2006 . 01 ) A61K 38 / 17 (2006 . 01 ) mental disorders in humans are described . C12Q 1 /6883 ( 2006 . 01 ) Specification includes a Sequence Listing . Patent Application Publication Aug. 8 , 2019 Sheet 1 of 15 US 2019 / 0242909 A1 * ** * * ** * * * * * * ** DNA *Proteins Metabolites TA Phenotype/Function Figure1 Genomics ov Proteomics ** Transcriptomics Sitter **** * Metabolomics - initie Interactome Patent Application Publication Aug. 8 , 2019 Sheet 2 of 15 US 2019 / 0242909 A1 assays Mechanismof Invitro Geneties Omics signatures Functional pathophysiology Statestation AlBasedDataDrivenInference Modelbuilding Datamining Biomarkers Figure2 Therapeutic target Qualityoflife Invivo/Clinical Genetics Omics sienature Outcome measurement studies Patent Application Publication Aug. 8 , 2019 Sheet 3 of 15 US 2019 / 0242909 A1 Metabolites . Lipids : : : : . Mechanismsof Pathophysiology *** ** ** * ** * * * 41431 AAAAA Proteins . WS Interactome Biomarker . 2! wy, . # RNA XV Figure3 TheInterrogativeBiology®Platform DNA InterrogativeMIMS Organelles *** * * **** * * ArtificialIntelligencebasedinformatics Cells Patent Application Publication Aug. 8 , 2019 Sheet 4 of 15 US 2019 / 0242909 A1 . * * . it . Figure4DModelInterventionSimulation Figure4BBayesianFragmentEnumeration. - , - , - , - , - , - , - , , - , - , - , - , - , , - , - , , - , , - , - - - - - - - - - - - - - - Figure4ADataProcessing Figure4CParallelEnsembleSampling Patent Application Publication Aug. 8 , 2019 Sheet 5 of 15 US 2019 / 0242909 A1 Figure5 - - - - CellularResponse),210 missingvaluesetc.),2012 - Generateensembleofinitialtrial fragments,216 ensemble,218 predictions,222 InputRawData (ExpressionlevelofPlurality Genes&FunctionalActivityor Pre-processrawdata(normalization, Generatenetworkfragmentlibraryfrom 214data,processedpre- networksfromlikelynetwork networkintrialeachevolveOptimize/ extractionand/orpredictivepurposes, 220 parametersand/orothersimulation - Simulationforquantitativeparameter Outputquantitativerelationship - Patent Application Publication Aug. 8 , 2019 Sheet 6 of 15 US 2019 / 0242909 A1 NNNNNNNNNNNNNNNNNNNNN . ) . .. 2 . .90* .* . 087Clusjsks Code,228 . wwww w . 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Device,126 Patent Application Publication Aug. 8 , 2019 Sheet 7 of 15 US 2019 / 0242909 A1 functionalactivityor cells22comparison, generatedcomparison. cellmodelnetworks,32 Obtainfourthdata responseof informationrelationship foreachrelationshipin setrepresenting basedonthirddatasetandfourth, quantitativeIdentify )System(s GenerateoneormoreBayesiannetworksof (generatedcomparisoncellmodelnetworks) probabilistic,quantitativeincludingand Establishcomparisonmodel forbiologicalprocessusing normallycellscomparison associatedwithbiological FunctionalAssay InformaticsPattonmcausalrelationshipsforcomparisoncellmodela directionalinformationregarding RelationshipQuantificationModule process,14 relationships,26 Obtainseconddata functionalactivityor responseofcells,20 informationforeach generatedcellmodel setrepresenting Identifyquantitative relationship relationshipin networks,30 D BiologicalcellModels AlBased Figure7 Obtainthirddataset representingexpression levelofaplurality genesincomparison cells,18 SignatureAnalysisSystem(s) significantlydifferentparameter,in. MRNAand/orProtein networksmodelgeneratedpresentcellin Establishmodelforbiological processusingcellsnormally associatedwithbiological GenerateoneormoreBayesiannetworks modelrelationshipsforcellcausalof (generatedcellmodelnetworks)basedon firstdatasetandsecond, Identifyoneormorecausalrelationships andabsent,orhavingatleastone generatedcomparisoncellmodel DifferentialNetworkCreationModule process,12 includingquantitativeprobabilistic directionalinformationregarding relationships,24 networks,28W Obtainfirstdataset representingexpression levelofapluralityfromcells ingenes model16 Patent Application Publication Aug. 8 , 2019 Sheet 8 of 15 US 2019 / 0242909 A1 Autism Autism TI:Investigational compounds AUDSM NetworkSimulation withAIbased Engineering Control Figure8 Multi-Omicssample analysis Lymphoblastsfromeachpatient 36 Patent Application Publication Aug. 8 , 2019 Sheet 9 of 15 US 2019 / 0242909 A1 : : : . : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 6?n! ateryrewson * * wasv? iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii. Patent Application Publication Aug . 8 , 2019 Sheet 10 of 15 US 2019 /0242909 A1 SPTAN1 SHP90B1 SERPINB9 LETM1 CUX1 EF3G LCP1 CORO1A ANXA6 CAPG ?????? COTL1 FKBP4 DIABLO HLA-DRA HLA-DQB1 FKBP4 IGLC1 TXNDC5 GLUD1 PCNA PDIA4 MGEA5 COR01Avrupa month comWA+ WE . wwwwww FIG.10. w GlobalDifferentialNetwork Hubs/NodesUniqueinAutismVersusNormal tot . HELMDEHSP905m SPTAN1 wie eoa800 Patent Application Publication Aug . 8 , 2019 Sheet 11 of 15 US 2019 /0242909 A1 . ! t * * Networkofmolecularentitiesdrivenby"diseasestatecommontoAutism DiseaseAlzheimer'sand ti Figure11 Patent Application Publication Aug . 8 , 2019 Sheet 12 of 15 US 2019 /0242909 A1 wwwwww w f ASTRA . Chief . GLUD1 ti my Sea w pcom . bat NO ACORO1A FIG.12 when TERRASKENKORB worthwest www. Wher BOMORADOR SPTAN1 eswarm Patent Application Publication Aug . 8 , 2019 Sheet 13 of 15 US 2019 /0242909 A1 DDX6 OCHILDNODE FIG.13 STX6 SERPINB9 NONONONEN PARENTNODE STRO SMC4 Patent Application Publication Aug . 8 , 2019 Sheet 14 of 15 US 2019 /0242909 A1 FKBP4 OSBP SVARE Figure14 SEPT2 min GLUDI RPL13 AP1S1 EIF3B, PDCL3 ParentNode ChildNode Patent Application Publication Aug . 8 , 2019 Sheet 15 of 15 US 2019 /0242909 A1 ERP44 EIF4A2 ChildNode HNRNPM ChildNode CORONA Figure15 speditorarpr *** ** * * * * * * ** ** * * * * * * * * SEC61A1 ParentNodeParentNode YWHAG sastriteistiepese **** GET4 LETM1 TJP2 US 2019 /0242909 A1 Aug. 8, 2019 COMPOSITIONS AND METHODS FOR derived from a subject afflicted with Autism or Alzheimer' s DIAGNOSIS AND TREATMENT OF disease , as compared to normal, control cells , e . g . , cells PERVASIVE DEVELOPMENTAL DISORDER derived from a subject that is not afflicted with Autism or Alzheimer ' s disease ( e . g . , cells derived from an unaffected CROSS -REFERENCE TO RELATED sibling or parent of the afflicted subject ) . Accordingly , the APPLICATIONS prevent invention provides methods for treating , alleviating [0001 ] This application is a continuation of U . S . patent symptoms of, inhibiting progression of, preventing , diag application Ser. No . 15 /493 ,383 , filed Apr. 21, 2017 , which nosing , or prognosing a pervasive developmental disorder in is a continuation of U . S . patent application Ser . No . 15/ 265 , a subject involving one or more of the proteins listed in 174 , filed on Sep . 14 , 2016 , which is a continuation of U . S . Tables 2 - 6 . patent application Ser. No . 14 / 383 , 450 , filed on Sep . 5 , 2014 , [0008 ] Specifically , in one aspect the invention provides which is a 35 U . S . C . § 371 national stage application of Int. methods of assessing whether a subject is afflicted with a Appl. No . PCT/ US2013 /029201 , filed on Mar. 5 , 2013 , pervasive developmental disorder , the method comprising : which claims priority to U . S . Provisional Appl. Ser . No . ( 1 ) determining a level of expression of one or more of the 61 /606 , 935 , filed on Mar. 5 , 2012. The entire contents of markers listed
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