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( 12 ) United States Patent US010184933B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 184 ,933 B2 Weinberger et al . (45 ) Date of Patent : Jan . 22 , 2019 ( 54 ) COMPOSITIONS , SYSTEMS AND METHODS FOREIGN PATENT DOCUMENTS FOR GENE EXPRESSION NOISE DRUG WO WO 2010 / 049182 A2 5 / 2010 SCREENING AND USES THEREOF wo WO 2010 /049182 A3 5 / 2010 WO WO 2013 /019710 A 2 / 2013 (71 ) Applicant : The J . David Gladstone Institutes , WO WO 2013 / 148197 Al 10 / 2013 San Francisco , CA (US ) OTHER PUBLICATIONS (72 ) Inventors : Leor Weinberger , Oakland , CA (US ); Roy Dar , Champaign , IL (US ) Boehm , Daniela et al. , “ BET bromodomain - targeting compounds reactive HIV from latency via a Tat - independentmechanism ,” Cell Cycle , Feb . 1 , 2013 , vol . 12 , Issue 3 , pp . 452 - 462 . ( 73 ) Assignee : The J . David Gladstone Industries , Gallastegui , E . et al . , “ Combination of Biological Screening in a San Francisco , CA (US ) Cellular Model of Viral Latency and Virtual Screening Identifies Novel Compounds That Reactivate HIV - 1 , ” Journal of Virology , Apr. 2012 , vol. 86 , Issue 7 , pp . 3795 - 3808 . ( * ) Notice : Subject to any disclaimer , the term of this Miller - Jensen , K . et al. , “ Genetic Selection for Context- Dependent patent is extended or adjusted under 35 Stochastic Phenotypes: Spl and TATA Mutations Increase Pheno U . S .C . 154 (b ) by 18 days. typic Noise in HIV - 1 Gene Expression , ” PLOS Computational Biology , Jul. 2013 , vol. 9 , Issue 7 , e1003135 . (21 ) Appl. No. : 15 /026 , 225 Turano , A . et al. , “ Inhibitory Effect of Papaverine on HIV Repli cation in Vitro ,” AIDS Research and Human Retroviruses, Apr. 1989 , vol . 5 , No. 2 , pp . 183 - 192 . ( 22 ) PCT Filed : Oct. 1 , 2014 Weinberger, L . et al. , “ Expression Noise and Acetylation Profiles Distinguish HDAC Functions, ” Molecular Cell , Jul. 27 , 2012 , vol . ( 86 ) PCT No. : PCT /US2014 /058687 47 , pp . 193 - 202 . Blazkova , J . et al ., “ CpG Methylation Controls Reactivation of HIV $ 371 (c )( 1 ), from Latency ,” PLoS Pathog . Aug. 21, 2009 ( Aug . 21 , 2009 ) , vol. 5 , No . 8 : e1000554 , pp . 1 - 14 . ( 2 ) Date : Mar. 30 , 2016 Dar, R . et al. , “ Transcriptional burst frequency and burst size are equally modulated across the human genome, ” Proc . Natl Acad . (87 ) PCT Pub . No .: WO2015 / 051035 Sci, . Oct . 11, 2012 (Oct . 11 , 2012 ) , vol. 109 , No . 43, pp . 17454 17459 . PCT Pub . Date : Apr. 9 , 2015 Weinberger, Leor; , et al ., International Preliminary Report on Pat entability for International Appl. No . PCT/ US2014 /058687 , filed (65 ) Prior Publication Data Oct . 1 , 2014 , dated Jan . 7 , 2015 , 3 pgs . Weinberger, Leor , et al .. Written Opinion of the international US 2016 / 0245796 A1 Aug . 25 , 2016 Searching Authority for International Appl . No . PCT/ US2014 / 058687 , filed Oct . 1 , 2014 , dated Jan . 7 , 2015 , 130pgs. Dar, R . et al ., “ Screening for Noise .in Gene Expression Identifies Related U . S . Application Data Drug Synergies , " Science , Jun . 5 , 2014 ( Jun . 5 , 2014 ) ; vol . 344 , No . 6190 , pp . 1392 - 1396 . ( 60 ) Provisional application No . 62/ 023 ,645 , filed on Jul. Li, Z . et al. , “ The BET bromodomain inhibitor JQ1 activates HIV 11 , 2014 , provisional application No . 61/ 885, 464 , latency through antagonizing Brd4 inhibition of Tat - transactiva filed on Oct . 1 , 2013 . tion , ” Nucleic Acids Res . Oct . 18 , 2012 (Oct . 18 , 2014 ) . vol . 41, No . 1 , pp . 277 - 287. Shishido . T . et al ., " Selected Drugs with Reported Secondary (51 ) Int. Ci. Cell - Differentiating Capacity Prime Latent HIV - 1 Infection . for Reac C120 1 / 68 ( 2018 . 01 ) tivation , ” J. Virol. Jun . 13 , 2012 ( Jun . 13 , 2012 ), vol . 86 , No. 17 , pp . GOIN 33 /50 ( 2006 .01 ) 9055 - 9069 . C120 1 / 6897 ( 2018 .01 ) Dar, R . et al. ( 2012 ) Transcriptional burst frequency and burst size C120 1 / 70 ( 2006 .01 ) are equally modulated across the human genome. PNAS , 109 (43 ) : A61K 31 / 22 ( 2006 .01 ) 17454 - 17459 . A61K 31/ 496 ( 2006 .01 ) ( Continued ) A61K 38 / 19 ( 2006 .01 ) ( 52 ) U . S . CI. Primary Examiner — James S Ketter CPC .. .. .. GOIN 33 /5023 ( 2013 .01 ) ; A61K 31/ 22 ( 74 ) Attorney , Agent, or Firm — Taylor English Duma (2013 .01 ) ; A61K 31/ 496 (2013 .01 ) ; A61K LLP ; Siegfried J . W . Ruppert 38 / 191 ( 2013. 01 ) ; C12Q 1 /6897 ( 2013 .01 ) ; C12Q 1/ 703 ( 2013 .01 ) ; GOIN 2333 / 16 (57 ) ABSTRACT ( 2013 .01 ) HIV - l ' s ability to enter a transcriptionally dormant state and (58 ) Field of Classification Search establish a reservoir of latently infected cells is considered None the major barrier to eradicating the virus from infected See application file for complete search history . patients . Stochastic noise ( i . e . fluctuations ) in an HIV - 1 transcriptional positive -feedback loop is one mechanism that enables HIV - 1 to establish latency . Here , Applicants ( 56 ) References Cited demonstrate that small -molecule modulation of noise in U . S . PATENT DOCUMENTS HIV - 1 gene expression radically perturbs HIV - 1 latency . 2008 /0118494 AL 5 / 2008 Kutsch et al . 45 Claims, 41 Drawing Sheets US 10 ,184 ,933 B2 Page 2 (56 ) References Cited OTHER PUBLICATIONS Dar , R . et al . (2014 ) Screening for Noise in Gene Expression Identifies Drug Synergies. Science, 344 (6190 ) : 1392 - 1396 . doi: 10 1126 / science . 1250220 . Shishido , T . et al . ( 2012 ) Selected Drugs with Reported Secondary Cell - Differentiating Capacity Prime Latent HIV - 1 Infection for Reactivation . Journal of Virology , 86 ( 17 ) : 9055 - 9069 . Li, Z et al. ( 2013 ) The BET bromodoman inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat transactivation Nucleic Acids Research , 41 ( 1 ) 277 -287 . doi 10 . 1093/ nar/ gks976 . Blazkova J . et al. ( 2009 ) COG Methylation Controls Reactivation of HIV Latency . PloS Pathogens 5 ( 8 ): e1000554 . doi : 10 . 1371/ journal. ppat. 1000554 . Written Opinion of the International Searching Authority for Inter national App . No . PCT /US2014 /058687 , dated Jan . 7 , 2015 , 10 pages . International Search Report for International App . No . PCT/ US2014 / 058687 , dated Jan . 7 , 2015 , 3 pages . U . S . Patent Jan . 22, 2019 Sheet 1 of 41 US 10 , 184 ,933 B2 M ( t) = actual time course of molecular population MolecularPopulation M ( t ) = deterministic time course of molecular population related to information encoded within M ( t ) time Noise = n (t ) = M (t ) - M (t ) FIG . 1A Cellular Processes Extrinsic Noise Source INNHO Reporterporter Gene RNA Polymerase Transcription Ribonucleotides mRNA intrinsic noise R ate Amino Acids Translation Ribosomes tRNA Cell Division Protein Decay FIG . 1B atent Jan . 22 , 2019 Sheet 2 of 41 US 10 , 184, 933 B2 active latent (latency) TIME Basalinsufficientfor+FBamplification GFP GFP active latent Basalsufficientfor (reactivation) FIG.2 +FBamplification mmmmmm TIME GFP GFP LTR Tat + LTR G?LTR)GFPTatH3LTR] positivefeedback(FB) Promoteronly 5'LTR)GFPH3] Promoter+ 2motifsdetermine anHIVfatedecision U . S . Patent Jan . 22 , 2019 Sheet 3 of 41 US 10 , 184 , 933 B2 ? Gene x ] Untreated ACTIVE - - - - - - - - WhyLATENT Armenima . - x> hominent ActivatorActivator ( (Drug Drug A A )) Variability Modulator ProductGeneProduct (Drug V ) ramy Maine Meny CV Mohm thistongens Drugs A + V TIME Variability ENHANCER (VE ) Variability SUPPRESSOR (VS ) Gene ta }, oo Ivansacrerespumana Am } o % NA + VE A + VS GeneProduct - - - am mmmTIME TIME FIG . 3A UU. S . Patent Janon .2 22. , 2019300 senteretSheet 4 of 41 US 10 ,184 ,933 B2 Gene x KenmRNA Variability Activators GeneX Modulators FIG . 3B o Activator Drugil A minDrugs A + VE ON OFF ????? Untreated Variability Drug VE FIG . 3C + VE + A + VE Noise(o?lx) Noise(6°/x) +A X - + A + VS - Transcript Abundance Transcript Abundance FIG . 3D U . S . Patent Jan . 22, 2019 Sheet 5 of 41 US 10 , 184 ,933 B2 Phenotypic A Untreated A Threshold A + VE #ofcells + VE + A + A + VE AX XX Transcript Level A + VS Phenotypic Threshold + VS + A + VS N #ofcells Untreated + A WWWXXXXXXXXX Transcript Level FIG . 3E U . S . Patent Jan . 22, 2019 Sheet 6 of 41 US 10 , 184 ,933 B2 Untreated Noise enhancer Active ? replication - (moleculesx10°) NWA ? AY Noise ? U ir Geneproduct . ? i. 1 - Mean wie- w -w -w -w w who wwwwwwwwwwwwww w wwwww * W WW . - - : - www . www . o ? 10 20 10 20 Time (hrs ) Time (hrs ) activity TILL Promoter Time Time Activator Activator + noise enhancer , . - - Geneproduct(moleculesx10°) + * w - wwwwwwwwwwwww . www . wwwww * ** 10 20 activityo Time (hrs ) Time ( hrs ) Promoter TTTT Time Time FIG . 3F U . S . Patent Jan . 22, 2019 Sheet 7 of 41 US 10 , 184 , 933 B2 Burst- Size ??? Akor Modulation OFF Akan Burst- Frequency Modulation OFF wwwtoWith Ak Burst- Size Akm ? ?? WWW AK , ' Modulation OFF - L OFFJ L - OFF 4 OFF Akon Akan ?kon Burst- Frequency Modulation OFF OFF OFF FIG . 4 atent Jan . 22 , 2019 Sheet 8 of 41 US 10 , 184 , 933 B2 Step 1 : Screening For Compounds That Modulate Variability Without Changing Mean Expression Low MOI Infection 16 Sort for 0 0 ( = Random Single Isoclone Integration ) own -regulated Up -regulated Stabilizers Reactivators LTR- dcome ,GFP NoiseMagnitude(CV) Model line <GFP > Step 2 : Screening For Synergistic Reactivation of Latent HIV - 1 Using Hits from Step 1 Noisy Drug Hit vif you enter Deal 5 utgag GFEST RUS) 3 ” pol to I LTR vor rev Transcription Activators ( TNF, SAHA , Prostratin ) FIG . 5 U . S . Patent Jan . 22, 2019 Sheet 9 of 41 US 10 , 184 , 933 B2 | LTRLTR > dd , GFP GFP VM Hit Regions Variability Enhancers 000 00 GFPNoiseMagnitude(CV) olyTNF
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