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WO 2018/107129 Al O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/107129 Al 14 June 2018 (14.06.2018) W !P O PCT (51) International Patent Classification: VARD COLLEGE [US/US]; 17 Quincy Street, Cam- C12N 15/09 (2006.01) C12N 15/11 (2006.01) bridge, MA 02138 (US). C12N 15/10 (2006.01) C12Q 1/68 (2006 .01) (72) Inventors: ABUDAYYEH, Omar; 77 Massachusetts Av (21) International Application Number: enue, Cambridge, MA 02139 (US). COLLINS, James PCT/US20 17/065477 Joseph; 77 Massachusetts Avenue, Cambridge, MA 02 139 (US). GOOTENBERG, Jonathan; 17 Quincy Street, (22) International Filing Date: Cambridge, MA 02138 (US). ZHANG, Feng; 415 Main 08 December 2017 (08.12.2017) Street, Cambridge, MA 02142 (US). LANDER, Eric, S.; (25) Filing Language: English 415 Main Street, Cambridge, MA 02142 (US). (26) Publication Language: English (74) Agent: NLX, F., Brent; Johnson, Marcou & Isaacs, LLC, 27 City Square, Suite 1, Hoschton, GA 30548 (US). (30) Priority Data: 62/432,553 09 December 20 16 (09. 12.20 16) US (81) Designated States (unless otherwise indicated, for every 62/456,645 08 February 2017 (08.02.2017) US kind of national protection available): AE, AG, AL, AM, 62/471,930 15 March 2017 (15.03.2017) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 62/484,869 12 April 2017 (12.04.2017) US CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 62/568,268 04 October 2017 (04.10.2017) US DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 415 Main Street, Cambridge, MA 02142 (US). MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, MASSACHUSETTS INSTITUTE OF TECHNOLO¬ OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, GY [US/US]; 77 Massachusetts Avenue, Cambridge, MA SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, 02138 (US). PRESIDENT AND FELLOWS OF HAR¬ TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (54) Title: CRISPR EFFECTOR SYSTEM BASED DIAGNOSTICS * r m m (57) Abstract: The embodiments disclosed herein utilized RNA targeting effectors to provide a robust CRISPR-based diagnostic with attomolar sensitivity. Embodiments disclosed herein can detect both DNA and RNA with comparable levels of sensitivity and o can differentiate targets from non-targets based on single base pair differences. Moreover, the embodiments disclosed herein can be prepared in freeze-dried format for convenient distribution and point-of-care (POC) applications. Such embodiments are useful in 0 0 multiple scenarios in human health including, for example, viral detection, bacterial strain typing, sensitive genotyping, and detection o of disease-associated cell free DNA. [Continued on nextpage] WO 2018/107129 Al llll II II 11III II I 11II III II II I III II I II (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) CRISPR EFFECTOR SYSTEM BASED DIAGNOSTICS STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0001] This invention was made with government support under grant numbers MH100706 and MHl 10049 granted by the National Institutes of Health, and grant number HDTRA1- 14- 1-0006 granted by the Defense Threat Reduction Agency. The government has certain rights in the invention. TECHNICAL FIELD [0002] The subj ect matter disclosed herein is generally directed to rapid diagnostics related to the use of CRISPR effector systems. BACKGROUND [0003] Nucleic acids are a universal signature of biological information. The ability to rapidly detect nucleic acids with high sensitivity and single-base specificity on a portable platform has the potential to revolutionize diagnosis and monitoring for many diseases, provide valuable epidemiological information, and serve as a generalizable scientific tool. Although many methods have been developed for detecting nucleic acids (Du et al., 2017; Green et al., 2014; Kumar et al., 2014; Pardee et al., 2014; Pardee et al., 2016; Urdea et al., 2006), they inevitably suffer from trade-offs among sensitivity, specificity, simplicity, and speed. For example, qPCR approaches are sensitive but are expensive and rely on complex instrumentation, limiting usability to highly trained operators in laboratory settings. Other approaches, such as new methods combining isothermal nucleic acid amplification with portable platforms (Du et al., 2017; Pardee et al., 2016), offer high detection specificity in a point-of-care (POC) setting, but have somewhat limited applications due to low sensitivity. As nucleic acid diagnostics become increasingly relevant for a variety of healthcare applications, detection technologies that provide high specificity and sensitivity at low cost would be of great utility in both clinical and basic research settings. SUMMARY [0004] In one aspect, the invention provides a nucleic acid detection system comprising: a CRISPR system comprising an effector protein and one or more guide RNAs designed to bind to corresponding target molecules; an RNA-based masking construct; and optionally, nucleic acid amplification reagents to amplify target RNA molecules in a sample. In another aspect, the embodiments provide a polypeptide detection system comprising: a CRISPR system comprising an effector protein and one or more guide RNAs designed to bind a trigger RNA, an RNA-based masking construct; and one or more detection aptamers comprising a masked RNA polymerase promoter binding site or a masked primer binding site. [0005] In further embodiments, the system may further comprise nucleic acid amplification reagents. The nucleic acid amplification reagents may comprise a primer comprising an RNA polymerase promoter. In certain embodiments, sample nucleic acids are amplified to obtain a DNA template comprising an RNA polymerase promoter, whereby a target RNA molecule may be generated by transcription. The nucleic acid may be DNA and amplified by any method described herein. The nucleic acid may be RNA and amplified by a reverse transcription method as described herein. The aptamer sequence may be amplified upon unmasking of the primer binding site, whereby a trigger RNA is transcribed from the amplified DNA product. The target molecule may be a target DNA and the system may further comprise a primer that binds the target DNA and comprises an RNA polymerase promoter. [0006] In one example embodiment, the CRISPR system effector protein is an RNA- targeting effector protein. Example RNA-targeting effector proteins include Casl3b and C2c2 (now known as Casl3a). It will be understood that the term "C2c2" herein is used interchangeably with "Casl3a". In another example embodiment, the RNA-targeting effector protein is C2c2. In other embodiments, the C2c2 effector protein is from an organism of a genus selected from the group consisting of: Leptotrichia, Listeria, Corynebacter, Sutterella, Legionella, Treponema, Filifactor, Eubacterium, Streptococcus, Lactobacillus, Mycoplasma, Bacteroides, Flaviivola, Flavobacterium, Sphaerochaeta, Azospirillum, Gluconacetobacter, Neisseria, Roseburia, Parvibaculum, Staphylococcus, Nitratifractor, Mycoplasma, Campylobacter, and Lachnospira, or the C2c2 effector protein is an organism selected from the group consisting of: Leptotrichia shahii, Leptotrichia. wadei, Listeria seeligeri, Clostridium aminophilum, Carnobacterium gallinarum, Paludibacter propionicigenes, Listeria weihenstephanensis, or the C2c2 effector protein is a L . wadei F0279 or L . wadei F0279 (Lw2) C2C2 effector protein. In another embodiment, the one or more guide RNAs are designed to detect a single nucleotide polymorphism, splice variant of a transcript, or a frameshift mutation in a target RNA or DNA. [0007] In other embodiments, the one or more guide RNAs are designed to bind to one or more target molecules that are diagnostic for a disease state. In still further embodiments, the disease state is an infection, an organ disease, a blood disease, an immune system disease, a cancer, a brain and nervous system disease, an endocrine disease, a pregnancy or childbirth- related disease, an inherited disease, or an environmentally-acquired disease. In still further embodiments, the disease state is cancer or an autoimmune disease or an infection. [0008] In further embodiments, the one or more guide RNAs are designed to bind to one or more target molecules comprising cancer specific somatic mutations. The cancer specific mutation may confer drug resistance. The drug resistance mutation may be induced by treatment with ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK, check point blockade therapy, or antiestrogen therapy. The cancer specific mutations may be present in one or more genes encoding a protein selected from the group consisting of Programmed Death-Ligand 1 (PD-L1), androgen receptor (AR), Bruton's Tyrosine Kinase (BTK), Epidermal Growth Factor Receptor
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