Prime editing assay for detecting the activity of DNA mismatch repair proteins

Abstract

The present disclosure relates to high-throughput prime editing assays and methods of use thereof for detecting the activity of mismatch repair (MMR) proteins.

Description

[0001] Docket No. 11676 -005 WO 1

[0002] PRIME EDITING ASSAY FOR DETECTING THE ACTIVITY OF DNA MISMATCH REPAIR PROTEINS

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63 / 687,402, filed August 27, 2024, which is incorporated by reference herein in its entirety.

[0005] REFERENCE TO SEQUENCE LISTING

[0006] The sequence listing submitted on August 27, 2025, as an .XML file entitled “11676- 005W01_08_27_2025” created on August 27, 2025, and having a file size of 554,829 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).

[0007] FIELD

[0008] The present disclosure relates to high-throughput prime editing assays and methods of use thereof for detecting the activity of mismatch repair (MMR) proteins.

[0009] BACKGROUND

[0010] Prime editing is a genome editing technology for modifying targeted DNA sequences that allows for various forms of nucleotide changes, including, but not limited to transversions, substitutions, insertions, and deletions. This technology has recently received mainstream attention for its ability to re-write / repair new genetic information into a target DNA site.

[0011] The prime editing system introduces single-stranded DNA breaks instead of the doublestranded DNA breaks observed in other gene editing tools. Furthermore, prime editing does not require a precisely positioned PAM sequence to target a specific nucleotide sequence thus allowing for more flexibility and editing precision. Because of these advantages, there is considerable interest in applying prime editing techniques to the treatment of diseases with a genetic component. However, there is a need to develop methods of screening small molecules for use as therapeutic molecules and further need to develop a prime editing assay that can identify small molecules to target specific DNA repair proteins and / or activities.

[0012] The assays and methods disclosed herein address these and other needs. Docket No. 11676 -005 WO 1

[0013] SUMMARY

[0014] The present disclosure provides a high-throughput prime editing assay for detecting mismatch repair (MMR) in a cell. The present disclosure also provides methods of detecting MMR and of screening small molecule inhibitors of MMR using the high-throughput prime editing assay.

[0015] In one aspect, disclosed herein is a high-throughput prime editing assay comprising a mismatch repair (MMR) sensor-specific reporter and a prime editor, wherein the MMR sensorspecific reporter comprises a prime editing guide RNA (pegRNA) and a reporter enzyme, wherein the reporter enzyme is encoded by a nucleic acid comprising a mutated start codon, and wherein the assay detects mismatch repair (MMR) activity of a component of MMR, including but not limited to a MSH3 / MutS0 MMR sensor, a MSH6 / MutSa MMR sensor, or other components thereof through prime editing at that codon.

[0016] In some embodiments, the MMR sensor-specific reporter comprises SEQ ID NO: 53 and SEQ ID NO: 56, or a variation thereof. In some embodiments, the MMR sensor-specific reporter comprises SEQ ID NO: 58 and SEQ ID NO: 56, or a variation thereof.

[0017] In some embodiments, the pegRNA targets at least 1 base pair (bp) mutated within the mutated start codon of a nucleic acid encoding the reporter enzyme. In some embodiments, the pegRNA targets 1-10 bps mutated within the mutated start codon. In some embodiments, the pegRNA targets 3-5 bps mutated within the mutated start codon. In some embodiments, the pegRNA targets 5 bps mutated within the mutated start codon. In some embodiments, the mutated start codon comprises an insertion, a substitution, or a deletion mutation.

[0018] In some embodiments, the pegRNA targets the mutated ATG start codons, or complement TAG codons, which have 1-10 bps inserted, deleted, or substituted into other bases from an ATG sequence, and re-installs ATG sequences by deleting, inserting, or substituting 1-10 bps.

[0019] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 53. In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 58.

[0020] In some embodiments, the prime editor comprises a Cas9 nuclease. In some embodiments, the Cas9 nuclease is fused to a reverse transcriptase.

[0021] In some embodiments, the assay is a cell-based prime editing assay. In some embodiments, the assay detects MMR activity in live cells. In some embodiments, the assay discriminates between MSH3 / MutSp activity and MSH6 / MutSa activity. Docket No. 11676 -005 WO 1

[0022] In one aspect, disclosed herein is a method of detecting mismatch repair (MMR) activity in a cell, the method comprising introducing into the cell at least one expression vector comprising a nucleic acid encoding a mismatch repair (MMR) sensor-specific reporter and a prime editor, wherein the mismatch repair (MMR) sensor- specific reporter and the prime editor are expressed in the cell: and detecting an activity level of a component of MMR, including but not limited to a MSH3 / MutSP component, a MSH6 / MutSa component, or other MMR components thereof relative to a control cell.

[0023] In one aspect, disclosed herein is a method of screening for a small molecule inhibitor of mismatch repair (MMR), the method comprising: (a) introducing into a cell at least one expression vector comprising a nucleic acid encoding a mismatch repair (MMR) sensorspecific reporter and a prime editor: (b) expressing the mismatch repair (MMR) sensor-specific reporter and the prime editor in the cell; (c) introducing into the cell a small molecule; and (d) detecting MMR activity in the cell, wherein the small molecule inhibits a MMR component, including but not limited to a MSH3 / MutS0 MMR, a MSH6 / MutSa MMR, or other MMR components thereof in die cell relative to a control cell.

[0024] In some embodiments, the method of any preceding aspect comprises the MMR sensorspecific reporter comprising SEQ ID NO: 53 and SEQ ID NO: 56, or a variant thereof. In some embodiments, the method of any preceding aspect comprises the MMR sensor-specific reporter comprising SEQ ID NO: 58 and SEQ ID NO: 56, or a variant thereof. In some embodiments, the MMR sensor-specific reporter comprises a prime editing guide RNA (pegRNA) and a reporter enzyme, and wherein the reporter enzyme is encoded by a nucleic acid comprising a mutated start codon.

[0025] In some embodiments, the method of any preceding aspect comprises the pegRNA targeting at least 1 base pairs (bps), including but not limited to 1-10 bps, 3-5 bps, or 5 bps inserted within the mutated start codon of the nucleic acid encoding the reporter enzyme. In some embodiments, the method of any preceding aspect comprises the mutated start codon comprising an insertion, a substitution, or a deletion mutation.

[0026] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 53. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 58.

[0027] In some embodiments, the method of any preceding aspect comprises the prime editor comprising a Cas9 nuclease. In some embodiments, the Cas9 nuclease is fused to a reverse transcriptase. Docket No. 11676 -005 WO 1

[0028] In some embodiments, the expression vector comprises a plasmid, a lentivirus, an adenovirus, an adeno-associated virus (AAV), or a lipid nanoparticle (LNP). In some embodiments, the nucleic acid comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO:29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41 , SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, or a variant thereof.

[0029] In some embodiments, the method detects mismatch repair (MMR) activity of a component of MMR, including but not limited to a MSH3 / MutSP component or a MSH6 / MutSa component. In some embodiments, the method detects MMR activity using a high-throughput prime editing assay of any preceding aspect. In some embodiments, the method detects MMR activity in live cells. In some embodiments, the method discriminates between MSH3 / MutSp activity and MSH6 / MutSa activity.

[0030] BRIEF DESCRIPTION OF THE FIGURES

[0031] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below.

[0032] Figure 1 depicts candidate prime edit designs conceived to turn on reporters. Candidate prime edits were designed using either 1 bp substitutions, herei n also called “alpha edits”, and 5bp deletions, herein also called “beta edits”, to install start codons that can be used in the reporter context.

[0033] Figure 2 shows the workflow of how candidate prime edits were examined using pooled prime screens.

[0034] Figures 3A and 3B show that the screens identified MMR-responsive edits that can install start codons. The Ibp substitution “alpha edits” were tested in WT and MLH1K0 cells, and many of them are highly MMR-responsi ve. The 5bp deletion “beta edits” were tested in WT and MSH6KO or MSH3KO cells, wherein “KO” refers to knockout of an indicated gene, and many of them responded to MSH3 / MutSp knocked out but showed little to no response to MSH6 / MutSa knocked out, meaning that most of them are MutSp specific edits. Docket No. 11676 -005 WO 1

[0035] Figures 4A and 4B show the configurations used to build sensor- specific luciferase reporters.

[0036] Figure 5 shows the sensor-specific luciferase reporters in cells with MMR genetically knocked out. Knocking out MSH6 or MSH3 turns on many “alpha reporters” (containing “alpha edits”) or “beta reporters” (containing “beta edits”), respectively and relative to WT cells, but not the counterpart. The loss of MLH1 turns on all of these reporters relative to WT cells, meaning that the reporters are robustly responding to the loss of MMR in a sensorspecific manner.

[0037] Figures 6A and 6B show that MutS fl- specific reporters, or “beta reporters”, respond to a chemical MSH3 inhibitor (Compound I - 2-chloro-N-(4-methyl-5-(4-methylbenzyl)thiazol- 2-yl)acetamide). It should be noted that the name Merck Inhibitor when used herein is referring to Compound I. The previously identified MSH3 inhibitor binds to MSH3 in vitro (Ruprecht B et al. Chemoproteomic profiling to identify activity changes and functional inhibitors of DNA -binding proteins. Cell Chem Biol. 2022 Nov 17;29(11): 1639-1648.e4. doi: 10.1016 / j.chembiol.2022.10.008. Epub 2022 Nov 9. PMID: 36356585). It is shown that a MSH3 / MutSP reporter responds to it, establishing the feasibility of using that reporter approach to perform small molecule screens.

[0038] Figures 7A and 7B show the toxicity and mechanism of action to establish the small molecule as a positivity control for the inhibitor screen.

[0039] Figures 8A and 8B show that Casl2 knockout (KO) of MSH3 increased MutS0 reporter signals.

[0040] Figures 9 A and 9B show that the SaCas9 KO did not work in the same way as Casl2 KO.

[0041] Figures 10A and 10B show that overexpression of MSH3 suppresses the MutSp reporter signal.

[0042] Figures 11 A and 1 IB show that the inhibitor of FIG. 6 has no activity on MSH6 / MutSa reporter (or “alpha reporter”).

[0043] Figures 12A and 12B show that the MutSp reporter worked across three common luciferases.

[0044] Figures 13 A and 13B show that the MutSp reporter system was acti vated by Compound I in U2OS cells with two different editor proteins.

[0045] Figures 14A and 14B show that the MutSp reporter system was activated by Compound I in HAP1 and HeLa cells with two different prime editor proteins. Docket No. 11676 -005 WO 1

[0046] Figures 15A and 15B show that the MutSp reporter system showed no positive response to the inhibitor of Figures 6 A and 6B in HEK293T and HCT116 cells with two different prime edi tor proteins.

[0047] FIG. 16 shows schematics of MutSp reporters for delivery into cells in different ways including on one expression vector with the pegRNA, or on two expression vectors separated from the pegRNA.

[0048] Figures 17A and 17B show the results of MutSp reporter activation in response to Merck inhibitor (Compound I) when reporter-pegRNA was delivered in a single lentiviral construct into cells with low MOI followed by sorting the cells with the constructs.

[0049] Figures 18A and 18B show the results of MutSp reporter activation in response to Merck inhibitor (Compound I) when delivering the reporter by lentivirus, sorting the cells with reporters, then delivering the pegRNA by another round of lentivirus.

[0050] Figures 19A and 19B show the results of similar experiments described in Figtire 18, with difference of the MOI of pegRNA lentivirus delivery into the MutSp reporter cells.

[0051] Figure 20 shows the schematic of how MutSp reporter can be introduced with different multiplicities of infection (MOI).

[0052] Figures 21 A and 21B show that 1-2 multiplicity of infection (MOI) of the MutSp reporter-pegRNA is good for signal-to-noise ratio, and that there is no need to sort the cells.

[0053] Figures 22A and 22B show the 2+2 days provides good results for a MutSp reporter.

[0054] Figures 23 A and 23B show results using epegRNAs and MutSp reporter .

[0055] Figures 24A and 24B show that our MutSp reporter assay is robust in both 96 well plates and 384 well plates.

[0056] Figures 25 A and 25B show that plate reading of MutSp reporter assay can be performed 1-2 hours after preparing the plate.

[0057] Figures 26A and 26B show that the plate position in the incubator had a subtle effect on MutSp reporter assay.

[0058] Figures 27A and 27B shows setup and results of a MutSp reporter assay test with the top plate showing the actual reads of the luminescence and bottom plate showing the concentration of compounds deposited into the plate for each well performed in a high- throughput test with Compound I.

[0059] Figure 28 shows the workflow of screening for small molecule inhibitors. Chemicals are pre-deposited into well plates (96 or 384), the reporter cells are added into the plates, and read out the luminescence signals 48 hours later using plate readers. Docket No. 11676 -005 WO 1

[0060] Figure 29 shows the composition of small molecule library used to screen with the MutSP reporter, including 5,923 bioactive molecules (screened at both lOpM and 20pM) and 66,020 general collection molecules (screened at lOpM).

[0061] Figures 30A and 30B show the measure of Z’ (Z-score) and Z’...robust (robust Z-score) of the activity of candidate MMR inhibitors in a high-throughput prime editing screen performed with a MutSp reporter.

[0062] Figures 31 A and 3 IB show coefficient of variation (CV%) between positive and negative controls in high-throughput prime editing screen performed with a MutSp reporter.

[0063] Figures 32A and 32B show that the signal-to -background (S / B) fluctuated a bit during the high-throughput prime editing screen performed with a MutSp reporter .

[0064] Figures 33A and 33B show that the signal-to-background (S / B) fluctuation during the high-throughput prime editing screen performed with a MutSp reporter was mostly caused by positive control.

[0065] Figures 34A and 34B show the results of screening with lOpM versus 20pM of the bioactive collection using a MutS0 reporter, with the difference between plots being the scale of y axis (top is linear and bottom is log 10).

[0066] Figure 35 shows the linear regression of % inhibition at both 10 pM and 20 pM of the bioactive collection screened with a MutSp reporter.

[0067] Figure 36 shows the interpretation of the outliers of the linear regression.

[0068] Figures 37 A and 37B show the results of screening with the general collection using a MutSp reporter, with the difference between plots being the scale of y axis (top is linear and bottom is log 10).

[0069] Figure 38 shows a schematic of the use of MSH6 / MutSa-specific luciferase reporters in dose-titration experiments.

[0070] Figure 39 shows schematics of MSH3 / MutS0-specific single and dual NanoLuc-Fluc Luciferase reporters.

[0071] Figure 40 shows the workflow of development of the use of sensor- specific reporters during the large-scale small molecule screen.

[0072] Figures 41 A and 41B show that knocking out MutLo / p / y complexes activated an MutS0 reporter, evidenced by a measure of luminescence of luciferase from the reporter.

[0073] Figures 42A and 42B show that knocking out MutLa complexes activated an MutSa reporter, evidenced by a measure of luminescence of the luciferase from the reporter.

[0074] Figure 43 shows summarized results from different reporters.

[0075] Figure 44 shows a workflow of the use of MutLa / p / y KO cells. Docket No. 11676 -005 WO 1

[0076] Figures 45A and 45B show identified MSH3 dominant negatives by sequencing the editing locus and quantifying percent of reads with desired HEK3 +1-5 deletion edits.

[0077] Figures 46A and 46B show' that nucleofection of all 4 MSH3 dominant negatives identified previously , but not MSH2, significantly activated MutSp reporter signal.

[0078] Figure 47 shows that knocking out MSH2, MSH3, MLH1, PMS2, PMS 1, and MLH3 by CRISPR-Cas9 activated an MutSp reporter, evidenced by a measure of luminescence of luciferase from the reporter (left); and that knocking out MSH2, MSH6, MLH1 , PMS2, and PMS1 by CRISPR-Cas9 activated an MutSa reporter, evidenced by a measure of luminescence of luciferase from the reporter.

[0079] DETAILED DESCRIPTION

[0080] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s). To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof.

[0081] Reference will now be made in detail to the embodiments of the invention, examples of which are illustrated in the drawings and the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0082] Terminology

[0083] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of’ and “consisting of’ can be used in place of Docket No. 11676 -005 WO 1

[0084] “comprising” and “including” to provide for more specific embodiments and are also disclosed. As used in this disclosure and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise.

[0085] The following definitions are provided for the full understanding of terms used in this specification.

[0086] The terms "about" and "approximately" are defined as being “close to” as understood by one of ordinary skill in the art. In one non-limiting embodiment the terms are defined to be within 10%. In another non-limiting embodiment, the terms are defined to be within 5%. In still another non-limiting embodiment, the terms are defined to be within 1%.

[0087] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed. It is also understood that throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0088] As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient. Docket No. 11676 -005 WO 1

[0089] “Composition” refers to any agent that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term “composition” is used, then, or when a particular composition is specifically identified, it is to be understood that the term includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector, polynucleotide, salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.

[0090] "Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. "Consisting essentially of" when used to define compositions and methods, shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of' shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and / or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of Ulis disclosure.

[0091] An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more increase so long as the increase is statistically significant.

[0092] A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be Docket No. 11676 -005 WO 1 a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.

[0093] "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction below, above, or in between the given ranges as compared to native or control levels.

[0094] By “prevent” or other forms of the word, such as “preventing” or “pre vention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.

[0095] As used herein, a “mutation” refers to changing the structure of a gene, resulting in a variant form that may be transmitted to later generations. A mutation is caused by the alteration of single nucleotides in DNA, or the deletion, insertion, substitution, or rearrangement of larger sections of DNA. A mutation can lead to the expression of a protein that has been changed physically or functionally leading to lethality, non-lethal dysfunction effects, or no effects.

[0096] As used herein, the term, “deletion,” also called gene deletion, deficiency, or deletion mutation, refers to part of a chromosome or a sequence of DNA being left out. Deletion, or gene deletions can cause any number of nucleotides to be deleted from a single base to an entire piece of chromosome.

[0097] Variants comprising deletions relative to a reference nucleotide sequence are contemplated herein. A “deletion” refers to a change in the nucleotide sequence that results in the absence of one or more nucleotides relative to a reference sequence. A deletion removes at least 1, 2, 3, 4, 5, 10, 20, 50, 100, or 200 nucleotides. A deletion may include an internal deletion or a terminal deletion (e.g., a 5'-terminal or 3'-terminal truncation or both of a reference polynucleotide).

[0098] Variants comprising a fragment of a reference nucleotide sequence are contemplated Docket No. 11676 -005 WO 1 herein. A “fragment” is a portion of a nucleotide sequence which is identical in sequence to but shorter in length than the reference sequence. A fragment may comprise up to the entire length of the reference sequence, minus at least one nucleotide. For example, a fragment may comprise from 5 to 1000 contiguous nucleotides of a reference polynucleotide, respectively. In some embodiments, a fragment may comprise at least 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 250, or 500 contiguous nucleotides of a reference polynucleotide, respectively. Fragments may be preferentially selected from certain regions of a molecule, for example the 5'-terminal region and / or the 3' terminal region of a polynucleotide. The term “at least a fragment” encompasses the full length polynucleotide.

[0099] Variants comprising insertions or additions relative to a reference sequence are contemplated herein. The words “insertion” and “addition” refer to changes in a nucleotide sequence resulting in the addition of one or more nucleotides. An insertion or addition may refer to 1 , 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or 200 nucleotides.

[0100] As used herein, a “substitution” refers to a type of mutation where at least one DNA base pair (bp) is replaced by another. It should be noted that this change can alter the amino acid sequence of a polypeptide and further alter the structure and / or function of the polypeptide.

[0101] A “nucleotide” is a compound consisting of a nucleoside, which consists of a nitrogenous base and a 5-carbon sugar, linked to a phosphate group forming the basic structural unit of nucleic acids, such as DNA or RNA. The four types of nucleotides are adenine (A), cytosine (C), guanine (G), and thymine (T), each of which are bound together by a phosphodiester bond to form a nucleic acid molecule.

[0102] A “nucleic acid” is a chemical compound that serves as the primary informationcarrying molecules in cells and make up the cellular genetic material. Nucleic acids comprise nucleotides, which are the monomers made of a 5-carbon sugar (usually ribose or deoxyribose), a phosphate group, and a nitrogenous base. A nucleic acid can also be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA). A chimeric nucleic acid comprises two or more of the same kind of nucleic acid fused together to form one compound comprising genetic material.

[0103] The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences. Percent identity for a nucleic acid sequence may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its Docket No. 11676 -005 WO 1 entirety). A suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403 410), which is available from several sources, including the NCBI, Bethesda, Md., at its website. The BLAST software suite includes various sequence analysis programs including “blastn,” that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called “BLAST 2 Sequences” that is used for direct pairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” can be accessed and used interactively at the NCBI website. The “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed above).

[0104] Percent identity may be measured over the length of an entire defined polynucleotide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured.

[0105] A “full length” polynucleotide sequence is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A “full length” polynucleotide sequence encodes a “full length” polypeptide sequence.

[0106] A “variant,” “mutant,” or “derivative” of a particular nucleic acid sequence may be defined as a nucleic acid sequence having at least 50% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences — a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett. 174:247-250). In some embodiments a variant polynucleotide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference polynucleotide.

[0107] The word “vector” or “expression vector” refers to any vehicle that carries a polynucleotide into a cell for the expression of the polynucleotide in the cell. The vector may be, for example, a plasmid, a virus, a phage particle, or a nanoparticle. Once transformed into a suitable host, the vector may replicate and function independently of the host genome, or may in some instances, integrate into the genome itself. In some embodiments, the vector is a DNA Docket No. 11676 -005 WO 1 construct containing a DNA sequence which is operably linked to a suitable control sequence capable of effecting the expression of the DNA in a suitable host cell. Such control sequences can include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences which control the termination of transcription and translation. In other embodiments, the vector is a lipid nanoparticle. Lipid nanoparticles can be used to deliver mRNA to a host cell for expression of the mRNA in the host cell.

[0108] “Inhibitors” or “antagonist” of expression or of activity are used to refer to inhibitory molecules, respectively, identified using in vitro and in vivo assays for expression or activity of a described target protein, e.g., ligands, antagonists, and their homologs and mimetics. Inhibitors are agents that, e.g., inhibit expression or bind to, partially or totally block stimulation or activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of the described target protein, e.g., antagonists. Control samples (untreated with inhibitors) are assigned a relative activity value of 100%. Inhibition of a described target protein is achieved when the activity value relative to the control is about 80%, optionally 50% or 25, 10%, 5%, or 1% or less.

[0109] The term “detect” or “detecting” refers to an output signal released for the purpose of sensing of physical phenomenon. An event or change in environment is sensed and signal output released in the form of light or any other activity.

[0110] A “variant” or a “derivative” of a particular inhibitor may be defined as a chemical or molecular compound having at least 50% identity to a parent or original inhibitor. In some embodiments a variant inhibitor may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater identity relative to a reference parent or original inhibitor.

[0111] A "gene" refers to a polynucleotide containing at least one open reading frame that is capable of encoding a particular polypeptide or protein after being transcribed and translated. Any of the polynucleotides sequences described herein may be used to identify larger fragments or full-length coding sequences of the gene with which they are associated.

[0112] The term “screening” refers to a method used in drag discovery in which data processing / control software, liquid handling devices, and sensitive detectors can allow for quick conductions of chemical, genetic, or pharmacological tests. This process allows one to quickly recognize active compounds, antibodies, or genes that modulate a particular biomolecular pathway. The results of these processes provide starting points for drug design. Docket No. 11676 -005 WO 1

[0113] High-throughput Prime Editing Assays

[0114] The present disclosure provides a high-throughput prime editing assay for detecting mismatch repair (MMR) in a cell.

[0115] MMR is a complex process that removes mispaired nucleotides and insertion / deletion loops (IDEs). In general, the mechanism of MMR involves four steps to ensure correction of mismatched DNA. Step 1 - Mismatch recognition: The MutS protein recognizes mismatches and IDLs in the DNA. Eukaryotic MMR deploys two MutS homologs for this step, MutSa (MSH2-MSH6) and MutS / ? (MSH2-MSH3). Step 2 - Complex formation and strand cleavage: MutS forms a complex with MutL and MutH, and MutH cleaves the unmethylated DNA strand at a GATC sequence. In eukaryotic MMR, MutSa / / ? recruit MutL homologs, MutLa, MutLy, and MutL / ?, of which MutLa and MutLy can act as endonucleases. Step 3 - Excision: Across species, the next step is to excise DN A to remove the mispair. Step 4 - Gap filling: DNA polymerase fills the gap using the other strand as a template, and DNA ligase seals it.

[0116] MMR affects numerous aspects of cellular biology including, but not limited to DNA- metabolic process, DNA recombination mechanisms, mutagenic process, and somatic hypermutation. When MMR is dysfunctional, the mutational rate of a cell increases significantly. What is needed in the field is an assay and methods of use thereof to identify MMR dysfunction and identify small molecule inhibitors (to promote MMR dysfunction).

[0117] The present disclosure provides a high-throughput prime editing assay for detecting MMR dysfunction, including during the recognition step of MMR. For instance, the present disclosure detects dysfunction in the MutS sensor proteins, such as for example MSH3 / MutSp, MSH6 / MutSa, or other components thereof through prime editing at the codon.

[0118] In one aspect, disclosed herein is a high-throughput prime editing assay comprising a mismatch repair (MMR) sensor- specific reporter and a prime editor, wherein the MMR sensorspecific reporter comprises a prime editing guide RNA (pegRNA) and a reporter enzyme, wherein the reporter enzyme is encoded by a nucleic acid comprising a mutated start codon, and wherein the assay detects mismatch repair (MMR) activity of a MMR component, including but not limited to a MSH3 / MutSP MMR sensor, a MSH6 / MutSa MMR sensor, or other components thereof.

[0119] In some embodiments, the MMR sensor-specific reporter comprises SEQ ID NO: 53 and SEQ ID NO: 56, or a variant thereof. In some embodiments, the MMR sensor-specific reporter comprises at least 80% sequence identity to SEQ ID NO: 53. In some embodiments. Docket No. 11676 -005 WO 1 the MMR sensor-specific reporter comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 53.

[0120] In some embodiments, the MMR sensor-specific reporter comprises SEQ ID NO: 58 and SEQ ID NO: 56, or a variation thereof. In some embodiments, the MMR sensor-specific reporter comprises at least 80% sequence identity to SEQ ID NO: 58. In some embodiments, the MMR sensor-specific reporter comprises 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 58.

[0121] In some embodiments, the MMR sensor- specific reporter comprises at least 80% sequence identity to SEQ ID NO: 56. In some embodiments, the MMR sensor-specific reporter comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 56.

[0122] As used herein, a “start codon” refers to the first codon in a messenger RNA (mRNA) transcript that a ribosome translates. The “start codon” is also the first base in a gene’s 5’- flanking region, wherein genetic information is translated into proteins. Generally, a start codon is made up of three bases including, but not limited to an adenine (A), uracil (U), and guanine (G); and adenine (A), thymine (T), and guanine (G), also referred to as an AUG codon or an ATG codon or the complement TAG or UAC.

[0123] In some embodiments, the nucleic acid encoding the MMR sensor-specific reporter comprises a mutated start codon, wherein a mutation of the start codon includes but is not limited an insertion, a deletion, and a substitution. In some embodiments, the pegRNA targets a mutated ATG start codon, wherein the ATG start codon comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 bps inserted, deleted, or substituted into other bases from an ATG sequence, and wherein the ATG sequence is re-installed by deleting, inserting, or substituting 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 bps. In some embodiments, the pegRNA targets a mutated complement of a start codon, specifically TAC. Thus, in some embodiments, the pegRNA targets a mutated TAC, wherein the TAC start codon comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 bps inserted, deleted, or substituted into other bases from an TAC sequence, and wherein the TAC sequence is re-installed by deleting, inserting, or substituting 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 bps. It should also be noted that the present disclosure allows for editing of other functional domains, including for example using any small edit that will “turn on” an element that allows expression of the selection marker or reporter enzyme. Docket No. 11676 -005 WO 1

[0124] In some embodiments, the pegRNA targets at least 1 base pair (bp) inserted within the mutated start codon of a nucleic acid encoding the reporter enzyme. In some embodiments, the pegRNA targets 1-10 bps inserted within the mutated start codon. In some embodiments, the pegRNA targets 3-9 bps inserted within the mutated start codon. In some embodiments, the pegRNA targets 3-5 bps inserted within the mutated start codon. In some embodiments, the pegRNA targets 5 bps inserted within the mutated start codon.

[0125] In some embodiments, the pegRNA targets at least 1 bp substituted within the mutated start codon on a nucleic acid encoding the reporter enzyme. In some embodiments, the pegRNA targets 1-10 bps substituted within the mutated start codon. In some embodiments, the pegRNA targets 3-9 bps substituted within the mutated start codon. In some embodiments, the pegRNA targets 3-5 bps substituted within the mutated start codon. In some embodiments, the pegRNA targets 5 bps substituted within the mutated start codon.

[0126] In some embodiments, the pegRNA targets at least 1 bp is deleted from the mutated start codon on a nucleic acid encoding the reporter enzyme. In some embodiments, the pegRNA targets 1-10 bps is deleted from the mutated start codon. In some embodiments, the pegRNA targets 3-9 bps is deleted from the mutated start codon. In some embodiments, the pegRNA targets 3-5 bps is deleted from the mutated start codon. In some embodiments, the pegRNA targets 5 bps is deleted from the mutated start codon.

[0127] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 53. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or 100% to SEQ ID NO: 53.

[0128] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 58. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 58.

[0129] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 64. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 64.

[0130] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 65. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 65. Docket No. 11676 -005 WO 1

[0131] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 66. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 66.

[0132] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 67. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 67.

[0133] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 68. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 68.

[0134] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 69. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or 100% to SEQ ID NO: 69.

[0135] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 70. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 70.

[0136] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 71. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 71.

[0137] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 72. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 72.

[0138] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 73. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 73.

[0139] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 74. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, Docket No. 11676 -005 WO 1

[0140] 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 74.

[0141] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 75. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 75.

[0142] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 76. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 76.

[0143] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 77. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 77.

[0144] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 78. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 78.

[0145] In some embodiments, the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 79. In some embodiments, the pegRNA comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 79.

[0146] In some embodiments, the prime editor comprises a Cas9 nuclease. A nuclease is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nuclease can possess properties to cause double or single stranded breaks to target nucleic acids. Nucleases are commonly used in CRISPR technology to modify a host genome to express or inhibit a target gene. Disclosed herein is a Cas9 nuclease or a fragment thereof. By “fragment” is meant a functional fragment or functional variant of a native Cas protein, or a protein that shares at least 30%, between 30% and 35%, at least 35%, between 35% and 40%, at least 40%, between 40% and 45%, at least 45%, between 45% and 50%, at least 50%, 50%, between 50% and 55%, at least 55%, between 55% and 60%, at least 60%, between 60% and 65%, at least 65%, between 65% and 70%, at least 70%, between 70% and 75%, at least 75%, between 75% and 80%, at least 80%, between 80% and 85%, at least 85%, between 85% and 90%, at least 90%, between 90% and 95%, at least 95%, between 95% and 96%, at least 96%, Docket No. 11676 -005 WO 1 between 96% and 97%, at least 97%, between 97% and 98%, at least 98%, between 98% and 99%', or at least 99% sequence identity to a parent Cas9 polypeptide. It is noted that “parent” and “native” are referred to alternatively herein, and have the same meaning, which is the naturally occurring Cas9 on which the variant or fragment thereof is based. In some embodiments, the Cas9 nuclease is fused to a reverse transcriptase.

[0147] In some embodiments, the reporter enzyme comprises luciferase (including, but not limited to a NanoLuc Luciferase), green fluorescent protein (GFP), yellow fluorescent protein (YFP), blue fluorescent protein (BFP), cyane fluorescent protein (CFP), monomeric red fluorescent protein (mRFP), Discosoma striata (DsRed), mCherry, mOrange, tdTomato, mSTrawberry, mPlum, photoactivatable GFP (PA-GFP), Venus, Kaede, monomeric kusabira orange (mKO), Dronpa, enhanced CFP (ECFP), Emerald, Cyan fluorescent protein for energy transfer (CyPet), super CFP (SCFP), Cerulean, photoswitchable CFP (PS-CFP2), photoactivatable RFPl (PA-RFP1), photoactivatable mCherry (PA-mCherry), monomeric teal fluorescent protein (mTFPl), Eos fluorescent protein (EosFP), Dendra, TagBFP, TagRFP, enhanced YFP (EYFP), Topaz, Citrine, yellow fluorescent protein for energy transfer (YPet), super YFP (SYFP), enhanced GFP (EGFP), Superfolder GFP, T-Sapphire, Fucci, mK02, mOrange2, mApple, Sirius, Azurite, EBFP, and / or EBFP2.

[0148] In some embodiments, the MMR sensor-specific reporter further comprises at least one promoter, an editing site located before the reporter (wherein the start codon is installed), and / or a selection marker (such as for example a reporter enzyme). In some embodiments, the MMR sensor-specific reporter comprises 2 promoters. In some embodiments, the MMR sensor-specific reporter comprises a promoter for the pegRNA, including but not limited to an m(J6 promoter, and / or a promoter for the reporter, including but not limited to an SFFV promoter.

[0149] In some embodiments, the promoter comprises at least 80% sequence identity to SEQ ID NO: 52 or SEQ ID NO: 54. In some embodiments, the promoter comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 52. In some embodiments, the promoter comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 54.

[0150] In some embodiments, the editing site comprises at least 90% sequence identity to SEQ ID NO: 55. In some embodiments, the editing site comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 55. Docket No. 11676 -005 WO 1

[0151] In some embodiments, the selection marker includes, but is not limited to luciferase, green fluorescent protein (GFP), yellow fluorescent protein (YFP), blue fluorescent protein (BFP), cyane fluorescent protein (CFP), monomeric red fluorescent protein (mRFP), Discosoma striata (DsRed), mCherry, mOrange, tdTomato, mSTrawberry, mPlum, photoactivatable GFP (PA-GFP), Venus, Kaede, monomeric kusabira orange (inKO), Dronpa, enhanced CFP (ECFP), Emerald, Cyan fluorescent protein for energy transfer (CyPet), super CFP (SCFP), Cerulean, photoswitchable CFP (PS-CFP2), photoactivatable RFP1 (PA-RFP1), photoactivatable mCherry (PA-mCherry), monomeric teal fluorescent protein (mTFPl), Eos fluorescent protein (EosFP), Dendra, TagBFP, TagRFP, enhanced YFP (EYFP), Topaz, Citrine, yellow fluorescent protein for energy transfer (YPet), super YFP (SYFP), enhanced GFP (EGFP), Superfolder GFP, T-Sapphire, Fucci, mK02, mOrange2, mApple, Sirius, Azurite, EBFP, and / or EBFP2. It should be noted that as used herein, a selection marker can also include a reporter enzyme. Further in some embodiments, the selection marker comprises a reporter enzyme. In some embodiments, the selection marker comprises a non-enzymatic selection marker.

[0152] In some embodiments, the selection marker comprises an mCherry protein. In some embodiments, the selection marker comprises at least 80% sequence identity to SEQ ID NO: 57. In some embodiments, the selection marker comprises 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 57.

[0153] In some embodiments, the assay is a cell-based prime editing assay. In some embodiments, the assay detects MMR activity in live cells. In some embodiments, the assay discriminates between MSH3 / MutSp activity and MSH6 / MutSa activity.

[0154] Methods of Using the High-throughput Prime Editing Assay

[0155] The present disclosure also provides methods of detecting MMR and methods of screening small molecule inhibitors of MMR using the high-throughput assay prime editing assay.

[0156] The present disclosure also provides methods for detecting dysfunction during the recognition step of MMR. For instance, said methods detect dysfunction in the MutS sensor proteins, such as for example MSH3 / MutSP or MSH6 / MutSa, of MMR. The present disclosure also identifies and / or screens small molecule inhibitors that prevent activity of a MMR component, including but not limited to MSH3 / MutSp. Docket No. 11676 -005 WO 1

[0157] In one aspect, disclosed herein is a method of detecting mismatch repair (MMR) activity in a cell, the method comprising introducing into the cell at least one expression vector comprising a nucleic acid encoding a mismatch repair (MMR) sensor-specific reporter and a prime editor, wherein the mismatch repair (MMR) sensor- specific reporter and the prime editor are expressed in the cell; and detecting an activity level of a MMR component, including but not limited to a MSH3 / MutSP component, a MSH6 / MutSa component, or other components thereof relative to a control cell.

[0158] In one aspect, disclosed herein is a method of screening for a small molecule inhibitor of mismatch repair (MMR), the method comprising: (a) introducing into a cell at least one expression vector comprising a nucleic acid encoding a mismatch repair (MMR) sensorspecific reporter and a prime editor: (b) expressing the mismatch repair (MMR) sensor-specific reporter and the prime editor in the cell; (c) introducing into the cell a small molecule; and (d) detecting MMR activity in the cell, wherein the small molecule inhibits a MMR component, including but not limited to a MSH3 / MutSP MMR component, a MSH6 / MutSa MMR component, or other MMR components thereof in the cell relative to a control cell.

[0159] In some embodiments, the method of any preceding aspect comprises the pegRNA targeting at least 1 base pairs (bps), including but not limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 bps, 3, 4, 5 bps, or 5 bps inserted within the mutated start codon of the nucleic acid encoding the reporter enzyme. In some embodiments, the MMR sensor- specific reporter is activated when the mutated start codon comprises an insertion mutation, a substitution mutation, a deletion mutation, or any mutation known in the art.

[0160] In some embodiments, the method of any preceding aspect comprises the MMR sensorspecific reporter of any preceding aspect. In some embodiments, the MMR sensor-specific reporter comprises a prime editing guide RNA (pegRNA) and a reporter enzyme, and wherein the reporter enzyme is encoded by a nucleic acid comprising a mutated stmt codon.

[0161] In some embodiments, the MMR sensor-specific reporter aspect further comprises at least one promoter, an editing site located before the reporter (wherein the start codon is installed), and / or a selection marker (including but not limited to reporter enzymes and non- enzymatic selection markers) of any preceding aspect.

[0162] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 53. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% sequence identity to SEQ ID NO: 53. Docket No. 11676 -005 WO 1

[0163] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 58. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%sequence identity to SEQ ID NO: 58.

[0164] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 64. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 64.

[0165] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 65. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 65.

[0166] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 66. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 66.

[0167] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80%' sequence identity to SEQ ID NO: 67. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 67.

[0168] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 68. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 68.

[0169] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 69. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81 %, 82%, 83%, Docket No. 11676 -005 WO 1

[0170] 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%' to SEQ ID NO: 69.

[0171] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 70. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 70.

[0172] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80%' sequence identity to SEQ ID NO: 71. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 71.

[0173] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 72. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 72.

[0174] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 73. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%' to SEQ ID NO: 73.

[0175] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 74. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 74.

[0176] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80%' sequence identity to SEQ ID NO: 75. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 75.

[0177] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 76. In some embodiments, the Docket No. 11676 -005 WO 1 method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%,

[0178] 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 76.

[0179] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 77. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 77.

[0180] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 78. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 78.

[0181] In some embodiments, the method of any preceding aspect comprises the pegRNA comprising at least 80% sequence identity to SEQ ID NO: 79. In some embodiments, the method of any preceding aspect comprises the pegRNA comprising 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% to SEQ ID NO: 79.

[0182] In some embodiments, the method of any preceding aspect comprises the prime editor comprising a Cas9 nuclease of any preceding aspect. In some embodiments, the Cas9 nuclease is fused to a reverse transcriptase.

[0183] In some embodiments, the small molecule inhibitor comprises a peptide, an antibody, a nucleic acid, or a deri vative thereof, an amino acid, or a derivative thereof, lipids, or any other molecule thereof.

[0184] In some embodiments, 1, 2, or more expression vectors are introduced into a cell. In some embodiments, a MMR sensor- specific reporter and a prime editor are encoded in the same nucleic acid within the expression vector. In some embodiments, the MMR-sensor- specific and tire prime editor are encoded on different nucleic acids within tire 1, 2, or more expression vector. In some embodiments, a first expression vector comprises a nucleic acid encoding the MMR sensor-specific reporter and the primer editor. In some embodiments, a first expression vector comprises a nucleic acid encoding the MMR sensor-specific reporter, and a second expression vector comprises a nucleic acid encoding the prime editor.

[0185] In some embodiments, the expression vector comprises a plasmid, a lentivirus, an adenovirus, an adeno-associated virus (AAV), or a lipid nanoparticle (LNP). In some Docket No. 11676 -005 WO 1 embodiments, the nucleic acid comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO:29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, or a variant thereof.

[0186] In some embodiments, the method detects MMR activity using a high-throughput prime editing assay. In some embodiments, tire method detects MMR activity in live cells. In some embodiments, the method discriminates between MSH3 / MutSP activity and MSH6 / MutSa activity.

[0187] In some embodiments, the method of any preceding treats or prevents a disease by detecting, screening, and / or identifying a small molecule of any preceding aspect, wherein said small molecule treats or prevents the disease. In some embodiments, the disease includes, but is not limited to a neurodegenerative disease, cancer, and a metabolic disease. A “neurodegenerative disease” is caused by the progressive loss of structure or function of neurons or glial cells, which make up the nervous system. These diseases include but are not limited to amyotrophic lateral sclerosis (AI..S), multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and prion diseases. Neurodegenerative diseases can lead to cognitive and physical impairments, neuroinflammation (inflammation of the brain and spinal cord), and deterioration of brain and spinal cord tissues. In some embodiments, the disease comprises Huntington’s disease.

[0188] A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0189] By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below. Docket No. 11676 -005 WO 1

[0190] SEQUENCES

[0191] 1. SEQ ID NO: 1 pYJ263„GYJ070„lYJ002„FAM53A„+5-

[0192] 9deletion_reverse_Nluc_reporter tcaatacggggtcattagttcatagcccatatatggagttccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccactggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgacctatgggacttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccatgacgtcaatgggagttgtttggcacc aaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggeggcgactggtgagtaegccaaaaatttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaatcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaacttagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt: tgtcctgggtctgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatatgtctggt atagtgcagcagcagaacaattgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagtggagtaataaatctctggaacagattggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattatggaattagataaatg ggcaagttgtggaatggtttaacataacaaatggctgtggtatataaaattattcataatgatagtaggaggcttggtaggttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaccattatcgtttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaactttaaaagaaaaggggggatggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattac tgc tgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggactgtgggagaagctcggctactcccctgcc ccggtaatttgcatataatatttcctagtaactatagaggctaatgtgcgataaaagacagataatctgttctttttaatactagctacatt acatgataggctggattctataacttcgtatagcatacatatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGCAGACGACCGCTCT TGI TCG1 TTAAGAGCTATGCTGGAA ACAGC ATAGCAAGT TTAAATAAGGCTAG fC Docket No. 11676 -005 WO 1

[0193] CGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCAGTATTCTGCGATGGAAC AAGAGCGGTCTTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagattttatttagtctccagaa aaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccatttgcaaggcatggaaaaataccaaacc aagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagttcggc cccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaacagatggtccccagatatggccc aaccctcagcagttcttaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgcctattgaataaccaatc agcctgctctcgcttctgttcgcgcgcttctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccga cagactgagtcgcccgggAGTATTCTGCGATAACCCGGAACAAGAGCGGTCGTCTGTGATC GTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaa cagggaggtgtgtccagttgttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaa gatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgtaccctgt ggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcggacggc cgtatgaaggcategcegtgttegacggcaaaaagatcactgtaaeagggaccctgtggaacggcaacaaaatatcgacgagcgc ctgatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcatctggcgTA Aaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgc ccctctccctcccccccccctaacgttactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttattttccaccatat gccgtctttggcaatgtgagggcccggaaacctggccctgtcttctgacgagcattcctaggggtctttcccctctcgccaaaggaat gcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagcttctgaagacaaacaacgtctgtagcgaccctttgcaggcagc ggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtg ccacgttgtgagtggatagtgtggaaagagtoaaatggctctoctcaagcgtatcaacaaggggctgaaggatgcccagaaggta ccccatgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggttaaaaaaacgtctaggccccccgaac cacggggacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccat catcaaggagttcatgcgctcaaggtgcacatggagggctocgtgaacggccacgagtcgagatcgagggcgagggcgagggc cgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctca gtcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtccttccccgagggctcaagtgg gagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggt gaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatg taccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaa gaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgagg actacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggeatggacgagctgtacaagtaactgaetga ctgagtcgacaatcaacctctggattacaaaatttgtgaaagattgactggtattctaactatgtgctcctttacgctatgtggatacgct gctttaatgcctttgtatcatgctatgctcccgtatggcttcatttctcctcctgtataaatcctggttgctgtctctttatgaggagtgtg gcccgtgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggtggggcatgccaccacctgtcagctcc tttccgggacttcgcttccccctccctatgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgt Docket No. 11676 -005 WO 1 tgggcactgacaatccgtggtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgtgccacctggattctgcgcggga cgtccttctgctacgteccttcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtcttcg cctcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagctcggtaccttaagaccaatgacttacaag gcagctgtagatcttagccacttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgcttttgct tgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgctaagcctcaataaagctg ccttgagtgcttcaagtagtgtgtgecegtetgttgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagttccgcccatctccgcctcatggctgactaattttttattatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgctttggaggccgaggcttgcaaagatcgaacaagagacaggacctgc aggttaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccatagg ctccgccx’ccctgacgagcatcacaaaaatcgaegctcaagtcagaggtggcgaaaex’cgacaggactataaagataccaggcgtt ccccctggaagctccctcgtgcgctctcctgttccgaccctgccgctaccggatacctgtccgcctttctcccttcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtogtcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgccttatccggtaactategtettgagtceaacccggtaagaeacgaettatcgcx’actggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtattggta tctgcgctctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttt tgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtggaacga aaactcacgtaagggatttggtcatgagatatcaaaaaggatctcacctagatccttaaataaaaatgaagtttaaatoaatctaa agtatatatgagtaaactggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctatttcgtcatccatagtg catttaaatggccggcctggLgcgccgtttaaacctagatattgatag tetgatcggtcaacgtataatcgagtcctagcttttgcaaacat ctatcaagagacaggatcagcaggaggcttcgcatgagtatcaacattccgtgtcgccctattccctttttgcggcattgcctcct gttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatcctgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagttctgctatgtggcgcggtatatccc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtattcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaatatgcagtgctgccataaccatgagtgataacactgcggccaactacttctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgcctgatcgtgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactcta gctcccggcaacagtgatagactggatggaggcggataaagtgcaggaccactctgcgctcggcccttccggctggctggttat tgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaacc gattcXaggtgeattggegcagaaaaaaatgcetgatgegacgcXgcgcgtcttataeteccacatatgccagatteagcaacggatac ggctccccaacttgcccactccatacgtgtcctcctaccagaaattatccttaagatcccgaatcgttaaacgcgatcgcagtaa Docket No. 11676 -005 WO 1

[0194] 2. SEQ ID NO: 2 ■■ pYJ264„GYJ07 l„lYJ002„PARS2„+5~9„deletion„reverse„Nluc„reporter tcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccatgacgtcaatgggagttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctrtta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtataagcgggggagaatagatcgcgatgggaaaaaattcggttaaggcx:agggggaaa gaaaaaatataaataaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaatgaaccataggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagct tgttccttgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgtgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggtgctctggaaaactcatttgcaccact gctgtgccttggaatgc tagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactcctaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaatatggaatagataaatg ggcaagttgtggaattggUtaacataacaaatggctgtggtatataaaatattcataatgatagtaggaggcUggtaggttaagaat agtttgctgtacttctatagtgaatagagttaggcagggatatcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaatttggctcccgatcgttgcgtacacacacaatactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctoggctactcccctgcc ccggttaattgcatataatatttcetagtaactatagaggettaatgtgcgataaaagacagataatctgttotttttaatactagctacatttt acatgataggctggattctataacttcgtatagcatacatatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGCTCGTGCGAGTGAT

[0195] AGACCGTTTAAGAGCTATGCTGGAAACAGCATAGC AAGTl'TAAAT AAGGC TA GT CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCCCGACGGCCTGATGGGT Docket No. 11676 -005 WO 1

[0196] CTATCACTCGCTTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagatttattagtctccaga aaaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccattttgcaaggcatggaaaaataccaaac caagaatagagaagttcagatcaagggcgggtacatgaaaatagcXaacgttgggccaaacaggatatcXgcggtgagcagtttcgg ccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaacagatggtccccagatatggcc caaccctcagcagttctaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgccttattgaataaccaat cagcctgctctcgctctgtcgcgcgctctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccg acagactgagtcgcccgggCCGACGGCC TGATTC 1 CCGGGTCl'ATCACTCGCACGAGCGG f CTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaaca gggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaaga tcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaattttaaggtggtgtaccctgtg gatgatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggtacgccgaacatgatcgactatttcggacggcc gtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgcct gatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAA aagtgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcc cctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttatttccaccatatg ccgtcttggcaatgtgagggcccggaaacctggccctgtotcttgacgagcattcctaggggtcttcccctctcgccaaaggaatg caaggtctgtgaatgtcgtgaaggaagcagtcctctggaagcttcttgaagacaaacaacgtctgtagcgaccctttgcaggcagcg gaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgc cacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccagaaggtac cccattgtatgggatctgatctggggcctcggtacacatgctttacatgtgtttagtegaggttaaaaaaacgtctaggccecccgaaec acggggacgtggtttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccatc atcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggcc gcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccctcgcctgggacatcctgtcccctcag ttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtccttccccgagggcttcaagtggg agcgcgtgatgaactcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagtcatctacaaggtg aagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgt accccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaag accacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgagga ctacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactgac tgagtcgacaatcaacx’tctggattaeaaaatttgtgaaagattgactggtattcttaactatgttgctcetttacgctatgtggatacgctg ctttaatgccttgtatcatgctatgctcccgtatggcttcatttctectecttgtataaaicctggtgetgtetetttatgaggagttgtgg cccgttgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggttggggcattgccaccacctgtcagctoctt tcx’gggactttcgetttccccctcex’tatgccaeggcggaactcatcgccgcctgccttgcx’cgctgctggacaggggctoggctgtt gggcactgacaattccgtggtgttgtcggggaagctgacgtccttccatggctgctcgcctgtgttgccacctggatctgcgcggga Docket No. 11676 -005 WO 1 cgtccttctgctacgtccctcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtctcg ccttcgccc tcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggtacctttaagaccaatgacttacaag geagctgtagatetagecacttttaaaagaaaaggggggactggaagggctaatcacteccaacgaagacaagatctgettttgct tgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgctaagcctcaataaagctg ccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttatttatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgcttttggaggccgaggctttgcaaagatcgaacaagagacaggacctgc aggttaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgtttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttt ccccctggaagctccctcgtgcgctctectgtccgaccctgccgctaccggatacctgtccgccttctcccttcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgtcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgcctatccggtaactatcgtctgagtccaacccggtaagacacgactatcgccactggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagttctgaagtggtggcctaactacggctacactagaagaacagtattggta tctgcgctctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttt tgtttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatccttgatctttctacggggtctgacgctcagtggaacga aaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaa agtatatatgagtaaacttggtctgaeagttaccaatgcttaatcagtgaggcaex’tateteagegatctgtetatttcgttcatccatagttg cattaaatggccggcctggcgcgccgtttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacat ctatcaagagacaggatcagcaggaggctttcgcatgagtattcaacatttccgtgtegcccttattcccttttttgcggcattttgccttcct gtttttgcteaeceagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatcctgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagttctgctatgtggcgcggtatatccc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctoagaatgacttggtgagtattcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacac tgcggccaacttacttctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacaigggggatcatgtaactcgccilgatcgtEgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactcta gcttcccggcaacagttgatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttat tgctgataaatctggagecggtgagcgtgggtctegcggtatcattgcagcactggggecagatggtaagcccteccgtatcgtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcatggtaacc gattctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatgccagattcagcaacggatac ggctccccaactgcccacttccatacgtgtcctcctaccagaaattatcctaagatcccgaatcgtttaaacgcgatcgcagtaa Docket No. 11676 -005 WO 1

[0197] 3. SEQ ID NO: 3 pYJ265„ GYJ072 J YJ002...TRIM 13.. +5-

[0198] 9_dele tion_reverseJN hi c_reporter tcaattaeggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtaeatgaecttatgggactttcctacttggcagtacatctacgtattagtcatcgctataccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctrtta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtataagcgggggagaatagatcgcgatgggaaaaaatcggtaaggccagggggaaa gaaaaaatataaataaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaaeaaaagtaagaceacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgtgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggtgctctggaaaactcatttgcaccact gctgtgccttggaatgc tagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagettaatacactectaattgaagaategcaaaaccagcaagaaaagaatgaacaagaatattggaattagataaatg ggcaagttgtggaattggUtaacataacaaatggctgtggtatataaaatattcataatgatagtaggaggcUggtaggttaagaat agttttgctgtactttctatagtgaatagagttaggcagggatatcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaatttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaattgcatataatatttcetagtaactatagaggetaatgtgcgataaaagacagataatctgtctttttaatactagctacattt acatgataggctggattctataacttcgtatagcatacatatacgaagtataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgtttigagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGTAGTCTGTTTGATG

[0199] ATCCAGrrrAAGAGCTA'rGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGT CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCGGGAGCAAGGCATGTGG Docket No. 11676 -005 WO 1

[0200] ATCATCAAACAGATTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagattatttagtctc cagaaaaaggggggaatgaaagaccocacctgtaggtttggcaagctagc tgcagtaacgccattttgcaaggcatggaaaaatacc aaaccaagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtt tcggccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaacagatggtccccagatatg gcccaaccctcagcagttctaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgcctatttgaattaacc aatcagcctgctctcgcttctgttcgcgcgctctgctcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctc cgacagactgagtcgcccgggGGGAGCAAGGCAI AACCCGTGGA'FCATCAAACAGACTACG GTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtcctgaa cagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcc tgagcggtgaaaatgggctgaa gatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaattttaaggtggtgtaccctgt ggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggtacgccgaacatgatcgactattcggacggc cgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgc ctgatcaaccccgacggctccctgctgtccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTA Aaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaatctgcagtcgacggtaccgcgggcccgggatccgc ccctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgtttgtctatatgttatttccaccatatt gccgtctttggcaatgtgagggcccggaaacctggccctgtctctgacgagcatcctaggggtcttcccctctcgccaaaggaat gcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagcttcttgaagacaaacaacgtctgtagcgaccctttgcaggcagc ggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtg ccacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcxcagaaggta ccccatgtatgggatctgatctggggcctcggtacacatgctttacatgtgttagtcgaggtaaaaaaacgtctaggccccccgaac cacggggacgtggtttccttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccat catcaaggagtcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggc cgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccctcgcctgggacatcctgtcccctca gtcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtccttccccgagggcttcaagtgg gagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggt gaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatg taccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaa gaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagtggacatcacctcccacaacgagg actacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactga ctgagtegaeaatcaacctctggattacaaaatttgtgaaagattgactggtattettaactatgtgctecttttacgctatgtggatacgct gctttaatgcctttgtatcatgctatgctcccgtatggcttcatttctcctcctgtataaatcctggttgctgtctctttatgaggagtgtg gcccgttgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggtggggcatgccaccacctgtcagctcc ttccgggactttcgcttccccctccctatgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgt tgggcactgacaatccgtggtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgtgccacctggattctgcgcggga Docket No. 11676 -005 WO 1 cgtccttctgctacgtccctcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtctcg ccttcgccc tcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggtacctttaagaccaatgacttacaag geagctgtagatetagecacttttaaaagaaaaggggggactggaagggctaatcacteccaacgaagacaagatctgettttgct tgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgctaagcctcaataaagctg ccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttatttatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgcttttggaggccgaggctttgcaaagatcgaacaagagacaggacctgc aggttaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgtttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttt ccccctggaagctccctcgtgcgctctectgtccgaccctgccgctaccggatacctgtccgccttctcccttcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgtcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgcctatccggtaactatcgtctgagtccaacccggtaagacacgactatcgccactggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagttctgaagtggtggcctaactacggctacactagaagaacagtattggta tctgcgctctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttt tgtttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatccttgatctttctacggggtctgacgctcagtggaacga aaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaa agtatatatgagtaaacttggtctgaeagttaccaatgcttaatcagtgaggcaex’tateteagegatctgtetatttcgttcatccatagttg cattaaatggccggcctggcgcgccgtttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacat ctatcaagagacaggatcagcaggaggctttcgcatgagtattcaacatttccgtgtegcccttattcccttttttgcggcattttgccttcct gtttttgcteaeceagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatcctgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagttctgctatgtggcgcggtatatccc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctoagaatgacttggtgagtattcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacac tgcggccaacttacttctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacaigggggatcatgtaactcgccilgatcgtEgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactcta gcttcccggcaacagttgatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttat tgctgataaatctggagecggtgagcgtgggtctegcggtatcattgcagcactggggecagatggtaagcccteccgtatcgtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcatggtaacc gattctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatgccagattcagcaacggatac ggctccccaactgcccacttccatacgtgtcctcctaccagaaattatcctaagatcccgaatcgtttaaacgcgatcgcagtaa Docket No. 11676 -005 WO 1

[0201] 4. SEQ ID NO: 4 pYJ266..GYJ073JYJ002..CREBZE.. +5-

[0202] 9_dele tion_reverseJN hi c_reporter tcaattaeggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtaeatgaecttatgggactttcctacttggcagtacatctacgtattagtcatcgctataccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctrtta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtataagcgggggagaatagatcgcgatgggaaaaaatcggtaaggccagggggaaa gaaaaaatataaataaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaaeaaaagtaagaceacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgtgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggtgctctggaaaactcatttgcaccact gctgtgccttggaatgc tagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagettaatacactectaattgaagaategcaaaaccagcaagaaaagaatgaacaagaatattggaattagataaatg ggcaagttgtggaattggUtaacataacaaatggctgtggtatataaaatattcataatgatagtaggaggcUggtaggttaagaat agttttgctgtactttctatagtgaatagagttaggcagggatatcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaatttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaattgcatataatatttcetagtaactatagaggetaatgtgcgataaaagacagataatctgtctttttaatactagctacattt acatgataggctggattctataacttcgtatagcatacatatacgaagtataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgttttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGTCCGAGCCTCCGCC

[0203] AGACGGTTTAAGAGCTATGCTGGAAACAGCA'rAGCAAGTrTAAATAAGGCTAGr CCGTTA fCAACTTGA AAAAGTGGCACCGAGTCGGTGC 1 CGCCGGGGCCATGCGT Docket No. 11676 -005 WO 1

[0204] CTGGCGGAGGCTCTTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagattttatttagtctcc agaaaaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccattttgcaaggcatggaaaaatacca aaccaagaatagagaagtcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagttt cggccccggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatg gcccaaccctcagcagttctaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgcctatttgaattaacc aatcagcctgctctcgcttctgttcgcgcgctctgctcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctc cgacagactgagtcgcccggg rCGCCGGGGCCATTCTCCGCGTCTGGCGGAGGCTCGGATCG TCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaac agggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaag atcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaattttaaggtggtgtaccctgtg gatgatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggtacgccgaacatgatcgactatttcggacggcc gtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgcct gatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAA aagtgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcc cctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttatttccaccatatg ccgtcttggcaatgtgagggcccggaaacctggccctgtotcttgacgagcattcctaggggtcttcccctctcgccaaaggaatg caaggtctgtgaatgtcgtgaaggaagcagtcctctggaagcttcttgaagacaaacaacgtctgtagcgaccctttgcaggcagcg gaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgc cacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccagaaggtac cccattgtatgggatctgatctggggcctcggtacacatgctttacatgtgtttagtegaggttaaaaaaacgtctaggccecccgaaec acggggacgtggtttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccatc atcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggcc gcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccctcgcctgggacatcctgtcccctcag ttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtccttccccgagggcttcaagtggg agcgcgtgatgaactcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagtcatctacaaggtg aagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgt accccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaag accacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgagga ctacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactgac tgagtcgacaatcaacx’tctggattaeaaaatttgtgaaagattgactggtattcttaactatgttgctcetttacgctatgtggatacgctg ctttaatgccttgtatcatgctatgctcccgtatggcttcatttctectecttgtataaaicctggtgetgtetetttatgaggagttgtgg cccgttgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggttggggcattgccaccacctgtcagctoctt tcx’gggactttcgetttocccctcex’tatgccaeggcggaactcatcgccgceXgccttgcx’cgctgctggacaggggctoggetgtt gggcactgacaattccgtggtgttgtcggggaagctgacgtccttccatggctgctcgcctgtgttgccacctggatctgcgcggga Docket No. 11676 -005 WO 1 cgtccttctgctacgtccctcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtctcg ccttcgccc tcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggtacctttaagaccaatgacttacaag geagctgtagatetagecacttttaaaagaaaaggggggactggaagggctaatcacteccaacgaagacaagatctgettttgct tgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgctaagcctcaataaagctg ccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttatttatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgcttttggaggccgaggctttgcaaagatcgaacaagagacaggacctgc aggttaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgtttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttt ccccctggaagctccctcgtgcgctctectgtccgaccctgccgctaccggatacctgtccgccttctcccttcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgtcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgcctatccggtaactatcgtctgagtccaacccggtaagacacgactatcgccactggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagttctgaagtggtggcctaactacggctacactagaagaacagtattggta tctgcgctctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttt tgtttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatccttgatctttctacggggtctgacgctcagtggaacga aaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaa agtatatatgagtaaacttggtctgaeagttaccaatgcttaatcagtgaggcaex’tateteagegatctgtetatttcgttcatccatagttg cattaaatggccggcctggcgcgccgtttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacat ctatcaagagacaggatcagcaggaggctttcgcatgagtattcaacatttccgtgtegcccttattcccttttttgcggcattttgccttcct gtttttgcteaeceagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatcctgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagttctgctatgtggcgcggtatatccc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctoagaatgacttggtgagtattcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacac tgcggccaacttacttctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacaigggggatcatgtaactcgccilgatcgtEgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactcta gcttcccggcaacagttgatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttat tgctgataaatctggagecggtgagcgtgggtctegcggtatcattgcagcactggggecagatggtaagcccteccgtatcgtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcatggtaacc gattctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatgccagattcagcaacggatac ggctccccaactgcccacttccatacgtgtcctcctaccagaaattatcctaagatcccgaatcgtttaaacgcgatcgcagtaa Docket No. I I 676-005 WO 1

[0205] 5. SEQ ID NO: 5 - pYJ267. GYJ074..IYJ002...TMEM35.. +5-9.. deletion. ,fwd.Nluc .reporter tcaattacggggtcattagttcatagcccatatatggagtccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccatgacgtcaataatgacgtatgtcccatagtaacgccaatagggacttccatgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggtttggc agtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctocaccccattgacgtcaatgggagtttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtotgttgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattogg ttaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc geaeageaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaatatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttctgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggattggggtgctotggaaaactoattgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaattagataaatg ggcaagtttgtggaattggttaaeataacaaattggctgtggtatataaaattattcataatgatagtaggaggctggtaggtttaagaat agttttgctgtactttctatagtgaatagagttaggcagggatatcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgatagtgaacggatctcgacggtatc ggttaacttttaaaagaaaaggggggattggggggtacagtgoaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaatcaaaatttggctcccgatcgttgcgtacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggettaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacageacaaaaggaaactcacxxtaactgtaaagt aattgtgtgttttgagactaTAAG TATCCC TTGGAGAACCACC TTG TTGGGACTATCAAGCTGA

[0206] CCCCCGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGT CCG IT A TCA ACT IGA A A AAGTGGC ACCGAG ICGGTGC AGGCG'fCCT I GCATGGG GGTC AGC 1 TGA I T I T I T I CTCG AG ACCGG I A TGC A fccgataaaataaaagattttatttagtctccaga Docket No. 11676 -005 WO 1 aaaaggggggaatgaaagaccccacctgtaggttggcaagctagctgcagtaacgccatttgcaaggcatggaaaaataccaaac caagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtttcgg ccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaacagatggtccccagatatggcc caaccctcagcagttctaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgccttattgaattaaccaat cagcctgcttctcgctctgttcgcgcgctctgctcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccg acagactgagtcgcccgggGGAC TATC AAGC TGACCCCC AGGC ICTGCAAGGACGCC ICGT CTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtcctgaaca gggaggtgtgtccagttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaaga tcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgtaccctgtg gatgatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggtacgccgaacatgatcgactattcggacggcc gtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgcct gatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAA aagtgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcc cctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttatttccaccatatg ccgtctttggcaatgtgagggcccggaaacctggccctgtcttctgacgagcatcctaggggtcttcccctctcgccaaaggaatg caaggtctgttgaatgtcgtgaaggaagcagtcctctggaagcttcttgaagacaaacaacgtctgtagcgacccttgcaggcagcg gaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgc cacgtgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtatcaacaaggggctgaaggatgcccagaaggtac cccattgtatgggatctgatctggggcctcggtacacatgctttacatgtgtttagtcgaggttaaaaaaacgtctaggccccccgaacc acggggacgtggttccttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccatc atcaaggagttcatgcgctcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggcc gcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttogcctgggacatcctgtcccctcag tcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaagtggg agcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggtg aagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgt accccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaag accacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgagga ctacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactgac tgagtcgacaatcaacctotggattacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgctatgtggatacgctg cttaatgcctttgtatcatgctattgcttcccgtatggcttcattttctcctccttgtataaatcctggttgctgtctcttatgaggagttgtgg cccgtgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggtggggcattgccaccacctgtcagctcctt tccgggactttcgcttccccctccctatgccacggcggaactcatcgccgcctgcctgcccgctgctggacaggggctcggctgtt gggcactgacaattccgtggtgtgtcggggaagctgacgtccttccatggctgctcgcctgtgttgccacctggattctgcgcggga cgtccttctgctacgtccctcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtctcg Docket No. 11676 -005 WO 1 ccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagctcggtacctttaagaccaatgacttacaag gcagctgtagatcttagccactttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgctttttgct tgtactgggtetctctggttagaex’agatctgagcctgggagctctetggctaaetagggaacccactgcttaagectoaataaagctg ccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtctttgaataaagtotgagtgagtggccgacagtgcccgtggagtctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagtccgcccattctccgcctcatggctgactaatttttatttatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgcttttttggaggccgaggcttttgcaaagatcgaacaagagacaggacctgc aggttaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttt ccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgcctttetcccttcgggaagcgtggcg ctttctcatagetcacgctgtaggtatctcagttcggtgtaggtcgttegctccaagctgggctgtgtgcacgaacex’cccgttcagcccg accgctgcgcctatccggtaactatcgtctgagtccaacccggtaagacacgactatcgccactggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagttctgaagtggtggcctaactacggctacactagaagaacagtatttggta tctgcgctctgctgaagccagttacxltcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttt tgttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatccttgatctttctacggggtctgacgctcagtggaacga aaactcacgtaagggattttggtcatgagattatcaaaaaggatcttcacctagatcctttaaattaaaaatgaagtttaaatcaatctaa agtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttg cattaaatggccggcctggcgcgccgttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcctagctttgcaaacat ctatcaagagacaggatcagcaggaggcttcgcatgagtatcaacattccgtgtcgcccttattccctttgcggcatttgcctcct gtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cageggtaagatccttgagagttttcgceccgaagaacgctttcxaatgatgagcacXtttaaagtctgctatgtggcgcggtattatcxc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggtgagtattcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacttactctgacaacgatt ggaggaccgaaggagctaaccgcttttttgcacaacatgggggateatgtaactcgccttgatcgttgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactataactggcgaactacttactcta gctcccggcaacagtgatagactggatggaggcggataaagttgcaggaccactctgcgctcggcccttccggctggctggttat tgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagtta tctacacgacggggagtcaggeaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgataagcattggtaacc gattctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatgccagattcagcaacggatac ggcttccccaactgcccacttccatacgtgtcctcctaccagaaatttatccttaagatcccgaatcgtttaaacgcgatcgcagtaa

[0207] 6. SEQ ID NO: 6 - pYJ268_GYJ075JYJ002_DPY30_+5-9_deletion„fwd_Nluc_reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcdggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGGTCCCTCCAGCATC TGCTCGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGTC CGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCAGGGTCCGCCACATGAGC AGATGCTGGAGGTTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagatttattagtctcca gaaaaaggggggaatgaaagaccccacctgtaggttggcaagctagctgcagtaacgccattttgcaaggcatggaaaaataccaa Docket No. 11676 -005 WO 1 accaagaatagagaagtcagatcaagggcgggtacatgaaaatagctaacgtgggccaaacaggatatctgcggtgagcagttc ggccccggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatgg cccaaccctcagcagttctaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccctgcgcctattgaataacca atcagcctgctctcgcttctgttcgcgcgcttctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctcc gacagactgagtcgcccgggTGTCCCTCCAGCATCTGCTCAGGCTCTGTGGCGGACCCTCGT CTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtcctgaaca gggaggtgtgtccagttgmcagaatctcggggtgtccgtaactcxgatccaaaggattgtcctgagcggtgaaaatgggctgaaga tcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaattttaaggtggtgtaccctgtg gatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcggacggcc gtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgcct gatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAA aagttgtctcctcctgcactgactgactgatacaatcgatttctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcc cctctccctcccccccccctaacgttactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttattttccaccatattg ccgtctttggcaatgtgagggcccggaaacctggccctgtcttctgacgagcatcctaggggtcttcccctctcgccaaaggaatg caaggtctgtgaatgtcgtgaaggaagcagttcctctggaagcttctgaagacaaacaacgtctgtagcgacccttgcaggcagcg gaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgc cacgtgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtatcaacaaggggctgaaggatgcccagaaggtac cccatgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggttaaaaaaacgtctaggccccccgaacc acggggacgtggtttccttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccatc atcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggcc gcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctcag ttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaagtggg agcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgaccx’aggactoctccetgcaggaeggegagteatotacaaggtg aagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgt accccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaag accacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgagga ctacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactgac tgagtcgacaatcaacctctggattacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgctatgtggatacgctg ctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagttgtgg cccgttgtcaggeaacgtggcgtggtgtgcactgtgtttgetgacgcaacecccactggttggggcattgccaccacetgtcagctcctt tecgggacttcgcttecccetccctatgccacggcggaaetcategccgcctgccttgcccgctgctggacaggggctcggctgt gggcactgacaatccgtggtgtgtcggggaagctgacgtccttccatggctgctcgcctgtgtgccacctggattctgcgcggga cgtccttctgctacgtcccttcggccctcaatccagcggacctccttcccgcggcctgctgccggctctgcggcctctccgcgtctcg ccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagctcggtacctttaagaccaatgacttacaag Docket No. 11676 -005 WO 1 gcagctgtagatctagccacttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgcttttgct tgtactgggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagctg ccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccx’tgcaggcctaactc cgcccatcccgcccctaactccgcccagtccgcccatctccgcctcatggctgactaatttttatttatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgctttttggaggccgaggcttttgcaaagatcgaacaagagacaggacctgc aggtaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgtt ccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccgccttctcccttcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgccttatccggtaacXatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggta tctgcgctctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggttttt tgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatccXttgatcttttctacggggtctgacgctcagtggaacga aaactcacgtaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttaaataaaaatgaagtttaaatcaatctaa agtatatatgagtaaacttggtctgacagtaccaatgcttaatcagtgaggcacctatctcagcgatctgtctattcgttcatccatagttg catttaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacat ctatcaagagacaggatcagcaggaggcttcgcatgagtatcaacattccgtgtcgcccttatcccttttgcggcatttgcctcct gttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatccc gtatgacgccgggcaagagcaactcggtcgccgcatacactatctcagaatgactggttgagtatcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaactactctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactcta gctcccggcaacagtgatagactggatggaggcggataaagttgcaggaccactctgcgctcggcccttccggctggctggttat tgctgataaatctggagccggtgagcgtgggtctcgcggtatcatgcagcactggggccagatggtaagccctcccgtatcgtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaacc gattctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgteXtatactcccacatatgccagattcagcaaeggatae ggcttccccaacttgcccacttccatacgtgtcctcctaccagaaatttatccttaagatcccgaatcgtttaaacgcgatcgcagtaa

[0208] 7. SEQ ID NO: 7 pYJ269_GYJ076JYJ002_PLSCR2_+5-

[0209] 9„delerion„revCTseJNluc„reponer Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagacXaT AAGT A ICCC ITGGAGAACCACC TTGTTGGGGGAAAC AGGC TG ACCACCGT 1 TAAGAGCTA 1 GCTGGAAACAGCA TAGC AAGTTTAAATAAGGC T AG

[0210] TCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTAGAAGGCCTGATGGG TGGIX?,AGCA?7XjTTTCCCATTTTTTTC'rCGAGACCGGTATGCATccgataaaataaaagattttat tagtctccagaaaaaggggggaatgaaagaccccacctgtaggttggcaagctagctgcagtaacgccatttgcaaggcatggaa Docket No. 11676 -005 WO 1 aaataccaaaccaagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtg agcagttcggccccggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtcccc agatatggcccaaccctcagcagtttcttaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccctgcgcctatttg aattaaccaatcagcctgcttctcgctctgttcgcgcgcttctgctcccgagctctataaaagagctcacaacccctcactcggcgcgc cagtcctccgacagactgagtcgcccgggTAGAAGGCCTGATAGCCCGGGTGGTCAGCCTGTTTC CCAGGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagt ccttgaacagggaggtgtgtccagtttgttcagaatctcggggtgtccgtaactccgatccaaaggatgtcctgagcggtgaaaatgg gctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgt accctgtggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcg gacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgac gagcgcctgatcaaccccgacggctccctgctgtccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctg gcgTAAaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaatctgcagtcgacggtaccgcgggcccgg gatccgcccctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttatttcca ccatattgccgtctttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcattcctaggggtcttcccctctcgccaa aggaatgcaaggtctgtgaatgtcgtgaaggaagcagtcctctggaagctcttgaagacaaacaacgtctgtagcgacccttgca ggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaacc ccagtgccacgtgtgagtggatagttgtggaaagagtcaaatggctctcctcaagcgtatcaacaaggggctgaaggatgcccag aaggtaccccattgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggtaaaaaaacgtctaggccccc cgaaccacggggacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatg gceatcatcaaggagttcatgcgcttcaaggtgcacatggagggctocgtgaacggecacgagttcgagatcgagggcgagggcga gggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcc cctcagttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaa gtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactoctccetgeaggacggcgagtcatctaca aggtgaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcg gatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggt caagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacg aggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttga ctgactgagtcgacaatcaacctctggattacaaaatttgtgaaagattgactggtattctaactatgttgctccttttacgctatgtggata cgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagt tgtggcccgtgteaggcaacgtggegtggtgtgcactgtgtttgctgacgcaacccx’cactggttggggcattgccaccaectgtcag ctccttccgggacttcgcttccccctccctatgccacggcggaactcatcgccgcctgcctgcccgctgctggacaggggctcgg ctgttgggcactgacaattccgtggtgtgtcggggaagctgacgtccttccatggctgctcgcctgtgtgccacctggattctgcgcg ggacgtcctctgctacgtccctcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtc ttcgccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaattcgagctcggtaccttaagaccaatgacta Docket No. 11676 -005 WO 1 caaggcagctgtagatctagccactttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgcttt ttgcttgtactgggtctctctggttagaccagatctgagcctgggagctetctggctaactagggaacccactgcttaagcctcaataaag cttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatcx’ctcagaccettttagtcagtgtggaaaat ctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgccc cccccacccccgcagcccacccctggtctttgaataaagtctgagtgagtggccgacagtgcccgtggagtctcgtgacctgaggtg cagggcxggcgctagggacacgtocgtgcacgtgccgaggccccxtgtgcagctgcaagggacaggcctagccxtgcaggccta actccgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaatttttattatgcagaggccgaggc cgcctcggcctctgagctattccagaagtagtgaggacgcttttggaggccgaggctttgcaaagatcgaacaagagacaggacc tgcaggttaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccat aggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccagg cgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgccttctcccttcgggaagcgt ggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgtca gcccgaccgctgcgccttatccggtaactatcgtcttgagtocaacccggtaagacacgacttatcgccactggcagcagccactggt aacaggattagcagagcgaggtatgtaggcggtgctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtat ttggtatctgcgctctgctgaagccagtaccttcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggt ggttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatotcaagaagatccttgatcttttctacggggtctgacgctcagtg gaacgaaaactcacgttaagggattttggtcatgagatatcaaaaaggatcttcacctagatccttttaaataaaaatgaagtttaaatc aatctaaagtatatatgagtaaactggtctgacagttaccaatgctaatcagtgaggcacctatctcagcgatctgtctatttcgtcatcc atagttgcattaaatggccggcctggcgcgccgttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcctagctttg caaacatctatcaagagacaggatcagcaggaggctttcgcatgagtatcaacatttccgtgtcgccctatccctttttgcggcatt gccttcctgtttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggtacatcgaactg gatctcaacagcggtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttttaaagttctgctatgtggcgcgg tatatcccgtatgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgactggtgagtattcaccagtcacag aaaagcatctacggatggcatgacagtaagagaatatgcagtgctgccataaccatgagtgataacactgcggccaactacttctga caacgattggaggaccgaaggagctaaccgctttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagct gaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaact acttactctagcttcccggcaacagttgatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctg gctggttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgt atcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagc attggtaaccgattctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgtctatactcccacatatgccagatcagc aacggatacggctccccaacttgcccacttccatacgtgtcctcctaccagaaattatccttaagatcccgaatcgttaaacgcgatc gcagtaa

[0211] 8. SEQ ID NO: 8 - pYJ270_GYJ077JYJ002_PDIA2_+5-9_deletion_reverse_Niuc_reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcdggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagacXaT AAGT A ICCC ITGGAGAACCACC TTGTTGGTGCGGAAGAACTIG

[0212] AGCGTGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGT CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTGGTGTGACGGATGACG CTCAAGTTCTTTTTTTCTCGAGACCGGTATGCATcegataaaataaaagattttatttagtctccagaaaa aggggggaatgaaagaccccacetgtaggttggcaagctagctgcagtaacgccattgcaaggcatggaaaaataceaaaccaa Docket No 11676 -005 WO 1 gaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtttcggccc cggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatggcccaa ccctcagcagtttcttaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccctgcgccttatttgaattaaccaatcag cctgcttctcgcttctgttcgcgcgcttctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccgaca gactgagtcgcccgggTGGTGTGACGGATTACCCGACGCTCAAGTTCTTCCGCAAGGTCTT CACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaacaggga ggtgtgtccagttgttcagaatctcggggtgtccgtaactccgatccaaaggatgtcctgagcggtgaaaatgggctgaagatcgac atccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgtaccctgtggatgat catcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcggacggccgtatgaa ggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaatatcgacgagcgcctgatcaac cccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAAaagttgtc tcctcctgcactgactgactgatacaatcgatttctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcccctctccc tcccccccccctaacgttactggccgaagccgcttggaataaggccggtgtgcgtttgtctatatgttattttccaccatattgccgtctttt ggcaatgtgagggcccggaaacctggccctgtctctgacgagcattcctaggggtcttcccctctcgccaaaggaatgcaaggtct gttgaatgtcgtgaaggaagcagttcctctggaagcttcttgaagacaaacaacgtctgtagcgaccctttgcaggcagcggaacccc ccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgccacgttgt gagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccagaaggtaccccatgt atgggatctgatctggggcctcggtacacatgctttacatgtgtttagtcgaggttaaaaaaacgtctaggccccccgaaccacgggga cgtggttttcctttgaaaaacacgatgataatatggLcacaaccatggtgagcaagggcgaggaggataacatggccatcatcaagga gttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggccgcccctac gagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctcagtcatgtac ggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaagtgggagcgcgtg atgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggtgaagctgcg cggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgtaccccgag gacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaagaccacctac aaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgaggactacaccat cgtggaacagtacgaacgcgccgagggccgceactccaccggcggcatggacgagctgtacaagtaacttgactgactgagtcga caatcaacctctggattacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgctatgtggatacgctgctttaatgc ctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagttgtggcccgttgtc aggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcattgccaccacctgtcagctcctttccgggac tttcgcttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactg acaattccgtggtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgttgccacctggattctgcgcgggacgtccttctg ctacgtcccttcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtcttcgccttcgccc tcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggtacctttaagaccaatgactacaaggcagctgt Docket No. 11676 -005 WO 1 agatcttagccacttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgctttgcttgtactgg gtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagt gctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctctagcagtc ctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgccccccccacccc cgcagcccacccctggtctttgaataaagtctgagtgagtggccgacagtgcccgtggagtctcgtgacctgaggtgcagggccgg cgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactccgccca tcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttattatgcagaggccgaggccgcctcggc ctctgagctatccagaagtagtgaggacgctttttggaggccgaggctttgcaaagatcgaacaagagacaggacctgcaggttaa ttaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccgcc cccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttccccctg gaagctccctcgtgcgctctcctgttccgaccctgccgctaccggatacctgtccgcctttctccctcgggaagcgtggcgcttctca tagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgct gcgcctatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggatagc agagcgaggtatgtaggcggtgctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtattggtatctgcgc tctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggttttttgttgc aageageagattacgcgcagaaaaaaaggatctcaagaagatecttgatctttctacggggtetgacgcteagtggaacgaaaacte acgtaagggatttggtcatgagattatcaaaaaggatctcacctagatccttaaattaaaaatgaagtttaaatcaatctaaagtatat atgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctattcgtcatccatagttgcattaa atggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacatctatca agagaeaggatcagcaggaggctttcgcatgagtattcaacatttecgtgtcgcecttattccetttttgeggcatttgcettcctgttttg ctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggttacatcgaactggatctcaacagcg gtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgtattg acgccgggcaagagcaactcggtcgccgcatacactatctcagaatgactggttgagtatcaccagtcacagaaaagcatcttacg gatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatggagg accgaaggagctaaccgctttttgcacaacatgggggatcatgtaactcgcctgatcgttgggaaccggagctgaatgaagccatac caaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactctagcttcc cggcaacagtgatagactggatggaggcggataaagttgcaggaccactctgcgctcggcccttccggctggctggttattgctga taaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatogtagtatctaca cgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaaccgattct aggtgcattggcgcagaaaaaaatgcx’tgatgcgacgetgegcgtcttatactcceaeatatgccagattcagcaacggatacggctc cccaacttgcccactccatacgtgtcctcctaccagaaattatccttaagatcccgaatcgtttaaacgcgatcgcagtaa

[0213] 9. SEQ ID NO: 9 - pYJ271_GYJ078_lYJ002_GRIK2_+5-9_deIetion_reverse_Nluc_reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgttttgagacXaTAAGTATCCCTTGGAGAACCACCTTGTTGGCTTCCAGCGGGTCT G1 ATGG n' TAAGAGC TATGC rGGAAACAGCATAGCAAG n' TAAA TAAGGC 1 AGT

[0214] CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCACGCTCTGGGAATGCAT ACAGACCCGCTTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagattttatttagtctccagaa aaaggggggaatgaaagaccccacctgtaggttggcaagctagctgcagtaacgccattgcaaggcatggaaaaataccaaacc Docket No. 11676 -005 WO 1 aagaatagagaagtcagatcaagggcgggtacatgaaaatagctaacgtgggccaaacaggatatctgcggtgagcagtttcggc cccggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatggccc aaccctcagcagttctaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgccttattgaattaaccaatc agcctgcttctcgcttctgtcgcgcgcttctgctcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccga cagactgagtegcccgggACGCTCTGGGAATTCCCCGCATACAGACCCGCTGGAAGCGGTC TTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtcctgaacagg gaggtgtgtccagtttgtrtcagaatotcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaagatcg acatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgtaccctgtggat gatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcggacggccgtat gaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgcctgat caaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAAaag ttgtctcctcctgcactgactgactgatacaatcgatttctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcccctc tccctcccccccccctaacgtactggccgaagccgcttggaataaggccggtgtgcgtttgtctatatgttatttccaccatatgccgt ctttggcaatgtgagggcccggaaacctggccctgtcttctgacgagcatcctaggggtctttcccctctcgccaaaggaatgcaag gtctgttgaatgtcgtgaaggaagcagttcctctggaagcttcttgaagacaaacaacgtctgtagcgaccctttgcaggcagcggaac cccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgccacgt tgtgagttggatagtgtggaaagagtcaaatggctctcctcaagcgtatcaacaaggggctgaaggatgcccagaaggtaccccatt gtatgggatctgatctggggcctcggtacacatgctttacatgtgtttagtcgaggtaaaaaaacgtctaggccccccgaaccacggg gacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccatcatcaag gagttcatgcgcttcaaggtgcacatggagggetecgtgaacggccacgagtcgagatcgagggcgagggcgagggccgcex’ct acgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctcagtcatgt acggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaagtgggagcgc gtgatgaacttcgaggacggcggcgtggtgacegtgacccaggactcctccctgcaggacggcgagttcatctacaaggtgaagct gegcggcaccaactKecctccgacggececgiaatgeagaagaagaccatgggctgggaggectcctcegagcggatgtaeccc gaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaagaccac ctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgaggactaca ccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactgactgagt cgacaatcaacctctggatacaaaattgtgaaagattgactggtatctaactatgttgctccttttacgctatgtggatacgctgctttaa tgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagttgtggcccgtt gtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggtggggcattgccaccacctgtcagctcctttccgg gacttcgcttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgtgggca ctgacaattccgtggtgtgtcggggaagctgacgtcctttccatggctgctcgcctgtgttgccacctggattctgcgcgggacgtcctt ctgctacgtccctcggccctcaatccagcggacctcctcccgcggcctgctgccggctctgcggcctctccgcgtcttcgcctcg ccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagctcggtaccttaagaccaatgactacaaggcagc Docket No. 11676 -005 WO 1 tgtagatcttagccactttttaaaagaaaaggggggactggaagggctaatcactcccaacgaagacaagatctgctttgcttgtact gggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttga gtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctctagcag tcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgccccccccaccc ccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcagggccg gcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactccgccc atcccgcccctaactccgcccagtccgcccattctccgcctcatggctgactaatttttattatgcagaggccgaggccgcctcgg cctctgagctatccagaagtagtgaggacgcttttttggaggccgaggcttttgcaaagatcgaacaagagacaggacctgcaggta attaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccgc ccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttccccct ggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccgccttctccctcgggaagcgtggcgcttctc atagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgc tgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattag cagagcgaggtatgtaggcggtgctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtattggtatctgcg ctctgctgaagccagtaccttcggaaaaagagttggtagctctgatccggcaaacaaaccaccgctggtagcggtggttttttgttg caagcagcagattacgegcagaaaaaaaggatetcaagaagatccttgatctttctaeggggtctgaegctcagtggaacgaaaact cacgtaagggatttggtcatgagatatcaaaaaggatctcacctagatcctttaaattaaaaatgaagttaaatcaatctaaagtat atatgagtaaactggtctgacagtaccaatgctaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcatt aaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacatctat caagagacaggatcagcaggaggctttcgcatgagtatcaacatttccgtgtcgccctatccctttttgcggcattgcctcctgtt ttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggttacatcgaactggatctcaacag cggtaagatccttgagagtttcgccccgaagaacgctttccaatgatgagcactttaaagttctgctatgtggcgcggtattatcccgta ttgacgecgggcaagagcaactcggtcgcegcatacactattctcagaatgacttggttgagtattcaccagtcaeagaaaagcatcta cggaiggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataaeactgeggccaactacttctgacaacgatlgga ggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgcctgatcgtgggaaccggagctgaatgaagcca taccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactctagctt cccggcaacagtgatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctggctggttattgct gataaatctggagccggtgagcgtgggtctcgcggtatcatgcagcactggggccagatggtaagccctcccgtatcgtagttatcta cacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaaccgatt ctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgtctatacteccacatatgccagatteagcaacggatacggct tccccaactgcccacttccatacgtgtcctccttaccagaaattatccrtaagatcccgaatcgtttaaacgcgatcgcagtaa

[0215] 10. SEQ ID NO: 10 - pYJ272_GYJ079JYJ002_PPP2R5B_+5-9_deletion_fwd_Nluc_reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgtttgagactaTAAGTATCCC ITGGAGAACCACC TTGTTGGCC AGTAT'Fl'GAGCA

[0216] GCCCCGTl TAAGAGC TATGC rGGAAACAGCATAGCAAG n' TAAA TAAGGCl AGT CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCATCTCCCACAGCATGGG GCTGCTCAAATACTTTTTTTCTCGAGACCGGTATGCATccgataaaataaaagatttatttagtctcc agaaaaaggggggaatgaaagaccccacctgtaggttggcaagctagctgcagtaacgccatttgcaaggcatggaaaaatacca Docket No. 11676 -005 WO 1 aaccaagaatagagaagtcagatcaagggcgggtacatgaaaatagctaacgtgggccaaacaggatatctgcggtgagcagtt cggccccggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatg gcccaaccctcagcagttcttaagacccatcagatgttccaggctcccccaaggacctgaaatgaccctgcgcctattgaataacc aatcagcctgctctcgcttctgttcgcgcgctctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctc cgacagactgagtogcccgggGCCAGTATTTGAGCAGCCCCAGGATCTGCTGTGGGAGATCG TCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaac agggaggtgtgtccagttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaag atcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgtaccctgtg gatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcggacggcc gtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgcct gatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctggcgTAA aagttgtctcctcctgcactgactgactgatacaatcgatttctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgcc cctctccctcccccccccctaacgttactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttattttccaccatattg ccgtctttggcaatgtgagggcccggaaacctggccctgtcttctgacgagcatcctaggggtcttcccctctcgccaaaggaatg caaggtctgtgaatgtcgtgaaggaagcagttcctctggaagcttctgaagacaaacaacgtctgtagcgacccttgcaggcagcg gaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgc cacgtgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtatcaacaaggggctgaaggatgcccagaaggtac cccatgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggttaaaaaaacgtctaggccccccgaacc acggggacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccatc atcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggcc gcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctcag ttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaagtggg agcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgaccx’aggactoctccetgcaggaeggegagtteatotacaaggtg aagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgt accccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaag accacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgagga ctacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaacttgactgac tgagtcgacaatcaacctctggattacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgctatgtggatacgctg ctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagttgtgg cccgttgtcaggeaacgtggcgtggtgtgcactgtgtttgetgacgcaacecccactggttggggcattgccaccacetgtcagctcctt tecgggacttcgcttecccetccctatgccacggcggaaetcategccgcctgccttgcccgctgctggacaggggctcggctgt gggcactgacaatccgtggtgtgtcggggaagctgacgtccttccatggctgctcgcctgtgtgccacctggattctgcgcggga cgtccttctgctacgtcccttcggccctcaatccagcggacctccttcccgcggcctgctgccggctctgcggcctctccgcgtctcg ccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagctcggtacctttaagaccaatgacttacaag Docket No. 11676 -005 WO 1 gcagctgtagatctagccacttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgcttttgct tgtactgggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagctg ccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccx’tgcaggcctaactc cgcccatcccgcccctaactccgcccagtccgcccatctccgcctcatggctgactaatttttatttatgcagaggccgaggccgc ctcggcctctgagctattccagaagtagtgaggacgctttttggaggccgaggcttttgcaaagatcgaacaagagacaggacctgc aggtaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgtt ccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccgccttctcccttcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgccttatccggtaacXatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacag gatagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggta tctgcgctctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggttttt tgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatccXttgatcttttctacggggtctgacgctcagtggaacga aaactcacgtaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttaaataaaaatgaagtttaaatcaatctaa agtatatatgagtaaacttggtctgacagtaccaatgcttaatcagtgaggcacctatctcagcgatctgtctattcgttcatccatagttg catttaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacat ctatcaagagacaggatcagcaggaggcttcgcatgagtatcaacattccgtgtcgcccttatcccttttgcggcatttgcctcct gttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatccc gtatgacgccgggcaagagcaactcggtcgccgcatacactatctcagaatgactggttgagtatcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaactactctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactcta gctcccggcaacagtgatagactggatggaggcggataaagttgcaggaccactctgcgctcggcccttccggctggctggttat tgctgataaatctggagccggtgagcgtgggtctcgcggtatcatgcagcactggggccagatggtaagccctcccgtatcgtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaacc gattctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgteXtatactcccacatatgccagattcagcaaeggatae ggcttccccaacttgcccacttccatacgtgtcctcctaccagaaatttatccttaagatcccgaatcgtttaaacgcgatcgcagtaa n. SEQ ID NO: 11 - pYJ273_GYJ080JYJ002_LPARl_+5-

[0217] 9_deletion_reverse_Nluc_reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaT AAGT A ICCC ITGGAGA ACCACC TTG TTGGT IC TGG ACCCCGGC GGAATG1 TTAAGAGC 1 A TGC 1 GGAAACAGCAT AGCAAGTTTAAATAAGGCTAGT

[0218] CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCGACTCATCACGATGATTC CGCCGGGGTTTTTTTCTCGAGACCGGTATGCATcx’gataaaataaaagattttatttagtcXccagaaaaa ggggggaatgaaagaececacctgtaggttggcaagetagctgcagtaaegceatttgcaaggcatggaaaaataecaaaccaag Docket No. 11676 -005 WO 1 aatagagaagtcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtttcggcccc ggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatggcccaac cctcagcagtttcttaagacccatcagatgttccaggcxcccccaaggacctgaaatgaccctgcgccttatttgaattaaccaatcagc ctgcttctcgcttctgtcgcgcgctctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccgacag actgagtcgcccgggGACTCATCACGATATCCCGATTCCGCCGGGGTCCAGAACGGTCTT CACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaacaggga ggtgtgtccagttgttcagaatctcggggtgtccgtaactccgatcxaaaggatgtcctgagcggtgaaaatgggctgaagatcgac atccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaattttaaggtggtgtaccctgtggatgat catcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactatttcggacggccgtatgaa ggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaatatcgacgagcgcctgatcaac cccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcatctggcgTAAaagtgtc tcctcctgcactgactgactgatacaatcgatttctgcggccaatctgcagtcgacggtaccgcgggcccgggatccgcccctctccc tcccccccccctaacgtactggccgaagccgcttggaataaggccggtgtgcgttgtctatatgtatttccaccatattgccgtctt ggcaatgtgagggcccggaaacctggccctgtctctgacgagcattcctaggggtcttcccctctcgccaaaggaatgcaaggtct gtgaatgtcgtgaaggaagcagtcctctggaagcttctgaagacaaacaacgtctgtagcgaccctttgcaggcagcggaacccc ccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgccacgtgt gagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccagaaggtaccccatgt atgggatctgatctggggcctcggtacacatgcttacatgtgttagtcgaggttaaaaaaacgtctaggccccccgaaccacgggga cgtggtttccttgaaaaacacgatgataatatggccacaaccatggtgagxaagggcgaggaggataacatggccatcatcaagga gtcatgcgcttcaaggtgeacatggagggctocgtgaacggccaegagttegagatcgagggcgagggcgagggccgcxcctac gagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctcagtcatgtac ggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggcttcaagtgggagcgcgtg atgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggtgaagctgcg cggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatgtaccccgag gacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaagaccacctac aaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacgaggactacaccat cgtggaacagtacgaacgcgccgagggccgccactccaecggcggeatggacgagctgtacaagtaaettgaetgactgagtcga caatcaacctctggattacaaaatttgtgaaagatgactggtatctaactatgtgctccttacgctatgtggatacgctgctttaatgc ctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagttgtggcccgttgtc aggcaaegtggcgtggtgtgcactgtgtttgctgacgcaacccceaetggttggggcattgccacx’acctgteagctectttccgggae tttcgcttccccctccctatgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgtgggcactg acaatccgtggtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgtgccacctggattctgcgcgggacgtcctctg ctacgtccctcggccctcaatccagcggaccttcctcccgcggcctgctgccggctctgcggcctctccgcgtcttcgcctcgccc tcagacgagtcggatctccctttgggccgcctccccgcctggaatcgagctcggtaccttaagaccaatgactacaaggcagctgt Docket No. 11676 -005 WO 1 agatcttagccacttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgctttgcttgtactgg gtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagt gctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctctagcagtc ctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgccccccccacccc cgcagcccacccctggtctttgaataaagtctgagtgagtggccgacagtgcccgtggagtctcgtgacctgaggtgcagggccgg cgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactccgccca tcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttattatgcagaggccgaggccgcctcggc ctctgagctatccagaagtagtgaggacgctttttggaggccgaggctttgcaaagatcgaacaagagacaggacctgcaggttaa ttaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccgcc cccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttccccctg gaagctccctcgtgcgctctcctgttccgaccctgccgctaccggatacctgtccgcctttctccctcgggaagcgtggcgcttctca tagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgct gcgcctatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggatagc agagcgaggtatgtaggcggtgctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtattggtatctgcgc tctgctgaagccagtacctcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggttttttgttgc aageageagattacgcgcagaaaaaaaggatctcaagaagatecttgatctttctacggggtetgacgcteagtggaacgaaaacte acgtaagggatttggtcatgagattatcaaaaaggatctcacctagatccttaaattaaaaatgaagtttaaatcaatctaaagtatat atgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctattcgtcatccatagttgcattaa atggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagcttttgcaaacatctatca agagaeaggatcagcaggaggctttcgcatgagtattcaacatttecgtgtcgcecttattccetttttgeggcatttgcettcctgttttg ctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggttacatcgaactggatctcaacagcg gtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttttaaagttctgctatgtggcgcggtattatcccgtattg acgccgggcaagagcaactcggtcgccgcatacactatctcagaatgactggttgagtatcaccagtcacagaaaagcatcttacg gatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatggagg accgaaggagctaaccgctttttgcacaacatgggggatcatgtaactcgcctgatcgttgggaaccggagctgaatgaagccatac caaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaactacttactctagcttcc cggcaacagtgatagactggatggaggcggataaagttgcaggaccactctgcgctcggcccttccggctggctggttattgctga taaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatogtagtatctaca cgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaaccgattct aggtgcattggcgcagaaaaaaatgcx’tgatgcgacgetgegcgtcttatactcceaeatatgccagattcagcaacggatacggctc cccaacttgcccactccatacgtgtcctcctaccagaaattatccttaagatcccgaatcgtttaaacgcgatcgcagtaa

[0219] 12. SEQ ID NO: 12 pYJ274_GYJ081JYJ002_RASSFl_+5-

[0220] 9_deletion_reverse_Nluc_reporter Docket No. I I 676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGTTCGTGTCCCGCTC

[0221] CACCGGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGT CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCGACCTGGGCTGATGCGG TGG AGCGGGACACGAT I T I T I TC TCGAGACCGGT A I GCATccgataaaataaaagattttatttagt ctccagaaaaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccatttgcaaggcatggaaaaat Docket No. 11676 -005 WO 1 accaaaccaagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgtgggccaaacaggatatctgcggtgagc agtttcggccccggcccggggccaagaacagatggtcaccgcagtttcggccccggcccgaggccaagaacagatggtccccaga tatggcecaaccctcagcagttcttaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccctgcgccttatttgaatt aaccaatcagcctgctctcgctctgtcgcgcgcttctgcttcccgagctctataaaagagctcacaacccctcactcggcgcgccag tcctccgacagactgagtcgcccgggGACCTGGGCTGATAACCCGCGGTGGAGCGGGACACGA ACGGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtc cttgaacagggaggtgtgtccagttgttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatggg ctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaattttaaggtggtgta ccctgtggatgatcatcacttaaggtgatectgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactattcgg acggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacg agcgcctgatcaaccccgacggctccctgctgtccgagtaaccatcaacggagtgaccggctggcggctgtgcgaacgcattctgg cgTAAaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccggg atccgcccctctccctcccccccccctaacgtactggccgaagccgcttggaataaggccggtgtgcgttgtctatatgtatttccac catattgccgtctttggcaatgtgagggcccggaaacctggccctgtctcttgacgagcattcctaggggtcttcccctctcgccaaa ggaatgcaaggtctgtgaatgtcgtgaaggaagcagtcctctggaagcttcttgaagacaaacaacgtctgtagcgacccttgcag gcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccc cagtgccacgttgtgagtggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccaga aggtaccccattgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggtaaaaaaacgtctaggcccccc gaaccacggggacgtggttttccttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatgg ccatcatcaaggagtcatgcgctteaaggtgcacatggagggctcegtgaacggccacgagtcgagatcgagggcgagggcgag ggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccctcgcctgggacatcctgtccc ctcagttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttccccgagggctcaa gtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccetgeaggacggcgagttcatctaca aggtgaagctgcgcggcaccaactcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggectcctccgagcg gatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggt caagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatcacctcccacaacg aggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggeatggacgagctgtacaagtaacttga ctgactgagtcgacaatcaacctctggatacaaaattgtgaaagatgactggtatcttaactatgttgctcctttacgctatgtggata cgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggtgctgtctctttatgaggagt tgtggcccgttgteaggcaacgtggegtggtgtgcactgtgtttgctgacgcaacccccactggtggggcattgccaccaectgtcag ctccttccgggacttcgcttccccctccctatgceacggcggaactcatcgccgcctgcctgcccgctgctggacaggggctcgg ctgtgggcactgacaatccgtggtgtgtcggggaagctgacgtccttccatggctgctcgcctgtgtgccacctggattctgcgcg ggacgtccttetgetacgtcccttcggccctcaatecagcggaccttccttcccgcggcetgetgccggctetgeggcctcttccgcgtc ttcgccttcgccctcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggtaecttaagaccaatgacta Docket No. 11676 -005 WO 1 caaggcagctgtagatctagccactttttaaaagaaaaggggggactggaagggctaattcactcccaacgaagacaagatctgcttt ttgcttgtactgggtctctctggttagaccagatctgagcctgggagctetctggctaactagggaacccactgcttaagcctcaataaag cttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatcx’ctcagaccettttagtcagtgtggaaaat ctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgccc cccccacccccgcagcccacccctggtctttgaataaagtctgagtgagtggccgacagtgcccgtggagtctcgtgacctgaggtg cagggcxggcgctagggacacgtocgtgcacgtgccgaggccccxtgtgcagctgcaagggacaggcctagccxtgcaggccta actccgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaatttttattatgcagaggccgaggc cgcctcggcctctgagctattccagaagtagtgaggacgcttttggaggccgaggctttgcaaagatcgaacaagagacaggacc tgcaggttaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccat aggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccagg cgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgccttctcccttcgggaagcgt ggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgtca gcccgaccgctgcgccttatccggtaactatcgtcttgagtocaacccggtaagacacgacttatcgccactggcagcagccactggt aacaggattagcagagcgaggtatgtaggcggtgctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtat ttggtatctgcgctctgctgaagccagtaccttcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggt ggttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatotcaagaagatccttgatcttttctacggggtctgacgctcagtg gaacgaaaactcacgttaagggattttggtcatgagatatcaaaaaggatcttcacctagatccttttaaataaaaatgaagtttaaatc aatctaaagtatatatgagtaaactggtctgacagttaccaatgctaatcagtgaggcacctatctcagcgatctgtctatttcgtcatcc atagttgcattaaatggccggcctggcgcgccgttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcctagctttg caaacatctatcaagagacaggatcagcaggaggctttcgcatgagtatcaacatttccgtgtcgccctatccctttttgcggcatt gccttcctgtttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggtacatcgaactg gatctcaacagcggtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttttaaagttctgctatgtggcgcgg tatatcccgtatgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgactggtgagtattcaccagtcacag aaaagcatctacggatggcatgacagtaagagaatatgcagtgctgccataaccatgagtgataacactgcggccaactacttctga caacgattggaggaccgaaggagctaaccgctttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagct gaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactattaactggcgaact acttactctagcttcccggcaacagttgatagactggatggaggcggataaagttgcaggaccacttctgcgctcggcccttccggctg gctggttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgt atcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagc attggtaaccgattctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgtctatactcccacatatgccagatcagc aacggatacggctccccaacttgcccacttccatacgtgtcctcctaccagaaattatccttaagatcccgaatcgttaaacgcgatc gcagtaa

[0222] 13. SEQ ID NO: 13 - pYJH 2_akapJY311_LASPl„250_+5GtoT_n„12_Niuc_reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGGAGCTCACTCTGTT

[0223] GCl'TGGl T1 AAGAGC1 ATGC1 GGAAACAGCAT AGCAAG1 T1 AAATAAGGCTAGTC CGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCCCTTCGCATCAAGCAACA GAGTGCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAGAATrTTTTTCTCGAG ACCGGTATGCATccgataaaataaaagattttattagtctccagaaaaaggggggaatgaaagaccccacctgtaggttg Docket No. 11676 -005 WO 1 gcaagctagctgcagtaacgccattgcaaggcatggaaaaataccaaaccaagaatagagaagttcagatcaagggcgggtacat gaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtttcggccccggcccggggccaagaacagatggtcaccgca gtttcggececggcccgaggceaagaacagatggtccecagatatggcecaaccctcagcagtttcttaagacccatcagatgttce aggctcccccaaggacctgaaatgaccctgcgcctatttgaattaaccaatcagcctgcttctcgcttctgttcgcgcgcttctgctccc gagctctataaaagagctcacaacccctcactcggcgcgccagtcctccgacagactgagtcgcccgggGGAGCTCACTC TGTTGCTTGAGGCGAAGGGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacag ccggctacaacctggaccaagtccttgaacagggaggtgtgtccagttgtttcagaatctcggggtgtccgtaactccgatccaaagg attgtcctgagcggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccaga tcgaaaaaatttttaaggtggtgtaccctgtggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttac gccgaacatgatcgactatttcggacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtg gaacggcaacaaaattatcgacgagcgcctgatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctg gcggctgtgcgaacgcattctggcgTAAaagttgtctcctcctgcactgactgactgatacaategatttctgcggccaattctgcagt cgacggtaccgcgggcccgggatccgcccctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtg tgcgttgtctatatgtatttccaccatattgccgtctttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcatcct aggggtcttcccctctcgccaaaggaatgcaaggtctgtgaatgtcgtgaaggaagcagtcctctggaagcttctgaagacaaac aacgtctgtagcgacccttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatac acctgcaaaggcggcacaaccccagtgccacgtgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaac aaggggctgaaggatgcccagaaggtaccccattgtatgggatctgatctggggcctoggtacacatgctttacatgtgttagtcgag gttaaaaaaacgtctaggccccccgaaccacggggacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtgag caagggcgaggaggataacatggcxatcatcaaggagtteatgcgcttcaaggtgcacatggagggctecgtgaacggccacgagt tcgagatcgagggcgagggcgagggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctg cccttcgcctgggacatcctgtcccctcagttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaa getgtcetccccgagggcttcaagtgggagcgegtgatgaacttcgaggacggeggcgtggtgaccgtgacccaggacXcctecet gcaggacggcgagttcatctacaaggtgaagctgcgcggcaccaactcccctccgacggccccgtaatgcagaagaagaccatgg gctgggaggcctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggac ggcggccactacgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatca agtggacatcacctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcat ggacgagctgtacaagtaacttgactgactgagtogacaatoaacctctggattacaaaatttgtgaaagattgactggtattcttaactat gttgctccttttacgctatgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatc eXggttgetgtctcttatgaggagtgtggeccgtgteaggcaacgtggegtggtgtgcactgtgttgctgacgcaacxcxcactggt tggggcatgecaxxacetgtcagctectticcgggacttcgettteccectcGetatgccaeggcggaax'tcategecgcctgGctg cccgctgctggacaggggctcggctgttgggcactgacaattccgtggtgttgtcggggaagctgacgtcctttccatggctgctcgcc tgtgtgccacctggattctgcgcgggacgtccttctgctacgteccttcggccctcaatceagcggaccttectcccgcggectgctg ccggctctgcggcctctccgcgtcttcgccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagct Docket No. 11676 -005 WO 1 cggtacctttaagaccaatgactacaaggcagctgtagatctagccactttaaaagaaaaggggggactggaagggctaattcact cccaacgaagacaagatctgctttttgcttgtactgggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaa cccactgctaagcctcaataaagcttgcctgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatocctca gaccctttagtcagtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgg gagccggcctggccctccgccccccccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgccc gtggagttctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggcccccXgtgcagctgcaaggg acaggcctagccctgcaggcctaactccgcccatcccgcccctaactccgcccagttccgcccatctccgcctcatggctgactaatt ttttattatgcagaggccgaggccgcctcggcctctgagctattccagaagtagtgaggacgctttttggaggccgaggctttgca aagatcgaacaagagacaggacctgcaggttaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaa ggccgcgtgctggcgtttttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaaccc gacaggactataaagataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgccgctaccggatacctgtc cgcctttctcccttcgggaagcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggc tgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatocggtaactatcgtcttgagtccaacccggtaagacacgacttatc gccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaacta cggctacactagaagaacagtattggtatctgcgctctgctgaagccagttacctcggaaaaagagttggtagctcttgatccggcaa acaaaccaccgctggtagcggtggtttttgttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatccttgatctt tctacggggtctgacgctcagtggaacgaaaactcacgttaagggatttggtcatgagattatcaaaaaggatcttcacctagatccttt aaattaaaaatgaagttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctc agcgatctgtctatttcgttcatccatagtgcattaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaa cgtataatcgagtccXagcttgcaaacatcXatcaagagacaggatcagcaggaggcttcgcatgagtatcaacattccgtgtcgc ccttatccctttttgcggcatttgccttcctgttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgc gcgagtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagcacttt taaagtctgctatgtggcgcggtatatcccgtatgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgactt ggtgagtattcaccagtcacagaaaagcatctacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgata acactgcggccaacttactctgacaacgatggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgc cttgatcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggvaacaaccttg cgtaaactataactggcgaactactactctagcttcccggcaacagtgatagactggatggaggcggataaagttgcaggaccactt ctgcgctcggccctccggctggctggtttatgctgataaatctggagccggtgagcgtgggtctcgcggtatcatgcagcactggg gccagatggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctga gataggtgcctcactgattaagcattggtaaccgattctaggtgcattggcgcagaaaaaaatgceXgatgcgacgctgcgcgtctata ctcccacatatgccagattcagcaacggatacggcttccccaacttgcccactccatacgtgtcctcctaccagaaatttatccttaaga tcccgaatcgtttaaacgcgatogcagtaa

[0224] 14. SEQ ID NO: 14 - pYJH 3_akapJY312_MAP7_464_+5GtoT_9_15_Nluc„reporter Docket No. 11676 -005 WO 1 tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttecattgacgtcaatgggtggagtatttac ggtaaaetgeceacttggcagtacatcaagtgtatcatatgceaagtacgecccctattgacgtcaatgaeggtaaatggccxgcctgg cattatgcccagtacatgacctatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaaegggacttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtetatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatotctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatacXgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatattgtctggt atagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcdggggatttggggttgctctggaaaactcatttgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacx’tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaatagataaatg ggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggtttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaex’attatcgtttcagaccx’acctcecaacccx’gaggggaccx’ gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctcggctactcccctgcc ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggcttggatttctataacttcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGCCTCTTCTTCCGCT CTTCCGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGTC CGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCCGAGAAGCACATGGAAGA GCGGAACXjCGGT’TCTA’rCTAG’rTACGCG’rTAAACCAAC’TAGAA’rT’rTrT'rCTCGA GACCGGTATGCATccgataaaataaaagatttatttagtctccagaaaaaggggggaatgaaagaccccacctgtaggttt Docket No. 11676 -005 WO 1 ggcaagctagctgcagtaacgccattgcaaggcatggaaaaataccaaaccaagaatagagaagttcagatcaagggcgggtaca tgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtttcggccccggcccggggccaagaacagatggtcaccgc agttcggccccggcccgaggccaagaacagatggtccccagatatggcccaaccctcagcagttcttaagacccatcagatgttc caggctcccccaaggacctgaaatgaccctgcgccttattgaataaccaatcagcctgcttctcgcttctgttcgcgcgcttctgctcc cgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccgacagactgagtcgcccgggCCTCTTCTTCC GCTCTTCCAGGTGCTTCTCGGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagac agccggctacaacctggaccaagtcctgaacagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaa ggatgtcctgagcggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggcca gatcgaaaaaatttttaaggtggtgtaccctgtggatgatcatcactttaaggtgatcctgcactatggcacac tggtaatcgacggggtt acgccgaacatgatcgactatttcggacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgt ggaacggcaacaaaattatcgacgagcgcctgatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggct ggcggctgtgcgaacgcattctggcgTAAaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgca gtcgacggtaccgcgggcccgggatccgcccctotccctcccccccccctaacgttactggccgaagccgctggaataaggccgg tgtgcgttgtctatatgttatttccaccatattgccgtctttggcaatgtgagggcccggaaacctggccctgtctcttgacgagcatc ctaggggtcttcccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagctctgaagacaaa caacgtctgtagcgacccttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagata cacctgcaaaggcggcacaaccccagtgccacgttgtgagtggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaa caaggggctgaaggatgcccagaaggtaccccattgtatgggatctgatctggggcctcggtacacatgcttacatgtgttagtcga ggttaaaaaaacgtctaggccccccgaaccacggggacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtga gcaagggcgaggaggataacatggccatcateaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacga gttcgagatcgagggcgagggcgagggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccc tgcccttcgcctgggacatcctgtcccctcagttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttg aagetgtccttccccgagggcttcaagtgggagcgegtgatgaacttcgaggacggeggcgtggtgaecgtgacccaggactccte cctgcaggacggcgagttcatctacaaggtgaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagacca tgggctgggaggcctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaagg acggcggccactacgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacat caagtggacatcacctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggc atggacgagctgtacaagtaactgactgactgagtcgacaatcaacctctggatacaaaattgtgaaagattgactggtatcttaact atgttgctccttttacgctatgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctectccttgtataaat cctggttgctgtctcttatgaggagttgtggcecgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccaetgg ttggggcattgcGaGcaectgtcagetcctttecgggactttcgcttccecetGectaUgccacggeggaaGicatcgccgGetgect gcccgctgctggacaggggctcggctgttgggcactgacaatccgtggtgttgtcggggaagctgacgtccttccatggctgctcg cctgtgttgccacctggattctgcgcgggacgtccttctgctacgtccctteggccctcaatceageggaccttecttcccgcggcctgc tgccggctctgcggcctctccgcgtctcgcctcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaattcga Docket No. 11676 -005 WO 1 gctcggtaccttaagaccaatgactacaaggcagctgtagatctagccacttttaaaagaaaaggggggactggaagggctaattc actcccaacgaagacaagatctgctttttgcttgtactgggtctctctggttagaccagatetgagcctgggagctctctggctaactagg gaacccactgcttaagcctcaataaagctgccxtgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatcxc tcagaccctttagtcagtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcc tgggagccggcctggccctccgccccccccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtg cccgtggagtctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaa gggacaggcctagccctgcaggcctaactccgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgact aattttttatttatgcagaggccgaggccgcctcggcctotgagctattccagaagtagtgaggacgctttttggaggccgaggcttt gcaaagatcgaacaagagacaggacctgcaggttaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgta aaaaggccgcgttgctggcgtttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaa acccgacaggactataaagataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatac ctgtccgcctttctcccttcgggaagcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagct gggctgtgtgcacgaacecex’cgttcagcccgaccgctgcgecttatceggtaactategtetgagtccaacccggtaagacacgac ttatcgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagtcttgaagtggtggccta actacggctacactagaagaacagtattggtatctgcgctctgctgaagccagttaccttcggaaaaagagtggtagctctgatccg gcaaacaaacxaccgctggtagcggtggtttttgtttgcaagcxigcagatacgcgcagaaaaaaaggatcteaagaagatcxtttg atctttctacggggtctgacgctcagtggaacgaaaactcacgtaagggattttggtcatgagatatcaaaaaggatcttcacctagat ccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacct atctcagcgatctgtctatttcgttcatccatagttgcatttaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcg gtcaacgtataatcgagtcctagctttgcaaacatctatcaagagaeaggateagcaggaggcttcgcatgagtattcaacatttcx’gt gtcgcccttatcccttttgcggcatttgccttcctgtttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgg gtgcgcgagtgggttacatcgaactggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgctttccaatgatgagc acttttaaagtteXgeXatgtggcgcggtattatcccgtattgacgccgggcaagagcaacXcggtcgccgcatacactattctcagaatg acttggttgagtattcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaatatgcagtgctgccataaccatgagtg ataacactgcggccaacttacttctgacaacgatggaggaccgaaggagctaaccgctttttgcacaacatgggggatcatgtaact cgccttgatcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaac ctgcgtaaactattaactggcgaaetactactetagctcccggcaacagtgatagactggatggaggeggataaagtgcaggacc acttctgcgctcggcccttccggctggctggtttattgctgataaatctggagccggtgagcgtgggtotcgcggtatcattgcagcact ggggccagatggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgc tgagataggtgcctcactgattaagcatggtaaccgatctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtct atactcccacatatgccagattcagcaacggatacggctccccaactgcccacttccatacgtgtcctccttaccagaaatttatcctta agatcccgaatcgtttaaacgcgatcgcagtaa Docket No. 11676 -005 WO 1

[0225] 15. SEQ pYJ275„GYJ082JKW002„TRIM52„279„+5GtoT„13„15„Nluc„reporter tcaatacggggtcattagtcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtaeatgaecttatgggactttcctacttggcagtacatctacgtattagtcatcgctataccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccatgacgtcaatgggagttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctrtta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtataagcgggggagaatagatcgcgatgggaaaaaatcggtaaggccagggggaaa gaaaaaatataaataaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccaee gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaatgaaccataggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagct tgttccttgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgtgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggtgctctggaaaactcatttgcaccact gctgtgccttggaatgc tagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactcctaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaatatggaatagataaatg ggcaagttgtggaattggUtaacataacaaatggctgtggtatataaaatattcataatgatagtaggaggcUggtaggttaagaat agtttgctgtacttctatagtgaatagagttaggcagggatatcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaatttggctcccgatcgttgcgtacacacacaatactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctoggctactcccctgcc ccggtaattgcatataatattcetagtaactatagaggetaatgtgcgataaaagacagataatctgtctttttaatactagctacattt acatgataggctggattctataacttcgtatagcatacatatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGCACACATCTTACTG

[0226] ATTAIWITAAGAGCTATGCTGGAAACAGCATAGCAAG’TTTAAATAAGGCTAGTC CGTTATCAACT fGAAAAAGTGGC ACCGAG fCGGI GCACAGCAAGGCATA TAA1 C Docket No. 11676 -005 WO 1

[0227] AGTAAGATGTCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAGAATTTTTTTCT CGAGACCGGTATGCATccgataaaataaaagatttatttagtetccagaaaaaggggggaatgaaagaccccacctgt aggtttggcaagcXagctgcagtaacgccatttgcaaggcatggaaaaataccaaaccaagaatagagaagttcagatcaagggcg ggtacatgaaaatagctaacgttgggccaaacaggatatctgcggtgagcagtttcggccccggcccggggccaagaacagatggt caccgcagtttcggccccggcccgaggccaagaacagatggtccccagatatggcccaaccctcagcagttcttaagacccatcag atgtttccaggctcccccaaggacctgaaatgaccctgcgcxltatttgaattaaccaatcagccXgcttctcgcttctgttcgcgcgcttct gctcccgagctctataaaagagctcacaacccctcactcggcgcgccagtcctccgacagactgagtcgcccgggTCACACA TCTTACTGATTATAGGCCTTGCTGTGTCTTCACACTCGAAGATTTCGTTGGggactggc gacagacagccggctacaacctggaccaagtccttgaacagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactcc gatccaaaggatgtcctgagcggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaa atgggccagatcgaaaaaattttaaggtggtgtaccctgtggatgatcatcacttaaggtgatectgcactatggcacactggtaatcg acggggttacgccgaacatgatcgactattcggacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacag ggaccctgtggaacggcaacaaaattatcgacgagcgcctgatcaaccccgacggctccctgctgtccgagtaaccatcaacggag tgaccggctggcggctgtgcgaacgcattctggcgTAAaagtgtctcctcctgcactgactgactgatacaatcgatttctgcggcc aattctgcagtcgacggtaccgcgggcccgggatccgcccctctccctcccccccccctaacgttactggccgaagccgcttggaata aggccggtgtgegtttgtctatatgttattttecaceatattgcxgtcttttggcaatgtgagggeceggaaacctggcxctgtcttctgac gagcattcctaggggtcttcccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagttcctctggaagctctg aagacaaacaacgtctgtagcgacccttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgt gtataagatacacctgcaaaggcggcacaaccccagtgccacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaa gcgtattcaacaaggggctgaaggatgcecagaaggtaccceattgtatgggatctgatctggggextcggtacacatgctttacatgt gtttagtcgaggtaaaaaaacgtctaggccccccgaaccacggggacgtggtttccttgaaaaacacgatgataatatggccacaa ccatggtgagcaagggcgaggaggataacatggccatcatcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaac ggccacgagttcgagatcgagggcgagggcgagggccgccxcXacgagggcacecagaccgecaagetgaaggtgaccaagg gtggccccctgccctcgcctgggacatcctgtcccctcagttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccc cgactacttgaagctgtccttccccgagggcttcaagtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgaccca ggactcctccctgcaggacggcgagttcatctacaaggtgaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaa gaagaccatgggctgggaggcctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaa gctgaaggacggcggccactacgacgctgaggtoaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaa cgtcaacatcaagttggacatcacctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactcca ccggcggcatggaegagctgtacaagtaaetgaeXgactgagtcgacaatcaacctetggattacaaaatttgtgaaagattgactggt attcttaactatgttgctcctttacgctatgtggatacgctgctttaatgccttgtatcatgctatgcttcccgtatggctttcatttctcctcc ttgtataaatcctggttgctgtctcttatgaggagtgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaac ccccactggtggggcatgccaccacctgtcagctccttccgggacttcgctttccccctccctatgccacggcggaactcatcgc cgcctgcctgcccgctgctggacaggggctcggctgttgggcactgacaattccgtggtgtgtcggggaagctgacgtcctttccat Docket No. 11676 -005 WO 1 ggctgctcgcctgtgttgccacctggatctgcgcgggacgtcctctgctacgtccctcggccctcaatccagcggacctcctccc gcggcctgctgccggctctgcggcctcttccgcgtcttcgccttcgccctcagacgagtcggatctccctttgggccgcctccccgcct ggaatcgagctcggtacctttaagaccaatgacttacaaggcagctgtagatcttagccacttttaaaagaaaaggggggactggaa gggctaatcactcccaacgaagacaagatctgctttgcttgtactgggtctctctggttagaccagatctgagcctgggagctctctg gctaactagggaacccactgctaagcctcaataaagctgccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaa ctagagatccctcagacxxttttagtcagtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgtt aagctggagcctgggagccggcctggccctccgccccccccacccccgcagcccacccctggtctttgaataaagtctgagtgagt ggccgacagtgcccgtggagtctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctg tgcagctgcaagggacaggcctagccctgcaggcctaactccgcccatcccgcccctaactccgcccagttccgcccattctccgcct catggctgactaattttttattatgcagaggccgaggccgcctcggcctctgagctatccagaagtagtgaggacgcttttggagg ccgaggctttgcaaagatcgaacaagagacaggacctgcaggttaataaattaaatcatgtgagcaaaaggccagcaaaaggcca ggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccgcccccctgacgagcateacaaaaatcgacgctcaagtcaga ggtggcgaaacex’gacaggactataaagatacx^aggcgtttccx’cctggaagctccctegtgcgcXctcetgttex’gaccctgccgct accggatacctgtccgccttctcccttcgggaagcgtggcgcttctcatagctcacgctgtaggtatctcagtcggtgtaggtcgttcg ctccaagctgggctgtgtgcacgaaccccccgtcagcccgaccgctgcgcctatccggtaactatcgtctgagtccaacccggtaa gacacgacttatcgccactggcagcagecactggtaacaggattageagagcgaggtatgtaggcggtgetacagagttottgaagt ggtggcctaactacggctacactagaagaacagtattggtatctgcgctctgctgaagccagttaccttcggaaaaagagttggtagct cttgatccggcaaacaaaccaccgctggtagcggtggttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaa gatcctttgatcttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatctt caccXagatccttaaattaaaaatgaagtttaaatcaatctaaagtatatatgagtaaactggtctgacagttaecaatgcttaateagtg aggcacctatctcagcgatctgtctatttcgttcatccatagtgcatttaaatggccggcctggcgcgccgttaaacctagatattgatag tctgatcggtcaacgtataatcgagtcctagcttttgcaaacatctatcaagagacaggatcagcaggaggctttcgcatgagtattcaac attccgtgtcgccctattcccttttgcggcatttgcctcctgtttgctcacccagaaacgctggtgaaagtaaaagatgctgaagat cagtgggtgcgcgagtgggtacatcgaactggatctcaacagcggtaagatccttgagagtttcgccccgaagaacgcttccaat gatgagcactttaaagttctgctatgtggcgcggtatatcccgtatgacgccgggcaagagcaactcggtcgccgcatacactattct cagaatgacttggttgagtattcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataac catgagtgataacactgcggccaacttactctgacaacgatggaggaccgaaggagctaaccgctttttgcacaacatgggggatc atgtaactcgccttgatcgtgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatgg caacaaccttgcgtaaactattaactggcgaactacttactctagcttcccggcaacagttgatagactggatggaggcggataaagttg caggaccactctgcgctcggccctccggctggctggttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattg cagcactggggccagatggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagac agatcgctgagataggtgcctcactgattaagcattggtaaccgattctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctg cgcgtctatactcccacatatgccagatcagcaacggatacggctccccaactgcccactccatacgtgtcctcctaccagaaatt tatccttaagatcccg aatcgtttaaacgcg atcgcag taa Docket No. 11676 -005 WO 1

[0228] 16. SEQ ID NO: 16 ■■ pYJ276„GYJ083JKW002„FGF5„387„+5GtoT„9„10„Nluc„reporter tcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccatgacgtcaatgggagttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctrtta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtataagcgggggagaatagatcgcgatgggaaaaaattcggttaaggc.cagggggaaa gaaaaaatataaataaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaatgaaccataggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagct tgttccttgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgtgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggtgctctggaaaactcatttgcaccact gctgtgccttggaatgc tagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactcctaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaatatggaatagataaatg ggcaagttgtggaattggUtaacataacaaatggctgtggtatataaaatattcataatgatagtaggaggcUggtaggttaagaat agtttgctgtacttctatagtgaatagagttaggcagggatatcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaatttggctcccgatcgttgcgtacacacacaatactgctgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggacttgtgggagaagctoggctactcccctgcc ccggttaattgcatataatatttcetagtaactatagaggettaatgtgcgataaaagacagataatctgttotttttaatactagctacatttt acatgataggctggattctataacttcgtatagcatacatatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aattgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGTCTTTGGCTTGATA GGGCTGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTT'AAAT'AAGGCTAGT CCG T TA TCA ACT T GA A A AAGTGGC ACCG AG T CGGTGCGCC ACATAGCCC T ATC A Docket No. 11676 -005 WO 1

[0229] AGCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAGAATTTTTTTCTCGAGACC GGTATGC ATccgataaaataaaagattttattagtctccagaaaaaggggggaatgaaagaccccacctgtaggtttggcaag ctagctgcagtaacgccatttgcaaggcatggaaaaataccaaaccaagaatagagaagtcagatcaagggcgggtacatgaaaat agctaacgtgggccaaacaggatatctgcggtgagcagttcggccccggcccggggccaagaacagatggtcaccgcagttcg gccccggcccgaggccaagaacagatggtccccagatatggcccaaccctcagcagtttcttaagacccatcagatgttccaggctc ccccaaggaectgaaatgaccctgcgccttatttgaattaaccaateagectgcttctcgcttctgttcgegcgcttctgcttcx’cgagetc tataaaagagctcacaacccctcactcggcgcgccagtcctccgacagactgagtcgcccgggATCTTTGGCTTGATA GGGCTAGGTGGCTTGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggct acaacctggaccaagtccttgaacagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcc tgagcggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaa aaattttaaggtggtgtaccctgtggatgatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaa catgatcgactattcggacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacgg caacaaaattatcgacgagcgcctgatcaaceccgaeggctccctgctgttccgagtaaccatcaacggagtgaecggctggcggct gtgcgaacgcattctggcgTAAaagtgtctcctcctgcactgactgactgatacaatcgatttctgcggccaatctgcagtcgacg gtaccgcgggcccgggatccgcccctctccctcccccccccctaacgtactggccgaagccgcttggaataaggccggtgtgcgttt gtctatatgttatttccaccatattgccgtcttttggcaatgtgagggcccggaaacctggcx’cXgtcttcttgacgagcattoctaggggt ctttcccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagcttctgaagacaaacaacgtct gtagcgacccttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgc aaaggcggcacaaccccagtgccacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaagggg ctgaaggatgcccagaaggtaccccatgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggtaaaa aaacgtctaggccccccgaaccacggggacgtggtttccttgaaaaacacgatgataatatggccacaaccatggtgagcaaggg cgaggaggataacatggccatcatcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagat cgagggcgagggcgagggccgceceXacgagggcacccagaccgccaagctgaaggtgaceaagggtggccccctgcex’ttcg cctgggacatcetgteccctcagttcatgtacggctceaaggcctacgtgaagcacccegccgacaiceccgaetactgaagctgtec ttccccgagggctcaagtgggagcgcgtgatgaactcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcagga cggcgagttcatctacaaggtgaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctggg aggcctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggc cactacgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagtgga catcacctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacga gctgtacaagtaacttgactgactgagtcgacaatcaacctctggatacaaaattgtgaaagattgactggtatctaactatgtgctc ctttacgctatgtggatacgctgcttaatgcctttgtatcatgctattgcttcccgtatggcttcatttctcctcctgtataaatcctggtg ctgtctcttatgaggagttgtggcccgtgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggtggggc atgccaccacctgtoagctccttccgggacttcgcttccccctccctatgccacggcggaactcatcgccgcctgccttgcccgct gctggacaggggctcggctgttgggcactgacaattccgtggtgtgtcggggaagctgacgtcctttccatggctgctcgcctgtgtt Docket No. 11676 -005 WO 1 gccacctggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcggaccttccttcccgcggcctgctgccggc tctgcggcctcttccgcgtcttcgccttcgccctcagacgagteggatctccctttgggccgcctccccgcctggaattcgagctcggta cctttaagaccaatgacttacaaggcagetgtagatcttagccactttttaaaagaaaaggggggactggaagggctaattcaetcccaa cgaagacaagatctgcttttgcttgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccac tgcttaagcctcaataaagctgccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccc ttttagteagtgtggaaaatctctageagtcetggccaaegtgagcaccgtgctgacctccaaatatcgtaagctggagectgggagc cggcctggccctccgccccccccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtgga gttctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacagg cctagccctgcaggcctaactccgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttttat ttatgcagaggccgaggccgcctcggcctctgagctatccagaagtagtgaggacgctttttggaggccgaggctttgcaaagatc gaacaagagacaggacctgcaggtaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccg cgttgctggcgtttttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacag gactataaagataccaggcgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgctaccggatacctgtccgcct ttctcccttcgggaagcgtggcgcttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgtcgctccaagctgggctgtgtg cacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccact ggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggcta cactagaagaacagtattggtatctgcgctctgctgaagccagttacctcggaaaaagagtggtagctcttgatccggcaaacaaac caccgctggtagcggtggtttttgttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatccttgatctttctacg gggtc tgacgctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaatta aaaatgaagtttaaatcaatctaaagtatatatgagtaaactggtctgacagtaecaatgctaatcagtgaggcacctatctcagcgat ctgtctatttogtcatccatagttgcatttaaatggccggcctggcgcgccgttaaacctagatattgatagtctgatcggtcaacgtata atcgagtcctagcttttgcaaacatctatcaagagacaggatcagcaggaggctttcgcatgagtattcaacatttccgtgtcgcccttatt cccttttttgcggcatttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagt gggttacatcgaactggatctcaacagcggtaagatcctgagagttcgccccgaagaacgcttccaatgatgagcacttaaagt ctgctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggtgag tatteaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgc ggccaactacttctgacaacgattggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgccttgatcg ttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaact attaactggcgaactacttactctagcttcccggcaacagttgatagactggatggaggcggataaagttgcaggaccacttctgcgctc ggcccttccggctggctggttatgctgataaatctggagccggtgagcgtgggtctcgcggtatcatgcagcactggggccagatg gtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgc ctcactgattaagcatggtaaccgatctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacat atgccagatcagcaacggatacggcttccccaactgcccactccatacgtgtcctcctaccagaaatttatccttaagatoccgaatc gttaaacgcgatcgcagtaa Docket No. 11676 -005 WO 1

[0230] 17. SEQ pYJ277_GYJ084JKW002_GPLDl_480_+5GtoT_ll_10_Nluc_reporter tcaatacggggtcattagttcatagcccatatatggagttccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtattac ggtaaactgcccactggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgacctatgggacttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttggc agtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccatgacgtcaatgggagttgtttggcacc aaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgcctgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggeggcgactggtgagtaegccaaaaatttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaatcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaacttagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttoctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgaegctgacggtacaggecagaeaatattgtetggt atagtgcagcagcagaacaattgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcatttgcaccact getgtgccttggaatgctagttggagtaataaatctctggaacagattggaateacacgacctggatggagtgggaeagagaaattaa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattatggaattagataaatg ggcaagttgtggaattggtttaacataacaaatggctgtggtatataaaatattcataatgatagtaggaggcttggtaggttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaccattatcgtttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaactttaaaagaaaaggggggatggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattac tgc tgatcgagtgtagccttc gaatctagagatccgacgcgccatctctaggcccgcgccggccccctcgcacggactgtgggagaagctcggctactcccctgcc ccggtaatttgcatataatatttcctagtaactatagaggctaatgtgcgataaaagacagataatctgttctttttaatactagctacatt acatgataggctggattctataacttcgtatagcatacatatacgaagttataaacagcacaaaaggaaactcaccctaactgtaaagt aatgtgtgtttgagactaTAAGTATCCCTTGGAGAACCACCTTGTTGGGCCATAGAGGTTCA

[0231] CCGTGG1 TTAAGAGCTATGCTGGAAACAGCATAGCAAGT fTAAATAAGGCTAG f Docket No. 11676 -005 WO 1

[0232] CCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCAAGGCATCACGGTGAAC CTCTCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAGAATTTTTTTCTCGAGAC CGGTATGCATccgataaaataaaagattattagtctccagaaaaaggggggaatgaaagaccccacctgtaggtttggca agctagctgcagtaacgccattttgcaaggcatggaaaaataccaaaccaagaatagagaagtcagatcaagggcgggtacatgaa aatagctaacgtgggccaaacaggatatctgcggtgagcagtttcggccccggcccggggccaagaacagatggtcaccgcagtt cggccccggcccgaggccaagaacagatggtccccagatatggcccaaccctcagcagttctaagacccatoagatgttccagg ctcccccaaggacctgaaatgaccctgcgccttattgaataaccaatcagcctgctctcgctctgttcgcgcgcttctgcttcccgag ctctataaaagagctcacaacccctcactcggcgcgccagtcctccgacagactgagtcgcccgggTGCCATAGAGGTT CACCGTGAGGCCTTTCGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccg gctacaacctggaccaagtccttgaacagggaggtgtgtccagtttgttcagaatctcggggtgtccgtaactccgatccaaaggattg tcctgagcggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcg aaaaaatttttaaggtggtgtaccctgtggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgcc gaacatgatcgactatttcggacggcegtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaa cggcaacaaaattatcgacgagcgcctgatcaaccccgacggctccctgctgtccgagtaaccatcaacggagtgaccggctggcg gctgtgcgaacgcattctggcgTAAaagtgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcga cggtaccgcgggcccgggatccgcccctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgc gttgtctatatgttatttccaccatattgccgtcttggcaatgtgagggcccggaaacctggccctgtcttctgacgagcattcctagg ggtctttcccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagcttcttgaagacaaacaacg tctgtagcgaccctttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacct gcaaaggcggcacaaccccagtgccacgtgtgagtggatagtgtggaaagagtcaaatggctctcctcaagcgtatcaacaagg ggctgaaggatgcccagaaggtaccccattgtatgggatctgatctggggcctcggtacacatgcttacatgtgtttagtcgaggttaa aaaaacgtctaggccccccgaaccacggggacgtggttttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaag ggcgaggaggataacatggcx’atcatcaaggagtteatgcgcttcaaggtgcacatggagggctecgtgaacggccacgagtcga gatcgagggcgagggcgagggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccct tcgcctgggacatcctgtcccctcagtcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagct gtccttccccgagggcttcaagtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgc aggacggcgagttcatctacaaggtgaagctgcgcggcaccaactcccctccgacggccccgtaatgcagaagaagaccatgggc tgggaggcctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacgg cggccactacgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaag tggacatcacctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatgg acgagctgtacaagtaactgactgactgagtcgacaatcaacctctggatacaaaattgtgaaagattgactggtattcttaactatgtt gctcctttacgctatgtggatacgctgctttaatgccttgtatcatgctatgctcccgtatggcttcatttctcctccttgtataaatcctg gtgctgtctcttatgaggagtgtggcccgtgtcaggcaacgtggcgtggtgtgcactgtgttgctgacgcaacccccactggtgg ggcattgccaccacctgtcagctccttccgggacttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttgccc Docket No. 11676 -005 WO 1 gctgctggacaggggctcggctgttgggcactgacaattccgtggtgttgtcggggaagctgacgtccttccatggctgctcgcctgt gttgccacctggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcggaccttccttcccgcggcctgctgccg getctgeggcctettccgcgtcttcgccttegccctcagaegagtcggatctccetttgggccgcctcccegcctggaattegagctcg gtacctttaagaccaatgactacaaggcagctgtagatctagccacttttaaaagaaaaggggggactggaagggctaatcactcc caacgaagacaagatctgcttttgctgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacc cactgctaagcxtcaataaagctgccttgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccxtcaga cccttttagtcagtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctggga gccggcctggccctccgccccccccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtg gagttctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggaca ggcctagccctgcaggcctaactccgcccatcccgcccctaactccgcccagttocgcccattctccgcctoatggctgactaattrtttt tatttatgcagaggccgaggccgcctcggcctctgagctattccagaagtagtgaggacgcttttttggaggccgaggcttttgcaaag atcgaacaagagacaggacctgcaggttaataaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaagg ccgcgttgctggcgtttttccataggctccgccccx’cXgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccga caggactataaagataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccg ccttctcccttcgggaagcgtggcgcttctcatagctcacgctgtaggtatctcagtcggtgtaggtcgtcgctccaagctgggctgt gtgcacgaaccecccgttcagcccgaccgetgegccttatccggtaactatcgtcttgagtecaacccggtaagacacgacttatcgcc actggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttctgaagtggtggcctaactacgg ctacactagaagaacagtattggtatotgcgctctgctgaagccagttaccttcggaaaaagagttggtagctottgatccggcaaaca aaccaccgctggtagcggtggtttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttcta eggggtetgaegeteagtggaaegaaaacteaegtaagggattttggteatgagattateaaaaaggatctteaectagatoctttaaa ttaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagc gatctgtctattcgttcatccatagttgcatttaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgt ataatcgagtcx’tagcttttgcaaacatctateaagagacaggatcagcaggaggctttogeatgagtattcaacatttocgtgtcgecct attccctttttgcggcattttgccttcctgtttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcga gtgggttacatcgaactggatctcaacagcggtaagatcctgagagtttcgccccgaagaacgctttccaatgatgagcactttaaa gttctgctatgtggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggtt gagtattcaccagtcacagaaaagcatctacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacac tgcggccaactacttctgacaacgattggaggaccgaaggagctaaccgctttgcacaacatgggggatcatgtaactcgcctga tcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaa actataactggcgaactacttactctagctcccggcaacagtgatagactggatggaggcggataaagtgcaggaccactctgcg ctcggcccttccggctggctggttatgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccag atggtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagatagg tgcctcactgattaagcattggtaaecgattctaggtgcattggcgcagaaaaaaatgectgatgcgacgctgcgcgteXtatactccca Docket No. 11676 -005 WO 1 catatgccagattcagcaacggatacggcttccccaactgcccacttccatacgtgtcctcctaccagaaattatcctaagatcccga atcgtttaaacgcgatcgcagtaa

[0233] 18. SEQ ID NO: 18 - pYJ278„GYJ085JKW002„THBS4 .29 l..+5GtoT„ 9. J 2„ Nine, reporter tcaatacggggtcattagttcatagcccatatatggagttccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gaeccccgcecattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtattac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgacctatgggacttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttggc agtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcacc aaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaatttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaatcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgatcgcagtaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaacttagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatcttcagacctggaggaggagatatgagggaoaattggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatatgtctggt atagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatoaacagctcctggggattggggtgctctggaaaactcatttgcaccact gctgtgcctggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaataa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattatggaattagataaatg ggcaagttgtggaatggtttaacataacaaatggctgtggtatataaaattattcataatgatagtaggaggcttggtaggttaagaat agtttgctgtacttctatagtgaatagagttaggcagggatattcaccattatcgttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggttaacttttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaatacaaaaaeaaatacaaaaatcaaaatttggetcccgatcgtgcgtacacacacaattactgctgatcgagtgtagcctc gaatetagagatecgacgcgccatctctaggcccgegceggcccmcgcaeggactigtgggagaagctcggctactccectgce ccggttaatttgcatataatatttcctagtaactatagaggcttaatgtgcgataaaagacagataatctgttctttttaatactagctacatttt acatgataggetggattctataactcgtatagcatacattatacgaagttataaacagcacaaaaggaaactcaccctaaetgtaaagt aattgtgtgtttgagactaT AAGl ATCCCT1 GGAGAACCACCTTGT TGGAAAG T1 CAGCCACC Docket No. 11676 -005 WO 1

[0234] ATCTTGTTTAAGAGCTATGCTGGAAACAGCATAGCAAGTTTAAATAAGGCTAGTC CGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTAAAGACATAAGATGGTG

[0235] GCTCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAGAATTTTTTTCTCGAGACC GGTATGCATccgataaaataaaagatttattagtctccagaaaaaggggggaatgaaagaccccacctgtaggttggcaag ctagctgcagtaacgccattttgcaaggcatggaaaaataccaaaccaagaatagagaagtcagatcaagggcgggtacatgaaaat agetaacgtgggccaaaeaggatatetgeggtgageagttcggecccggcccggggccaagaaeagatggtcaccgcagtteg gccccggcccgaggccaagaacagatggtccccagatatggcccaaccctcagcagtttcttaagacccatcagatgtttccaggctc ccccaaggacctgaaatgaccctgcgccttattgaataaccaatcagcctgctctcgctctgttcgcgcgctctgctcccgagctc tataaaagagctcacaacccctcactoggcgcgccagtcctccgacagactgagtcgcccgggAAAAGTTCAGCCAC CATCTTAGGTCTTTAGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggc tacaacctggaccaagtccttgaacagggaggtgtgtccagttgttcagaatctcggggtgtccgtaactccgatccaaaggattgtc ctgagcggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaa aaaattttaaggtggtgtaccctgtggatgatcatcactttaaggtgatcx’tgcactatggcacactggtaategacggggtacgecga acatgatcgactattcggacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacg gcaacaaaatatcgacgagcgcctgatcaaccccgacggctccctgctgtccgagtaaccatcaacggagtgaccggctggcggc tgtgcgaacgcatctggcgTAAaagttgtctcctectgcactgactgactgatacaatcgattctgcggccaatctgcagtcgacg gtaccgcgggcccgggatccgcccctctccctcccccccccctaacgttactggccgaagccgcttggaataaggccggtgtgcgtt gtctatatgttatttccaccatattgccgtcttttggcaatgtgagggcccggaaacctggccctgtctctgacgagcattcctaggggt cttteccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagttcctctggaagcttcttgaagacaaacaacgtct gtagcgaccctttgcaggcagcggaacccex’cacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgc aaaggcggcacaaccccagtgccacgttgtgagtggatagtgtggaaagagtcaaatggctctcctcaagcgtattcaacaagggg ctgaaggatgcccagaaggtaccccattgtatgggatctgatctggggcctcggtacacatgctttacatgtgtttagtcgaggttaaaa aaacgtctaggeccxxcgaaexacggggacgtggtttcctttgaaaaacacgatgataatatggccacaaecatggtgagcaaggg cgaggaggataacatggccatcatcaaggagtcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagtcgagat cgagggcgagggcgagggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccctcg cctgggacatcctgtcccctcagttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtcc ttccccgagggcttcaagtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcagga cggcgagttcatctacaaggtgaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctggg aggcctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggc cactacgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtoaacatcaagttgga catcacctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacga gctgtacaagtaacttgactgactgagtcgacaatcaacctctggatacaaaattgtgaaagatgactggtattcttaactatgtgctc cttacgctatgtggatacgctgctttaatgccttgtatcatgctatgctcccgtatggcttcatttctcctccttgtataaatoctggtg ctgtctcttatgaggagttgtggcccgtgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggtggggc Docket No. 11676 -005 WO 1 attgccaccacctgtcagctcctttccgggactttcgctttccccctccctatgccacggcggaactcatcgccgcctgccttgcccgct gctggacaggggctcggctgttgggcactgacaattccgtggtgttgtcggggaagctgacgtectttccatggctgctcgcctgtgtt gccacctggattctgcgcgggacgtccttctgctacgtcccttcggccctoaatccagcggacctccttcccgcggcctgctgccggc tctgcggcctcttccgcgtcttcgccttcgccctcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggta cctttaagaccaatgacttacaaggcagctgtagatcttagccacttttaaaagaaaaggggggactggaagggctaattcactcccaa cgaagacaagatctgcttttgctgtactgggtotctctggttagaccagatctgagcctgggagctctctggctaactagggaacccac tgcttaagcctcaataaagctgccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccc tttagtcagtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagc cggcctggccctccgccccccccacccccgcagcccacccctggtctttgaataaagtctgagtgagtggccgacagtgcccgtgga gtctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacagg cctagccctgcaggcctaactccgcccatcccgcccctaactccgcccagttccgcccatctccgcctcatggctgactaattttttat ttatgcagaggccgaggccgcctcggcctctgagctattccagaagtagtgaggacgcttttttggaggccgaggctttgcaaagatc gaacaagagacaggacctgcaggtaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccg cgtgctggcgtttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacag gactataaagataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccgcct tctcccttcgggaagcgtggcgcttctcatagctcacgctgtaggtatctcagtcggtgtaggtcgttcgctccaagctgggctgtgtg cacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgactatcgccact ggcagcagccactggtaacaggatagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggcta cactagaagaacagtatttggtatctgcgc tctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggcaaacaaac caccgctggtagcggtggttttgttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatccttgatcttttctacg gggtctgacgctcagtggaacgaaaactcacgttaagggatttggtcatgagattatcaaaaaggatcttcacctagatccttttaaata aaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgat ctgtctattcgttcatccatagttgcatttaaatggccggcetggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtata atcgagtcctagctttgcaaacatctatcaagagacaggatcagcaggaggcttcgcatgagtattcaacattccgtgtcgcccttatt cccttttgcggcatttgccttcctgttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagt gggttacatcgaactggatetcaacagcggtaagatccttgagagtttcgccccgaagaacgctttccaatgatgagcactttaaagtt ctgctatgtggcgcggtatatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactatctcagaatgacttggtgag tattcaccagtcacagaaaagcatettacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgc ggccaadtacttctgacaacgattggaggaccgaaggagctaaccgcttttttgcacaacatgggggatcatgtaactcgccttgatcg ttgggaaccggagctgaatgaagceatacx’aaacgacgagcgtgaeaccacgatgcctgtagcaatggcaaeaaccttgcgtaaact attaactggcgaactacttactctagcttcccggcaacagttgatagactggatggaggcggataaagtgcaggaccactctgcgctc ggcccttccggctggctggttatgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatg gtaagccctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgc ctcactgattaagcatggtaaccgattctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacat Docket No. 11676 -005 WO 1 atgccagattcagcaacggatacggctccccaactgcccacttccatacgtgtcctcctaccagaaattatccttaagatcccgaatc gtttaaacgcgatcgcagtaa

[0236] 19. SEQ ID NO: pYJ285„GYJ091„LASPl„250„+5GtoT„ll„12„Nluc„reporter„nopegconstnict tcaatacggggtcatagtcatagcccatatatggagtccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtatttac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagteatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccatgacgtcaatgggagtttgtttggcacc aaaatcaacgggactttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggttaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccataggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttccttgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgeageagcagaacaattgctgagggctatgaggcgcaacagcatctgttgcaactcacagtetggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggattggggttgctctggaaaactcattgcaccact gctgtgcctggaatgctagtggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaataa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaattagataaatg ggcaagtttgtggaatggtttaacataacaaattggctgtggtatataaaatattcataatgatagtaggaggcttggtaggttaagaat agttttgctgtacttctatagtgaatagagttaggcagggatattcaccatatcgtttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaaetttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacataeaaacta aagaaUacaaaaaeaaaUacaaaaatcaaaaOggetcccgategUgcgtacacacacaatactgctgatcgagtgtagccUc gaacgggaggtggtccctgcagttacgccaatgataacccccgccagaaaaatcttagtagccttcccttttgttttecgtgccccaactcggcggatgactcggccccttccggaaacacccgaatcaactctagtcaaattattgttcacgccgcaatgacccacccctggcccg cgtctgtggaactgacccctggtgtacaggagagtcgctgctgaaagtggtcccaaaggggtactagttttaagctcccaactcccc Docket No. 11676 -005 WO 1 ctcccccagcgtctggaggattccacaccctcgcaccgcaggggcgaggaagtgggcggagtccggttggcgccagccgctga ggctgccaagcagaaaagccaccgctgaggagactccggtcactgtcctcgccccgcctcccccttccctccccttggggaccacc gggcgccacgccgcgaacggtaagtgccgcggtcgtcggcgcctocgccctccxxctagggcccxaattcccagcgggcgcggc gcgcggccccgcgcgcagctcccggctccctccccctcggatgtggctgagctgtaggcgcggagtcctgcagccccgataaaa taaaagatttattagtctccagaaaaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccatttgc aaggcatggaaaaataccaaacxaagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacagg atatctgcggtgagcagttcggccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaa cagatggtccccagatatggcccaaccctcagcagtttctaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccc tgcgccttattgaataaccaatcagcctgctctcgcttctgttogcgcgcttctgctcccgagctctataaaagagctcacaacccctc actcggcgcgccagtcctccgacagactgagtcgcccgggGGAGCTCACTCTGTTGCTTGAGGCGAAGG GTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaa cagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaa gatcgacatccatgtcatoatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttaaggtggtgtaccctgt ggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactattcggacggc cgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgc ctgatcaaccccgacggctocx’tgctgttecgagtaaccatcaacggagtgaccggctggcggctgtgcgaaegcattotggcgTA Aaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgc ccctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttatttccaccatatt gccgtcttttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcattcctaggggtctttcccctctcgccaaaggaat gcaaggtctgtgaatgtogtgaaggaagcagttcctctggaagcttctgaagacaaacaacgtctgtagcgacccttgcaggcagc ggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtg ccacgttgtgagttggatagtgtggaaagagtcaaatggctctcctcaagcgtatcaacaaggggctgaaggatgxccagaaggta ccex’attgtatgggatcXgatcXggggcctcggtacacatgctttacatgtgtttagtegaggttaaaaaaacgtctaggccececgaae cacggggacgtggttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccat catcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggc cgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctca gttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtcctccccgagggcttcaagtgg gagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggt gaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatg taccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaa gaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagtggacatcacctcccacaacgagg actacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaactgactga ctgagtcgacaatcaacctctggattacaaaattgtgaaagatgactggtatcttaactatgtgctccttacgctatgtggatacgct gcttaatgccttgtatcatgctatgcttcccgtatggcttcattctcctcctgtataaatcctggttgctgtctctttatgaggagtgtg Docket No. 11676 -005 WO 1 gcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcattgccaccacctgtcagctcc tttccgggactttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgt tgggcactgacaattccgtggtgttgtcggggaagctgacgtcx’tttccatggctgctcgcctgtgttgccacctggattcXgcgcggga cgtccttctgctacgtcccttcggccctcaatccagcggaccttcctcccgcggcctgctgccggctctgcggcctcttccgcgtcttcg ccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaattcgagctcggtaccttaagaccaatgacttacaag gcagctgtagatcttagceaeXttaaaagaaaaggggggactggaagggctaatcactcecaacgaagaeaagatctgcttttgct tgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagctg ccttgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttatttatgcagaggccgaggccgc ctcggectctgagetattccagaagtagtgaggacgctttttggaggccgaggettttgcaaagatcgaacaagagacaggaectgc aggtaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttt ccccctggaagctccctcgtgcgctotcctgtccgaccctgccgcttaccggatacctgtccgccttctccctcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgcctatccggtaactatcgtctgagtccaacccggtaagacacgactatcgccactggcagcagccactggtaacag gattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggta totgcgctotgctgaagceagttaccteggaaaaagagtggtagetcttgatccggcaaacaaaccacegctggtagcggtggttttt tgttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatcctttgatcttctacggggtctgacgctcagtggaacga aaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaa agtatatatgagtaaacttggtctgacagtaccaatgctaatcagtgaggcacctatctcagcgatctgtctattcgtcatocatagtg catttaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagctttgcaaacat ctatcaagagacaggatcagcaggaggctttcgcatgagtatcaacatttccgtgtcgccctattcccttttttgcggcattttgcctcct gtttttgctcacccagaaac gctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatcctgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagtctgctatgtggcgcggtattatccc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtatcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactataactggcgaactacttactcta gcttcccggcaacagtgatagactggatggaggcggataaagtgcaggaccactctgcgctcggcccttccggctggctggttat tgeXgataaatotggagceggtgagcgtgggtctcgcggtatcattgcagcactggggceagatggtaagccctcecgtatogtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgataagcatggtaacc Docket No. 11676 -005 WO 1 gatctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatgccagatcagcaacggatac ggctccccaacttgcccacttccatacgtgtcctccttaccagaaattatccttaagatcccgaatcgtttaaacgcgatcgcagtaa

[0237] 20. SEQ ID NO: 20 pYJ286„GYJ092„GPLDl„480„+5GtoT„ll„10„Nluc„reporter„nopegconstnict tcaattacggggtcatagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgac.cgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtatttac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagteatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccatgacgtcaatgggagtttgtttggcacc aaaatcaacgggactttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagcttgccttgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgtagaaacatcagaag gctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaagaccacc gcacagcaagcggc.cgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaattgaaccataggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttccttgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgeageagcagaacaattgctgagggctatgaggcgcaacagcatctgttgcaactcacagtetggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggattggggttgctctggaaaactcattgcaccact gctgtgcctggaatgctagtggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaattagataaatg ggcaagtttgtggaatggtttaacataacaaattggctgtggtatataaaatattcataatgatagtaggaggcttggtaggttaagaat agtttgctgtacttctatagtgaatagagttaggcagggatattcaccatatcgtttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggtaaetttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacataeaaacta aagaaUacaaaaaeaaaUacaaaaatcaaaaOggetcccgategUgcgtacacacacaatactgctgatcgagtgtagccUc gaacgggaggtggtccctgcagttacgccaatgataacccccgccagaaaaatcttagtagccttcccttttgttttecgtgccccaact eggcggatgaetcggrceettccggaaacacccgaateaarttctagtcaaattattgttcaegccgcaatgacceaeccctggcecg cgtctgtggaactgacccctggtgtacaggagagtcgctgctgaaagtggtcccaaaggggtactagttttaagctcccaactcccc Docket No. 11676 -005 WO 1 ctcccccagcgtctggaggattccacaccctcgcaccgcaggggcgaggaagtgggcggagtccggttggcgccagccgctga ggctgccaagcagaaaagccaccgctgaggagactccggtcactgtcctcgccccgcctcccccttccctccccttggggaccacc gggcgccacgccgcgaacggtaagtgccgcggtcgtcggcgcctocgccctccxxctagggcccxaattcccagcgggcgcggc gcgcggccccgcgcgcagctcccggctccctccccctcggatgtggctgagctgtaggcgcggagtcctgcagccccgataaaa taaaagatttattagtctccagaaaaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccatttgc aaggcatggaaaaataccaaacxaagaatagagaagttcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacagg atatctgcggtgagcagttcggccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaa cagatggtccccagatatggcccaaccctcagcagtttctaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccc tgcgccttattgaataaccaatcagcctgctctcgcttctgttogcgcgcttctgctcccgagctctataaaagagctcacaacccctc actcggcgcgccagtcctccgacagactgagtcgcccgggTGCCATAGAGGTTCACCGTGAGGCCTTTC GTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaacctggaccaagtccttgaa cagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagcggtgaaaatgggctgaa gatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatttttaaggtggtgtaccctgt ggatgatcatcactttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatgatcgactattcggacggc cgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaacaaaattatcgacgagcgc ctgatcaaccccgacggctecxtgctgttecgagtaaccatcaacggagtgaccggctggcggctgtgcgaaegcatctggcgTA Aaagttgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtaccgcgggcccgggatccgc ccctctccctcccccccccctaacgtactggccgaagccgctggaataaggccggtgtgcgttgtctatatgttatttccaccatatt gccgtcttttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcattcctaggggtctttcccctctcgccaaaggaat gcaaggtctgttgaatgtcgtgaaggaageagttcctctggaagcttcXtgaagacaaacaaegtetgtagcgaccetttgcaggcagc ggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaaggcggcacaaccccagtg ccacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccagaaggta ccccatgtatgggatctgatctggggcctcggtacacatgcttacatgtgttagtcgaggttaaaaaaacgtctaggccccccgaac cacggggacgtggttcctttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgaggaggataacatggccat catcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagggcgagggcgagggc cgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgggacatcctgtcccctca gttcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtcctccccgagggcttcaagtgg gagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggcgagttcatctacaaggt gaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggcctcctccgagcggatg taccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccactacgacgctgaggtcaa gaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagtggacatcacctcccacaacgagg actacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgtacaagtaactgactga ctgagtcgacaatcaacctctggattacaaaattgtgaaagatgactggtatcttaactatgtgctcctttacgctatgtggatacgct gcttaatgccttgtatcatgctatgcttcccgtatggcttcattctcctcctgtataaatcctggttgctgtctctttatgaggagtgtg Docket No. 11676 -005 WO 1 gcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcattgccaccacctgtcagctcc tttccgggactttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgt tgggcactgacaattccgtggtgttgtcggggaagctgacgtcx’tttccatggctgctcgcctgtgttgccacctggattcXgcgcggga cgtccttctgctacgtcccttcggccctcaatccagcggaccttcctcccgcggcctgctgccggctctgcggcctcttccgcgtcttcg ccttcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaattcgagctcggtaccttaagaccaatgacttacaag gcagctgtagatcttagceaeXttaaaagaaaaggggggactggaagggctaatcactcecaacgaagaeaagatctgcttttgct tgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagctg ccttgagtgctcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctct agcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctggccctccgcccccc ccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgtgacctgaggtgcag ggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagccctgcaggcctaactc cgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttatttatgcagaggccgaggccgc ctcggectctgagetattccagaagtagtgaggacgctttttggaggccgaggettttgcaaagatcgaacaagagacaggaectgc aggtaataaattaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttt ccccctggaagctccctcgtgcgctotcctgtccgaccctgccgcttaccggatacctgtccgccttctccctcgggaagcgtggcg ctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccg accgctgcgcctatccggtaactatcgtctgagtccaacccggtaagacacgactatcgccactggcagcagccactggtaacag gattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggta totgcgctotgctgaagceagttaccteggaaaaagagtggtagetcttgatccggcaaacaaaccacegctggtagcggtggttttt tgttgcaagcagcagatacgcgcagaaaaaaaggatctcaagaagatcctttgatcttctacggggtctgacgctcagtggaacga aaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaa agtatatatgagtaaacttggtctgacagtaccaatgctaatcagtgaggcacctatctcagcgatctgtctattcgtcatocatagtg catttaaatggccggcctggcgcgccgtttaaacctagatattgatagtctgatcggtcaacgtataatcgagtcctagctttgcaaacat ctatcaagagacaggatcagcaggaggctttcgcatgagtatcaacatttccgtgtcgccctattcccttttttgcggcattttgcctcct gtttttgctcacccagaaac gctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatcgaactggatctcaa cagcggtaagatcctgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagtctgctatgtggcgcggtattatccc gtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtatcaccagtcacagaaaagcat cttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacttacttctgacaacgatt ggaggaccgaaggagctaaccgcttttgcacaacatgggggatcatgtaactcgccttgatcgttgggaaccggagctgaatgaag ccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactataactggcgaactacttactcta gcttcccggcaacagtgatagactggatggaggcggataaagtgcaggaccactctgcgctcggcccttccggctggctggttat tgeXgataaatotggagceggtgagcgtgggtctcgcggtatcattgcagcactggggceagatggtaagccctcecgtatogtagtta tctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgataagcatggtaacc Docket No. 11676 -005 WO 1 gatctaggtgcatggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatgccagatcagcaacggatac ggcttccccaacttgcccacttccatacgtgtcctccttaccagaaatttatccttaagatcccgaatcgtttaaacgcgatcgcagtaa

[0238] 21. SEQ ID NO: 21 - pYJ287...GYJ093.. CREBZF.4-5-

[0239] 9.. deletion. reverse__Nluc__reporter„ nopegconstruct tcaatacggggtcatagtcatagcccatatatggagtccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggactttccatgacgtcaatgggtggagtatttac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctatgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccatgacgtcaatgggagtttgtttggcacc aaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagcttgecttgagtgetcaagtagtgtgtgcccgtctgtgtgtgaetetggtaactagagatcectcagaccctttta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggttaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaactagatcatatataatacagtagcaaccctct attgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaagaocacc gcacagcaagcggccgetgatctteagacctggaggaggagatatgagggacaattggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttccttgggttcttgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaattattgtctggt atagtgeageagcagaacaattgctgagggctattgaggcgcaacagcatctgttgcaactcacagtetggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggattggggttgctctggaaaactcattgcaccact gctgtgcctggaatgctagtggagtaataaatctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaa caattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaattagataaatg ggcaagtttgtggaatggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttggtaggttaagaat agtttgctgtacttctatagtgaatagagttaggcagggatatcaccatatcgtttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatc ggttaaetttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacataeaaacta aagaattacaaaaacaaattacaaaaattcaaaatttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaacgggaggtggtccctgcagttacgccaatgataacccccgccagaaaaatcttagtagccttcccttttgttttccgtgccccaact eggcggatgaetcggceccttccggaaacacccgaatcaaetctagtcaaattattgttcaegccgcaatgacceaeccctggcecg cgtctgtggaactgacccctggtgtacaggagagtcgctgctgaaagtggtcccaaaggggtactagttttaagctcccaactcccc Docket No. 11676 -005 WO 1 ctcccccagcgtctggaggattccacaccctcgcaccgcaggggcgaggaagtgggcggagtccggttggcgccagccgctga ggctgccaagcagaaaagccaccgctgaggagactccggteactgtcctcgccccgcctcccccttccctccccttggggaccacc gggcgccacgccgcgaacggtaagtgccgcggtcgtcggcgcctocgccctccxxctagggcccxaattcccagcgggcgcggc gcgcggccccgcgcgcagctcccggctccctccccctcggatgtggctgagctgtaggcgcggagtcctgcagccccgataaaa taaaagatttattagtctccagaaaaaggggggaatgaaagaccccacctgtaggtttggcaagctagctgcagtaacgccatttgc aaggcatggaaaaataccaaacxaagaatagagaagtcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacagg atatctgcggtgagcagttcggccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaa cagatggtccccagatatggcccaaccctcagcagtttctaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccc tgcgccttatttgaattaaccaatcagcctgcttctcgcttctgttegcgcgcttctgcttcccgagctctataaaagagctcacaacccctc actcggcgcgccagtcctccgacagactgagtcgcccgggTCGCCGGGGCCATTCTCCGCGTCTGGCGG AGGCTCGGATCGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaac ctggaccaagtccttgaacagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgagc ggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatt ttaaggtggtgtaccctgtggatgatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggtacgccgaacatga tcgactatttcggacggccgtatgaaggcatcgccgtgtcgacggcaaaaagatcactgtaacagggaccctgtggaacggcaaca aaattatcgacgagcgcctgatcaaccccgacggctccctgcXgttccgagtaaccatcaacggagtgaccggctggcggctgtgcg aacgcattctggcgTAAaagttgtctcctcctgcactgactgactgatacaatcgatttctgcggccaattctgcagtcgacggtaccg cgggcccgggatccgcccctctccctcccccccccctaacgttactggccgaagccgcttggaataaggccggtgtgcgtttgtctat atgttattttccaccatattgccgtcttttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcattcctaggggtctttec cctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagctcttgaagacaaacaacgtctgtagc gaccctttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaagg cggcacaaccccagtgccacgttgtgagttggatagttgtggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaa ggatgcccagaaggtaccccattgtatgggatctgatctggggcctcggtacacatgcttacatgtgttagtcgaggtaaaaaaacg tctaggccccccgaaccacggggacgtggtttccttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgagg aggataacatggccatcatcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgagg gcgagggcgagggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgcccttcgcctgg gacatcctgtcccctcagtcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactactgaagctgtcctccc cgagggcttcaagtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacggc gagtcatctacaaggtgaagctgcgcggcaccaacttcccctccgacggccccgtaatgcagaagaagaccatgggctgggaggc ctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccacta cgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatca cctcccacaacgaggactacaccatcgtggaacagtacgaacgcgccgagggccgccactccaccggcggcatggacgagctgta caagtaactgactgactgagtcgacaatcaacctctggattacaaaatttgtgaaagattgactggtattcttaactatgttgctcctttac gctatgtggatacgctgcttaatgcctttgtatcatgctattgctcccgtatggcttcatttctcctccttgtataaatcctggttgctgtctc Docket No. 11676 -005 WO 1 ttatgaggagtgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcattgcca ccacctgtcagctcctttccgggactttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctgga caggggctcggctgttgggcactgacaattccgtggtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgttgccacct ggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcggacctcctcccgcggcctgctgccggctctgcgg cctctccgcgtctcgccttcgccctcagacgagtcggatctccctttgggccgcctccccgcctggaattcgagctcggtaccttaag accaatgacttacaaggcagctgtagatcttagccactttttaaaagaaaaggggggactggaagggctaatcactcccaacgaaga caagatctgctttgctgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaa gcctcaataaagctgcctgagtgctcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccctttagtc agtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgttaagctggagcctgggagccggcctg gccctccgccccccccacccccgcagcccacccctggtcttgaataaagtctgagtgagtggccgacagtgcccgtggagttctcgt gacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcctagcc ctgcaggcctaactccgcccatcccgcccctaactccgcccagttccgcccattctccgcctcatggctgactaattttttttatttatgcag aggccgaggccgcctcggcctctgagctattccagaagtagtgaggacgcttttttggaggccgaggcttttgcaaagatcgaacaag agacaggacctgcaggttaattaaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctg gcgttttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataa agataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccgccttctccct cgggaagcgtggcgcttctcatagctcacgctgtaggtatctcagtcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaac cccccgttcagcccgaccgctgcgcctatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagca gccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaa gaacagtattggtatctgcgctctgctgaagccagtaccttcggaaaaagagttggtagctcttgatccggcaaacaaaceaccgetg gtagcggtggtttttgttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatccttgatctttctacggggtctgac gctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaag ttttaaatcaatctaaagtatatatgagtaaactggtctgacagttaecaatgcttaatcagtgaggcacctatctcagcgatetgtctatte gtcatccatagttgcattaaatggccggcctggcgcgccgttaaacctagatatgatagtctgatcggtcaacgtataatcgagtcct agcttgcaaacatctatcaagagacaggatcagcaggaggctttcgcatgagtattcaacatttccgtgtcgcccttattccctttttgc ggcattttgccttcctgtttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcgcgagtgggttacatc gaactggatctcaacagcggtaagatcctgagagttcgccccgaagaacgcttccaatgatgagcacttaaagtctgctatgtg gcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactatctcagaatgacttggtgagtattcaccag tcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgataacactgcggccaacta cttctgacaacgatggaggaccgaaggagctaaccgctttttgcacaacatgggggatcatgtaactcgcctgatcgtgggaacc ggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaacctgcgtaaactattaactgg cgaactacttactctagcttcccggcaacagttgatagactggatggaggcggataaagtgcaggaccactctgcgctcggcccttc cggctggctggttatgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggtaagcc ctcccgtatcgtagttatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactg Docket No. 11676 -005 WO 1 attaagcatggtaaccgatctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgtctatactcccacatatgccag attcagcaacggatacggcttccccaacttgcccacttccatacgtgtcctccttaccagaaatttatccttaagatcccgaatcgtttaaa cgcgategcagtaa

[0240] 22. SEQ ID NO: 22 - pYJ288„GYJ094„PLSCR2„+5-

[0241] 9_deletion_reverse_Nluc_reporter_nopegconstruct tcaattacggggtcattagtcatagcccatatatggagtccgcgtacataactacggtaaatggcccgcctggctgaccgcccaac gacccccgcccattgacgtcaataatgacgtatgtcccatagtaacgccaatagggacttccatgacgtcaatgggtggagtatttac ggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctgg cattatgcccagtacatgaccttatgggactttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggtttggc agtacatcaatgggcgtggatagcggtttgactcacggggattccaagtctccaccccattgacgtcaatgggagttgtttggcacc aaaatcaacgggaetttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatat aagcagagctcgtttagtgaaccggggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgct taagcctcaataaagctgccttgagtgcttoaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttrta gtcagtgtggaaaatctctagcagtggcgcccgaacagggacctgaaagcgaaagggaaaccagagctctctcgacgcaggactc ggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaatttgactagcggaggctagaagg agagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccagggggaaa gaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgatcgcagttaatcctggcctgttagaaacatcagaag gctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctct atgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaagaecacc gcacagcaagcggccgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaattatataaatataaagtagta aaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctt tgttcctgggttctgggagcagcaggaagcactatgggcgcagcctcaatgacgctgacggtacaggccagacaatatgtctggt atagtgcagcagcagaacaatttgctgagggctatgaggcgcaacagcatctgttgcaactcacagtctggggcatcaagcagctcc aggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaactcattgcaccact gctgtgccttggaatgctagttggagtaataaatctctggaacagatttggaatcacacgacc tggatggagtgggacagagaaattaa caattacacaagctaatacactccttaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaattagataaatg ggcaagtttgtggaatggttaacataacaaattggctgtggtatataaaatattcataatgatagtaggaggcttggtaggttaagaat agtttttgctgtactttctatagtgaatagagttaggcagggatattcaccattatcgtttcagacccacctcccaaccccgaggggaccc gacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccatcgatagtgaacggatctcgacggtate ggtaactttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaacta aagaattacaaaaacaaattacaaaaattcaaaattttggctcccgatcgttgcgttacacacacaattactgctgatcgagtgtagccttc gaacgggaggtggtccctgcagttacgccaatgataacxcccgccagaaaaatcttagtagecttocctttttgttttecgtgccceaact cggcggatgaetGggceccttccggaaacacccgaaicaaettetagtcaaatattgttcaegccgcaatgacceaeccctggcecg Docket No. 11676 -005 WO 1 cgtctgtggaactgacccctggtgtacaggagagtcgctgctgaaagtggtcccaaaggggtactagttttaagctcccaactcccc ctcccccagcgtctggaggattccacaccctcgcaccgcaggggcgaggaagtgggcggagtccggttttggcgccagccgctga ggctgccaagcagaaaagccaccgctgaggagactccggtcaetgtcctcgccccgcctcx’cccttccctccccttggggaceacc gggcgccacgccgcgaacggtaagtgccgcggtcgtcggcgcctccgccctccccctagggccccaattcccagcgggcgcggc gcgcggccccgcgcgcagctcccggctccctccccctcggatgtggctgagctgtaggcgcggagtcctgcagccccgataaaa taaaagattttatttagtctceagaaaaaggggggaatgaaagacx’ccaectgtaggtttggcaagctagctgcagtaacgccattttgc aaggcatggaaaaataccaaaccaagaatagagaagtcagatcaagggcgggtacatgaaaatagctaacgttgggccaaacagg atatctgcggtgagcagttcggccccggcccggggccaagaacagatggtcaccgcagttcggccccggcccgaggccaagaa cagatggtccccagatatggcccaaccctcagcagtttcttaagacccatcagatgtttccaggctcccccaaggacctgaaatgaccc tgcgccttattgaattaaccaatcagcctgctctcgcttctgttcgcgcgcttctgctcccgagctctataaaagagctcacaacccctc actcggcgcgccagtcctccgacagactgagtcgcccgggTAGAAGGCCTGATAGCCCGGGTGGTCAG CCTGTTTCCCAGGTCTTCACACTCGAAGATTTCGTTGGggactggcgacagacagccggctacaa cctggaccaagtccttgaacagggaggtgtgtccagtttgtttcagaatctcggggtgtccgtaactccgatccaaaggattgtcctgag cggtgaaaatgggctgaagatcgacatccatgtcatcatcccgtatgaaggtctgagcggcgaccaaatgggccagatcgaaaaaatt ttaaggtggtgtaccctgtggatgatcatcacttaaggtgatcctgcactatggcacactggtaatcgacggggttacgccgaacatg atcgactatttcggacggccgtatgaaggcatcgccgtgttcgacggcaaaaagatcactgtaacagggaccxtgtggaacggcaac aaaattatcgacgagcgcctgatcaaccccgacggctccctgctgttccgagtaaccatcaacggagtgaccggctggcggctgtgc gaacgcattctggcgTAAaagtgtctcctcctgcactgactgactgatacaatcgattctgcggccaattctgcagtcgacggtacc gcgggcccgggatccgcccctctccctcccccccccctaacgttactggccgaagccgcttggaataaggccggtgtgcgtttgtcta tatgtattccaccatattgccgtctttggcaatgtgagggcccggaaacctggccctgtctcttgacgagcatcctaggggtcttc ccctctcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagtcctctggaagcttctgaagacaaacaacgtctgtag cgaccctttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaaaagccacgtgtataagatacacctgcaaag geggcacaaccecagtgccacgttgtgagttggatagttgtggaaagagtcaaatggctctceXcaagcgtattcaaeaaggggetga aggatgcccagaaggtaccccatgtatgggatctgaictggggecteggtaeacatgcttacatgtgttagtcgaggttaaaaaaac gtctaggccccccgaaccacggggacgtggttccttgaaaaacacgatgataatatggccacaaccatggtgagcaagggcgag gaggataacatggccatcatcaaggagttcatgcgcttcaaggtgcacatggagggctccgtgaacggccacgagttcgagatcgag ggcgagggcgagggccgcccctacgagggcacccagaccgccaagctgaaggtgaccaagggtggccccctgccctcgcctg ggacatcctgtcccctcagtcatgtacggctccaaggcctacgtgaagcaccccgccgacatccccgactacttgaagctgtccttcc ccgagggcttcaagtgggagcgcgtgatgaacttcgaggacggcggcgtggtgaccgtgacccaggactcctccctgcaggacgg cgagtcatotacaaggtgaagctgcgcggcaccaacttcccctocgacggccccgtaatgcagaagaagaccatgggctgggagg cctcctccgagcggatgtaccccgaggacggcgccctgaagggcgagatcaagcagaggctgaagctgaaggacggcggccact acgacgctgaggtcaagaccacctacaaggccaagaagcccgtgcagctgcccggcgcctacaacgtcaacatcaagttggacatc acctcccaeaacgaggactacaceatcgtggaacagtacgaacgcgccgagggccgccacXccaecggcggeatggacgagctgt acaagtaactgactgactgagtcgacaatcaacctctggatacaaaattgtgaaagatgactggtattcttaactatgtgctcctttta Docket No. 11676 -005 WO 1 cgctatgtggatacgctgcttaatgccttgtatcatgctattgctcccgtatggcttcattctcctcctgtataaatcctggtgctgtct ctttatgaggagttgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcattgcc accacctgtcagctcctttccgggacttcgcttccccctccctattgccacggcggaactcatogccgcctgcctgcccgctgctgg acaggggctcggctgtgggcactgacaattccgtggtgtgtcggggaagctgacgtccttccatggctgctcgcctgtgtgccac ctggatctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcggaccttccttcccgcggcctgctgccggctctgc ggcctctccgcgtctcgcctcgccctcagacgagtcggatctcccttgggccgcctccccgcctggaatcgagctcggtacctt aagaccaatgacttacaaggcagctgtagatcttagccactttttaaaagaaaaggggggactggaagggctaattcactcccaacga agacaagatctgcttttgctgtactgggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccactgc ttaagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagacccttt agtcagtgtggaaaatctctagcagtcctggccaacgtgagcaccgtgctgacctccaaatatcgtaagctggagcctgggagccgg cctggccctccgccccccccacccccgcagcccacccctggtctttgaataaagtctgagtgagtggccgacagtgcccgtggagtt ctcgtgacctgaggtgcagggccggcgctagggacacgtccgtgcacgtgccgaggccccctgtgcagctgcaagggacaggcct agccctgcaggcctaactccgcccatcccgcccctaactocgcccagttccgcccatctccgcctcatggctgactaatttttttattat gcagaggccgaggccgcctcggcctctgagctattccagaagtagtgaggacgcttttggaggccgaggctttgcaaagatcgaa caagagacaggacctgcaggttaataaatttaaatcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtt gctggcgttttccataggctocgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggact ataaagataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgccgcttaccggatacctgtccgccttctc ccttcgggaagcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgtcgctccaagctgggctgtgtgcac gaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgacttatogccactggc ageagecactggtaaeaggattageagagcgaggtatgtaggcggtgetacagagttettgaagtggtggcx’taactacggctacact agaagaacagtattggtatctgcgctctgctgaagccagttacctcggaaaaagagttggtagctctgatccggcaaacaaaccac cgctggtagcggtggttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggt ctgacgctcagtggaacgaaaactcacgtaagggattggtcatgagattatcaaaaaggatctcacctagatcctttaaataaaaa tgaagtttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgctaatcagtgaggcacctatctcagcgatctgt ctatttcgtcatccatagtgcattaaatggccggcctggcgcgccgtttaaacctagatatgatagtctgatcggtcaacgtataatcg agtcctagctttgcaaacatctatcaagagacaggatcagcaggaggcttcgcatgagtatcaacattccgtgtcgcccttattccct ttttgcggcatttgcctcctgttttgctcacccagaaacgctggtgaaagtaaaagatgctgaagatcagtgggtgcgcgagtgggt tacatcgaactggatctcaacagcggtaagatccttgagagtttcgccccgaagaacgcttccaatgatgagcactttaaagttctgct atgtggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgagtattc accagtcacagaaaagcatctacggatggcatgacagtaagagaattatgcagtgeXgccataaccatgagtgataacactgcggcc aacttactctgacaacgattggaggaccgaaggagctaaccgctttttgcacaacatgggggatcatgtaactcgccttgatcgtgg gaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagcaatggcaacaaccttgcgtaaactata actggcgaactacttactctagctcccggcaacagtgatagactggatggaggcggataaagtgcaggaccactctgcgctcggc ccttccggctggctggttattgctgataaatctggagccggtgagcgtgggtctcgcggtatcattgcagcactggggccagatggta Docket No. 11676 -005 WO 1 agccctcccgtatcgtagtatctacacgacggggagtcaggcaactatggatgaacgaaatagacagatcgctgagataggtgcctc actgattaagcattggtaaccgattctaggtgcattggcgcagaaaaaaatgcctgatgcgacgctgcgcgtcttatactcccacatatg ccagatcagcaacggatacggctccccaacttgcccactccatacgtgtcctcctaccagaaattatccttaagatcccgaatcgtt taaacgcgatcgcagtaa

[0242] 23. SEQ NO: 23 pYJ289„GYJ095„LASPl„250„+5GtoT„U„12„pegRNA„PuroR„TagBFP gctaagcggtcgacggatcgggagatctcccgatcccctatggtgcactctcagtacaatctgctctgatgccgcatagttaagccagt atctgctccctgcttgtgtgtggaggtcgctgagtagtgcgcgagcaaaatttaagctacaacaaggcaaggcttgaccgacaatgc atgaagaatctgcttagggttaggcgtttgcgctgcttcgcgatgtacgggccagatatacgcgttgacattgattattgactagttattaa tagtaatcaatacggggtcatagtcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgc ccaacgacccccgcccatgacgtcaataatgacgtatgttcccatagtaacgccaatagggacttccattgacgtcaatgggtggagt attacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccg cctggcattatgcccagtacatgaccttatgggacttcctactggcagtacatctacgtattagtcatcgctattaccatggtgatgcggt ttggcagtacatcaatgggcgtggatagcggttgactcacggggatttccaagtctccaccccatgacgtcaatgggagtttgttg geaecaaaatcaacgggacttccaaaatgtcgtaacaactccgccccattgacgeaaatgggcggtaggcgtgtacggtgggaggt ctatataagcagcgcgttttgcctgtactgggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccact gctaagcctcaataaagcttgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccct tttagtcagtgtggaaaatctctagcagtggcgcccgaacagggacttgaaagcgaaagggaaaccagaggagctctctcgacgca ggactcggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattgactagcggaggcta gaaggagagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggttaaggccaggg ggaaagaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcc tgttagaaacatc agaaggctgtagacaaataetgggacagctacaaceatccctcagacaggatcagaagaacttagateattatataatacagtagcaa ccctctatgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaaga ccaccgcacagcaagcggccggccgcgctgatcttcagacctggaggaggagatatgagggacaatggagaagtgaatatataa atataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgg gaataggagcttgtccttgggtcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagac aattattgtctggtatagtgcagcagcagaacaattgctgagggctattgaggcgcaacagcatctgtgcaactcacagtctggggca tcaagcagctccaggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggttgctctggaaaact cattgcaccactgctgtgcctggaatgctagtggagtaataaatctctggaacagattggaatcacacgacctggatggagtggga cagagaaataacaatacacaagcttaatacactcctaatgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattatgg aattagataaatgggcaagtttgtggaatggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggctgg taggttaagaatagttttgetgtactttctatagtgaatagagtaggcagggatattcaccattatcgttcagacccacctoccaaccec gaggggaecegaeaggcecgaaggaatagaagaagaaggtggagagagagacagagaeagatecattogattagtgaacggatc Docket No. 11676 -005 WO 1 ggcactgcgtgcgccaatctgcagacaaatggcagtatcatccacaatttaaaagaaaaggggggatggggggtacagtgcag gggaaagaatagtagacataatagcaacagacatacaaactaaagaattacaaaaacaaattacaaaaattcaaaattttcgggtttatta cagggacagcagagatccagtttggttagtacx’gggcccgctctagagatccgacgcgccatctctaggcccgcgccggccccctc gcacggactgtgggagaagctcggctactcccctgccccggttaattgcatataatattcctagtaactatagaggctaatgtgcgat aaaagacagataatctgttctttttaatactagctacattttacatgataggcttggatttctataacttcgtatagcatacattatacgaagtta taaacagcacaaaaggaaactcaccctaactgtaaagtaatgtgtgtttgagactataaGtatccctggagaaCCAcctTGTT

[0243] GGGAGCTC AC 1 CTG1 TGC1 TGGT TTAAGAGC1 ATGC1 GGAAACAGCAT AGCAAG1

[0244] TTAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCCCT

[0245] TCGCATCAAGCAACAGAGTGCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAG AATTTTTTTCtcgagtactaggatccattaggcggccgcgtggataaccgtattaccgccatgcatGTGCCCGTCAG TGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGC AATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTC GTG I A CTGGC I CCGCC I T1 " ITCCCG AGGG’ FGGGGG AG A ACCGT A’ F A I A AGTGC AG TAGTCGCCG FGAACGTTCl Fl TTCGC AACGGG T1 TGCCGCCAGAACACAGG1 A AG TGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTG CCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGT TGGAAG1 GGGTGGGAGAG ITCGAGGCCTTGCGC1 TAAGGAGCCCC1 TCGCCTCG1 GCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGG CACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTG ATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAA GATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTG CGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAA TCGGACGGGGG I AGTC TCAAGCTGGCCGGCCTGC TCTGGTGCCTGGCCTCGCGCC GCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGC GTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAG GACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGG CCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTC CAGGCACCTCGATTAGTTCTCGcGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGG AGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAG GCCAGCTrGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGAT CTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAG

[0246] GTGTCGTGAgCTAGCCCACCATGACCGAGTACAAGCCCACGGTGCGCCTCGCCAC CCGCGACGACGTCCCCCGGGCCGTACGCACCCTCGCCGCCGCGTTCGCCGACTAC CCCGCCACGCGCCACACCGTCGACCCGGACCGCCACATCGAGCGGGTCACCGAG Docket No. 11676 -005 WO 1

[0247] CTGCAAGAACTCTTCCTCACGCGCGTCGGGCTCGACATCGGCAAGGTGTGGGTCG CGGACGACGGCGCCGCGGTGGCGGTCTGGACCACGCCGGAGAGCGTCGAAGCG GGGGCGGTG I TCGCCGAGA ICGGCCCGCGC A IGGCCGAGT TGAGCGG TTCCCGG CTGGCCGCGCAGCAACAGATGGAAGGCCTCCTGGCGCCGCACCGGCCCAAGGAG CCCGCGTGGTTCCTGGCCACCGTCGGCGTCTCGCCCGACCACCAGGGCAAGGGTC TGGGC AGCGCCG ICGTGCTCCCCGGAG I GGAGGCGGCCGAGCGCGCCGGGG TGC CCGCCTTCCTGGAGACCTCCGCGCCCCGCAACCTCCCCTTCTACGAGCGGCTCGG CTTCACCGTCACCGCCGACGTCGAGGTGCCCGAAGGACCGCGCACCTGGTGCAT GACCCGCAAGCCCGGTGCCGGATCGGGAGAGGGCAGAGGAAGTCTGCTAACATG CGG1 GACGTCGAGGAGAATCC 1 GGCCCAccggtcgccaccAGCGAGC 1 GATT AAGGAG AACATGCACATGAAGCTGTACATGGAGGGCACCGTGGACAACCATCACTTCAAG

[0248] TGCACATCCGAGGGCGAAGGCAAGCCCTACGAGGGCACCCAGACCATGAGAATC AAGGTGGTCGAGGGCGGCCCTCTCCCCTTCGCCTTCGACATCCTGGCTACTAGCT TCCTCTACGGCAGCAAGACCTTCATCAACCACACCCAGGGCATCCCCGACTTCTT

[0249] CAAGCAGTCCTTCCCTGAGGGCTTCACATGGGAGAGAGTCACCACATACGAAGA CGGGGGCGTGCTGACCGCTACCCAGGACACCAGCCTCCAGGACGGCTGCCTCAT CTACAACGTCAAGATCAGAGGGGTGAACTTCACATCCAACGGCCCTGTGATGCA GAAGAAAACACTCGGCTGGGAGGCCTTCACCGAGACGCTGTACCCCGCTGACGG CGGCCTGGAAGGCAGAAACGACATGGCCCTGAAGCTCGTGGGCGGGAGCCATCT GATCGCAAACATCAAGACCACATATAGATCCAAGAAACCCGCTAAGAACCTCAA GATGCCTGGCGTCTACTATGTGGACTACAGACTGGAAAGAATCAAGGAGGCCAA CAACGAGACCTACGTCGAGCAGCACGAGGTGGCAGTGGCCAGATACTGCGACCT CCCTAGCAAACTGGGGCACAAGCTTAATtaagaattcgtcgagggacctaataactcgtatagcatacatta tacgaagttatacatgttaagggttccggttccactaggtacaattcgatatcaagcttatcgataatcaacctctggattacaaaattgtg aaagattgactggtattctaactatgttgctcctttacgctatgtggatacgctgctttaatgcctttgtatcatgctatgcttcccgtatgg ctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggagttgtggcccgttgtcaggcaacgtggcgtggtgtgcactgt gttgctgacgcaacccccactggttggggcattgccaccacctgtcagctccttccgggactttcgcttccccctccctattgccacg gcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactgacaatccgtggtgtgtcggggaaat catcgtcctttccttggctgctcgcctgtgttgccacctggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcg gacettccttecegcggcctgctgccggetetgcggcctettccgcgtctcgccttcgccctcagaegagtcggatctccctttgggcc gcctccccgcatcgataccgtcgacctcgatcgagacctagaaaaacatggagcaatcacaagtagcaatacagcagctaccaatgc tgattgtgcctggctagaagcacaagaggaggaggaggtgggttccagtcacacctcaggtacctttaagaccaatgacttacaag gcagctgtagatcttagceactttttaaaagaaaaggggggactggaagggctaatcactcecaacgaagaeaagatatocttgatct gtggatctaccacacacaaggctactccctgattggcagaactacacaccagggccagggatcagatatccactgacctttggatggt Docket No. 11676 -005 WO 1 gctacaagctagtaccagtgagcaagagaaggtagaagaagccaatgaaggagagaacacccgctgtacaccctgtgagcctg catgggatggatgacccggagagagaagtattagagtggaggtttgacagccgcctagcatttcatcacatggcccgagagctgcat ccggactgtactgggtctctetggttagaecagatctgagcctgggagctetctggctaactagggaacccactgcttaagcctcaataa agctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttagtcagtgtggaa aatctctagcagcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgtgctggcgtttttccataggctccg ccccx’ctgacgagcatcacaaaaatcgaegctcaagtcagaggtggcgaaaeccgaeaggactataaagataccaggcgtttcx’cc ctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgccttctcccttcgggaagcgtggcgcttc tcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgtcagcccgacc gctgcgccttatccggtaactatcgtcttgagtecaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggatt agcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggtatctg cgctctgctgaagccagtaccttcggaaaaagagtggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgt tgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtggaacgaaaa ctcacgttaagggattttggtcatgagattateaaaaaggatettcacctagatcctttaaattaaaaatgaagttttaaatcaatetaaagt atatatgagtaaactggtctgacagtaccaatgctaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcct gactccccgtcgtgtagataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctcac cggctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaacttatccgcctccatccagtc tattaatgtgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgttgttgccattgctacaggcatcgtggtgtcac gctcgtcgttggtatggctcattcagctccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggtag ctccttcggtcctccgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataattctettactgtcat gccatccgtaagatgcttctgtgactggtgagtactcaaccaagtcatctgagaatagtgtatgcggcgaccgagtgctctgcccg gcgtcaatacgggataataccgcgccacatagcagaacttaaaagtgctcatcattggaaaacgttctcggggcgaaaactctcaag gatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtttctgggtg agcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaatgtgaatactcatactcttccttttcaatat attgaagcatttatcagggttatgtctcatgagcggatacatattgaatgtattagaaaaataaacaaataggggttccgcgcacattc cccgaaaagtgccacctgac

[0250] 24. SEQ ID NO: 24 pYJ290...GYJ096...GPLD1..480...+5GtoT..11...10...pegRNA. PuroR.TagBFP gcttaagcggtcgacggatcgggagatctcccgatcccctatggtgcactctcagtacaatctgctctgatgccgcatagttaagccagt atctgctccctgctgtgtgtggaggtcgctgagtagtgcgcgagcaaaattaagctacaacaaggcaaggcttgaccgacaatgc atgaagaatctgcttagggttaggcgtttgcgctgcttcgcgatgtacgggccagatatacgcgttgacattgattatgactagtattaa tagtaatcaatacggggtcatagtcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgc ccaacgacccccgcccatgacgtcaataatgacgtatgttcccatagtaacgccaatagggacttccattgacgtcaatgggtggagt atttacggtaaactgcccactggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccg Docket No. 11676 -005 WO 1 cctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatetacgtattagtcatcgctattaccatggtgatgcggt tttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttg geaecaaaatcaacgggacttccaaaatgtcgtaacaactccgccccattgacgeaaatgggcggtaggcgtgtacggtgggaggt ctatataagcagcgcgttgcctgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccact gctaagcctcaataaagcttgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagaccct ttagtcagtgtggaaaatctctagcagtggcgecegaacagggacttgaaagcgaaagggaaaccagaggagetctctcgacgca ggactcggctgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaatttgactagcggaggcta gaaggagagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggttaaggccaggg ggaaagaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagttaatcctggcc tgttagaaacatc agaaggctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaacttagatcatatataatacagtagcaa ccctctatgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaaga ccaccgcacagcaagcggccggccgcgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaattatataa atataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgg gaataggagcttgtccttgggtcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagac aattattgtctggtatagtgcagcagcagaacaattgctgagggctattgaggcgcaacagcatctgtgcaactcacagtctggggca tcaagcagctecaggcaagaatcctggctgtggaaagatacctaaaggatcaacagctectggggatttggggttgctctggaaaact catttgcaccactgctgtgcctggaatgctagtggagtaataaatctctggaacagatttggaatcacacgacctggatggagtggga cagagaaataacaatacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattgg aattagataaatgggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttgg taggttaagaatagttttgctgtacttctatagtgaatagagtaggcagggatattcaccattatcgttcagacccacctcccaacccc gaggggacccgacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgatagtgaacggatc ggcactgcgtgcgccaattctgcagacaaatggcagtattcatccacaattttaaaagaaaaggggggattggggggtacagtgcag gggaaagaatagtagacataatagcaaeagacatacaaactaaagaattacaaaaacaaattacaaaaattcaaaattttogggtttata cagggacagcagagatccagtttggttagtaccgggcccgctctagagatccgacgcgccatctctaggcccgcgccggccccctc gcacggactgtgggagaagctcggctactcccctgccccggttaattgcatataatattcctagtaactatagaggcttaatgtgcgat aaaagacagataatctgttctttttaatactagctacattttacatgataggcttggatttctataacttcgtatagcatacattatacgaagtta taaacagcacaaaaggaaactcaccctaactgtaaagtaatgtgtgttgagactataaGtatcccttggagaaCCAcctTGTT

[0251] GGGCCATAGAGGTTCACCGTGGTTTAAGAGCTATGCTGGAAACAGCATAGCAAG TTTAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCA AGGCATCACGGTGAACCTCTCGCGGTTCTATCTAGTTACGCGTTAAACCAACTAG AATTTTTTTCtcgagtactaggatccattaggcggccgcgtggataaccgtattaccgccatgcatGTGCCCGTCAG TGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGC A AT TGAACCGGTGCC TA GAGA AGGTGGCGCGGGGT A A AC TGGG AAAGTG ATGTC GTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAG Docket No. 11676 -005 WO 1

[0252] TAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAG

[0253] TGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTG

[0254] CCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGT

[0255] TGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGT

[0256] GCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGG

[0257] CACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTITTG

[0258] ATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAA

[0259] GATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTG

[0260] CGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAA

[0261] TCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCC

[0262] GCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGC

[0263] GTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAG

[0264] GACGCGGCGC TCGGGAGAGCGGGCGGG1 GAGTCACCCACACAAAGGAAAAGGG

[0265] CCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTC

[0266] CAGGCACCTCGATTAGTTCTCGcGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGG

[0267] AGGGGT TTTATGCGATGGAGTTTCCCC ACACTGAGTGGGTGGAGACTGAAGTTAG

[0268] GCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGAT

[0269] CTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAG

[0270] GTGTCGTGAgCTAGCCCACCATGACCGAGTACAAGCCCACGGTGCGCCTCGCCAC

[0271] CCGCGACGACGTCCCCCGGGCCGTACGCACCCTCGCCGCCGCGTTCGCCGACTAC

[0272] CCCGCCACGCGCCACACCGTCGACCCGGACCGCCACATCGAGCGGGTCACCGAG

[0273] CTGCAAGAACTCTTCCTCACGCGCGTCGGGCTCGACATCGGCAAGGTGTGGGTCG

[0274] CGGACGACGGCGCCGCGGTGGCGGTCTGGACCACGCCGGAGAGCGTCGAAGCG

[0275] GGGGCGGTGTTCGCCGAGATCGGCCCGCGCATGGCCGAGTTGAGCGGTTCCCGG

[0276] CTGGCCGCGCAGCAACAGATGGAAGGCCTCCTGGCGCCGCACCGGCCCAAGGAG

[0277] CCCGCGTGGTTCCTGGCCACCGTCGGCGTCTCGCCCGACCACCAGGGCAAGGGTC

[0278] TGGGCAGCGCCGTCGTGCTCCCCGGAGTGGAGGCGGCCGAGCGCGCCGGGGTGC

[0279] CCGCCTTCCTGGAGACCTCCGCGCCCCGCAACCTCCCCTTCTACGAGCGGCTCGG

[0280] CTTCACCGTCACCGCCGACGTCGAGGTGCCCGAAGGACCGCGCACCTGGTGCAT

[0281] GACCCGCAAGCCCGGTGCCGGATC-GGGAGAGGGCAGAGGAAGTCTGC TAACATG

[0282] CGGTGACGTCGAGGAGAATCC 1 GGCCCAccggtcgccaccAGCGAGC 1 GATT AAGGAG

[0283] AACATGCACATGAAGCTGTACATGGAGGGCACCGTGGACAACCATCACTTCAAG

[0284] TGCACATCCGAGGGCGAAGGCAAGCCCTACGAGGGCACCCAGACC ATGAGAATC

[0285] AAGGTGGTCGAGGGCGGCCCTCTCCCCTTCGCCTTCGACATCCTGGCTACTAGCT Docket No. 11676 -005 WO 1

[0286] TCCTCTACGGCAGCAAGACCTTCATCAACCACACCCAGGGCATCCCCGACTTCTT CAAGCAGTCCTTCCCTGAGGGCTTCACATGGGAGAGAGTCACCACATACGAAGA CGGGGGCGTGCTGACCGCTACCCAGGACACCAGCCTCCAGGACGGCTGCCTCAT CTACAACGTCAAGATCAGAGGGGTGAACTTCACATCCAACGGCCCTGTGATGCA GAAGAAAACACTCGGCTGGGAGGCCTTCACCGAGACGCTGTACCCCGCTGACGG CGGCC TGGA AGGC AGAAACGACATGGCCC TGAAGCTCGTGGGCGGGAGCC A I CT GATCGCAAACATCAAGACCACATATAGATCCAAGAAACCCGCTAAGAACCTCAA GATGCCTGGCGTCTACTATGTGGACTACAGACTGGAAAGAATCAAGGAGGCCAA CAACGAGACCTACGTCGAGCAGCACGAGGTGGCAGTGGCCAGATACTGCGACCT CCCTAGCAAACTGGGGCACAAGCTTAATtaagaattcgtcgagggacctaataactcgtatagcatacata tacgaagttatacatgttaagggtccggtccactaggtacaattcgatatcaagcttatcgataatcaacctctggattacaaaattgtg aaagattgactggtattctaactatgttgctcctttacgctatgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatgg cttcatttctoctcctgtataaatcctggtgctgtctcttatgaggagtgtggcccgtgtcaggcaacgtggcgtggtgtgcactgt gttgctgacgcaacccccactggttggggcattgccaccacctgtcagctccttccgggactttcgcttccccctccctattgccacg gcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactgacaatccgtggtgtgtcggggaaat catcgtcctttccttggctgctcgcctgtgttgccacctggatctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcg gaccttccttcccgcggcctgctgccggctctgcggcctctccgcgtcttcgcctcgccctcagacgagtcggatctcccttgggcc gcctccccgcatcgataccgtcgacctcgatcgagacctagaaaaacatggagcaatcacaagtagcaatacagcagctaccaatgc tgattgtgcctggctagaagcacaagaggaggaggaggtgggttttecagtcacacctcaggtacctttaagaccaatgacttacaag gcagctgtagatcttagceacttttaaaagaaaaggggggactggaagggctaatcactcecaacgaagaeaagatatocttgatct gtggatctaccacacacaaggctactccctgatggcagaactacacaccagggccagggatcagatatccactgacctttggatggt gctacaagctagtaccagttgagcaagagaaggtagaagaagccaatgaaggagagaacacccgc ttgttacaccctgtgagcctg catgggatggatgacccggagagagaagtatagagtggaggttgacagccgcctagcattcatcacatggcccgagagctgcat ccggactgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataa agctgcctgagtgcttcaagtagtgtgtgcccgtctgtgtgtgactctggtaactagagatccctcagacccttagtcagtgtggaa aatctctagcagcatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccg cccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgttcccc ctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgccttctcccttcgggaagcgtggcgcttc tcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgacc getgegccttatocggtaactatcgtcttgagtccaaeccggtaagacacgacttatcgccactggeageagecactggtaaeaggatt agcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagaacagtatttggtatctg cgctctgctgaagccagtaccttcggaaaaagagtggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgt tgcaagcagcagatacgegcagaaaaaaaggatcteaagaagatccttgatctttctacggggtctgacgctcagtggaacgaaaa ctcacgttaagggattggtcatgagattatcaaaaaggatctcacctagatcctttaaataaaaatgaagttttaaatcaatctaaagt Docket No. 11676 -005 WO 1 atatatgagtaaactggtctgacagtaccaatgctaatcagtgaggcacctatctcagcgatctgtctatttcgtcatccatagttgcct gactccccgtcgtgtagataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctcac cggctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaacttatccgcctccatccagtc tattaatgtgccgggaagctagagtaagtagtcgccagttaatagttgcgcaacgttgttgccattgctacaggcatcgtggtgtcac gctcgtcgttggtatggctcattcagctccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggtag ctccttcggtcctccgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataattctcttactgtcat gccatccgtaagatgctttctgtgactggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccgagttgctcttgcccg gcgtcaatacgggataataccgcgccacatagcagaacttaaaagtgctcatcattggaaaacgttctcggggcgaaaactctcaag gatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtttctgggtg agcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaatgttgaatactcatactcttccttttcaatatt attgaagcattatcagggttatgtctcatgagcggatacatatttgaatgtattagaaaaataaacaaataggggttccgcgcacattc cccg aaaagtgcc acctgac

[0287] 25. SEQ ID NO: 25 - pYJ291_GYJ097_CREBZF„+5-

[0288] 9„deletion„reverse„pegRNA„PuroR„TagBFP gctaagcggtcgacggatcgggagatctcccgatcccctatggtgcactctcagtacaatctgctctgatgccgcatagttaagccagt atctgctccctgctgtgtgtggaggtcgctgagtagtgcgcgagcaaaatttaagctacaacaaggcaaggcttgaccgacaatgc atgaagaatctgcttagggttaggcgtttgcgctgcttcgcgatgtacgggccagatatacgcgttgacatgattatgactagtataa tagtaatcaatacggggtcattagtcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgc ccaacgacccccgcccatgacgtcaataatgacgtatgttcccatagtaacgccaatagggacttccattgacgtcaatgggtggagt atttacggtaaactgcccactggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccg cctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggt ttggcagtacatcaatgggegtggatagcggttgactcacggggattccaagtetccaccceattgacgtcaatgggagtttgtttg gcaccaaaatcaacgggacttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggt ctatataagcagcgcgttgcctgtactgggtctctctggtagaccagatctgagcctgggagctctctggctaactagggaacccact gcttaagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccct tttagtcagtgtggaaaatctctagcagtggcgcccgaacagggacttgaaagcgaaagggaaaccagaggagctctctcgacgca ggactcggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggcta gaaggagagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggttaaggccaggg ggaaagaaaaaatataaattaaaacatatagtatgggcaageagggagctagaacgatcgcagttaatcctggcctgttagaaaeatc agaaggctgtagacaaatactgggacagctacaaccatcccttcagacaggatcagaagaacttagatcatatataatacagtagcaa ccctctatgtgtgcatcaaaggatagagataaaagacaccaaggaagcttagacaagatagaggaagagcaaaacaaaagtaaga ccaccgcacagcaagcggccggccgcgctgatctcagacctggaggaggagatatgagggacaatggagaagtgaatatataa atataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgg Docket No. 11676 -005 WO 1 gaataggagcttgtccttgggtcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagac aattattgtctggtatagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctggggca tcaagcagctcx’aggcaagaatcctggetgtggaaagatacctaaaggatcaacagctcx’tggggatttggggttgctctggaaaact catttgcaccactgctgtgcctggaatgctagtggagtaataaatctctggaacagatttggaatcacacgacctggatggagtggga cagagaaataacaattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattatgg aattagataaatgggcaagttgtggaatggtttaacataacaaattggctgtggtatataaaattattcataatgatagtaggaggcttgg taggttaagaatagtttgctgtactttctatagtgaatagagtaggcagggatattcaccattatcgtttcagacccacctcccaacccc gaggggacccgacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgatagtgaacggatc ggcactgcgtgcgccaattctgcagacaaatggcagtatcatccacaatttaaaagaaaaggggggattggggggtacagtgcag gggaaagaatagtagacataatagcaacagacatacaaactaaagaattacaaaaacaaatacaaaaattcaaaatttcgggtttata cagggacagcagagatccagttggttagtaccgggcccgctctagagatccgacgcgccatctctaggcccgcgccggccccctc gcacggactgtgggagaagctcggctactcccctgccccggttaatttgcatataatattcctagtaactatagaggcttaatgtgcgat aaaagacagataatctgttettttaatactagcXacattttacatgataggctggatttctataacttcgtatageatacatataegaagtta taaacagcacaaaaggaaactcaccctaactgtaaagtaatgtgtgttgagactataaGtatcccttggagaaCCAcctTGTT GGTCCGAGCCTCCGCCAGACGGTTTAAGAGCTATGCTGGAAACAGCATAGCAAG TTTAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTC

[0289] GCCGGGGCCATGCGTCTGGCGGAGGCTCT T1 T1 'FTCtcgagtactaggatccattaggcggccgcgt ggataaccgtataccgccatgcatGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCC CCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGG CGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGG GTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAA CGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGG CCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGT ACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGC CTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCG CTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTC GATAAGTCTCTAGCCATTTAAAATTTTTGATGACCT€JCTGCGACGCTTTTTTTCT€J GCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTT GGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGG CGGGGCC1GCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTC AAGCTGGC CGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGG

[0290] CAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCG GCCC TGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGC ICGGGAGAGCGGGCG GGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCAT Docket No. 11676 -005 WO 1

[0291] GTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGcGCTT

[0292] TTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCC

[0293] CACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCT

[0294] CCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACA

[0295] GTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGAgCTAGCCCACCATGACC

[0296] GAGTACAAGCCCACGGTGCGCCTCGCCACCCGCGACGACGTCCCCCGGGCCGTA

[0297] CGCACCCTCGCCGCCGCGTTCGCCGACTACCCCGCCACGCGCCACACCGTCGACC

[0298] CGGACCGCCACATCGAGCGGGTCACCGAGCTGCAAGAACTCTTCCTCACGCGCG

[0299] TCGGGCTCGACATCGGCAAGGTGTGGGTCGCGGACGACGGCGCCGCGGTGGCGG

[0300] TCTGGACCACGCCGGAGAGCGTCGAAGCGGGGGCGGTGTTCGCCGAGATCGGCC

[0301] CGCGCATGGCCGAGTTGAGCGGTTCCCGGCTGGCCGCGCAGCAACAGATGGAAG

[0302] GCCTCCTGGCGCCGCACCGGCCCAAGGAGCCCGCGTGGTTCCTGGCCACCGTCG

[0303] GCGTCTCGCCCGACCACCAGGGCAAGGGTCTGGGC AGCGCCGTCGTGCTCCCCG

[0304] GAGTGGAGGCGGCCGAGCGCGCCGGGGTGCCCGCCTTCCTGGAGACCTCCGCGC

[0305] CCCGCAACCTCCCCTTCTACGAGCGGCTCGGCTTCACCGTCACCGCCGACGTCGA

[0306] GGTGCCCGAAGGACCGCGCACCTGGTGCATGACCCGCAAGCCCGGTGCCGGATC

[0307] GGGAGAGGGCAGAGGAAGTCTGCTAACATGCGGTGACGTCGAGGAGAATCCTG

[0308] GCCCAccggtcgccaccAGCGAGCTGATTAAGGAGAACATGCACATGAAGCTGTACAT

[0309] GGAGGGCACCGTGGACAACCATCACTTCAAGTGCACATCCGAGGGCGAAGGCAA

[0310] GCCC I ACGAGGGCACCCAGACCATGAGAATCAAGGTGG TCGAGGGCGGCCCTCT

[0311] CCCCTTCGCCTTCGACATCCTGGCTACTAGCTTCCTCTACGGCAGCAAGACCTTC

[0312] ATCAACCACACCCAGGGCATCCCCGACTTCTTCAAGCAGTCCTTCCCTGAGGGCT TCACA TGGG AGAGAGTC ACC AC A I ACGAAGACGGGGGCG TGCTGACCGC I ACCC AGGACACCAGCCTCCAGGACGGC TGCCTCA 1 C fACAACGTCAAGATCAGAGGGG TGAACTTCACATCCAACGGCCCTGTGATGCAGAAGAAAACACTCGGCTGGGAGG CCTTCACCGAGACGCTGTACCCCGCTGACGGCGGCCTGGAAGGCAGAAACGACA TGGCCCTGAAGCTCG1 GGGCGGGAGCCATC TGATCGCAAACATCAAGACCACAT

[0313] ATAGATCCAAGAAACCCGCTAAGAACCTCAAGATGCCTGGCGTCTACTATGTGG

[0314] ACTACAGACTGGAAAGAATCAAGGAGGCCAACAACGAGACCTACGTCGAGCAG

[0315] CACGAGGIGGCAG1 GGCCAGATAC IGCGACC TCCC TAGCAAAC IGGGGCACAAG

[0316] CTTAATtaagaatcgtcgagggacctaataacttcgtatagcatacatatacgaagttatacatgttaagggttccggttccacta ggtacaattcgatatcaagctatcgataatcaacctctggattacaaaattgtgaaagatgactggtattcttaactatgttgctccttta cgctatgtggatacgctgcttaatgcx’tttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtct ctttatgaggagttgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcatgcc Docket No. 11676 -005 WO 1 accacctgtcagctcctttccgggacttcgcttccccctccctatgccacggcggaactcatcgccgcctgccttgcccgctgctgg acaggggctcggctgttgggcactgacaattccgtggtgttgtcggggaaatcatcgtcctttccttggctgctcgcctgtgttgccacct ggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcggaccttcctcccgcggcctgctgccggctctgcgg cctctccgcgtctcgccttcgccctcagacgagtcggatctccctttgggccgcctccccgcatcgataccgtcgacctcgatcgaga cctagaaaaacatggagcaatcacaagtagcaatacagcagctaccaatgctgattgtgcctggctagaagcacaagaggaggagg aggtgggtttccagtcacacctcaggtaccttaagaccaatgacttacaaggcagctgtagatcttagccacttttaaaagaaaaggg gggactggaagggctaatcactcccaacgaagacaagatatcctgatctgtggatctaccacacacaaggctacttccctgattggc agaactacacaccagggccagggatcagatatccactgaccttggatggtgctacaagctagtaccagtgagcaagagaaggtag aagaagccaatgaaggagagaacacccgcttgttacaccctgtgagcctgcatgggatggatgacccggagagagaagtattagag tggaggttgacagccgcctagcatttcatcacatggcccgagagctgcatccggactgtactgggtctctctggtagaccagatctga gcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgcctgagtgctcaagtagtgtgtgcccgtctgt tgtgtgactctggtaactagagatccctcagaccctttagtcagtgtggaaaatctctagcagcatgtgagxaaaaggccagcaaaag gccaggaaccgtaaaaaggccgcgttgctggcgttttccataggctccgccx’ccctgacgagcatcacaaaaatcgacgctcaagto agaggtggcgaaacccgacaggactataaagataccaggcgttccccctggaagctccctcgtgcgctctcctgtccgaccctgcc gctaccggatacctgtccgccttctcccttcgggaagcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcg tcgctccaagctgggctgtgtgcacgaaccccccgtcagcccgaccgctgcgccttatccggtaactatcgtctgagtccaacccg gtaagacacgactatcgccactggcagcagccactggtaacaggatagcagagcgaggtatgtaggcggtgctacagagttcttga agtggtggcctaactacggctacactagaagaacagtattggtatctgcgctctgctgaagccagtacctcggaaaaagagttggta gctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaa gaagatccttgatcttctacggggtctgacgctcagtggaacgaaaactcacgtaagggatttggtcatgagatatcaaaaagga tcttcacctagatccttttaaattaaaaatgaagtttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgctaatca gtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgtagataactacgatacgggagggctta ccatctggccccagtgctgcaatgataccgcgagacccacgctoaccggctocagattatcagcaataaaccagccagccggaagg gccgagcgcagaagtggtcctgcaacttatccgcctccatccagtctataattgttgccgggaagctagagtaagtagttcgccagt aatagtttgcgcaacgttgttgccatgctacaggcatcgtggtgtcacgctcgtcgttggtatggctcatcagctccggtcccaacg atcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttvggtcctccgatcgttgtcagaagtaagttggccgc agtgttatcactcatggttatggcagcactgcataattctcttactgtcatgccatccgtaagatgcttttctgtgactggtgagtactcaacc aagtcattctgagaatagtgtatgcggcgaccgagtgctctgcccggcgtcaatacgggataataccgcgccacatagcagaactt aaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctgttgagatccagttcgatgtaacccactcgt geaeccaactgatcttcagcateXtttactttcaccagcgttctgggtgageaaaaacaggaaggcaaaatgecgcaaaaaagggaat aagggcgacacggaaatgttgaatactcatactottccttttcaatattartgaagcarttatcagggttattgtctcatgagcggatacata tttgaatgtattagaaaaataaacaaataggggtccgcgcacattccccgaaaagtgccacctgac Docket No. 11676 -005 WO 1

[0317] 26. SEQ ID NO: 26 pYJ292.. GYJ098.. PLSCR2...+5-

[0318] 9„deletion„reverse_pegRNA_PuroR„TagBFP gcttaagcggtcgacggatcgggagatctcccgatcccctatggtgcactctcagtacaatctgctctgatgccgcatagttaagccagt atctgctccctgctgtgtgtggaggtcgctgagtagtgcgcgagcaaaatttaagctacaacaaggcaaggcttgaccgacaatgc atgaagaatctgcttagggttaggcgtttgcgctgcttcgcgatgtacgggccagatatacgcgttgacattgattattgactagttataa tagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgtacataacttacggtaaatggcccgectggctgaccgc ccaacgacccccgcccatgacgtcaataatgacgtatgtcccatagtaacgccaatagggacttccattgacgtcaatgggtggagt atttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccg cctggcattatgcccagtacatgaccttatgggacttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggt tttggcagtacatcaatgggcgtggatagcggttgactcacggggattccaagtctccaccccatgacgtcaatgggagttgttttg gcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccatgacgcaaatgggcggtaggcgtgtacggtgggaggt ctatataagcagcgcgttttgcctgtactgggtctctctggttagaccagatctgagcctgggagctctctggctaactagggaacccact gcttaagcctcaataaagcttgecttgagtgetteaagtagtgtgtgcccgtctgttgtgtgactetggtaactagagatcectcagaccct tttagtcagtgtggaaaatctctagcagtggcgcccgaacagggacttgaaagcgaaagggaaaccagaggagctctctcgacgca ggactcggcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagcggaggcta gaaggagagagatgggtgegagagcgtcagtattaagcgggggagaattagatcgcgatgggaaaaaattcggtaaggccaggg ggaaagaaaaaatataaattaaaacatatagtatgggcaagcagggagctagaacgattcgcagtaatcctggcctgttagaaacatc agaaggctgtagacaaatactgggacagctacaaccatccctcagacaggatcagaagaactagatcatatataatacagtagcaa ccctctattgtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaaaagtaaga ccacx:gcacagcaagcggccggccgcgctgatcttcagacctggaggaggagatatgagggacaattggagaagtgaatatataa atataaagtagtaaaaattgaaccataggagtagcacccaccaaggcaaagagaagagtggtgcagagagaaaaaagagcagtgg gaataggagctttgttccttgggttcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagac aatattgtctggtatagtgcagcagcagaacaatttgetgagggetattgaggegcaaeagcatctgtgcaactcacagtctggggca tcaagcagctccaggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctggggatttggggtgctctggaaaact catttgcaccactgctgtgcctggaatgctagtggagtaataaatctctggaacagatttggaatcacacgacctggatggagtggga cagagaaattaacaattacacaagcttaatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattgg aattagataaatgggcaagttgtggaatggtttaacataacaaattggctgtggtatataaaattatcataatgatagtaggaggctgg taggtttaagaatagtttgctgtacttctatagtgaatagagtaggcagggatattcaccattatcgtttcagacccacctcccaacccc gaggggacccgacaggcccgaaggaatagaagaagaaggtggagagagagacagagacagatccattcgattagtgaacggatc ggcactgcgtgcgccaattctgcagacaaatggcagtattcatccacaattttaaaagaaaaggggggatggggggtaeagtgcag gggaaagaatagtagacataatagcaacagacatacaaactaaagaattacaaaaacaaattacaaaaattcaaaatttcgggtttata cagggacagcagagatccagttggttagtaccgggcccgctctagagatccgacgcgccatctctaggcccgcgccggccccctc gcacggacttgtgggagaagctcggctactcccetgecccggttaattgcatataatatttcctagtaactatagaggcttaatgtgcgat aaaagacagataatctgtctttttaatactagctacattttacatgataggcttggatttctataacttcgtatagcatacattatacgaagtta Docket No. 11676 -005 WO 1 taaacagcacaaaaggaaactcaccctaactgtaaagtaatgtgtgttgagactataaGtatcccttggagaaCCAcctTGTT GGGGGAAACAGGCTGACCACCGTTTAAGAGCTATGCTGGAAACAGCATAGCAAG TTTAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTA GAAGGCCTGATGGGTGGTCAGCCTGTTTCCCATTTTTTTCTCGAGCtcgagtactaggatcc attaggcggccgcgtggataaccgtattaccgccatgcatGTGCCCGTCAGTGGGCAGAGCGCACATCGC CC AC AG TCCCCG AG A AGT TGGGGGG AGGGG ICGGC A AT TG A ACCGGTGCC I A G A

[0319] GAAGGTGGCGCGGGG1 AAACTGGGAAAG1 GATG rCGl GTAC1 GGCTCCGCC IT T TTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTC TTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCG

[0320] CGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCT

[0321] GGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGA GTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTG

[0322] GCC IGGGCGCTGGGGCCGCCGCG TGCGAA I C TGG I GGCACC TTCGCGCCTGTCTC GCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCT TTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATT TCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCG' rGCGTCCCAGCGCACATG' fl' CGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTC AAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCC

[0323] CTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCC GC ITCCCGGCCCTGC1 GCAGGGAGCTC AAAATGGAGGACGCGGCGCTCGGGAGA GCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGT CGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTC TCGcGCT TT TGG AG TACGTCG TOT T T AGG'fTGGGGGG AGGGGT IT TATGCGATGG AGITICCCCACAC1 GAGTGGGTGGAGACTGAAG ITAGGCCAGCTTGGCACTTGAT

[0324] GTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGC CTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGAgCTAGCCCA CCATGACCGAGTACAAGCCCACGGTGCGCCTCGCCACCCGCGACGACGTCCCCC

[0325] GGGCCGTACGCACCCTCGCCGCCGCGTTCGCCGACTACCCCGCCACGCGCCACAC

[0326] CGTCGACCCGGACCGCCACATCGAGCGGGTCACCGAGCTGCAAGAACTCTTCCT CACGCGCGTCGGGC ICGACATCGGC AAGGTG TGGGTCGCGGACGACGGCGCCGC

[0327] GGTGGCGGTCTGGACCACGCCGGAGAGCGTCGAAGCGGGGGCGGTGTTCGCCGA GATCGGCCCGCGCATGGCCGAGTTGAGCGGTTCCCGGCTGGCCGCGCAGCAACA

[0328] GATGGAAGGCCTCCTGGCGCCGCACCGGCCCAAGGAGCCCGCGTGGrTCCrGGC CACCGTCGGCGTCTCGCCCGACCACCAGGGCAAGGGTCTGGGCAGCGCCGTCGT Docket No. 11676 -005 WO 1

[0329] GCTCCCCGGAGTGGAGGCGGCCGAGCGCGCCGGGGTGCCCGCCTTCCTGGAGAC CTCCGCGCCCCGCAACCTCCCCTTCTACGAGCGGCTCGGCTTCACCGTCACCGCC

[0330] GACG ICGAGGTGCCCGAAGGACCGCGC ACC IGGTGC ATGACCCGCAAGCCCGG'f GCCGGATCGGGAGAGGGCAGAGGAAGTCTGCTAACATGCGGTGACGTCGAGGA GAATCCTGGCCCAccggtcgccaccAGCGAGCTGATTAAGGAGAACATGCACATGAAG C TGTACATGGAGGGCACCGTGGAC AACCATCAC TTC A AG FGCACATCCGAGGGC GAAGGCAAGCCCTACGAGGGCACCCAGACC A TGAGAA rCAAGGTGGTCGAGGG CGGCCCTCTCCCCTTCGCCTTCGACATCCTGGCTACTAGCTTCCTCTACGGCAGCA AGACCTTCATCAACCACACCCAGGGCATCCCCGACTTCTTCAAGCAGTCCTTCCC TGAGGGCTTCACATGGGAGAGAGTCACCACATACGAAGACGGGGGCGTGCTGAC CGCTACCCAGGACACCAGCCTCCAGGACGGCTGCCTCATCTACAACGTCAAGAT CAGAGGGGTGAACTTCACATCCAACGGCCCTGTGATGCAGAAGAAAACACTCGG C TGGGAGGCC ITCACCGAGACGCTG FACCCCGC TGACGGCGGCCTGGAAGGCAG AAACGACATGGCCCTGAAGCTCGTGGGCGGGAGCCATCTGATCGCAAACATCAA GACCACATATAGATCCAAGAAACCCGCTAAGAACCTCAAGATGCCTGGCGTCTA CTA TG1 GGACTAC AG AC TGGAAAGAATCAAGGAGGCCAACAACGAGACCTACGT CGAGCAGCACGAGGTGGCAGTGGCCAGATACTGCGACCTCCCTAGCAAACTGGG GCACAAGCTTAATtaagaattcgtcgagggacctaataacttcgtatagcatacattatacgaagttatacatgtttaagggtt ccggttccactaggtacaattcgatatcaagcttatcgataatcaacctctggattacaaaatttgtgaaagattgactggtattcttaactat gttgctocttttacgetatgtggataegctgctttaatgex’ttgtatcatgctattgcttcccgtatggctttcattttctcx’tccttgtataaatc ctggttgctgtctctttatgaggagttgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggt tggggcattgccaccacctgtcagctcctttccgggactttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttg cccgctgctggacaggggctcggctgttgggcactgaeaattccgtggtgttgtcggggaaatcatcgtccttccttggctgctcgcx’t gtgttgccacctggatctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcggaccttcctcccgcggcctgctgc cggctctgcggcctctccgcgtcttcgccttcgccctcagacgagtcggatctcccttgggccgcctccccgcatcgataccgtcga cctcgatcgagacctagaaaaacatggagcaatcacaagtagcaatacagcagctaccaatgctgattgtgcctggctagaagcaca agaggaggaggaggtgggtttccagtcacacctcaggtaccttaagaccaatgacttacaaggcagctgtagatcttagccactttt aaaagaaaaggggggactggaagggctaatcactcccaacgaagacaagatatccttgatctgtggatctaccacacacaaggcta cttccctgattggcagaactacacaccagggccagggatcagatatccactgacctttggatggtgctacaagctagtaccagttgagc aagagaaggtagaagaagecaatgaaggagagaacacxxgcttgtacaccctgtgagectgcatgggatggatgacccggagag agaagtattagagtggaggttgacagccgcctagcatttcatcacatggcccgagagctgcatccggactgtactgggtctctctggt agaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgcctgagtgctcaagtagt gtgtgcccgtctgttgtgtgactetggtaactagagatcectoagacccXtttagtcagtgtggaaaatctctagcageatgtgagcaaaa ggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgttttccataggctccgcccccctgacgagcatcacaaaaat Docket No. 11676 -005 WO 1 cgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgtttccccctggaagctccctcgtgcgctctcct gttccgaccctgccgcttaccggatacctgtccgcctttctccctcgggaagcgtggcgctttctcatagctcacgctgtaggtatctca gttcggtgtaggtogttcgctccaagctgggctgtgtgcacgaaccccccgttoagcccgaccgctgcgccttatccggtaactatcgt cttgagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggt gctacagagtcttgaagtggtggcctaactacggctacactagaagaacagtatttggtatctgcgctctgctgaagccagttacctcg gaaaaagagttggtagctcttgatccggcaaaeaaaccaccgctggtagcggtggttttttgtttgcaageageagattacgcgcaga aaaaaaggatctcaagaagatccttgatctttctacggggtctgacgctcagtggaacgaaaactcacgttaagggatttggtcatga gatatcaaaaaggatctcacctagatcctttaaataaaaatgaagtttaaatcaatctaaagtatatatgagtaaacttggtctgacagt taccaatgcttaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgtagataactacg atacgggagggctaccatctggccccagtgctgcaatgataccgcgagacccacgctcaccggctccagatttatcagcaataaacc agccagccggaagggccgagcgcagaagtggtcctgcaacttatccgcctccatccagtctataatgttgccgggaagctagagt aagtagttcgccagttaatagtttgcgcaacgttgttgccattgctacaggcatcgtggtgtcacgctcgtcgttggtatggcttcattcag ctccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggtcctccgatcgtgtcag aagtaagtggccgcagtgttatcactcatggtatggcagcactgcataattctctactgtcatgccatccgtaagatgctttctgtgact ggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccgagttgctcttgcccggcgtcaatacgggataataccgcgcc acatagcagaacttaaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctgttgagatccagttcg atgtaacccactcgtgcacccaactgatcttcagcatcttacttcaccagcgtttctgggtgagcaaaaacaggaaggcaaaatgcc gcaaaaaagggaataagggcgacacggaaatgtgaatactcatactcttccttttcaatatattgaagcattatcagggttatgtctc atgagcggatacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgac

[0331] 27. ...

Claims

Docket No. 11676-005 WO 1CLAIMSWhat is claimed is:

1. A high-throughput prime editing assay comprising a mismatch repair (MMR) sensorspecific reporter and a prime editor, wherein the MMR sensor-specific reporter comprises a prime editing guide RNA (pegRNA) and a reporter enzyme, wherein the reporter enzyme is encoded by a nucleic acid comprising a mutated start codon, and wherein the assay detects mismatch repair (MMR) activity of a component of MMR.

2. The high-throughput assay of claim 1 , wherein the component of MMR comprises aMSH3 / MutSP MMR sensor or a MSH6 / MutSa MMR sensor.

3. The high-throughput assay of claim 1 or claim 2, wherein the MMR sensor-specific reporter comprises SEQ ID NO: 53 and SEQ ID NO: 56, or a variant thereof.

4. The high-throughput assay of claim 1 or claim 2, wherein the MMR sensor-specific reporter comprises SEQ ID NO: 58 and SEQ ID NO: 56, or a variant thereof.

5. The high-throughput assay of any one of claims 1-4, wherein the pegRNA targets at least 1 base pair (bp) mutated within the mutated start codon of a nucleic acid encoding the reporter enzyme.

6. The high-throughput assay of any one of claims 1-4, wherein the pegRNA targets 1-10 bps mutated within the mutated start codon.

7. The high-throughput assay of any one of claims 1-4, wherein the pegRNA targets 3-5 bps mutated within the mutated start codon.

8. The high-throughput assay of any one of claims 1-4, wherein the pegRNA targets 5 bps mutated within the mutated start codon.

9. The high-throughput assay of any one of claims 1 -8, wherein the mutated start codon comprises an insertion, a substitution, or a deletion mutation.Docket No. 11676-005 WO 110. The high-throughput assay of any one of claims 1-9, wherein the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 53.

11. The high-throughput assay of any one of claims 1-9, wherein the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 58.

12. The high-throughput assay of any one of claims 1-11 , wherein the prime editor comprises a Cas9 nuclease.

13. The high-throughput assay of claim 12, wherein the Cas9 nuclease is fused to a reverse transcriptase.

14. The high-throughput assay of any one of claims 1-13, wherein the assay is a cell-based prime editing assay.

15. The high-throughput assay of any one of claims 1-14, wherein the assay detects MMR activity in live cells.

16. The high-throughput assay of any one of claims 1-15, wherein the assay discriminates between MSH3 / MutSp activity and MSH6 / MutSa activity.

17. A method of detecting mismatch repair (MMR) activity in a cell, the method comprising: introducing into the cell at least one expression vector comprising a nucleic acid encoding a mismatch repair (MMR) sensor- specific reporter and a prime editor, wherein the mismatch repair (MMR) sensor-specific reporter and the prime editor are expressed in the cell; and detecting an activity level of a component of MMR relative to a control cell.

18. A method of screening for a small molecule inhibitor of mismatch repair (MMR), the method comprising: a. introducing into a cell at least one expression vector comprising a nucleic acid encoding a mismatch repair (MMR) sensor-specific reporter and a prime editor; b. expressing the mismatch repair (MMR) sensor-specific reporter and the prime editor in the cell; c. introducing into the cell a small molecule; andDocket No. 11676 -005 WO 1 d. detecting MMR activity in the cell, wherein the small molecule inhibits a component of MMR in the cell relative to a control cell.

19. The method of claim 17 or 18, wherein the component of MMR comprises a MSH3 / MutSp MMR sensor or a MSH6 / MutSa MMR sensor.

20. The method of any one of claims 17-19, wherein the MMR sensor-specific reporter comprises SEQ ID NO: 53 and SEQ ID NO: 56, or any variants thereof.

21. The method of any one of claims 17-19, wherein the MMR sensor-specific reporter comprises SEQ ID NO: 58 and SEQ ID NO: 56, or any variants thereof.The method of any one of claims 1 / -21 , wherein the MMR sensor-specific reporter comprises a prime editing guide RNA (pegRNA) and a reporter enzyme, and wherein the reporter enzyme is encoded by a nucleic acid comprising a mutated start codon.

23. The method of claim 22, wherein the pegRNA targets at least 1 base pair (bp) mutated within the mutated start codon of the nucleic acid encoding the reporter enzyme.

24. The method of claim 22, wherein the pegRNA targets 1-10 bps mutated within the mutated start codon.

25. The method of claim 22, wherein the pegRNA targets 3-5 bps mutated within the mutated start codon.

26. The method of claim 22, wherein tire pegRNA targets 5 bps mutated within the mutated start codon.

27. The method of any one of claims 22-26, wherein the mutated start codon comprises an insertion, a substitution, or a deletion mutation.

28. The method of any one of claims 22-27, wherein the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 53.Docket No. 11676-005 WO 129. The method of any one of claims 22-27, wherein the pegRNA comprises at least 80% sequence identity to SEQ ID NO: 58.

30. The method of any one of claims 17-29, wherein the prime editor comprises a Cas9 nuclease.31 . The method of claim 30, wherein the Cas9 nuclease is fused to a reverse transcriptas‘32. The method of any one of claims 17-31, wherein the at least one expression vector comprises a plasmid, a lentivirus, an adenovirus, an adeno-associated virus (AAV), or a lipid nanoparticle (LNP).

33. The method of any one of claims 17-32, wherein the nucleic acid comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO:29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, or a variant thereof.

34. The method of any one of claims 17-33, wherein the method detects mismatch repair (MMR) activity of MSH3 / MutSp or MSH6 / MutSa.

35. The method of any one of claims 17-34, wherein the method detects MMR activity using a high-throughput prime editing assay.

36. The method of any one of claims 17-35 , wherein the method detects MMR acti vity in live cells.

37. The method of any one of claims 17-36, wherein the method discriminates betweenMSH3 / MutSP activity and MSH6 / MutSa activity.

Images