Prime editor for correcting EYS gene and use thereof

Abstract

One of the most important technical problems to be solved in the present specification is that of providing a prime editor capable of exhibiting an actual therapeutic effect by selecting a prime editor exhibiting an effect of correcting c.4957dupA mutation of an EYS gene of actual human retinal cells from among numerous theoretically designable prime editors and specifying a configuration thereof. In order to solve this technical problem, the present specification provides a prime editor and a component thereof, wherein the prime editor is screened through a high-throughput screening method, is verified in actual human retinal cells, and can actually correct the c.4957dupA mutation of the EYS gene. The prime editor disclosed in the present specification acts on human retinal cells including the c.4957dupA mutation in the EYS gene, thereby being able to correct the EYS gene to a normal state. Therefore, the prime editor can be used as a therapeutic agent for retinitis pigmentosa caused by the c.4957dupA mutation in the EYS gene.

Description

EYS Gene Editing Prime Editor and its Uses

[0001] The invention disclosed herein relates to a technique for treating genetic diseases using a prime editor.

[0002]

[0003] retinitis pigmentosa

[0004] retinitis pigmentosa

[0005] Retinitis pigmentosa (RPE) is a hereditary eye disease that can cause serious complications ranging from night blindness and visual field narrowing to blindness in both eyes. It is a relatively common eye condition, with a high prevalence worldwide, affecting approximately 1 in 3,000 people. However, there are currently few effective treatments for RPE.

[0006] c.4957dupA mutation in the EYS gene

[0007] Recent advancements in Next Generation Sequencing (NGS) technology have led to the discovery of over 50 different genetic mutations that can cause RPE. Among these, mutations in the Eyes Shut Homolog (EYS) gene are known to be a single mutation that can cause RPE. EYS mutations are particularly prevalent in Asian RPE patients.

[0008] Among single-gene mutations that cause RPE, there is the c.4957dupA mutation, which occurs when an adenine nucleotide is duplicated at position 4957 of the EYS gene. Research has shown that a significant number of Asian RPE patients, particularly those in Korea and Japan, are caused by the c.4957dupA mutation in the EYS gene.

[0009] Therefore, it is expected that there will be many patients who can be treated for retinitis pigmentosa by correcting the c.4957dupA mutation in the EYS gene.

[0010] Limitations of existing treatment strategies

[0011] For diseases caused by genetic mutations, strategies were mainly used to deliver the wild-type gene of the mutated gene into cells. The methods for delivering the wild-type gene include 1) a method using adeno-associated virus, 2) a method using lentivirus, and 3) a method of directly delivering mRNA to cells. However, 1) adeno-associated virus can only deliver genes of 4.8 kb or less, but the EYS gene exceeds 10 kb, so it must be divided into multiple viruses and delivered separately, which drastically reduces delivery efficiency, 2) although lentiviruses are free in the size of the gene that can be delivered, there is a risk of the cell randomly inserting it into the genome, and 3) mRNA is unstable, so the gene expression time is limited, so there are disadvantages in that the therapeutic agent must be continuously administered.

[0012] Using the recently spotlighted CRISPR / Cas gene scissors, 1) a treatment strategy that aims for a knockout or knockdown effect by repeatedly cutting the double-stranded DNA of the target gene to create indels in the target gene, and 2) a treatment strategy that uses donor DNA to insert the information of the donor DNA into the gene through the homologous recombination (HDR) mechanism and shows a corrective effect. However, 1) the gene knockout / knockdown strategy is not suitable for treating retinitis pigmentosa targeting mutations in the EYS gene, and 2) the method of correcting genes using donor DNA has limitations in that its efficiency is too low to see a significant therapeutic effect.

[0013]

[0014] Prime Editor

[0015] Prime editor refers to a protein-nucleic acid complex used in a gene editing technology called prime editing. The prime editor comprises a prime editor protein including a CRISPR / Cas protein with a mutated double-strand cleavage activity and a reverse transcriptase enzyme, and a prime editing guide RNA (pegRNA). Prime editing is a technology that corrects a gene as intended by 1) binding the prime editor protein to a target gene by the guide of the pegRNA, 2) reverse transcribing the correction sequence included at the 3' end of the pegRNA into cDNA, and 3) inserting the reverse transcribed cDNA in place of the mutated sequence of the target gene.

[0016]

[0017] In this specification, we disclose a prime editor capable of correcting the c.4957dupA mutation of the EYS gene.

[0018] Applying the above prime editor to correct only the c.4957dupA mutation in retinitis pigmentosa caused by the c.4957dupA mutation in the EYS gene is a very effective treatment strategy that overcomes the limitations of the existing treatment strategies mentioned above. Theoretically, thousands or tens of thousands of prime editors, especially pegRNAs, that can correct the c.4957dupA mutation in the EYS gene can be designed. However, not all of the thousands or tens of thousands of theoretically designed prime editors actually work to correct the c.4957dupA mutation in the EYS gene. To date, very little has been revealed about which components of the above prime editor affect the prime editing efficiency. Therefore, it is nearly impossible to predict whether the theoretically designed prime editor will actually work based only on its components.

[0019] Therefore, one of the most important technical challenges to be solved in this specification is to select a prime editor that exhibits an effect of correcting the c.4957dupA mutation of the EYS gene in actual human retinal cells from among numerous prime editors that can be theoretically designed, and to specify its composition, thereby providing a prime editor that can exhibit an actual therapeutic effect.

[0020]

[0021] To address the above technical challenges, the present disclosure provides a prime editor and its components that can correct the c.4957dupA mutation of the EYS gene by screening through a high-throughput screening method and validating it in actual human retinal cells.

[0022] In particular, we aim to provide a pegRNA that can correct the c.4957dupA mutation of the EYS gene by working together with a prime editing protein comprising a Nickase mutant of the Cas9 protein derived from Streptococcus pyogenes.

[0023]

[0024] The prime editor disclosed herein can act on human retinal cells containing the c.4957dupA mutation in the EYS gene, thereby correcting the EYS gene to a normal state. Therefore, the prime editor can be used as a therapeutic agent for retinitis pigmentosa caused by the c.4957dupA mutation in the EYS gene.

[0025]

[0026] Figure 1 is a schematic diagram showing the structure of pegRNA and extended pegRNA.

[0027] Figure 2 is a schematic diagram illustrating the relationship between the guide domain of pegRNA, the primer binding site (PBS), the reverse transcriptase template (RTT), and the target nucleic acid. Specifically, the prime editor recognizes the PAM of the non-target strand of the target nucleic acid, and the guide domain complementarily binds to the target sequence of the target strand of the target nucleic acid.

[0028] Figure 3 is a schematic diagram illustrating the relationship between the guide domain of pegRNA, the primer binding site (PBS), the reverse transcriptase template (RTT), and the target nucleic acid. Specifically, it shows the positional relationship of the PBS and RTT sequences after the target nucleic acid is nicked by the prime editor.

[0029]

[0030] Hereinafter, the best mode for carrying out the invention is exemplified. This includes some, but not all, implementations of the invention disclosed herein. The embodiments described in this paragraph are merely exemplary, and the implementations described in this paragraph should not be construed as the "best mode for carrying out the invention." Those skilled in the art will likely envision numerous variations and more desirable implementations of the examples described in this paragraph, and such variations should also be considered to be included within the best mode for carrying out the invention.

[0031] Disclosed herein is a pegRNA for a prime editor for correcting the c.4957dupA variant of the EYS gene, having the following structure:

[0032] 5' - [Guide Domain] - [Scaffold] - [Prime Editing Domain] - 3'

[0033] Here, the scaffold can interact with the prime editor to form a complex,

[0034] The above guide domain and the above prime editing domain are composed of a combination selected from the following:

[0035] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11534 to 11552 and SEQ ID NOs: 12104 to 12122, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3343 to 3482;

[0036] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11553 to 11571 and SEQ ID NOs: 12123 to 12141, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3483 to 3573;

[0037] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11572 to 11590 and SEQ ID NOs: 12142 to 12160, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3574 to 3710;

[0038] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11591 to 11609 and SEQ ID NOs: 12161 to 12179, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3711 to 3829;

[0039] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11610 to 11628 and SEQ ID NOs: 12180 to 12198, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3830 to 3888;

[0040] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11629 to 11647 and SEQ ID NOs: 12199 to 12217, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3889 to 4022;

[0041] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11648 to 11666 and SEQ ID NOs: 12218 to 12236, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4023 to 4169;

[0042] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11667 to 11685 and SEQ ID NOs: 12237 to 12255, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4170 to 4309;

[0043] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11686 to 11704 and SEQ ID NOs: 12256 to 12274, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4310 to 4450;

[0044] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11705 to 11723 and SEQ ID NOs: 12275 to 12293, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4451 to 4578;

[0045] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11724 to 11742 and SEQ ID NOs: 12294 to 12312, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4579 to 4608;

[0046] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11743 to 11761 and SEQ ID NOs: 12313 to 12331, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4609 to 4671;

[0047] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11762 to 11780 and SEQ ID NOs: 12332 to 12350, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4672 to 4736;

[0048] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11781 to 11799 and SEQ ID NOs: 12351 to 12369, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4737 to 4878;

[0049] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11800 to 11818 and SEQ ID NOs: 12370 to 12388, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4879 to 5024;

[0050] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11819 to 11837 and SEQ ID NOs: 12389 to 12407, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5025 to 5101;

[0051] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11838 to 11856 and SEQ ID NOs: 12408 to 12426, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5102 to 5214;

[0052] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11857 ​​to 11875 and SEQ ID NOs: 12427 to 12445, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5215 to 5311;

[0053] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11876 to 11894 and SEQ ID NOs: 12446 to 12464, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5312 to 5441;

[0054] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11895 to 11913 and SEQ ID NOs: 12465 to 12483, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5442 to 5550;

[0055] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11914 to 11932 and SEQ ID NOs: 12484 to 12502, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5551 to 5681;

[0056] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11933 to 11951 and SEQ ID NOs: 12503 to 12521, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5682 to 5804;

[0057] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11952 to 11970 and SEQ ID NOs: 12522 to 12540, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5805 to 5831;

[0058] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11971 to 11989 and SEQ ID NOs: 12541 to 12559, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5832 to 5923;

[0059] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11990 to 12008 and SEQ ID NOs: 12560 to 12578, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5924 to 5966;

[0060] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 12009 to 12027 and SEQ ID NOs: 12579 to 12597, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5967 to 5993;

[0061] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 12028 to 12046 and SEQ ID NOs: 12598 to 12616, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5994 to 6040;

[0062] A guide domain targeting a target sequence consisting of a nucleic acid sequence selected from among SEQ ID NOs: 12047 to 12065 and SEQ ID NOs: 12617 to 12635 and a prime editing domain consisting of a nucleic acid sequence selected from among SEQ ID NOs: 6041 to 6054; and

[0063] A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 12066 to 12103 and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 6055 to 6057.

[0064] In one embodiment, the scaffold may be a pegRNA comprised of a nucleic acid sequence selected from SEQ ID NO: 11531 to SEQ ID NO: 11533.

[0065] Disclosed herein is a prime editor composition for correcting the c.4957dupA variant of the EYS gene, comprising:

[0066] a prime editor protein, or a nucleic acid encoding said prime editor protein; and

[0067] The pegRNA, or a nucleic acid encoding the pegRNA,

[0068] Here, the prime editor protein comprises a Cas9 protein derived from Streptococcus pyogenes or a variant thereof, and a reverse transcriptase,

[0069] The scaffold of the above pegRNA interacts with the prime editor protein to form a complex.

[0070] In one embodiment, the prime editor composition may include the prime editor protein and the pegRNA, and the prime editor protein and the pegRNA may be combined to form a complex.

[0071] In one embodiment, the prime editor composition may comprise a nucleic acid encoding the prime editor and a nucleic acid encoding the pegRNA.

[0072] In one embodiment, the prime editor protein may be selected from the following: NRCH-PE2max; NRCH-hyPE2max; NRCH-PE2; and PE2max.

[0073]

[0074] Hereinafter, the present invention will be described in more detail through specific implementations and examples with reference to the attached drawings. It should be noted that the attached drawings include some, but not all, implementations of the invention. The invention disclosed by this specification may be implemented in various ways and is not limited to the specific implementations described herein. These implementations should be considered as provided to satisfy the legal requirements applicable to this specification. Those skilled in the art will be able to think of many modifications and other implementations of the invention disclosed herein. Therefore, the invention disclosed herein is not limited to the specific implementations described herein, and it should be understood that modifications and other implementations thereof are also included within the scope of the claims.

[0075]

[0076] Definition of Terms

[0077] approximately

[0078] The term "about" as used herein means an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by about 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1%, or 0% with respect to a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0079] Nucleic acid sequence notation

[0080] The symbols A, T, C, G, and U used herein are to be interpreted as meanings understood by a person skilled in the art. They may be appropriately interpreted as bases, nucleosides, or nucleotides in DNA or RNA, depending on the context and technology. For example, when referring to a base, they may be interpreted as adenine (A), thymine (T), cytosine (C), guanine (G), or uracil (U) themselves, respectively; when referring to a nucleoside, they may be interpreted as adenosine (A), thymidine (T), cytidine (C), guanosine (G), or uridine (U), respectively; and when referring to a nucleotide in a sequence, they should be interpreted to mean a nucleotide containing each of the above nucleosides.

[0081] target gene or target nucleic acid

[0082] As used herein, "target gene" or "target nucleic acid" basically refers to a gene or nucleic acid within a cell that is the target of gene editing. The terms "target gene" and "target nucleic acid" may be used interchangeably and may refer to the same subject. Unless otherwise specified, the target gene or target nucleic acid may refer to either a gene or nucleic acid inherent to the target cell or an exogenous gene or nucleic acid, and is not particularly limited as long as it can be the target of gene editing. The target gene or target nucleic acid may be single-stranded DNA, double-stranded DNA, and / or RNA. Furthermore, the terms encompass all meanings recognizable to those skilled in the art and may be appropriately interpreted depending on the context.

[0083] Target strand and non-target strand

[0084] When the terms "target strand" and "nontarget strand" are used herein to refer to a target nucleic acid, they should be understood in the context of the Cas9 protein (and the prime editor protein including it) and the guide RNA (and pegRNA). When the target nucleic acid is a double-stranded nucleic acid and is targeted by the prime editor, the target strand and the nontarget strand are distinguished according to the following criteria. The nontarget strand is a strand that includes a protospacer adjacent motif (PAM) sequence that the Cas9 protein can recognize, and to which the guide RNA (and pegRNA) does not complementarily bind. The target strand refers to a strand to which the guide domain of the guide RNA (and pegRNA) complementarily binds after the Cas9 protein recognizes the PAM sequence of the nontarget strand. In addition, the terms include all meanings that can be recognized by a person skilled in the art, and can be appropriately interpreted depending on the context.

[0085]

[0086] EYS Gene Editing Prime Editor

[0087] EYS Gene Editing Prime Editor Overview

[0088] Disclosed herein are a prime editor capable of correcting the c.4957dupA mutation of the EYS gene and components thereof. The prime editor comprises a prime editor protein and pegRNA. Here, the prime editor protein comprises a Cas9 nickase variant derived from Streptococcus pyogenes and a reverse transcriptase. The pegRNA comprises a guide domain, a scaffold, and a prime editing domain, wherein the guide domain, the scaffold, and the prime editing domain are sequentially linked from the 5' end to the 3' end. Here, the prime editing domain comprises a reverse transcriptase template (RTT) and a primer binding site (PBS). The pegRNA forms a complex with the prime editor protein via the scaffold. The pegRNA 1) guides the prime editor protein to the target nucleic acid around the c.4957dupA mutation of the EYS gene, and 2) provides a normal gene sequence template so that the c.4957dupA mutation of the EYS gene can be corrected through the reverse transcriptase included in the prime editor protein. The prime editor protein 1) generates a nick in the target nucleic acid so that the PBS of the pegRNA can bind to the target nucleic acid and position it appropriately, and 2) reverse transcribes DNA using the RTT as a template so that gene correction can be induced.

[0089] If the sequences of the mutant and normal genes to be corrected are clearly specified, a pegRNA that enables gene correction can theoretically be designed using Prime Editor. When designing the pegRNA, the main design variables are 1) a guide domain capable of targeting the target nucleic acid around the correction target, 2) an RTT sequence and its length according to the sequence of the target nucleic acid and the nick occurrence position, and 3) a PBS sequence length according to the sequence of the target nucleic acid and the nick occurrence position. By changing these, thousands or tens of thousands of pegRNAs can be designed in theory. However, since very little is known about which pegRNA configuration will exhibit the prime editing effect, it is nearly impossible to select a pegRNA sequence that can actually be used for gene correction based only on the theoretically designed sequence information.

[0090] Therefore, the inventors of the present invention selected a method of selecting pegRNAs by confirming through actual experiments whether each pegRNA truly exhibits a prime editing effect. Specifically, the inventors of the present invention synthesized almost all pegRNAs that could be theoretically designed to select a pegRNA capable of correcting the c.4957dupA mutation of the EYS gene, and screened pegRNAs capable of gene editing using a high-throughput screening method. Furthermore, the inventors verified that the pegRNAs showing prime editing efficiency as a result of the screening could correct the c.4957dupA mutation of the EYS gene in actual human retinal cells, thereby completing the present invention by specifying the sequence of the pegRNA that can be used to correct the c.4957dupA mutation of the EYS gene.

[0091] Prime Editor Protein

[0092] The prime editor disclosed herein, capable of correcting the c.4957dupA mutation in the EYS gene, comprises a prime editor protein. The prime editor protein is an artificial protein comprising a Cas protein having nickase activity and a reverse transcriptase enzyme. In particular, the Cas protein having nickase activity is a mutant of the Cas9 protein derived from Streptococcus pyogenes. The above prime editor protein can cleave only one of the two strands of the target double-stranded nucleic acid (hereinafter referred to as "nicking"). Specifically, the prime editor protein generates a nick in a non-target strand of the target double-stranded nucleic acid. Here, since the position of the target double-stranded nucleic acid is specified, it is also possible to know at which position the prime editor protein will generate a nick, and thus, each configuration (e.g., RTT and PBS sequences) of pegRNA for prime editing correction can be designed based on this.

[0093] The composition of the above prime editor protein is specifically exemplified in the “Prime Editor Protein” section of “Possible Embodiments of the Invention” below.

[0094] pegRNA for EYS gene correction

[0095] The prime editor capable of correcting the c.4957dupA mutation of the EYS gene disclosed herein comprises a pegRNA. The pegRNA comprises a guide domain, a scaffold, a reverse transcriptase template (RTT), and a primer binding site (PBS). Here, the reverse transcriptase template and the primer binding site are collectively referred to as the prime editing domain. Optionally, the pegRNA may additionally comprise an RNA linker and a tmpknot at the 3' end.

[0096] [Figure 1] schematically shows the structure of the pegRNA and extended pegRNA.

[0097] The above pegRNA can be designed in countless forms by changing the sequence of the guide domain, the reverse transcriptase template sequence, and the primer binding site sequence.

[0098] The composition of the above pegRNA is specifically exemplified in the “pegRNA” section of “Possible Embodiments of the Invention” below.

[0099] Method for designing pegRNA for gene editing

[0100] A pegRNA for gene correction can be designed to 1) specify the target gene site for correction (the c.4957dupA mutation site of the EYS gene) and 2) specify the prime editor protein to be used and the position where the nick is generated in the target nucleic acid.

[0101] Specifically, pegRNA for gene correction can be designed in the following manner: The following description is an example to explain the design method, and although the numbers are given in order, it does not necessarily have to be performed in that order, and it can be designed in other ways as long as the purpose is achieved.

[0102] 1) Specify the sequence before and after correction of the target gene to be corrected.

[0103] 2) Depending on the prime editor protein to be used, the guide domain of pegRNA is designed so that the prime editor can be guided to a predetermined target nucleic acid near the gene site to be corrected.

[0104] 3) Depending on the sequence of the target nucleic acid, the position where a nick is generated by the prime editor protein is specified.

[0105] 4) Based on the position where the above nick occurs, the primer binding site (PBS) of pegRNA is designed so that it can complementarily bind to the 5'-terminal nucleotide of the non-target strand.

[0106] 5) A reverse transcriptase template (RTT) of pegRNA is designed so that the sequence can be reverse transcribed after proofreading by a reverse transcriptase in the 3' end direction of the non-target strand to which the above primer binding site binds.

[0107] The relationship between the guide domain of the above pegRNA, the primer binding site (PBS), the reverse transcriptase template (RTT), and the target nucleic acid is schematically shown in [Figure 2] and [Figure 3].

[0108] Figures 2 and 3 only show a portion of the target nucleic acid and pegRNA, and the portions indicated as 3' and 5' are not the actual nucleic acid ends but are shown to indicate the direction. Figure 2 shows a state in which the prime editor recognizes the PAM of the non-target strand of the target nucleic acid, and the guide domain complementarily binds to the target sequence of the target strand of the target nucleic acid. In this case, a single-stranded cleavage (nick) occurs at a specific position of the non-target strand. Figure 3 shows the positional relationship of the PBS and RTT sequences after a nick occurs in the target nucleic acid by the prime editor. The primer binding site of the pegRNA complementarily binds to the 5' end of the non-target strand of the cleaved target nucleic acid to establish a position, and allows prime editing to occur using the reverse transcriptase template as a template.

[0109] As above, the guide domain, primer binding site, and reverse transcriptase template of the pegRNA can be designed.

[0110] In addition, 1) the guide domain can be designed in various ways by varying the position and length of the target nucleic acid, 2) the PBS can be designed in various ways by varying the length that complementarily binds to the 5'-terminal nucleotide of the non-target strand, and 4) the RTT can be designed in various ways by varying the length of the sequence after proofreading reverse transcribed using a reverse transcriptase. Therefore, theoretically, thousands or tens of thousands of pegRNAs can be designed by varying the guide domain, PBS, and RTT, respectively.

[0111] The difficulty of selecting a functional pegRNA

[0112] As mentioned above, if 1) the target gene site for correction (the c.4957dupA mutation site of the EYS gene) is specified, and 2) the prime editor protein to be used and the position where the nick occurs in the target nucleic acid are specified, a pegRNA for correcting the target gene site can be designed. However, although the number of pegRNAs that can be theoretically designed reaches thousands or tens of thousands, the pegRNA pattern with high gene editing efficiency and the factors that determine the efficiency have not been properly identified yet. Therefore, it is very difficult to select a pegRNA that can be used for actual gene correction based only on the sequence information of the designed pegRNA.

[0113] The inventors' approach to this specification - selection and validation through high-throughput screening.

[0114] The inventors of this specification employed a method to select pegRNAs capable of correcting the c.4957dupA mutation in the EYS gene through actual experiments. First, the inventors of this specification designed nearly all pegRNAs capable of correcting the c.4957dupA mutation in the EYS gene using prime editor proteins capable of recognizing various PAMs. They then experimentally confirmed whether each pegRNA actually exhibited a prime editing effect, and selected pegRNAs capable of correcting the c.4957dupA mutation in the EYS gene. To efficiently handle the above task, a high-throughput screening method was introduced. This high-throughput screening method was based on the method disclosed in Kim et al. (Predicting the efficiency of prime editing guide RNAs in human cells, Nature Biotechnology, Vol. 39, Feb. 2021). Furthermore, by verifying whether the pegRNA showing a corrective effect in the high-throughput screening method can correct the endogenous EYS gene of actual human retinal cells (ARPE19), it was shown that the pegRNA selected by the high-throughput screening method can correct the c.4957dupA mutation of the EYS gene in actual retinal cells.

[0115] The following examples and experimental examples describe in detail the prime editor and its configuration capable of correcting the c.4957dupA mutation of the EYS gene.

[0116]

[0117] Possible embodiments of the invention

[0118] Below, possible embodiments of the invention are disclosed. The description below provides examples of embodiments that can be derived from the technical concepts described in this specification. It should be understood that the invention disclosed in this specification is not limited to the specific embodiments described below, and that variations and other implementations thereof are also included within the scope of the invention disclosed in this specification.

[0119]

[0120] Prime Editor Protein

[0121] Example 1: SpCas9-based prime editor protein

[0122] Prime Editor proteins including:

[0123] A Cas9 protein derived from Streptococcus pyogenes, a variant of the Cas9 protein derived from Streptococcus pyogenes, or a Cas9 protein exhibiting nickase activity among the variants of the Cas9 protein derived from Streptococcus pyogenes; and

[0124] Reverse transcriptase enzyme.

[0125] Example 2: Specific location of nick occurrence

[0126] In Example 1, the Cas9 protein exhibiting the nickase activity can recognize the PAM (protospacer adjacent motif) sequence of the non-target strand of the target double-stranded nucleic acid, and can cleave between the 3rd nucleotide and the 4th nucleotide in the 5'-terminal direction from the 5'-terminal nucleotide of the PAM sequence.

[0127] Example 3, SpCas9-derived nickase

[0128] In any one of Examples 1 to 2, the Cas9 protein exhibiting the nickase activity comprises at least one mutation selected from the following, based on the amino acid sequence (SEQ ID NO: 1) of the Cas9 protein derived from Streptococcus pyogenes:

[0129] H840A; R222K; and N394K.

[0130] Example 4, PAM mutant

[0131] In any one of Examples 1 to 3, the Cas9 protein exhibiting the nickase activity can recognize a PAM sequence different from 5'-NGG-3'.

[0132] Example 5, PAM specificity

[0133] In Example 4, the Cas9 protein exhibiting the nickase activity can recognize one or more PAM sequences selected from the group consisting of:

[0134] 5'-NGG-3'; 5'-NG-3'; 5'-TAG-3'; 5'-AAT-3'; 5'-TTG-3'; 5'-TGA-3'; 5'-GTA-3'; 5'-TAC-3'; 5'-GAT-3'; 5'-GAA-3'; 5'-AGA-3'; 5'-GGA-3'; 5'-AGT-3'; 5'-AAA-3'; 5'-CAT-3'; 5'-AAG-3'; 5'-CAA-3'; 5'-CCC-3'; 5'-TAT-3'; 5'-TAA-3'; 5'-GTC-3'; 5'-AAC-3'; 5'-CTA-3'; 5'-ATA-3'; and 5'-NGAG-3'.

[0135] Example 6, PAM mutation specificity

[0136] In any one of Examples 4 to 5, the Cas9 protein, the variant of the Cas9 protein, or the Cas9 protein exhibiting nickase activity among the variants of the Cas9 protein comprises at least one mutation selected from the following, based on the amino acid sequence of the Cas9 protein derived from Streptococcus pyogenes (SEQ ID NO: 1):

[0137] I322V, S409I, E427G, R654L, R753G, R1114G, D1135N, E1219V, D1332N, R1335Q, T1337N, S1338T, and H1349R;

[0138] L1111R, D1135V, G1218R, E1219F, A1322R, R1335V, and T1337R; and

[0139] D1135V, G1218R, R1335Q, and T1337R.

[0140] Example 7, Reverse Transcriptase Limited

[0141] In any one of Examples 1 to 6, the reverse transcriptase is selected from the following:

[0142] Sequence number 13187 to sequence number 13188.

[0143] Example 8, Other Domains

[0144] In any one of Examples 1 to 7, the prime editor protein further comprises one or more domains selected from the following:

[0145] One or more Nuclear Localization Signals (NLS); Rad51; and a linker.

[0146] Example 9, NLS sequence limitation

[0147] In Example 8, each of the one or more NLSs independently comprises a sequence selected from the following:

[0148] Sequence number 13189 to sequence number 13190.

[0149] Example 10, Rad51 sequence restriction

[0150] In any one of Examples 8 to 9, the Rad51 comprises the amino acid sequence AMQMQLEANADTSVEEESFGPQPISRLEQCGINANDVKKLEEAGFHTVEAVAYAPKKELINIKGISEAKADKILAEAAKLVPMGFTTATEFHQRRSEIIQITTGSKELDKLLQ (SEQ ID NO: 13200).

[0151] Example 11, linker-specific

[0152] In any one of Examples 8 to 9, the linker comprises a sequence selected from SEQ ID NO: 13193:

[0153] Example 12, Prime Editor Protein Limited

[0154] In any one of Examples 1 to 11, the prime editor protein is selected from the group consisting of:

[0155] PE2; PE2max; NRCH-PE2; NRCH-PE2max; NRCH-hyPE2max; VRQR-PE2; and VRQR-PE2max.

[0156] Example 13, Prime Editor Protein Sequence Limitation

[0157] In Example 12, the prime editor protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 2 to SEQ ID NO: 5, SEQ ID NO: 13195 to SEQ ID NO: 13196, and SEQ ID NO: 13203.

[0158] Example 14, Prime Editor, Structure Limited

[0159] Prime Editor proteins including:

[0160] [NLS1] - [Cas9 protein] - [Linker1] - [Rad51] - [Linker2] - [Reverse transcriptase] - [NLS2]

[0161] Here, the NLS1 is the first NLS (Nuclear Localization Signal) or is absent,

[0162] The above NLS2 is a second NLS or is absent,

[0163] The above Cas9 protein comprises a sequence selected from SEQ ID NO: 13204 and SEQ ID NO: 13207 to SEQ ID NO: 13209,

[0164] The above linker 1 is an amino acid linker or is absent,

[0165] The above Rad51 is a Rad51 domain or is absent,

[0166] The above linker 2 is an amino acid linker or is absent,

[0167] The above reverse transcriptase comprises a sequence selected from SEQ ID NO: 13187 to SEQ ID NO: 13188.

[0168] Example 15, NLS and linker sequence definition

[0169] In Example 14,

[0170] The above NLS1 and NLS2 each independently comprise an amino acid sequence selected from SEQ ID NO: 13189 to SEQ ID NO: 13190,

[0171] The above amino acid linker comprises an amino acid sequence selected from SEQ ID NO: 13193 and SEQ ID NO: 13201.

[0172] Example 16, Prime Editor Full-Length Sequence Limitation

[0173] In Example 14,

[0174] The above prime editor protein comprises an amino acid sequence selected from SEQ ID NO: 2 to SEQ ID NO: 5, SEQ ID NO: 13195 to SEQ ID NO: 13196, and SEQ ID NO: 13203.

[0175]

[0176] pegRNA

[0177] Example 17, pegRNA

[0178] pegRNA for Prime Editor to correct the c.4957dupA variant in the EYS gene.

[0179] Example 18, Prime Editor Protein Limited

[0180] In Example 17, the prime editor comprises a prime editor protein of any one of Examples 1 to 16.

[0181] Example 19, pegRNA structure

[0182] In any one of Examples 17 to 18, the pegRNA has the following structure:

[0183] 5' - [Guide Domain] - [Scaffold] - [Prime Editing Domain] - 3'

[0184] Here, the guide domain can target a target nucleic acid contained in the EYS gene,

[0185] The above scaffold can interact with the prime editor protein of the above prime editor to form a complex,

[0186] The above prime editing domain includes a reverse transcriptase template (RTT) and a primer binding site (PBS).

[0187] Example 20, pegRNA structure #1

[0188] In any one of Examples 17 to 19, the pegRNA comprises a guide domain, a scaffold, and a prime editing domain,

[0189] The above prime editing domain comprises a reverse transcriptase template (RTT) and a primer binding site (PBS),

[0190] The above pegRNA has a guide domain, a scaffold, and a prime editing domain sequentially connected from the 5' end to the 3' end.

[0191] The above guide domain can target a target nucleic acid contained in the EYS gene,

[0192] The above scaffold can interact with the prime editor protein of the above prime editor to form a complex,

[0193] The above prime editing domain is sequentially connected to a reverse transcriptase template (RTT) and a primer binding site (PBS) in the 5'-to-3'-end direction.

[0194] Example 21: What it means to target a target nucleic acid

[0195] In any one of Examples 17 to 20,

[0196] The above target nucleic acid refers to double-stranded DNA which is part of the EYS gene,

[0197] The above target nucleic acid comprises a target strand and a nontarget strand,

[0198] Since the sequence of the target strand and the sequence of the non-target strand are complementary sequences to each other, the sequence of the target nucleic acid can be specified only by the sequence of the target strand or the sequence of the non-target strand.

[0199] The description that the above guide domain targets the above target sequence contained in the above EYS gene has the following selected meanings:

[0200] The guide domain can complementarily bind to and / or hybridize with the target strand of the target nucleic acid;

[0201] The sequence of the above guide domain includes a sequence complementary to all or part of the sequence of the target strand of the above target nucleic acid;

[0202] The sequence of the above guide domain is identical to, matches, homologous to, and / or equivalent to the entire or a portion of the sequence of the non-target strand of the target nucleic acid; and

[0203] Any suitable combination of the above descriptions, within the scope recognizable by a person skilled in the art.

[0204] Example 22, Non-target strand sequence limitation

[0205] In Example 21,

[0206] The sequence of the non-target strand of the target nucleic acid comprises a sequence selected from the group consisting of SEQ ID NO: 11534 to SEQ ID NO: 12084 and SEQ ID NO: 12085 to SEQ ID NO: 12635,

[0207] The sequence of the guide domain of the above pegRNA comprises a sequence that is identical, matched, homologous, and / or equivalent to all or part of the sequence of the non-target strand of the target nucleic acid.

[0208] Example 23, Sequence limitation similar to non-target strand

[0209] In Example 21,

[0210] The sequence of the non-target strand of the target nucleic acid comprises a sequence selected from the group consisting of SEQ ID NO: 11534 to SEQ ID NO: 12084 and SEQ ID NO: 12085 to SEQ ID NO: 12635,

[0211] The sequence of the guide domain of the pegRNA comprises a sequence that is identical, matched, homologous, and / or equivalent to all or part of the sequence of the non-target strand of the target nucleic acid by at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0212] Example 24, same as the non-target strand, but with mismatches

[0213] In Example 21,

[0214] The sequence of the non-target strand of the target nucleic acid comprises a sequence selected from the group consisting of SEQ ID NO: 11534 to SEQ ID NO: 12084 and SEQ ID NO: 12085 to SEQ ID NO: 12635,

[0215] The sequence of the guide domain of the above pegRNA comprises a sequence that is identical, matched, homologous, and / or equivalent to the entire or a portion of the non-target strand of the target nucleic acid except for 1, 2, 3, 4, or 5 nucleotide bases.

[0216] Example 25, target strand sequence limitation, complementary sequence

[0217] In Example 21,

[0218] The sequence of the target strand of the above target nucleic acid comprises a sequence selected from the group consisting of SEQ ID NO: 12636 to SEQ ID NO: 13186,

[0219] The sequence of the guide domain of the above pegRNA includes a sequence complementary to all or part of the sequence of the target strand.

[0220] Example 26, restriction of sequences similar to the target strand sequence

[0221] In Example 21,

[0222] The sequence of the target strand of the above target nucleic acid comprises a sequence selected from the group consisting of SEQ ID NO: 12636 to SEQ ID NO: 13186,

[0223] The sequence of the guide domain of the pegRNA comprises a sequence that is at least 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% complementary to all or part of the sequence of the target strand.

[0224] Example 27, complementary to the target strand, but containing a mismatch

[0225] In Example 21,

[0226] The sequence of the target strand of the above target nucleic acid comprises a sequence selected from the group consisting of SEQ ID NO: 12636 to SEQ ID NO: 13186,

[0227] The sequence of the guide domain of the above pegRNA includes a sequence in which all or part of the sequence of the target strand is complementary to the remaining bases except for 1, 2, 3, 4, or 5 nucleotide bases.

[0228] Example 28, Mismatch Pattern Limitation

[0229] In Example 27, the portion where the sequence of the guide domain of the pegRNA does not match the sequence of the target strand is a base mismatch, a bulge occurs in the pegRNA, or a bulge occurs in the target strand.

[0230] Example 29, target strand sequence limitation, binding relationship limitation

[0231] In any one of Examples 17 to 28,

[0232] The guide domain of the pegRNA can complementarily bind and / or hybridize with the target strand.

[0233] Example 30, limiting the length of the guide domain

[0234] In any one of Examples 17 to 29, the nucleotide length of the guide domain is 8 nt, 9 nt, 10 nt, 11 nt, 12 nt, 13 nt, 14 nt, 15 nt, 16 nt, 17 nt, 18 nt, 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, 26 nt, 27 nt, 28 nt, 29 nt, or 30 nt, or has a length within a range comprised of the above numerical ranges (e.g., a length between 12 nt and 30 nt).

[0235] Example 31, Guide Domain Limited

[0236] In any one of Examples 17 to 30, the sequence of the guide domain comprises a nucleic acid sequence selected from the group consisting of:

[0237] A nucleic acid sequence selected from SEQ ID NO: 48 to SEQ ID NO: 627; and

[0238] A sequence that is identical, matches, homologous, and / or equivalent to a nucleic acid sequence selected from SEQ ID NO: 48 to SEQ ID NO: 627 by at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0239] Example 32, including G or GG at the 5' end of the guide domain

[0240] In Example 31, the sequence of the guide domain further includes G or GG at the 5' end.

[0241] Example 33, Scaffold Sequence Limitation

[0242] In any one of Examples 17 to 32, the sequence of the scaffold comprises a nucleic acid sequence selected from the group consisting of:

[0243] A nucleic acid sequence selected from SEQ ID NO: 11531 to SEQ ID NO: 11533; and

[0244] A sequence that is at least about 80% identical, at least about 81% identical, at least about 82% identical, at least about 83% identical, at least about 84% identical, at least about 85% identical, at least about 86% identical, at least about 87% identical, at least about 88% identical, at least about 89% identical, at least about 90% identical, at least about 91% identical, at least about 92% identical, at least about 93% identical, at least about 94% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, or at least about 99% identical, identical, matched, homologous, and / or equivalent to a nucleic acid sequence selected from SEQ ID NO: 11531 to SEQ ID NO: 11533, and capable of interacting with the prime editor protein to form a complex.

[0245] Example 34, RTT and PBS each limited

[0246] In any one of Examples 17 to 33, the sequence of the prime editing domain is the following sequence sequentially connected from the 5' end to the 3' end:

[0247] A reverse transcriptase template sequence selected from SEQ ID NO: 8816 to SEQ ID NO: 11530; and

[0248] A primer binding site sequence selected from SEQ ID NO: 628 to SEQ ID NO: 3342.

[0249] Example 35, Guide Domain, RTT, and PBS Matching

[0250] In any one of Examples 17 to 34, the sequence of the guide domain of the pegRNA and the sequence of the prime editing domain are expressed in a combination selected from the group consisting of:

[0251] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 48 to SEQ ID NO: 67, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 8816 to SEQ ID NO: 8955 and a primer binding site sequence selected from SEQ ID NO: 628 to SEQ ID NO: 767 are sequentially connected from the 5' end to the 3' end;

[0252] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 68 to SEQ ID NO: 87, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 8956 to SEQ ID NO: 9046 and a primer binding site sequence selected from SEQ ID NO: 768 to SEQ ID NO: 858 are sequentially connected from the 5' end to the 3' end;

[0253] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 107, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9047 to SEQ ID NO: 9183 and a primer binding site sequence selected from SEQ ID NO: 859 to SEQ ID NO: 995 are sequentially connected from the 5' end to the 3' end;

[0254] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 108 to SEQ ID NO: 127, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9184 to SEQ ID NO: 9302 and a primer binding site sequence selected from SEQ ID NO: 996 to SEQ ID NO: 1114 are sequentially connected from the 5' end to the 3' end;

[0255] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 128 to SEQ ID NO: 147, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9303 to SEQ ID NO: 9361 and a primer binding site sequence selected from SEQ ID NO: 1115 to SEQ ID NO: 1173 are sequentially connected from the 5' end to the 3' end;

[0256] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 148 to SEQ ID NO: 167, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9362 to SEQ ID NO: 9495 and a primer binding site sequence selected from SEQ ID NO: 1174 to SEQ ID NO: 1307 are sequentially connected from the 5' end to the 3' end;

[0257] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 168 to SEQ ID NO: 187, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9496 to SEQ ID NO: 9642 and a primer binding site sequence selected from SEQ ID NO: 1308 to SEQ ID NO: 1454 are sequentially connected from the 5' end to the 3' end;

[0258] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 188 to SEQ ID NO: 207, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9643 to SEQ ID NO: 9782 and a primer binding site sequence selected from SEQ ID NO: 1455 to SEQ ID NO: 1594 are sequentially connected from the 5' end to the 3' end;

[0259] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 208 to SEQ ID NO: 227, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9783 to SEQ ID NO: 9923 and a primer binding site sequence selected from SEQ ID NO: 1595 to SEQ ID NO: 1735 are sequentially connected from the 5' end to the 3' end;

[0260] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 228 to SEQ ID NO: 247, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 9924 to SEQ ID NO: 10051 and a primer binding site sequence selected from SEQ ID NO: 1736 to SEQ ID NO: 1863 are sequentially connected from the 5' end to the 3' end;

[0261] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 248 to SEQ ID NO: 267, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10052 to SEQ ID NO: 10081 and a primer binding site sequence selected from SEQ ID NO: 1864 to SEQ ID NO: 1893 are sequentially connected from the 5' end to the 3' end;

[0262] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 268 to SEQ ID NO: 287, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10082 to SEQ ID NO: 10144 and a primer binding site sequence selected from SEQ ID NO: 1894 to SEQ ID NO: 1956 are sequentially connected from the 5' end to the 3' end;

[0263] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 288 to SEQ ID NO: 307, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10145 to SEQ ID NO: 10209 and a primer binding site sequence selected from SEQ ID NO: 1957 to SEQ ID NO: 2021 are sequentially connected from the 5' end to the 3' end;

[0264] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 308 to SEQ ID NO: 327, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10210 to SEQ ID NO: 10351 and a primer binding site sequence selected from SEQ ID NO: 2022 to SEQ ID NO: 2163 are sequentially connected from the 5' end to the 3' end;

[0265] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 328 to SEQ ID NO: 347, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10352 to SEQ ID NO: 10497 and a primer binding site sequence selected from SEQ ID NO: 2164 to SEQ ID NO: 2309 are sequentially connected from the 5' end to the 3' end;

[0266] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 348 to SEQ ID NO: 367, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10498 to SEQ ID NO: 10574 and a primer binding site sequence selected from SEQ ID NO: 2310 to SEQ ID NO: 2386 are sequentially connected from the 5' end to the 3' end;

[0267] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 368 to SEQ ID NO: 387, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10575 to SEQ ID NO: 10687 and a primer binding site sequence selected from SEQ ID NO: 2387 to SEQ ID NO: 2499 are sequentially connected from the 5' end to the 3' end;

[0268] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 388 to SEQ ID NO: 407, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10688 to SEQ ID NO: 10784 and a primer binding site sequence selected from SEQ ID NO: 2500 to SEQ ID NO: 2596 are sequentially connected from the 5' end to the 3' end;

[0269] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 408 to SEQ ID NO: 427, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10785 to SEQ ID NO: 10914 and a primer binding site sequence selected from SEQ ID NO: 2597 to SEQ ID NO: 2726 are sequentially connected from the 5' end to the 3' end;

[0270] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 428 to SEQ ID NO: 447, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 10915 to SEQ ID NO: 11023 and a primer binding site sequence selected from SEQ ID NO: 2727 to SEQ ID NO: 2835 are sequentially connected from the 5' end to the 3' end;

[0271] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 448 to SEQ ID NO: 467, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11024 to SEQ ID NO: 11154 and a primer binding site sequence selected from SEQ ID NO: 2836 to SEQ ID NO: 2966 are sequentially connected from the 5' end to the 3' end;

[0272] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 468 to SEQ ID NO: 487, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11155 to SEQ ID NO: 11277 and a primer binding site sequence selected from SEQ ID NO: 2967 to SEQ ID NO: 3089 are sequentially connected from the 5' end to the 3' end;

[0273] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 488 to SEQ ID NO: 507, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11278 to SEQ ID NO: 11304 and a primer binding site sequence selected from SEQ ID NO: 3090 to SEQ ID NO: 3116 are sequentially connected from the 5' end to the 3' end;

[0274] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 508 to SEQ ID NO: 527, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11305 to SEQ ID NO: 11396 and a primer binding site sequence selected from SEQ ID NO: 3117 to SEQ ID NO: 3208 are sequentially connected from the 5' end to the 3' end;

[0275] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 528 to SEQ ID NO: 547, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11397 to SEQ ID NO: 11439 and a primer binding site sequence selected from SEQ ID NO: 3209 to SEQ ID NO: 3251 are sequentially connected from the 5' end to the 3' end;

[0276] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 548 to SEQ ID NO: 567, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11440 to SEQ ID NO: 11466 and a primer binding site sequence selected from SEQ ID NO: 3252 to SEQ ID NO: 3278 are sequentially connected from the 5' end to the 3' end;

[0277] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 568 to SEQ ID NO: 587, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11467 to SEQ ID NO: 11513 and a primer binding site sequence selected from SEQ ID NO: 3279 to SEQ ID NO: 3325 are sequentially connected from the 5' end to the 3' end; and

[0278] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 588 to SEQ ID NO: 607, and the sequence of the above prime editing domain comprises a nucleic acid sequence in which a reverse transcriptase template sequence selected from SEQ ID NO: 11514 to SEQ ID NO: 11527 and a primer binding site sequence selected from SEQ ID NO: 3326 to SEQ ID NO: 3339 are sequentially connected from the 5' end to the 3' end.

[0279] Example 36, Prime Editing Domain Limited

[0280] In any one of Examples 17 to 35, the sequence of the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3343 to SEQ ID NO: 6057.

[0281] Example 37: Guide domain and prime editing domain matching

[0282] In any one of Examples 17 to 36, the sequence of the guide domain of the pegRNA and the sequence of the prime editing domain are expressed in a combination selected from the group consisting of:

[0283] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 48 to SEQ ID NO: 67, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3343 to SEQ ID NO: 3482;

[0284] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 68 to SEQ ID NO: 87, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3483 to SEQ ID NO: 3573;

[0285] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 107, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3574 to SEQ ID NO: 3710;

[0286] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 108 to SEQ ID NO: 127, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3711 to SEQ ID NO: 3829;

[0287] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 128 to SEQ ID NO: 147, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3830 to SEQ ID NO: 3888;

[0288] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 148 to SEQ ID NO: 167, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3889 to SEQ ID NO: 4022;

[0289] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 168 to SEQ ID NO: 187, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4023 to SEQ ID NO: 4169;

[0290] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 188 to SEQ ID NO: 207, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4170 to SEQ ID NO: 4309;

[0291] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 208 to SEQ ID NO: 227, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4310 to SEQ ID NO: 4450;

[0292] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 228 to SEQ ID NO: 247, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4451 to SEQ ID NO: 4578;

[0293] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 248 to SEQ ID NO: 267, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4579 to SEQ ID NO: 4608;

[0294] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 268 to SEQ ID NO: 287, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4609 to SEQ ID NO: 4671;

[0295] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 288 to SEQ ID NO: 307, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4672 to SEQ ID NO: 4736;

[0296] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 308 to SEQ ID NO: 327, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4737 to SEQ ID NO: 4878;

[0297] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 328 to SEQ ID NO: 347, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 4879 to SEQ ID NO: 5024;

[0298] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 348 to SEQ ID NO: 367, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5025 to SEQ ID NO: 5101;

[0299] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 368 to SEQ ID NO: 387, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5102 to SEQ ID NO: 5214;

[0300] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 388 to SEQ ID NO: 407, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5215 to SEQ ID NO: 5311;

[0301] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 408 to SEQ ID NO: 427, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5312 to SEQ ID NO: 5441;

[0302] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 428 to SEQ ID NO: 447, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5442 to SEQ ID NO: 5550;

[0303] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 448 to SEQ ID NO: 467, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5551 to SEQ ID NO: 5681;

[0304] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 468 to SEQ ID NO: 487, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5682 to SEQ ID NO: 5804;

[0305] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 488 to SEQ ID NO: 507, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5805 to SEQ ID NO: 5831;

[0306] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 508 to SEQ ID NO: 527, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5832 to SEQ ID NO: 5923;

[0307] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 528 to SEQ ID NO: 547, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5924 to SEQ ID NO: 5966;

[0308] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 548 to SEQ ID NO: 567, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5967 to SEQ ID NO: 5993;

[0309] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 568 to SEQ ID NO: 587, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 5994 to SEQ ID NO: 6040; and

[0310] The sequence of the above guide domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 588 to SEQ ID NO: 607, and the prime editing domain comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 6041 to SEQ ID NO: 6054.

[0311] Example 38, pegRNA full-length sequence limitation

[0312] In any one of Examples 17 to 37, the sequence of the pegRNA comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 6058 to SEQ ID NO: 8815.

[0313] Example 39, adding tmpknot

[0314] In any one of Examples 17 to 38, the pegRNA additionally comprises a tmpknot at the 3' end.

[0315] Example 40, tmpknot sequence limitation

[0316] In Example 39, the sequence of tmpknot includes the nucleic acid sequence of SEQ ID NO: 6.

[0317] Example 41, linking via tmpknot linker

[0318] In any one of Examples 39 to 40, the pegRNA further comprises an RNA linker, and the tmpknot is connected to the 3' end of the pegRNA via the RNA linker.

[0319] Example 42, linker sequence limitation

[0320] In Example 41, the sequence of the RNA linker includes a nucleic acid sequence of SEQ ID NO: 7 to SEQ ID NO: 47.

[0321] Example 43, including Poly-U

[0322] In any one of Examples 17 to 42, the pegRNA additionally comprises a Poly-U sequence at the 3' end.

[0323] Example 44, poly-U sequence limitation

[0324] In Example 43, the Poly-U sequence is 5'-UUUUUU-3'.

[0325] Example 45, Markushi-type claim

[0326] pegRNA for Prime Editor to correct the c.4957dupA variant of the EYS gene, represented by the following structure:

[0327] 5'-[5'-end appendage]-[guide domain]-[scaffold]-[reverse transcriptase template (RTT)]-[primer binding site (PBS)]-[linker]-[tmpknot]-3'

[0328] Here, the sequence of the 5' terminal addition is 5'-G-3', or 5'-GG-3', or the 5' terminal addition is absent,

[0329] The sequence of the above guide domain comprises a sequence selected from the group consisting of SEQ ID NO: 48 to SEQ ID NO: 627,

[0330] The sequence of the above scaffold comprises a sequence selected from the group consisting of SEQ ID NO: 11531 to SEQ ID NO: 11533,

[0331] The sequence of the above reverse transcriptase template comprises a sequence selected from the group consisting of SEQ ID NO: 8816 to SEQ ID NO: 11530,

[0332] The sequence of the above primer binding site includes a sequence selected from the group consisting of SEQ ID NO: 628 to SEQ ID NO: 3342,

[0333] The sequence of the above linker comprises a sequence selected from the group consisting of SEQ ID NO: 7 to SEQ ID NO: 47, or the linker is absent,

[0334] The sequence of the above tmpknot is sequence number 6, or tmpknot does not exist.

[0335] Example 46, DNA encoding pegRNA

[0336] DNA encoding the pegRNA of any one of Examples 17 to 45.

[0337]

[0338] Prime Editor Complex

[0339] Example 47, Prime Editor Complex

[0340] Prime Editor Complex including:

[0341] A prime editor protein of any one of Examples 1 to 16; and

[0342] Any one of the pegRNAs of Examples 17 to 46,

[0343] Here, the scaffold of the pegRNA interacts with the prime editor protein to form a complex.

[0344] Example 48, Validation, PE2max

[0345] In Example 47,

[0346] The above prime editor protein is PE2max,

[0347] The above pegRNA has the following structure:

[0348] 5' - [Guide Domain] - [Scaffold] - [Prime Editing Domain] - 3'

[0349] Here, the '] - [' part means that the 3' end and 5' end of each domain are directly connected or connected through an appropriate linker,

[0350] Here, the guide domain and the prime editing domain are a combination selected from the group consisting of:

[0351] The sequence of the target nucleic acid targeted by the above guide domain includes the nucleic acid sequence of ACAATTTTATCCTCATCCT (SEQ ID NO: 407), and the sequence of the prime editing domain includes TCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATA (SEQ ID NO: 5302), AATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAAT (SEQ ID NO: 5303), CAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTG (SEQ ID NO: 5304), AATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTGTT (SEQ ID NO: 5305), AAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTGTT (SEQ ID NO: 5306). A nucleic acid sequence selected from the group consisting of ACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAA (SEQ ID NO: 5307), TCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTGT (SEQ ID NO: 5308), ATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTGT (SEQ ID NO: 5309), ACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTG (SEQ ID NO: 5310), and ACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTGT (SEQ ID NO: 5311); and

[0352] The sequence of the target nucleic acid targeted by the above guide domain includes a nucleic acid sequence of CATCCTTGGAAGAATCCAT (SEQ ID NO: 107), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of CCAAATTACTTGATAGGGTAATGGATTCTTCCA (SEQ ID NO: 3707), CATCCAAATTACTTGATAGGGTAATGGATTCTTCCA (SEQ ID NO: 3708), TTAACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGA (SEQ ID NO: 3709), and TAACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGA (SEQ ID NO: 3710);

[0353] The above scaffold can interact with the PE2max to form a complex,

[0354] The above prime editing domain comprises a sequence selected from the group consisting of SEQ ID NO: 3707 to SEQ ID NO: 3710 and SEQ ID NO: 5302 to SEQ ID NO: 5311.

[0355] Example 49, Validation, NRCH-PE2

[0356] In Example 47,

[0357] The above prime editor protein is NRCH-PE2 or NRCH-PE2max,

[0358] The above pegRNA has the following structure:

[0359] 5' - [Guide Domain] - [Scaffold] - [Prime Editing Domain] - 3'

[0360] Here, the '] - [' part means that the 3' end and 5' end of each domain are directly connected or connected through an appropriate linker,

[0361] Here, the guide domain and the prime editing domain are a combination selected from the group consisting of:

[0362] The sequence of the target nucleic acid targeted by the above guide domain includes a nucleic acid sequence of AACAATTTTATCCTCATCC (SEQ ID NO: 267), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of ATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGAT (SEQ ID NO: 4605), CAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATT (SEQ ID NO: 4606), CATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAAATTGTTC (SEQ ID NO: 4607), and TCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATA (SEQ ID NO: 4608);

[0363] The sequence of the target nucleic acid targeted by the above guide domain includes a nucleic acid sequence of ATTTTATCCTCATCCTTGG (SEQ ID NO: 367), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of AATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGA (SEQ ID NO: 5098), TAACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGA (SEQ ID NO: 5099), ACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGA (SEQ ID NO: 5100), and AACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGA (SEQ ID NO: 5101);

[0364] The sequence of the target nucleic acid targeted by the above guide domain includes a nucleic acid sequence of CATCCTTGGAAGAATCCAT (SEQ ID NO: 107), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of AATTACTTGATAGGGTAATGGATTCTTCCAAGGA (SEQ ID NO: 3703), AATTACTTGATAGGGTAATGGATTCTTCCAAGGAT (SEQ ID NO: 3704), AACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGA (SEQ ID NO: 3705), and AAATTACTTGATAGGGTAATGGATTCTTCCAAGGA (SEQ ID NO: 3706);

[0365] The sequence of the target nucleic acid targeted by the above guide domain includes a nucleic acid sequence of CCTCATCCTTGGAAGAATC (SEQ ID NO: 127), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of AATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAG (SEQ ID NO: 3826), AAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAG (SEQ ID NO: 3827), CATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGG (SEQ ID NO: 3828), and TAACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAG (SEQ ID NO: 3829);

[0366] The sequence of the target nucleic acid targeted by the above guide domain includes the nucleic acid sequence of TCCATTACCCTATCAAAGT (SEQ ID NO: 67), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of AAATTACTTGATAGGGT (SEQ ID NO: 3479), AAATTACTTGATAGGGTAAT (SEQ ID NO: 3480), AACATCCAAATTACTTGATAGGGTA (SEQ ID NO: 3481), and AAATTACTTGATAGGGTA (SEQ ID NO: 3482); and

[0367] The sequence of the target nucleic acid targeted by the above guide domain includes the nucleic acid sequence of TTTTATCCTCATCCTTGGA (SEQ ID NO: 87), and the sequence of the prime editing domain includes CCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGA (SEQ ID NO: 3568), TCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGA (SEQ ID NO: 3569), ATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAA (SEQ ID NO: 3570), TCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAAA (SEQ ID NO: 3571), ACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGATAA (SEQ ID NO: 3572), and Contains a nucleic acid sequence selected from the group consisting of ACATCCAAATTACTTGATAGGGTAATGGATTCTTCCAAGGATGAGGA (SEQ ID NO: 3573);

[0368] The sequence of the target nucleic acid targeted by the above guide domain includes a nucleic acid sequence of AGAATCCATTACCCTATCA (SEQ ID NO: 626), and the sequence of the prime editing domain includes a nucleic acid sequence selected from the group consisting of CAAATTACTTGATAGGGTAATGGAT (SEQ ID NO: 6055), CAAATTACTTGATAGGGTAATGGATT (SEQ ID NO: 6056), and AAATTACTTGATAGGGTAATGGAT (SEQ ID NO: 6057);

[0369] The above scaffold can interact with the PE2max to form a complex,

[0370] The above prime editing domain comprises a sequence selected from the group consisting of SEQ ID NO: 3479 to SEQ ID NO: 3482, SEQ ID NO: 3568 to SEQ ID NO: 3573, SEQ ID NO: 3703 to SEQ ID NO: 3706, SEQ ID NO: 3826 to SEQ ID NO: 3829, SEQ ID NO: 4605 to SEQ ID NO: 4608, SEQ ID NO: 5098 to SEQ ID NO: 5101, and SEQ ID NO: 6055 to SEQ ID NO: 6057.

[0371]

[0372] Prime Editor Expression Vector

[0373] Example 50, Prime Editor Expression Vector

[0374] Prime Editor expression vectors containing:

[0375] A nucleic acid encoding a prime editor protein of any one of Examples 1 to 16; and

[0376] A nucleic acid encoding a pegRNA of any one of Examples 17 to 46,

[0377] Here, the scaffold of the pegRNA can interact with the prime editor protein to form a complex,

[0378] The above prime editor expression vector is capable of expressing the prime editor protein and the pegRNA respectively in a cell.

[0379] Example 51, Validation

[0380] In Example 50, the prime editor expression vector is capable of expressing the prime editor protein and pegRNA included in the prime editor complex of Example 48 or Example 49, respectively.

[0381] Example 52, vectors of two or more molecules

[0382] In Example 50, the prime editor expression vector includes the prime editor protein encoding nucleic acid sequence information and the pegRNA encoding nucleic acid sequence information divided into two or more vector molecules.

[0383] Example 53, Prime Editor Codon Limited

[0384] In any one of Examples 50 to 52, the nucleic acid encoding the prime editor protein comprises a nucleic acid sequence selected from SEQ ID NO: 13210 to SEQ ID NO: 13213.

[0385] Example 54, nucleic acid limitation

[0386] In any one of Examples 50 to 53, the nucleic acid means DNA or RNA.

[0387]

[0388] Prime Editor Composition

[0389] Example 55, Prime Editor Composition

[0390] Prime Editor composition comprising:

[0391] A prime editor protein of any one of Examples 1 to 16, or a nucleic acid encoding said prime editor protein; and

[0392] Any one of the pegRNAs of Examples 17 to 46, or a nucleic acid encoding the pegRNA,

[0393] Here, the scaffold of the pegRNA can interact with the prime editor protein to form a complex.

[0394] Example 56, Composition comprising a complex

[0395] In any one of Examples 55, the prime editor composition comprises the prime editor protein and the pegRNA in the form of a complex of any one of Examples 47 to 49.

[0396] Example 57, Composition containing a vector

[0397] In any one of Examples 55 to 56, the prime editor composition comprises a nucleic acid encoding the prime editor protein and a nucleic acid encoding the pegRNA in the form of a vector of any one of Examples 50 to 54.

[0398] Example 58, Composition containing mRNA

[0399] In any one of Examples 55 to 57, the prime editor composition comprises an mRNA encoding the prime editor protein and the pegRNA or a nucleic acid encoding the pegRNA.

[0400]

[0401] Pharmaceutical composition comprising a prime editor

[0402] Example 59, Pharmaceutical Composition

[0403] A pharmaceutical composition comprising:

[0404] A therapeutically effective amount of a prime editor complex selected from any one of Examples 47 to 49, a prime editor expression vector selected from any one of Examples 50 to 54, or a prime editor composition selected from any one of Examples 55 to 58; and

[0405] Pharmaceutically acceptable carrier.

[0406]

[0407] Prime Editor's therapeutic uses and treatment methods for retinitis pigmentosa

[0408] Example 60, Use for treating retinitis pigmentosa

[0409] Use of a prime editor complex selected from any one of Examples 47 to 49, a prime editor expression vector selected from any one of Examples 50 to 54, a prime editor composition selected from any one of Examples 55 to 58, or a pharmaceutical composition selected from any one of Example 59 for the treatment of retinitis pigmentosa.

[0410] Example 61, Preparation of a drug for treating retinitis pigmentosa

[0411] A use for manufacturing a drug for treating retinitis pigmentosa, comprising a prime editor complex selected from any one of Examples 47 to 49, a prime editor expression vector selected from any one of Examples 50 to 54, a prime editor composition selected from any one of Examples 55 to 58, or a pharmaceutical composition selected from any one of Example 59.

[0412] Example 62, Method for Treating Retinitis Pigmentosa

[0413] A method for treating retinitis pigmentosa, comprising administering, introducing, injecting, and / or delivering to a patient a prime editor complex selected from any one of Examples 47 to 49, a prime editor expression vector selected from any one of Examples 50 to 54, a prime editor composition selected from any one of Examples 55 to 58, or a pharmaceutical composition selected from any one of Example 59.

[0414] Example 63, Retinitis Pigmentosa Limited

[0415] In any one of Examples 60 to 62, the retinitis pigmentosa is caused by a c.4957dupA mutation in the EYS gene.

[0416]

[0417] Experimental example

[0418] Hereinafter, the invention provided by this specification will be described in more detail through experimental examples and examples. These examples are intended solely to illustrate the subject matter disclosed by this specification, and it will be apparent to those skilled in the art that the scope of the subject matter disclosed by this specification is not limited by these examples.

[0419]

[0420] Experimental Example 1. Experimental Method and Materials

[0421] Experimental Example 1.1. Plasmid Library Preparation Method

[0422] A plasmid library containing the pegRNA coding sequence and its corresponding target sequence was constructed through the following two-step cloning process:

[0423] (Step I) Gibson assembly process; and

[0424] (Step II) Restriction enzyme-induced cutting (cut) and ligation (lysate) process.

[0425] The two-step cloning process described above effectively prevents uncoupling of the pegRNA and the target sequence corresponding to each pegRNA during PCR amplification. The two-step process was implemented using a previously reported method, modified appropriately.

[0426] Step I: Construction of an initial plasmid library containing pegRNA-encoding and target sequence pairs.

[0427] Oligonucleotide pools containing each pegRNA coding sequence and its corresponding target sequence were amplified by PCR for 20 cycles using Phusion Polymerase (NEB), and the amplicons were then gel-purified. The Lenti_gRNA-Puro vector (Addgene #84752) was digested with BsmBI enzyme (NEB) at 55°C for more than 6 hours. After digestion, the linearized vector was gel-purified. The linearized Lenti_gRNA-Puro vector and the amplified oligonucleotide pool were assembled by Gibson assembly. After column purification, the assembled product was transformed into electrocompetent cells (Lucigen) using a MicroPulser (Bio-Rad). Luria-Bertani (LB) medium (1 ml) was added to the transformation mixture and incubated at 37°C for 1 hour. The cells were then plated on LB agar plates containing 100 μg / ml carbenicillin and cultured. Aliquots (10, 1, and 0.1 μl) of each culture were plated separately to determine the library coverage. Plasmids were extracted from the harvested colonies. The initial plasmid library coverage was calculated to be 25X.

[0428] Step II: Insertion of the sgRNA scaffold

[0429] The initial plasmid library generated in Step I was digested with BsmBI for 9 h. The digested product was size-selected on a 1% agarose gel and gel-purified. The sgRNA-optimized scaffold sequence (Dang et al., 2015) was chemically synthesized as an oligonucleotide (IDT) and PCR-amplified for 20 cycles using Pfu polymerase and primer pairs containing BsmBI restriction sites in each pair. The PCR-amplified product was inserted into the PCR-Blunt II-TOPO vector (Solgent), digested with BsmBI for 4 h, and gel-purified on a 4% agarose gel. The purified inserts were ligated with the digested initial plasmid library vector at a molar ratio of 20:1 using T4 ligase (Enzynomics) overnight at room temperature (25°C). The ligation products were purified by isopropanol precipitation and electroporated into Endura electrocompetent cells (Lucigen). Colonies were harvested, and the final plasmid library was extracted using the QIAGEN Plasmid Maxi kit. The coverage of the final plasmid library was calculated to be 112X.

[0430] Experimental Example 1.2. Construction of a Prime Editor Protein Expression Vector

[0431] BSD (blasticidin) Selection vector

[0432] The pLenti-PE2max-BSD plasmid (Addgene #191102) was used for the PE2max prime editor protein, the pLenti-NRCH-hyPE2max-BSD plasmid for the NRCH-hyPE2max prime editor protein, and the pLenti-NRCH-PE2-BSD (Addgene #191101) plasmid for the NRCH-PE2 prime editor.

[0433] The above vector construction method refers to the method described in Yu et al., Prediction of efficiencies for diverse prime editing systems in multiple cell types, 2023, Cell 186, 2256-2272. In the case of the NRCH-hyPE2max plasmid, it was created with reference to the research result that adding the rad51 sequence between the NRCH nickase and MMLV RT increases the prime editing efficiency (Song et al., Generation of a more efficient prime editor 2 by addition of the RAD51 DNA-binding domain, 2021, Nat Commun 12, 5617).

[0434] Puromycin Selection Vector

[0435] The pLenti-PE2max-puro plasmid was used for the PE2max prime editor protein, the pLenti-NRCH-PE2max-puro plasmid was used for the NRCH-PE2max prime editor protein, and the pLenti-NRCH-PE2-puro plasmid was used for the NRCH-PE2 prime editor protein.

[0436] The construction method for each plasmid is as follows:

[0437] The BSD antibiotic resistance gene region of the pLenti-PE2max-BSD plasmid (Addgene #191102), the pLenti-NRCH-PE2max-BSD (Addgene #191103) plasmid for the NRCH-PE2max prime editor protein, and the pLenti-NRCH-PE2-BSD (Addgene #191101) plasmid for the NRCH-PE2 prime editor were converted to the puromycin (puro) antibiotic resistance gene sequence. The puro antibiotic resistance gene was amplified by PCR for 20 cycles in lentiGuide-puro (Addgene #52963) and inserted into the plasmid from which the BSD antibiotic resistance gene region was cut out using the Gibson assembly method.

[0438] Experimental Example 1.3. Lentivirus Production

[0439] HEK293T cells (1.0 Х 10 7) were seeded in 150 mm cell culture dishes containing DMEM (Dulbecco's Modified Eagle Medium). After 21 h, the library plasmid psPAX2 (Addgene #12260) was mixed with pMD2.G (Addgene #12259) at a mass ratio of 4:3:1 and co-transfected into HEK293T cells using polyethylenimine. 20 h after transfection, the medium was replaced with maintenance medium. 48 h after transfection, the supernatant containing lentivirus was collected and treated with benzonase (50 U / ml) and 10X benzonase buffer (500 mM Tris-HCl, 10 mM MgCl2, 1 mg / ml Recombinant Albumin, and ultra-pure water). The benzonase-treated supernatant was filtered through a Millex-HV 0.45-μm low-protein binding membrane (Millipore), aliquoted, and stored at -80°C. To determine the virus titer, serial dilutions of the aliquoted virus were transduced into HEK293T cells in the presence of polybrene (10 μg / ml). Both untransduced cells and cells treated with serially diluted viruses were cultured in the presence of 2 μg / ml puromycin (Invitrogen). When most of the untransduced cells were dead, the number of viable cells in the virus-treated population was counted to estimate the virus titer. The production of lentivirus containing the prime editor expressing plasmid (PE2max, NRCH PE2max) followed the same protocol as above.

[0440] Experimental Example 1.4. Generation of Prime Editor Protein-Expressing Cell Lines

[0441] HEK293T cells were plated in 150 mm cell culture dishes at a density of 1.0 х 10 per plate. 7Cells were seeded at a cell density of 10 and cultured overnight. Lentivirus expressing the prime editor (PE2max, NRCH-PE2max) prepared in Experimental Example 1.5 was transduced into the cells at a multiplicity of infection (MOI) of 0.1 to 0.3. After transduction, the cells were cultured for 19 hours and maintained in 20 μg / ml BSD (blasticidin) for the next 7 days to remove untransduced cells. After BSD selection, each cell line was continuously maintained in 10 μg / ml BSD.

[0442] Experimental Example 1.5. Library Transduction

[0443] A lentivirus containing the library prepared according to Experimental Example 1.3 was transduced into a prime editor protein-expressing cell line according to Experimental Example 1.4. The specific process is as follows:

[0444] 1) Cell lines according to Experimental Example 1.4 were placed in two 150 mm dishes per cell line, 2.0 Х 10 per dish. 7 The cells were seeded at a density of 10 cells and cultured for 21 hours.

[0445] 2) The lentiviral library prepared according to Experimental Example 1.3 was transduced into the cells of 1) at a multiplicity of infection (MOI) of 0.5 together with 10 μg / ml of polybrene, so that the library coverage was > 500x.

[0446] 3) The cells in 2) were cultured overnight and cultured for 6 days in the presence of 2 μg / ml of puromycin to remove non-transduced cells.

[0447] 4) Cells were harvested and used 8 days after transduction.

[0448] Experimental Example 1.6. Deep Sequencing

[0449] For Experimental Example 2, genomic DNA was extracted from harvested cells using the Wizard Genomic DNA Purification Kit (Promega). For high-throughput experiments, integrated barcode and target sequences were PCR amplified using 2X Taq PCR Smart mix (SolGent). For each cell library, the first PCR contained a total of 240 μg of genomic DNA per cell line screen. This corresponds to 10 6 Assuming 10 μg of genomic DNA per cell, this represents at least a 1,000-fold increase in library size. Forty-eight independent 50-μl PCR reactions were performed with an initial genomic DNA concentration of 5 μg per reaction, and the products were pooled and gel-purified using the MEGAquick-spin Whole Fragment DNA Purification Kit (iNtRON Biotechnology).

[0450] The first PCR was performed under the following conditions: 95°C for 1 min; followed by 22 cycles of 95°C for 1 min, 55°C for 30 s, and 72°C for 30 s; followed by a final extension at 72°C for 2 min.

[0451] Then, 50 ng of purified DNA was amplified by PCR using primers containing both Illumina adapter and barcode sequences.

[0452] Secondary PCR was performed under the following conditions: 95°C for 1 min; followed by 10 cycles of 95°C for 30 s, 55°C for 30 s, and 72°C for 30 s; followed by a final extension at 72°C for 30 s.

[0453] The products of the second PCR were gel-purified and deep sequenced.

[0454] For Experimental Example 3, to measure the efficiency of prime editing at the endogenous site in ARPE19 cells, an independent first PCR was performed in a 50 μL reaction volume containing 50 ng of initial genomic DNA template per sample. A second PCR to attach Illumina adapters and barcode sequences was performed for 20 cycles in a 30 μL reaction volume containing 1 μL template of the first PCR product. After gel purification, the resulting amplicons were analyzed using HiSeq or iSeq (Illumina, San Diego, CA).

[0455] Experimental Example 1.7. Prime Editing Efficiency Analysis

[0456] Each pegRNA and target sequence pair was verified by a 21-nt sequence (a 17-nt barcode and a 4-nt sequence upstream of the barcode). Reads containing the designated edits without unintended mutations within the broad target sequence were considered to represent prime editor-induced mutations. To exclude background prime editing frequency arising from array synthesis and PCR amplification procedures, the background prime editing frequency derived in the absence of the prime editor was subtracted from the observed prime editing frequency as follows.

[0457]

[0458] Deep sequencing data was filtered to improve analysis accuracy. Deep sequencing reads with fewer than 100 reads or a background prime editing frequency of 3% or higher were excluded from analysis.

[0459] Experimental Example 1.8. Predicting Deeprime Prime Editing Efficiency

[0460] For prediction using DeepPrime, we used the web tool (http: / deepcrispr.info / DeepPrime / ) (Kim et al., 2023). We predicted the efficiency of the prime editing guide RNA that can revert the EYS c.4957dupA genetic mutation to its normal form, and performed experiments by selecting the pegRNA sequence expected to be most efficient.

[0461]

[0462] Experimental Example 2. Screening for pegRNAs capable of correcting the EYS c.4957dupA mutation.

[0463] Experimental Example 2.1. Preparation of a pegRNA Screening Library

[0464] To identify the most efficient pegRNA and target sequence for correcting the EYS c.4957dupA target, we designed all possible pegRNAs for a total of 28 guide sequences and conducted pegRNA screening. Specifically, for each target sequence (guide sequence), pegRNAs were designed with all possible combinations of reverse transcriptase template sequence length (minimum editable length ~ 40 nt) and primer binding site sequence length (6 nt to 17 nt) and included in the library.

[0465] According to the above design, an oligonucleotide pool containing 4,116 pairs of pegRNA and target sequences prepared by Experimental Example 1.1 was synthesized by Twist Bioscience (San Francisco, CA). Specifically, each oligonucleotide contained a 19-nt guide sequence, a BsmBI restriction site #1, a 15-nt barcode stuffer sequence, a BsmBI restriction site #2, a reverse transcriptase template sequence, a primer binding site sequence, a poly T sequence, a 17-nt barcode sequence (identification barcode) sequence, and a corresponding 64-nt target sequence including a PAM and a reverse transcriptase template binding region. Here, the barcode stuffer sequence was later removed by cleavage with BsmBI, and the identification barcode sequence was located upstream of the target sequence, so that individual pegRNA and target sequence pairs could be identified after deep sequencing. Oligonucleotides containing unintended BsmBI restriction sites within the sequence were excluded from the screening. To identify the most efficient pegRNA for the target, pegRNAs were generated with all possible combinations of reverse transcriptase template sequence length (minimum editable length ~ 40 nt) and primer binding site sequence length (6 nt to 17 nt) for a total of 61 guide sequence pairs.

[0466] Experimental Example 2.2. High-throughput evaluation of cell libraries

[0467] A lentivirus containing the library of Experimental Example 2.1 was prepared according to Experimental Example 1.5, and the prime editor protein-expressing cell line of Experimental Example 1.6 was transduced according to Experimental Example 1.7. The resulting sequence was deep sequenced according to Experimental Example 1.7, and the prime editing efficiency was analyzed according to Experimental Example 1.8. The prime editing efficiency was measured twice, and the average value was used.

[0468] The pegRNA screening results are summarized in the following paragraph, ‘Experimental Example 4.1. PegRNA and screening result data used in Experimental Example 2.’

[0469] As a result of the experiment in Experimental Example 2, if the prime editing efficiency (the value excluding the background prime editing frequency) exceeds 0, it can be concluded that the pegRNA is capable of prime editing the c.4957dupA mutation of the EYS gene.

[0470]

[0471] Experimental Example 3. Measurement of Prime Editing Efficiency at the Endogenous Site of the EYS c.4957dupA ARPE19 Cell Line

[0472] Experimental Example 3.1. Prime Editor and pegRNA Information Used in Experimental Example 3

[0473] Some of the experimental results screened in Experimental Example 2 were selected to test whether the c.4957dupA mutation in the endogenous EYS gene of ARPE19 could be corrected by prime editing.

[0474] The prime editor and pegRNA used in the experimental example are 1) sequences showing prime editing efficiency as a result of the screening experiment of Experimental Example 2, and 2) pegRNAs showing high prime editing efficiency were selected based on the Deeprime efficiency prediction according to Experimental Example 1.9.

[0475] The Prime Editor and pegRNA information used in the experiment are summarized in the following paragraphs, ‘Experimental Example 4.2. PegRNA and Result Data Used in Experimental Example 3.’

[0476] Experimental Example 3.2. Measuring Prime Editing Efficiency in ARPE19 Cell Lines

[0477] To measure the prime editing efficiency for the c.4957dupA mutation in the endogenous EYS gene in the ARPE19 cell line, the following experiments were performed:

[0478] 1) ARPE19 cells containing the c.4957dupA mutation in the endogenous EYS gene were prepared and cultured in DMEM / F12 (1:1) medium containing 10% FBS (Fetal Bovine Serum) and 1% PS (Penicillin-Streptomycin).

[0479] 2) To transfect pegRNA and prime editor according to Experimental Example 3.1, 1.0 x 10 ARPE19 cells of 1) were transfected per well in a 12-well plate. 5 Seeded at a density of 1000 sq.

[0480] 3) 24 hours after seeding, cells were transfected with the prime editor protein expression vector (pLenti-PE2max-puro, pLenti-NRCH PE2max-puro, or pLenti-NRCH PE2 puro) according to Experimental Example 1.4 and the pegRNA encoding plasmid according to Experimental Example 3.1. Here, the prime editor protein expression vector was transfected at 1.0 x 10 5 600 ng per cell, pegRNA encoding plasmid is 1.0 x 10 5 200 ng per cell was added, and this was treated according to the manufacturer's instructions using 1.6 μL of Lipofectamine 2000 per 800 ng of DNA.

[0481] 4) After culturing the mixture of 3) overnight, the culture medium was replaced with DMEM / F12 medium containing puromycin (4 μg / mL).

[0482] 5) Three days after transfection, cells were harvested from 4).

[0483] 6) The prime editing efficiency of the harvested cells was measured according to Experimental Examples 1.7 and 1.8.

[0484] The experimental results are summarized in the following paragraphs: ‘Experimental Example 4.2. pegRNA and result data used in Experimental Example 3.’

[0485] As a result of the experiment in Experimental Example 3, it was found that the pegRNA that was determined to be capable of prime editing as a result of the screening in Experimental Example 2 could correct the c.4957dupA mutation of the endogenous EYS gene in ARPE19 cells, which are human retinal epithelial cells.

[0486] According to the results of this experiment, it can be expected that the pegRNA (Experimental Example 2.3) that showed an editing efficiency exceeding 0% in the screening experiment of Experimental Example 2 will also show a prime editing effect in human retinal cells.

[0487]

[0488] Experimental Example 4. Summary of the results of Experimental Examples 2 and 3.

[0489] Experimental Example 4.1. pegRNA and screening result data used in Experimental Example 2

[0490] The pegRNA and screening results data used in Experimental Example 2 are summarized in the table below:

[0491] LabelPE proteinSEQ ID NOof pegRNAPrime editing efficiency,1st rep (%)Prime editing efficiency,2nd rep (%)Average prime editing efficiency 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0.4464peg-3740PE2max79970.54790.64240.5952peg-3742PE2max62662.99530.91821.9567peg-3745PE2max73157.02083.66015.3405peg-3761PE2max62670.59290.15200.3724peg-3765PE2max79980.86020.61440.7373peg-3769PE2max85420.28740.11200.1997peg-3782PE2max74420.00000.20560.1028peg-3792PE2max74430.00000.52980.2649peg-3793PE2max80193.92160.00001.9608peg-3797PE2max87620.21230.00000.1062peg-3799PE2max73830.2430-0.09750.0728peg-3810PE2max87410.09370.00000.0469peg-3813PE2max80202.26761.38681.8272peg-3817PE2max65991.38120.00000.6906peg-3818PE2max73840.00000.25770.1289peg-3819PE2max87420.00000.18020.0901peg-3824PE2max8743-0.08130.24790.0833peg-3841PE2max77960.78130.00000.3906peg-3842PE2max86710.00001.18340.5917peg-3850PE2max80000.65790.34720.5026peg-3854PE2max87630.00000.33560.1678peg-3859PE2max80010.58312.31091.4470peg-3868PE2max80020.32150.18900.2553peg-3875PE2max73850.00000.40320.2016peg-3879PE2max80030.00000.55870.2793peg-3880PE2max77990.00000.48660.2433peg-3885PE2max87460.07750.00000.0388peg-3888PE2max80214.60531.48513.0452peg-3889PE2max78000.42920.00000.2146peg-3894PE2max66010.00000.24810.1241peg-3902PE2max78010.00000.38310.1916peg-3903PE2max87030.34840.00000.1742peg-3911PE2max74480.00000.54640.2732peg-3912PE2max80222.29013.33332.8117peg-3919PE2max80040.48082.67181.5763peg-3927PE2max73170.00000.16640.0832peg-3928PE2max80050.00000.97560.4878peg-3929PE2max78021.14940.00000.5747peg-3930PE2max86740.98040.00000.4902peg-3934PE2max74490.00000.30670.1534peg-3935PE2max80061.13640.00000.5682peg-3936PE2max78030.00000.48190.2410peg-3944PE2max80070.79640.07360.4350peg-3955PE2max80080.40650.00000.2033peg-3956PE2max78041.00500.00000.5025peg-3959PE2max87640.3735-0.08010.1467peg-3973PE2max78060.33000.00000.1650peg-3981PE2max80090.00000.37040.1852peg-3985PE2max62760.42550.00000.2128peg-3986PE2max87490.00000.10470.0524peg-3987PE2max73180.12050.08670.1036peg-3989PE2max80100.33360.00310.1683peg-3991PE2max87060.00000.21870.1093peg-3993PE2max62770.76920.00000.3846peg-3997PE2max80231.68070.37111.0259peg-3999PE2max86770.00000.25770.1289peg-4008PE2max80110.00000.32360.1618peg-4009PE2max78070.82640.00000.4132peg-4010PE2max86781.15830.00000.5792peg-4014PE2max66031.29870.00000.6494peg-4023PE2max80120.00000.55250.2762peg-4031PE2max80130.65360.00000.3268peg-4040PE2max74511.06010.00000.5300peg-4041PE2max80240.00001.73610.8681peg-4042PE2max78080.37170.00000.1859peg-4048PE2max87520.00000.14270.0713peg-4050PE2max80140.77220.00000.3861peg-4060PE2max62800.59700.40080.4989peg-4065PE2max80253.14140.00001.5707peg-4072PE2max87540.00000.32410.1621peg-4077PE2max86810.43670.30860.3727peg-4081PE2max62810.31150.00000.1558peg-4085PE2max80151.03311.68631.3597peg-4091PE2max8016-0.31800.37070.0264peg-4096PE2max80263.5327-0.36501.5839peg-4097PE2max78110.49260.00000.2463peg-4104PE2max78120.00000.84030.4202.

[0492]

[0493] LabelPE proteinSEQ ID NOof pegRNAPrime editing efficiency,1st rep (%)Prime editing efficiency,2nd rep (%)Average prime editing efficiency (%)peg-0001NRCH-hyPE2max75940.22620.11440.1703peg-0002NRCH-hyPE2max75950.02860.05200.0403peg-0004NRCH-hyPE2max7596-0.11210.17940.0337peg-0005NRCH-hyPE2max75970.18520.11640.1508peg-0006NRCH-hyPE2max71660.0295-0.01380.0079peg-0008NRCH-hyPE2max8027-0.00330.03960.0181peg-0009NRCH-hyPE2max75980.05650.01410.0353peg-0010NRCH-hyPE2max60580.09580.03100.0634peg-0011NRCH-hyPE2max75990.12340.01130.0673peg-0012NRCH-hyPE2max7025-0.00730.20850.1006peg-0014NRCH-hyPE2max6059-0.00820.17440.0831peg-0015NRCH-hyPE2max76010.06980.11970.0947peg-0016NRCH-hyPE2max82660.1564-0.01530.0706peg-0017NRCH-hyPE2max7167-0.00720.01800.0054peg-0019NRCH-hyPE2max76020.04070.18600.1133peg-0020NRCH-hyPE2max71680.0300-0.01350.0083peg-0021NRCH-hyPE2max60600.27500.17200.2235peg-0022NRCH-hyPE2max80290.01500.04680.0309peg-0023NRCH-hyPE2max60610.09530.51020.3027peg-0024NRCH-hyPE2max76030.00000.12780.0639peg-0025NRCH-hyPE2max76040.05740.04160.0495peg-0027NRCH-hyPE2max60620.31010.11200.2111peg-0028NRCH-hyPE2max76050.00000.03050.0153peg-0029NRCH-hyPE2max82670.00000.05460.0273peg-0030NRCH-hyPE2max67380.12330.36660.2450peg-0031NRCH-hyPE2max71690.12120.15260.1369peg-0032NRCH-hyPE2max70260.08080.07760.0792peg-0034NRCH-hyPE2max76060.06520.10280.0840peg-0035NRCH-hyPE2max82680.00000.12090.0605peg-0036NRCH-hyPE2max7170-0.01040.06720.0284peg-0037NRCH-hyPE2max70270.10640.39160.2490peg-0038NRCH-hyPE2max60630.23570.31580.2758peg-0039NRCH-hyPE2max80300.0539-0.00530.0243peg-0040NRCH-hyPE2max71710.1679-0.00980.0791peg-0041NRCH-hyPE2max60640.37410.20250.2883peg-0042NRCH-hyPE2max80310.06720.02460.0459peg-0043NRCH-hyPE2max76070.01810.03580.0269peg-0044NRCH-hyPE2max76080.01350.11650.0650peg-0045NRCH-hyPE2max82690.02390.05480.0394peg-0046NRCH-hyPE2max82700.03470.03780.0362peg-0049NRCH-hyPE2max60650.23520.26490.2501peg-0050NRCH-hyPE2max71730.09820.22670.1624peg-0051NRCH-hyPE2max7174-0.02340.04230.0095peg-0052NRCH-hyPE2max67390.07080.14260.1067peg-0053NRCH-hyPE2max70280.06700.11370.0904peg-0055NRCH-hyPE2max80320.01300.00000.0065peg-0056NRCH-hyPE2max76100.13100.05330.0921peg-0057NRCH-hyPE2max82710.10210.04840.0752peg-0058NRCH-hyPE2max67400.00000.44760.2238peg-0059NRCH-hyPE2max70290.37890.01510.1970peg-0060NRCH-hyPE2max60660.03580.31830.1771peg-0061NRCH-hyPE2max80330.00830.00570.0070peg-0064NRCH-hyPE2max70300.09520.18130.1383peg-0065NRCH-hyPE2max60671.47921.46281.4710peg-0066NRCH-hyPE2max80340.01940.02210.0207peg-0067NRCH-hyPE2max76110.04040.04980.0451peg-0068NRCH-hyPE2max60680.69500.66060.6778peg-0069NRCH-hyPE2max80350.18420.06620.1252peg-0070NRCH-hyPE2max76120.0519-0.03780.0071peg-0071NRCH-hyPE2max76130.34430.22430.2843peg-0072NRCH-hyPE2max60691.38101.48201.4315peg-0074NRCH-hyPE2max67410.24230.74290.4926peg-0075NRCH-hyPE2max80360.02170.03970.0307peg-0077NRCH-hyPE2max80370.39670.05360.2252peg-0078NRCH-hyPE2max82720.13180.03160.0817peg-0079NRCH-hyPE2max7614-0.00780.01630.0043peg-0080NRCH-hyPE2max74520.0800-0.00820.0359peg-0081NRCH-hyPE2max82730.18250.00000.0912peg-0082NRCH-hyPE2max67420.09910.24900.1741peg-0083NRCH-hyPE2max70310.19700.05040.1237peg-0084NRCH-hyPE2max80380.23260.01830.1255peg-0085NRCH-hyPE2max7615-0.00800.09910.0455peg-0086NRCH-hyPE2max82740.20580.06110.1335peg-0087NRCH-hyPE2max67430.09250.44390.2682peg-0089NRCH-hyPE2max70320.25420.02630.1403peg-0090NRCH-hyPE2max60700.49290.08000.2865peg-0092NRCH-hyPE2max82750.12690.09310.1100peg-0093NRCH-hyPE2max71780.32220.07550.1988peg-0094NRCH-hyPE2max70330.14830.19740.1729peg-0095NRCH-hyPE2max80390.02920.04010.0346peg-0096NRCH-hyPE2max76160.19630.08590.1411peg-0097NRCH-hyPE2max71790.00000.07360.0368peg-0098NRCH-hyPE2max70340.00950.08660.0481peg-0099NRCH-hyPE2max60710.57240.78210.6773peg-0100NRCH-hyPE2max76170.00170.11230.0570peg-0102NRCH-hyPE2max60721.11841.30251.2105peg-0103NRCH-hyPE2max80400.04380.00000.0219peg-0104NRCH-hyPE2max76180.02430.09670.0605peg-0105NRCH-hyPE2max60730.16290.19140.1771peg-0106NRCH-hyPE2max76190.08990.05350.0717peg-0108NRCH-hyPE2max82760.00000.02870.0144peg-0109NRCH-hyPE2max60741.90131.73741.8193peg-0110NRCH-hyPE2max60750.59080.32730.4591peg-0111NRCH-hyPE2max60760.85220.87310.8626peg-0112NRCH-hyPE2max76200.01650.00290.0097peg-0113NRCH-hyPE2max7453-0.05020.08500.0174peg-0114NRCH-hyPE2max82770.00670.01000.0083peg-0115NRCH-hyPE2max67440.37420.23000.3021peg-0119NRCH-hyPE2max60770.0459-0.01790.0140peg-0120NRCH-hyPE2max80410.01210.03380.0230peg-0121NRCH-hyPE2max7621-0.01850.20910.0953peg-0122NRCH-hyPE2max74540.0781-0.05820.0099peg-0123NRCH-hyPE2max82780.02980.08260.0562peg-0124NRCH-hyPE2max67450.44230.29860.3705peg-0125NRCH-hyPE2max71800.17530.00000.0877peg-0126NRCH-hyPE2max70360.07710.10140.0892peg-0128NRCH-hyPE2max76220.00000.08010.0401peg-0129NRCH-hyPE2max82790.02420.00000.0121peg-0130NRCH-hyPE2max67460.06330.21670.1400peg-0131NRCH-hyPE2max7181-0.01140.09040.0395peg-0132NRCH-hyPE2max70370.78280.39270.5878peg-0133NRCH-hyPE2max60790.16580.55370.3598peg-0134NRCH-hyPE2max80420.03670.17940.1081peg-0136NRCH-hyPE2max67470.04170.23920.1404peg-0138NRCH-hyPE2max70380.08100.00780.0444peg-0139NRCH-hyPE2max60801.0190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1NRCH-hyPE2max62750.00000.56500.2825peg-3956NRCH-hyPE2max78041.01010.00000.5051peg-3961NRCH-hyPE2max66020.00000.20490.1025peg-3968NRCH-hyPE2max78050.42020.00000.2101peg-3973NRCH-hyPE2max78060.42740.00000.2137peg-3974NRCH-hyPE2max86760.00000.23750.1188peg-3977NRCH-hyPE2max85460.00000.58390.2920peg-3978NRCH-hyPE2max87480.00000.44640.2232peg-3980NRCH-hyPE2max74502.67860.00001.3393peg-3991NRCH-hyPE2max87060.00000.07010.0350peg-3992NRCH-hyPE2max87650.00000.35970.1799peg-3993NRCH-hyPE2max62771.55440.63091.0927peg-3999NRCH-hyPE2max86770.14660.09330.1200peg-4005NRCH-hyPE2max87500.00000.24810.1241peg-4008NRCH-hyPE2max80110.00000.26530.1326peg-4010NRCH-hyPE2max86780.90500.00000.4525peg-4023NRCH-hyPE2max80120.00000.66230.3311peg-4031NRCH-hyPE2max80130.00000.81630.4082peg-4033NRCH-hyPE2max86790.00000.23750.1188peg-4037NRCH-hyPE2max62781.93551.20971.5726peg-4038NRCH-hyPE2max87510.29240.00000.1462peg-4040NRCH-hyPE2max74510.00000.86390.4320peg-4042NRCH-hyPE2max78080.00000.27860.1393peg-4044NRCH-hyPE2max87660.79370.00000.3968peg-4048NRCH-hyPE2max87520.22620.00000.1131peg-4050NRCH-hyPE2max80140.66450.23920.4518peg-4051NRCH-hyPE2max78090.25970.00000.1299peg-4058NRCH-hyPE2max62790.90910.75190.8305peg-4060NRCH-hyPE2max62800.56340.38760.4755peg-4065NRCH-hyPE2max80252.23880.41841.3286peg-4066NRCH-hyPE2max87530.00000.04620.0231peg-4070NRCH-hyPE2max86800.00000.25250.1263peg-4077NRCH-hyPE2max86810.00000.37450.1873peg-4081NRCH-hyPE2max62810.31350.00000.1567peg-4085NRCH-hyPE2max80150.5621-0.13810.2120peg-4086NRCH-hyPE2max78100.55250.00000.2762peg-4087NRCH-hyPE2max87070.00001.16280.5814peg-4090NRCH-hyPE2max73190.00000.31350.1567peg-4099NRCH-hyPE2max87080.00000.40570.2028peg-4100NRCH-hyPE2max87670.24450.00000.1222peg-4102NRCH-hyPE2max87550.25640.00000.1282peg-4106NRCH-hyPE2max87680.00000.09830.0492peg-4107NRCH-hyPE2max62820.3980-0.29850.0498peg-4109NRCH-hyPE2max8769-0.11950.44620.1633peg-4112NRCH-hyPE2max73220.00001.22950.6148.

[0494]

[0495] 실험예 4.2. 실험예 3에 사용돤 pegRNA 및 결과 데이터

[0496] The pegRNA and result data used in Experimental Example 3 are summarized in the table below:

[0497] LabelPE proteinSEQ ID NOof pegRNAPrime editing efficiency,1st rep (%)Prime editing efficiency,2nd rep (%)Average prime editing efficiency (%)peg-3299-tmpknotNRCH PE2Max87933.06510.10021.5827peg-3299-tmpknotNRCH PE287930.16960.58310.3763peg-3625-tmpknotNRCH PE288029.09733.71656.4069peg-2563-tmpknotNRCH PE287842.34040.07311.2067peg-4112-tmpknotNRCH PE288120.88170.27090.5763peg-3888-tmpknotPE2max88061.65241.82551.7389peg-3997-tmpknotPE2max88081.27300.49830.8857peg-3912-tmpknotPE2max88079.50549.37799.4417peg-3349-tmpknotPE2max87951.91226.05173.9820peg-3793-tmpknotPE2max88042.92200.03301.4775peg-3813-tmpknotPE2max88056.13651.84043.9884peg-3309-tmpknotPE2max87942.27423.34632.8103peg-4041-tmpknotPE2max88090.77931.41101.0951peg-4096-tmpknotPE2max88111.99760.26901.1333peg-4065-tmpknotPE2max881011.14140.63205.8867peg-deeprime-3-1-tmpNRCH PE2Max88138.66650.80784.7371peg-deeprime-3-1-tmpNRCH PE288135.60850.13102.8697peg-deeprime-3-2-tmpNRCH PE288140.95441.21331.0839peg-deeprime-3-3-tmpNRCH PE288150.47612.93231.7042peg-3550-tmpknotNRCH PE2879914.274026.625220.4496peg-3550-tmpknotNRCH PE2Max87993.98612.29583.1409peg-3294-tmpknotNRCH PE287923.11857.56125.3398peg-3438-tmpknotNRCH PE287960.68232.27641.4793peg-2611-tmpknotNRCH PE287854.06302.10263.0828peg-2122-tmpknotNRCH PE2Max87792.34448.91615.6302peg-2122-tmpknotNRCH PE287792.63763.70323.1704peg-2034-tmpknotNRCH PE287781.31725.77653.5468peg-2171-tmpknotPE2max87812.44570.99341.7195peg-3133-tmpknotNRCH PE287892.14260.28231.2124peg-2130-tmpknotNRCH PE2878039.67155.340022.5057peg-3285-tmpknotPE2max879115.40101.08978.2454peg-3107-tmpknotPE2max87882.65661.81242.2345peg-1889-tmpknotPE2max87772.80742.46472.6360peg-3493-tmpknotNRCH PE287986.18031.40913.7947peg-3493-tmpknotNRCH PE2Max87983.66662.91903.2928peg-3250-tmpknotNRCH PE287901.34620.71911.0327peg-2527-tmpknotNRCH PE287833.21800.02301.6205peg-2423-tmpknotNRCH PE287822.89930.23301.5662peg-0257-tmpknotNRCH PE2Max87744.86880.01312.4409peg-0257-tmpknotNRCH PE287742.16760.70001.4338peg-0418-tmpknotNRCH PE287754.17320.05472.1140peg-0191-tmpknotNRCH PE287732.00440.92761.4660peg-0886-tmpknotNRCH PE287763.45750.36641.9120peg-3454-tmpknotNRCH PE287972.86940.77981.8246peg-3454-tmpknotNRCH PE2Max87973.07390.11561.5947peg-3086-tmpknotNRCH PE287873.50245.07194.2872peg-3791-tmpknotNRCH PE288030.856113.16827.0122peg-3596-tmpknotNRCH PE288001.10730.05320.5802peg-3606-tmpknotNRCH PE288010.04030.66650.3534peg-2960-tmpknotNRCH PE287864.16244.77404.4682.

[0498]

[0499] The prime editor disclosed herein can act on human retinal cells containing the c.4957dupA mutation in the EYS gene, thereby correcting the EYS gene to a normal state. Therefore, the prime editor can be used as a therapeutic agent for retinitis pigmentosa caused by the c.4957dupA mutation in the EYS gene.

[0500]

[0501] The following is a list of sequences containing fewer than 10 nucleotides or fewer than 4 amino acids. A list of sequences containing more than 10 nucleotides or more than 4 amino acids is provided in the sequence listing file attached to this specification. In accordance with the ST26 sequence listing standard, both DNA and RNA are listed using the symbols A, T, C, and G. In the table below, if the Type column is RNA, the base corresponding to T in the sequence should be understood to mean uracil (U):

[0502] TypeSequenceDescriptionSEQ ID NORNATACAACAAlinker for tmpknot7RNAAATAATGClinker for tmpknot8RNACCCAGCTTlinker for tmpknot9RNAAGATAAGClinker for tmpknot10RNAGGGCAAATlinker for tmpknot11RNAAAGTGAGAlinker for tmpknot12RNACACAGAAAlinker for tmpknot13RNAAATAACAAlinker for tmpknot14RNAAACGACGClinker for tmpknot15RNAAAAGAAGAlinker for tmpknot16RNACACAGCATlinker for tmpknot17RNAAAGTAGAClinker for tmpknot18RNAAAGAAAGAlinker for tmpknot19RNAAGCATAGAlinker for tmpknot20RNAACCGCATAlinker for tmpknot21RNACCAGCCTClinker for tmpknot22RNACCCATATAlinker for tmpknot23RNACTCCACGClinker for tmpknot24RNACTAAATAAlinker for tmpknot25RNAAATATATAlinker for tmpknot26RNACCAAACAClinker for tmpknot27RNATCGCTACTlinker for tmpknot28RNAATATACGTlinker for tmpknot29RNACAATTTATlinker for tmpknot30RNACTTCATAAlinker for tmpknot31RNAATATACTTlinker for tmpknot32RNATTACAAATlinker for tmpknot33RNAATAAATAAlinker for tmpknot34RNACACATATAlinker for tmpknot35RNAATTATTAClinker for tmpknot36RNAACAAATTAlinker fortmpknot37RNACAAATAGClinker for tmpknot38RNACCATATTAlinker for tmpknot39RNAATCCCTAAlinker for tmpknot40RNATAAGGTAClinker for tmpknot41RNATTATAAGAlinker for tmpknot42RNATAAAGTGAlinker for tmpknot43RNACTCCAGGAlinker for tmpknot44RNAAGGACAGClinker for tmpknot45RNAAGATAGCTlinker for tmpknot46RNAAGAACGGAlinker for tmpknot47RNATTGATAGsequence of primer binding site of pegRNA No:0010628RNATTGATAsequence of primer binding site of pegRNA No:0014629RNATTGATAGsequence of primer binding site of pegRNA No:0021630RNATTGATAGGsequence of primer binding site of pegRNA No:0023631RNATTGATAGGGsequence of primer binding site of pegRNA No:0027632RNATTGATAGsequence of primer binding site of pegRNA No:0038633RNATTGATAGGsequence of primer binding site of pegRNA No:0041634RNATTGATAGsequence of primer binding site of pegRNA No:0060636RNATTGATAGGsequence of primer binding site of pegRNA No:0065637RNATTGATAGGGsequence of primer binding site of pegRNA No:0068638RNATTGATAGGsequence of primer binding site of pegRNANo:0072639RNATTGATAGsequence of primer binding site of pegRNA No:0090640RNATTGATAGGGsequence of primer binding site of pegRNA No:0099641RNATTGATAsequence of primer binding site of pegRNA No:0119647RNATTGATAGsequence of primer binding site of pegRNA No:0127648RNATTGATAGGsequence of primer binding site of pegRNA No:0133649RNATTGATAGGGsequence of primer binding site of pegRNA No:0139650RNATTGATAGsequence of primer binding site of pegRNA No:0174651RNATTGATAGGsequence of primer binding site of pegRNA No:0182652RNATTGATAGGGsequence of primer binding site of pegRNA No:0188653RNATTGATAsequence of primer binding site of pegRNA No:0223658RNATTGATAGGsequence of primer binding site of pegRNA No:0238659RNATTGATAGGGsequence of primer binding site of pegRNA No:0245660RNATTGATAsequence of primer binding site of pegRNA No:0273664RNATTGATAGsequence of primer binding site of pegRNA No:0291665RNATTGATAGGsequence of primer binding site of pegRNA No:0300666RNATTGATAGGGsequence of primer binding site ofpegRNA No:0309667RNATTGATAGsequence of primer binding site of pegRNA No:0376673RNATTGATAGGsequence of primer binding site of pegRNA No:0386674RNATTGATAGGGsequence of primer binding site of pegRNA No:0394675RNATTGATAGGsequence of primer binding site of pegRNA No:0431682RNATTGATAsequence of primer binding site of pegRNA No:0453683RNATTGATAGsequence of primer binding site of pegRNA No:0462684RNATTGATAGGGsequence of primer binding site of pegRNA No:0481685RNATTGATAGGsequence of primer binding site of pegRNA No:0535694RNATTGATAGGGsequence of primer binding site of pegRNA No:0588696RNATTGATAGsequence of primer binding site of pegRNA No:0659704RNATTGATAGGGsequence of primer binding site of pegRNA No:0700706RNATTGATAGGsequence of primer binding site of pegRNA No:0811715RNATTGATAGGGsequence of primer binding site of pegRNA No:0819716RNATTGATAGGGsequence of primer binding site of pegRNA No:0945724RNAAAGGATsequence of primer binding site of pegRNA No:2075768RNAAAGGATGsequence of primer bindingsite of pegRNA No:2083769RNAAAGGATGAsequence of primer binding site of pegRNA No:2169770RNAAAGGATGsequence of primer binding site of pegRNA No:2187771RNAAAGGATGAGsequence of primer binding site of pegRNA No:2264772RNAAAGGATGsequence of primer binding site of pegRNA No:2283773RNAAAGGATGAsequence of primer binding site of pegRNA No:2381774RNAAAGGATGAGsequence of primer binding site of pegRNA No:2493776RNAAAGGATsequence of primer binding site of pegRNA No:2579779RNAAAGGATGAsequence of primer binding site of pegRNA No:2599780RNAAAGGATGAsequence of primer binding site of pegRNA No:2662785RNAAAGGATGsequence of primer binding site of pegRNA No:2796789RNAAAGGATGAsequence of primer binding site of pegRNA No:2804790RNAAAGGATGAGsequence of primer binding site of pegRNA No:2817791RNAAAGGATsequence of primer binding site of pegRNA No:3038804RNAAAGGATGsequence of primer binding site of pegRNA No:3050805RNAAAGGATGAsequence of primer binding site of pegRNA No:3259812RNAAAGGATGAsequence of primerbinding site of pegRNA No:3425817RNAAAGGATGAGsequence of primer binding site of pegRNA No:3434818RNAAAGGATGAGsequence of primer binding site of pegRNA No:3547824RNAGATTCTsequence of primer binding site of pegRNA No:0791859RNAGATTCTsequence of primer binding site of pegRNA No:0910860RNAGATTCTTsequence of primer binding site of pegRNA No:0921861RNAGATTCTTCsequence of primer binding site of pegRNA No:1008862RNAGATTCTsequence of primer binding site of pegRNA No:1035863RNAGATTCTTCsequence of primer binding site of pegRNA No:1160864RNAGATTCTsequence of primer binding site of pegRNA No:1166865RNAGATTCTTsequence of primer binding site of pegRNA No:1174866RNAGATTCTTCCsequence of primer binding site of pegRNA No:1190867RNAGATTCTTsequence of primer binding site of pegRNA No:1296868RNAGATTCTTCsequence of primer binding site of pegRNA No:1303869RNAGATTCTTCCsequence of primer binding site of pegRNA No:1311870RNAGATTCTTCsequence of primer binding site of pegRNA No:1390872RNAGATTCTsequence of primerbinding site of pegRNA No:1412873RNAGATTCTTsequence of primer binding site of pegRNA No:1416874RNAGATTCTTCCsequence of primer binding site of pegRNA No:1430875RNAGATTCTsequence of primer binding site of pegRNA No:1542878RNAGATTCTTsequence of primer binding site of pegRNA No:1546879RNAGATTCTTCsequence of primer binding site of pegRNA No:1550880RNAGATTCTTCCsequence of primer binding site of pegRNA No:1557881RNAGATTCTTsequence of primer binding site of pegRNA No:1666885RNAGATTCTTCsequence of primer binding site of pegRNA No:1670886RNAGATTCTTCCsequence of primer binding site of pegRNA No:1675887RNAGATTCTTsequence of primer binding site of pegRNA No:1770892RNAGATTCTTCsequence of primer binding site of pegRNA No:1773893RNAGATTCTTCsequence of primer binding site of pegRNA No:1861898RNAGATTCTTCCsequence of primer binding site of pegRNA No:1863899RNAGATTCTsequence of primer binding site of pegRNA No:1866900RNAGATTCTTsequence of primer binding site of pegRNA No:1873901RNAGATTCTsequence of primerbinding site of pegRNA No:1984906RNAGATTCTTsequence of primer binding site of pegRNA No:1989907RNAGATTCTTsequence of primer binding site of pegRNA No:2078915RNAGATTCTTCsequence of primer binding site of pegRNA No:2085916RNAGATTCTTCCsequence of primer binding site of pegRNA No:2092917RNAGATTCTsequence of primer binding site of pegRNA No:2175925RNAGATTCTTCsequence of primer binding site of pegRNA No:2189926RNAGATTCTTCCsequence of primer binding site of pegRNA No:2193927RNAGATTCTTCCsequence of primer binding site of pegRNA No:2265935RNAGATTCTTsequence of primer binding site of pegRNA No:2278936RNAGATTCTTCsequence of primer binding site of pegRNA No:2287937RNAGATTCTTCsequence of primer binding site of pegRNA No:2354944RNAGATTCTTCCsequence of primer binding site of pegRNA No:2383946RNAGATTCTTCCsequence of primer binding site of pegRNA No:2490951RNATCTTCCsequence of primer binding site of pegRNA No:1290996RNATCTTCCAsequence of primer binding site of pegRNA No:1298997RNATCTTCCsequence ofprimer binding site of pegRNA No:1400998RNATCTTCCAsequence of primer binding site of pegRNA No:1417999RNATCTTCCAAsequence of primer binding site of pegRNA No:14241000RNATCTTCCsequence of primer binding site of pegRNA No:15241001RNATCTTCCAsequence of primer binding site of pegRNA No:15471002RNATCTTCCAAsequence of primer binding site of pegRNA No:15521003RNATCTTCCAAGsequence of primer binding site of pegRNA No:16471004RNATCTTCCsequence of primer binding site of pegRNA No:16631005RNATCTTCCAAsequence of primer binding site of pegRNA No:16721006RNATCTTCCAsequence of primer binding site of pegRNA No:17471008RNATCTTCCsequence of primer binding site of pegRNA No:17541009RNATCTTCCAAsequence of primer binding site of pegRNA No:17561010RNATCTTCCAAGsequence of primer binding site of pegRNA No:17781011RNATCTTCCsequence of primer binding site of pegRNA No:18681014RNATCTTCCAAsequence of primer binding site of pegRNA No:18801015RNATCTTCCsequence of primer binding site of pegRNANo:19861020RNATCTTCCAAGsequence of primer binding site of pegRNA No:20041021RNATCTTCCAAGsequence of primer binding site of pegRNA No:20941025RNATCTTCCAsequence of primer binding site of pegRNA No:21841030RNATCTTCCAAsequence of primer binding site of pegRNA No:21901031RNATCTTCCAAGsequence of primer binding site of pegRNA No:21951032RNATCTTCCAsequence of primer binding site of pegRNA No:22791038RNATCTTCCAAsequence of primer binding site of pegRNA No:22881039RNATCTTCCsequence of primer binding site of pegRNA No:23411046RNATCTTCCAsequence of primer binding site of pegRNA No:23701048RNATCTTCCAAsequence of primer binding site of pegRNA No:23771049RNATCTTCCAsequence of primer binding site of pegRNA No:24761057RNACCAAGGAsequence of primer binding site of pegRNA No:17711115RNACCAAGGsequence of primer binding site of pegRNA No:18691116RNACCAAGGAsequence of primer binding site of pegRNA No:18751117RNACCAAGGATGsequence of primer binding site of pegRNA No:20051118RNACCAAGGATsequence of primerbinding site of pegRNA No:20871119RNACCAAGGsequence of primer binding site of pegRNA No:21551120RNACCAAGGATsequence of primer binding site of pegRNA No:21911121RNACCAAGGsequence of primer binding site of pegRNA No:22721124RNACCAAGGATsequence of primer binding site of pegRNA No:22891125RNACCAAGGATGsequence of primer binding site of pegRNA No:22911126RNACCAAGGAsequence of primer binding site of pegRNA No:23531128RNACCAAGGATGsequence of primer binding site of pegRNA No:23851129RNACCAAGGATsequence of primer binding site of pegRNA No:24421132RNACCAAGGAsequence of primer binding site of pegRNA No:24461133RNACCAAGGATGsequence of primer binding site of pegRNA No:24551134RNACCAAGGsequence of primer binding site of pegRNA No:24711135RNACCAAGGsequence of primer binding site of pegRNA No:26741140RNACCAAGGAsequence of primer binding site of pegRNA No:26851141RNACCAAGGATsequence of primer binding site of pegRNA No:26961142RNACCAAGGATGsequence of primer binding site of pegRNANo:27041143RNACCAAGGsequence of primer binding site of pegRNA No:27831148RNACCAAGGATsequence of primer binding site of pegRNA No:30581154RNATAATGGsequence of primer binding site of pegRNA No:03451174RNATAATGGAsequence of primer binding site of pegRNA No:03781175RNATAATGGsequence of primer binding site of pegRNA No:04541176RNATAATGGAsequence of primer binding site of pegRNA No:04631177RNATAATGGATsequence of primer binding site of pegRNA No:04721178RNATAATGGsequence of primer binding site of pegRNA No:05361179RNATAATGGAsequence of primer binding site of pegRNA No:05731180RNATAATGGATsequence of primer binding site of pegRNA No:05811181RNATAATGGAsequence of primer binding site of pegRNA No:06801182RNATAATGGATsequence of primer binding site of pegRNA No:06921183RNATAATGGATTsequence of primer binding site of pegRNA No:07021184RNATAATGGATTsequence of primer binding site of pegRNA No:07781186RNATAATGGsequence of primer binding site of pegRNA No:07941187RNATAATGGAsequence of primer binding siteof pegRNA No:08021188RNATAATGGATsequence of primer binding site of pegRNA No:08131189RNATAATGGATTsequence of primer binding site of pegRNA No:08931192RNATAATGGAsequence of primer binding site of pegRNA No:09021193RNATAATGGsequence of primer binding site of pegRNA No:09131195RNATAATGGATsequence of primer binding site of pegRNA No:09351196RNATAATGGATTsequence of primer binding site of pegRNA No:10061198RNATAATGGsequence of primer binding site of pegRNA No:10381200RNATAATGGAsequence of primer binding site of pegRNA No:10461201RNATAATGGATsequence of primer binding site of pegRNA No:10541202RNATAATGGsequence of primer binding site of pegRNA No:11701205RNATAATGGAsequence of primer binding site of pegRNA No:11771206RNATAATGGATsequence of primer binding site of pegRNA No:11841207RNATAATGGsequence of primer binding site of pegRNA No:12721212RNATAATGGATTsequence of primer binding site of pegRNA No:12761213RNATAATGGATsequence of primer binding site of pegRNA No:13051214RNATAATGGAsequence ofprimer binding site of pegRNA No:14191219RNATAATGGATsequence of primer binding site of pegRNA No:14261220RNATAATGGATTsequence of primer binding site of pegRNA No:14331221RNATAATGGAsequence of primer binding site of pegRNA No:15111228RNATAATGGATsequence of primer binding site of pegRNA No:15291230RNATAATGGsequence of primer binding site of pegRNA No:15371231RNATAATGGATTsequence of primer binding site of pegRNA No:15611232RNATAATGGsequence of primer binding site of pegRNA No:16321237RNATAATGGATsequence of primer binding site of pegRNA No:16371238RNATAATGGATTsequence of primer binding site of pegRNA No:16481239RNATAATGGAsequence of primer binding site of pegRNA No:16691240RNATAATGGATsequence of primer binding site of pegRNA No:17571247RNATAATGGAsequence of primer binding site of pegRNA No:17581248RNATAATGGATTsequence of primer binding site of pegRNA No:17791250RNATAATGGATTsequence of primer binding site of pegRNA No:18621257RNATAATGGATsequence of primer binding site of pegRNANo:18821258RNATAATGGATTsequence of primer binding site of pegRNA No:20061267RNAAATTTGsequence of primer binding site of pegRNA No:00301308RNAAATTTGsequence of primer binding site of pegRNA No:00521309RNAAATTTGGsequence of primer binding site of pegRNA No:00581310RNAAATTTGGAsequence of primer binding site of pegRNA No:00741311RNAAATTTGsequence of primer binding site of pegRNA No:00821312RNAAATTTGGsequence of primer binding site of pegRNA No:00871313RNAAATTTGsequence of primer binding site of pegRNA No:01151314RNAAATTTGGsequence of primer binding site of pegRNA No:01241315RNAAATTTGGAsequence of primer binding site of pegRNA No:01301316RNAAATTTGGATsequence of primer binding site of pegRNA No:01361317RNAAATTTGGsequence of primer binding site of pegRNA No:01571318RNAAATTTGsequence of primer binding site of pegRNA No:01641319RNAAATTTGGAsequence of primer binding site of pegRNA No:01791320RNAAATTTGGATsequence of primer binding site of pegRNA No:01861321RNAAATTTGsequence of primer binding siteof pegRNA No:02121323RNAAATTTGGsequence of primer binding site of pegRNA No:02261325RNAAATTTGGAsequence of primer binding site of pegRNA No:02351326RNAAATTTGGATsequence of primer binding site of pegRNA No:02431327RNAAATTTGsequence of primer binding site of pegRNA No:02781329RNAAATTTGGsequence of primer binding site of pegRNA No:02861330RNAAATTTGGAsequence of primer binding site of pegRNA No:02951331RNAAATTTGGATsequence of primer binding site of pegRNA No:03051332RNAAATTTGGsequence of primer binding site of pegRNA No:03481335RNAAATTTGsequence of primer binding site of pegRNA No:03631338RNAAATTTGGAsequence of primer binding site of pegRNA No:03821339RNAAATTTGsequence of primer binding site of pegRNA No:04341342RNAAATTTGGsequence of primer binding site of pegRNA No:04591343RNAAATTTGGAsequence of primer binding site of pegRNA No:04661344RNAAATTTGGATsequence of primer binding site of pegRNA No:04761345RNAAATTTGGsequence of primer binding site of pegRNA No:05481352RNAAATTTGsequence of primerbinding site of pegRNA No:05541354RNAAATTTGGAsequence of primer binding site of pegRNA No:05771355RNAAATTTGGATsequence of primer binding site of pegRNA No:05851356RNAAATTTGGsequence of primer binding site of pegRNA No:06551361RNAAATTTGsequence of primer binding site of pegRNA No:06631362RNAAATTTGGAsequence of primer binding site of pegRNA No:06841363RNAAATTTGGATsequence of primer binding site of pegRNA No:06961364RNAAATTTGGAsequence of primer binding site of pegRNA No:07611372RNAAATTTGGATsequence of primer binding site of pegRNA No:07641373RNAAATTTGGsequence of primer binding site of pegRNA No:07681374RNAAATTTGsequence of primer binding site of pegRNA No:07871376RNAAATTTGsequence of primer binding site of pegRNA No:08841384RNAAATTTGGsequence of primer binding site of pegRNA No:09171386RNAAATTTGGAsequence of primer binding site of pegRNA No:09271387RNAAATTTGGATsequence of primer binding site of pegRNA No:09381388RNAAATTTGGATsequence of primer binding site of pegRNANo:10091397RNAAATTTGGAsequence of primer binding site of pegRNA No:10231400RNAAATTTGGsequence of primer binding site of pegRNA No:10411401RNAAATTTGGAsequence of primer binding site of pegRNA No:11791408RNAAATTTGGATsequence of primer binding site of pegRNA No:13081417RNAGGGTAAsequence of primer binding site of pegRNA No:01181455RNAGGGTAATsequence of primer binding site of pegRNA No:01551456RNAGGGTAAsequence of primer binding site of pegRNA No:01681457RNAGGGTAAsequence of primer binding site of pegRNA No:02221458RNAGGGTAATsequence of primer binding site of pegRNA No:02301459RNAGGGTAATGsequence of primer binding site of pegRNA No:02371460RNAGGGTAAsequence of primer binding site of pegRNA No:02821461RNAGGGTAATsequence of primer binding site of pegRNA No:02901462RNAGGGTAATGsequence of primer binding site of pegRNA No:02991463RNAGGGTAATGGsequence of primer binding site of pegRNA No:03081464RNAGGGTAAsequence of primer binding site of pegRNA No:03661465RNAGGGTAATsequence of primer binding siteof pegRNA No:03751466RNAGGGTAATGsequence of primer binding site of pegRNA No:03851467RNAGGGTAATGGsequence of primer binding site of pegRNA No:03931468RNAGGGTAAsequence of primer binding site of pegRNA No:04521470RNAGGGTAATsequence of primer binding site of pegRNA No:04611471RNAGGGTAATGsequence of primer binding site of pegRNA No:04701472RNAGGGTAATGGsequence of primer binding site of pegRNA No:04801473RNAGGGTAATsequence of primer binding site of pegRNA No:05331476RNAGGGTAATGGsequence of primer binding site of pegRNA No:05491477RNAGGGTAAsequence of primer binding site of pegRNA No:05601478RNAGGGTAATGsequence of primer binding site of pegRNA No:05791479RNAGGGTAAsequence of primer binding site of pegRNA No:06681485RNAGGGTAATsequence of primer binding site of pegRNA No:06781486RNAGGGTAATGsequence of primer binding site of pegRNA No:06891487RNAGGGTAATGGsequence of primer binding site of pegRNA No:06991488RNAGGGTAATsequence of primer binding site of pegRNA No:08001491RNAGGGTAATGGsequence ofprimer binding site of pegRNA No:08181492RNAGGGTAAsequence of primer binding site of pegRNA No:09121500RNAGGGTAATsequence of primer binding site of pegRNA No:09231501RNAGGGTAATGsequence of primer binding site of pegRNA No:09331502RNAGGGTAATGGsequence of primer binding site of pegRNA No:09441503RNAGGGTAATGGsequence of primer binding site of pegRNA No:10171508RNAGGGTAATsequence of primer binding site of pegRNA No:10451510RNAGGGTAATGGsequence of primer binding site of pegRNA No:11441516RNAGGGTAAsequence of primer binding site of pegRNA No:11691519RNAGGGTAATsequence of primer binding site of pegRNA No:11761520RNAGGGTAATGsequence of primer binding site of pegRNA No:11831521RNAGGGTAATGsequence of primer binding site of pegRNA No:12681526RNAGGGTAAsequence of primer binding site of pegRNA No:12911528RNAGGGTAATsequence of primer binding site of pegRNA No:12991529RNAGGGTAATGGsequence of primer binding site of pegRNA No:13131530RNAGGGTAATGsequence of primer binding site of pegRNANo:14251536RNAGGGTAATGGsequence of primer binding site of pegRNA No:14321537RNAGGGTAATGsequence of primer binding site of pegRNA No:15531549RNAGGGTAATGGsequence of primer binding site of pegRNA No:15601550RNAGGGTAATGGsequence of primer binding site of pegRNA No:16761559RNATAATTTsequence of primer binding site of pegRNA No:00121595RNATAATTTsequence of primer binding site of pegRNA No:00321596RNATAATTTGsequence of primer binding site of pegRNA No:00371597RNATAATTTsequence of primer binding site of pegRNA No:00531598RNATAATTTGsequence of primer binding site of pegRNA No:00591599RNATAATTTGGsequence of primer binding site of pegRNA No:00641600RNATAATTTsequence of primer binding site of pegRNA No:00831601RNATAATTTGsequence of primer binding site of pegRNA No:00891602RNATAATTTGGsequence of primer binding site of pegRNA No:00941603RNATAATTTGGAsequence of primer binding site of pegRNA No:00981604RNATAATTTsequence of primer binding site of pegRNA No:01171605RNATAATTTGsequence of primer bindingsite of pegRNA No:01261606RNATAATTTGGsequence of primer binding site of pegRNA No:01321607RNATAATTTGGAsequence of primer binding site of pegRNA No:01381608RNATAATTTsequence of primer binding site of pegRNA No:01661610RNATAATTTGsequence of primer binding site of pegRNA No:01731611RNATAATTTGGsequence of primer binding site of pegRNA No:01811612RNATAATTTGGAsequence of primer binding site of pegRNA No:02141616RNATAATTTsequence of primer binding site of pegRNA No:02201617RNATAATTTGsequence of primer binding site of pegRNA No:02281618RNATAATTTGGsequence of primer binding site of pegRNA No:02361619RNATAATTTsequence of primer binding site of pegRNA No:02801622RNATAATTTGsequence of primer binding site of pegRNA No:02881623RNATAATTTGGsequence of primer binding site of pegRNA No:02971624RNATAATTTGGAsequence of primer binding site of pegRNA No:03461630RNATAATTTsequence of primer binding site of pegRNA No:03651631RNATAATTTGsequence of primer binding site of pegRNA No:03731632RNATAATTTGGsequence ofprimer binding site of pegRNA No:03831633RNATAATTTsequence of primer binding site of pegRNA No:04491639RNATAATTTGsequence of primer binding site of pegRNA No:04601640RNATAATTTGGsequence of primer binding site of pegRNA No:04681641RNATAATTTGGAsequence of primer binding site of pegRNA No:04781642RNATAATTTGGAsequence of primer binding site of pegRNA No:05301647RNATAATTTGGsequence of primer binding site of pegRNA No:05381648RNATAATTTsequence of primer binding site of pegRNA No:05561650RNATAATTTGsequence of primer binding site of pegRNA No:05681651RNATAATTTGGAsequence of primer binding site of pegRNA No:06431657RNATAATTTsequence of primer binding site of pegRNA No:06531659RNATAATTTGsequence of primer binding site of pegRNA No:06741660RNATAATTTGGsequence of primer binding site of pegRNA No:06861661RNATAATTTGGsequence of primer binding site of pegRNA No:07761669RNATAATTTsequence of primer binding site of pegRNA No:07881670RNATAATTTGsequence of primer binding site of pegRNANo:07981671RNATAATTTGsequence of primer binding site of pegRNA No:09181680RNATAATTTGGsequence of primer binding site of pegRNA No:09291681RNATAATTTGGAsequence of primer binding site of pegRNA No:09401682RNATAATTTGGsequence of primer binding site of pegRNA No:10121688RNATAATTTGGAsequence of primer binding site of pegRNA No:10291690RNATAATTTGGAsequence of primer binding site of pegRNA No:11881702RNATGATAGsequence of primer binding site of pegRNA No:00061736RNATGATAGsequence of primer binding site of pegRNA No:00171737RNATGATAGGsequence of primer binding site of pegRNA No:00201738RNATGATAGsequence of primer binding site of pegRNA No:00311739RNATGATAGGsequence of primer binding site of pegRNA No:00361740RNATGATAGGGsequence of primer binding site of pegRNA No:00401741RNATGATAGsequence of primer binding site of pegRNA No:00481742RNATGATAGGsequence of primer binding site of pegRNA No:00501743RNATGATAGGGTsequence of primer binding site of pegRNA No:00511744RNATGATAGGGsequence of primer bindingsite of pegRNA No:00631745RNATGATAGsequence of primer binding site of pegRNA No:00731746RNATGATAGGsequence of primer binding site of pegRNA No:00881747RNATGATAGGGsequence of primer binding site of pegRNA No:00931748RNATGATAGGGTsequence of primer binding site of pegRNA No:00971749RNATGATAGGsequence of primer binding site of pegRNA No:01251750RNATGATAGGGsequence of primer binding site of pegRNA No:01311751RNATGATAGsequence of primer binding site of pegRNA No:01651755RNATGATAGGGsequence of primer binding site of pegRNA No:01801756RNATGATAGGGTsequence of primer binding site of pegRNA No:01871757RNATGATAGsequence of primer binding site of pegRNA No:02191760RNATGATAGGGTsequence of primer binding site of pegRNA No:02441761RNATGATAGsequence of primer binding site of pegRNA No:02791765RNATGATAGGsequence of primer binding site of pegRNA No:02871766RNATGATAGGGsequence of primer binding site of pegRNA No:02961767RNATGATAGGGsequence of primer binding site of pegRNA No:03491771RNATGATAGsequence ofprimer binding site of pegRNA No:03641772RNATGATAGGGTsequence of primer binding site of pegRNA No:03921773RNATGATAGGsequence of primer binding site of pegRNA No:04441779RNATGATAGsequence of primer binding site of pegRNA No:04481780RNATGATAGGGsequence of primer binding site of pegRNA No:04671781RNATGATAGGGTsequence of primer binding site of pegRNA No:04771782RNATGATAGGGsequence of primer binding site of pegRNA No:05341790RNATGATAGsequence of primer binding site of pegRNA No:05551791RNATGATAGGsequence of primer binding site of pegRNA No:05671792RNATGATAGGGTsequence of primer binding site of pegRNA No:05861793RNATGATAGsequence of primer binding site of pegRNA No:06641803RNATGATAGGsequence of primer binding site of pegRNA No:07971810RNATGATAGGGsequence of primer binding site of pegRNA No:08061811RNATGATAGGGTsequence of primer binding site of pegRNA No:08161812RNATGATAGGGsequence of primer binding site of pegRNA No:09281823RNATGATAGGGTsequence of primer binding site of pegRNANo:09391824RNATGATAGGGTsequence of primer binding site of pegRNA No:10581828RNATGAGGATAsequence of primer binding site of pegRNA No:25911864RNATGAGGATAsequence of primer binding site of pegRNA No:26881865RNATGAGGATAAsequence of primer binding site of pegRNA No:28061866RNATGAGGAsequence of primer binding site of pegRNA No:28991868RNATGAGGATAsequence of primer binding site of pegRNA No:29211869RNATGAGGATAsequence of primer binding site of pegRNA No:30521870RNATGAGGAsequence of primer binding site of pegRNA No:31341872RNATGAGGATAsequence of primer binding site of pegRNA No:34171877RNATGAGGATsequence of primer binding site of pegRNA No:25631890RNATGAGGATAsequence of primer binding site of pegRNA No:32991893RNACAAGGAsequence of primer binding site of pegRNA No:18701894RNACAAGGAsequence of primer binding site of pegRNA No:19871895RNACAAGGATsequence of primer binding site of pegRNA No:19931896RNACAAGGAsequence of primer binding site of pegRNA No:20741897RNACAAGGATsequence of primer bindingsite of pegRNA No:20821898RNACAAGGATGAsequence of primer binding site of pegRNA No:21561899RNACAAGGAsequence of primer binding site of pegRNA No:21781900RNACAAGGATsequence of primer binding site of pegRNA No:21861901RNACAAGGATGsequence of primer binding site of pegRNA No:21921902RNACAAGGAsequence of primer binding site of pegRNA No:22731904RNACAAGGATGAsequence of primer binding site of pegRNA No:22921905RNACAAGGAsequence of primer binding site of pegRNA No:23631906RNACAAGGATGsequence of primer binding site of pegRNA No:23801907RNACAAGGAsequence of primer binding site of pegRNA No:24521909RNACAAGGATGAsequence of primer binding site of pegRNA No:24921910RNACAAGGATGsequence of primer binding site of pegRNA No:25981912RNACAAGGATsequence of primer binding site of pegRNA No:26861915RNACAAGGATGsequence of primer binding site of pegRNA No:26971916RNACAAGGAsequence of primer binding site of pegRNA No:27841921RNACAAGGATGAsequence of primer binding site of pegRNA No:28161922RNACAAGGATsequence ofprimer binding site of pegRNA No:28811925RNACAAGGAsequence of primer binding site of pegRNA No:29081927RNACAAGGATsequence of primer binding site of pegRNA No:30491931RNACAAGGATGAsequence of primer binding site of pegRNA No:33141939RNAGGATGAsequence of primer binding site of pegRNA No:20691957RNAGGATGAsequence of primer binding site of pegRNA No:21521958RNAGGATGAGsequence of primer binding site of pegRNA No:21811959RNAGGATGAsequence of primer binding site of pegRNA No:22691960RNAGGATGAGsequence of primer binding site of pegRNA No:22761961RNAGGATGAsequence of primer binding site of pegRNA No:23591962RNAGGATGAGsequence of primer binding site of pegRNA No:23661963RNAGGATGAGGsequence of primer binding site of pegRNA No:23741964RNAGGATGAsequence of primer binding site of pegRNA No:24641965RNAGGATGAGsequence of primer binding site of pegRNA No:24741966RNAGGATGAGGsequence of primer binding site of pegRNA No:24801967RNAGGATGAGGsequence of primer binding site of pegRNANo:25921968RNAGGATGAGGAsequence of primer binding site of pegRNA No:26011969RNAGGATGAGGsequence of primer binding site of pegRNA No:26611972RNAGGATGAsequence of primer binding site of pegRNA No:26671973RNAGGATGAGGsequence of primer binding site of pegRNA No:27711974RNAGGATGAGsequence of primer binding site of pegRNA No:27881975RNAGGATGAGGAsequence of primer binding site of pegRNA No:28071976RNAGGATGAsequence of primer binding site of pegRNA No:29001980RNAGGATGAGGsequence of primer binding site of pegRNA No:29221981RNAGGATGAGGAsequence of primer binding site of pegRNA No:29331982RNAGGATGAsequence of primer binding site of pegRNA No:30321985RNAGGATGAGsequence of primer binding site of pegRNA No:30411986RNAGGATGAsequence of primer binding site of pegRNA No:31521992RNAGGATGAGsequence of primer binding site of pegRNA No:31581993RNAGGATGAGGAsequence of primer binding site of pegRNA No:33081999RNAAGGGTAsequence of primer binding site of pegRNA No:00802022RNAAGGGTAsequence of primer bindingsite of pegRNA No:01132023RNAAGGGTAAsequence of primer binding site of pegRNA No:01222024RNAAGGGTAsequence of primer binding site of pegRNA No:01562025RNAAGGGTAAsequence of primer binding site of pegRNA No:01712026RNAAGGGTAATsequence of primer binding site of pegRNA No:01772027RNAAGGGTAATsequence of primer binding site of pegRNA No:02102028RNAAGGGTAsequence of primer binding site of pegRNA No:02172029RNAAGGGTAAsequence of primer binding site of pegRNA No:02252030RNAAGGGTAATGsequence of primer binding site of pegRNA No:02412031RNAAGGGTAAsequence of primer binding site of pegRNA No:02742033RNAAGGGTAsequence of primer binding site of pegRNA No:02762034RNAAGGGTAATsequence of primer binding site of pegRNA No:02942035RNAAGGGTAATGsequence of primer binding site of pegRNA No:03032036RNAAGGGTAsequence of primer binding site of pegRNA No:03612037RNAAGGGTAAsequence of primer binding site of pegRNA No:03702038RNAAGGGTAATsequence of primer binding site of pegRNA No:03802039RNAAGGGTAATGsequence ofprimer binding site of pegRNA No:03892040RNAAGGGTAsequence of primer binding site of pegRNA No:04472043RNAAGGGTAAsequence of primer binding site of pegRNA No:04572044RNAAGGGTAATsequence of primer binding site of pegRNA No:04652045RNAAGGGTAATGsequence of primer binding site of pegRNA No:04742046RNAAGGGTAsequence of primer binding site of pegRNA No:05522050RNAAGGGTAATsequence of primer binding site of pegRNA No:05762051RNAAGGGTAATGsequence of primer binding site of pegRNA No:05832052RNAAGGGTAsequence of primer binding site of pegRNA No:06512056RNAAGGGTAAsequence of primer binding site of pegRNA No:06722057RNAAGGGTAATsequence of primer binding site of pegRNA No:06822058RNAAGGGTAATGsequence of primer binding site of pegRNA No:06942059RNAAGGGTAsequence of primer binding site of pegRNA No:07852068RNAAGGGTAAsequence of primer binding site of pegRNA No:07952069RNAAGGGTAATsequence of primer binding site of pegRNA No:08042070RNAAGGGTAATGsequence of primer binding site of pegRNANo:08152071RNAAGGGTAsequence of primer binding site of pegRNA No:09072075RNAAGGGTAAsequence of primer binding site of pegRNA No:09152076RNAAGGGTAATsequence of primer binding site of pegRNA No:09252077RNAAGGGTAsequence of primer binding site of pegRNA No:10332085RNAAGGGTAAsequence of primer binding site of pegRNA No:10402086RNAAGGGTAATsequence of primer binding site of pegRNA No:10482087RNAAGGGTAATGsequence of primer binding site of pegRNA No:10562088RNAAGGGTAATGsequence of primer binding site of pegRNA No:11322096RNAAGGGTAATsequence of primer binding site of pegRNA No:11472099RNAAGGGTAsequence of primer binding site of pegRNA No:11642101RNAAGGGTAAsequence of primer binding site of pegRNA No:11712102RNAAGGGTAATsequence of primer binding site of pegRNA No:12602108RNAAGGGTAAsequence of primer binding site of pegRNA No:12932111RNAAGGGTAATGsequence of primer binding site of pegRNA No:13072112RNAAGGGTAATGsequence of primer binding site of pegRNA No:13952119RNAAGGGTAATsequence of primerbinding site of pegRNA No:14042121RNAAGGGTAATGsequence of primer binding site of pegRNA No:15332129RNAAAGTAAsequence of primer binding site of pegRNA No:00012164RNAAAGTAATsequence of primer binding site of pegRNA No:00022165RNAAAGTAAsequence of primer binding site of pegRNA No:00042166RNAAAGTAAsequence of primer binding site of pegRNA No:00052167RNAAAGTAATsequence of primer binding site of pegRNA No:00092168RNAAAGTAATTsequence of primer binding site of pegRNA No:00112169RNAAAGTAATTsequence of primer binding site of pegRNA No:00132170RNAAAGTAAsequence of primer binding site of pegRNA No:00152171RNAAAGTAATsequence of primer binding site of pegRNA No:00192172RNAAAGTAATTTsequence of primer binding site of pegRNA No:00242173RNAAAGTAATTsequence of primer binding site of pegRNA No:00252174RNAAAGTAAsequence of primer binding site of pegRNA No:00282175RNAAAGTAATsequence of primer binding site of pegRNA No:00342176RNAAAGTAATTTsequence of primer binding site of pegRNA No:00432177RNAAAGTAAsequenceof primer binding site of pegRNA No:00472179RNAAAGTAATsequence of primer binding site of pegRNA No:00562180RNAAAGTAATTTsequence of primer binding site of pegRNA No:00672181RNAAAGTAAsequence of primer binding site of pegRNA No:00792184RNAAAGTAATsequence of primer binding site of pegRNA No:00852185RNAAAGTAATTTsequence of primer binding site of pegRNA No:00962186RNAAAGTAAsequence of primer binding site of pegRNA No:01122190RNAAAGTAATsequence of primer binding site of pegRNA No:01212191RNAAAGTAATTsequence of primer binding site of pegRNA No:01282192RNAAAGTAAsequence of primer binding site of pegRNA No:01622197RNAAAGTAATsequence of primer binding site of pegRNA No:01702198RNAAAGTAATTsequence of primer binding site of pegRNA No:01762199RNAAAGTAATTTsequence of primer binding site of pegRNA No:01842200RNAAAGTAATsequence of primer binding site of pegRNA No:02062205RNAAAGTAAsequence of primer binding site of pegRNA No:02162207RNAAAGTAATTsequence of primer binding site of pegRNANo:02332208RNAAAGTAATTTsequence of primer binding site of pegRNA No:02402209RNAAAGTAATsequence of primer binding site of pegRNA No:02842215RNAAAGTAATTsequence of primer binding site of pegRNA No:02932216RNAAAGTAATTTsequence of primer binding site of pegRNA No:03022217RNAAAGTAAsequence of primer binding site of pegRNA No:03602227RNAAAGTAATsequence of primer binding site of pegRNA No:03692228RNAAAGTAATTsequence of primer binding site of pegRNA No:03792229RNAAAGTAATTTsequence of primer binding site of pegRNA No:03882230RNAAAGTAAsequence of primer binding site of pegRNA No:04462239RNAAAGTAATsequence of primer binding site of pegRNA No:04562240RNAAAGTAATTsequence of primer binding site of pegRNA No:04642241RNAAAGTAATTTsequence of primer binding site of pegRNA No:04732242RNAAAGTAATsequence of primer binding site of pegRNA No:05642250RNAAAGTAATTsequence of primer binding site of pegRNA No:05752251RNAAAGTAATTTsequence of primer binding site of pegRNA No:05822252RNAAAGTAATTTsequence of primerbinding site of pegRNA No:08142268RNAAGGATGsequence of primer binding site of pegRNA No:19832310RNAAGGATGsequence of primer binding site of pegRNA No:20702311RNAAGGATGAsequence of primer binding site of pegRNA No:21822312RNAAGGATGsequence of primer binding site of pegRNA No:22482313RNAAGGATGAGGsequence of primer binding site of pegRNA No:22572314RNAAGGATGAGGsequence of primer binding site of pegRNA No:23392315RNAAGGATGAGsequence of primer binding site of pegRNA No:23752316RNAAGGATGAsequence of primer binding site of pegRNA No:24592318RNAAGGATGAGsequence of primer binding site of pegRNA No:24812319RNAAGGATGsequence of primer binding site of pegRNA No:25732322RNAAGGATGAGsequence of primer binding site of pegRNA No:25942323RNAAGGATGsequence of primer binding site of pegRNA No:26692324RNAAGGATGAGGsequence of primer binding site of pegRNA No:27002325RNAAGGATGsequence of primer binding site of pegRNA No:27792330RNAAGGATGAsequence of primer binding site of pegRNANo:27902331RNAAGGATGAGsequence of primer binding site of pegRNA No:27982332RNAAGGATGAGGsequence of primer binding site of pegRNA No:28092333RNAAGGATGAGGsequence of primer binding site of pegRNA No:29352339RNAAGGATGAGsequence of primer binding site of pegRNA No:30062341RNAAGGATGAGGsequence of primer binding site of pegRNA No:30642343RNAAGGATGAGsequence of primer binding site of pegRNA No:33002351RNAAGGATGAGGsequence of primer binding site of pegRNA No:35442358RNAAGGATGAsequence of primer binding site of pegRNA No:32942384RNATGGATGsequence of primer binding site of pegRNA No:02212387RNATGGATGTsequence of primer binding site of pegRNA No:02292388RNATGGATGsequence of primer binding site of pegRNA No:02812389RNATGGATGTsequence of primer binding site of pegRNA No:02892390RNATGGATGTTsequence of primer binding site of pegRNA No:02982391RNATGGATGTTAsequence of primer binding site of pegRNA No:03512392RNATGGATGsequence of primer binding site of pegRNA No:03542393RNATGGATGTsequence of primerbinding site of pegRNA No:03742394RNATGGATGTTsequence of primer binding site of pegRNA No:03842395RNATGGATGsequence of primer binding site of pegRNA No:04512396RNATGGATGTTsequence of primer binding site of pegRNA No:04692397RNATGGATGTTAsequence of primer binding site of pegRNA No:04792398RNATGGATGsequence of primer binding site of pegRNA No:05582400RNATGGATGTTsequence of primer binding site of pegRNA No:05782401RNATGGATGTTAsequence of primer binding site of pegRNA No:05872402RNATGGATGsequence of primer binding site of pegRNA No:06662405RNATGGATGTsequence of primer binding site of pegRNA No:06762406RNATGGATGTTsequence of primer binding site of pegRNA No:06882407RNATGGATGTTAsequence of primer binding site of pegRNA No:06982408RNATGGATGTsequence of primer binding site of pegRNA No:07722411RNATGGATGTTAsequence of primer binding site of pegRNA No:07752412RNATGGATGsequence of primer binding site of pegRNA No:07902413RNATGGATGTTsequence of primer binding site of pegRNANo:08082414RNATGGATGsequence of primer binding site of pegRNA No:09092418RNATGGATGTsequence of primer binding site of pegRNA No:09202419RNATGGATGTTsequence of primer binding site of pegRNA No:09312420RNATGGATGTTAsequence of primer binding site of pegRNA No:09422421RNATGGATGsequence of primer binding site of pegRNA No:10312427RNATGGATGsequence of primer binding site of pegRNA No:11352432RNATGGATGTsequence of primer binding site of pegRNA No:11732433RNATGGATGTTsequence of primer binding site of pegRNA No:11812434RNATGGATGTTAsequence of primer binding site of pegRNA No:11892435RNATGGATGsequence of primer binding site of pegRNA No:12872442RNATGGATGTsequence of primer binding site of pegRNA No:12952443RNATGGATGTTsequence of primer binding site of pegRNA No:13022444RNATGGATGsequence of primer binding site of pegRNA No:14112449RNATGGATGTTsequence of primer binding site of pegRNA No:14222450RNATGGATGTTAsequence of primer binding site of pegRNA No:14292451RNATGGATGTTsequence of primer bindingsite of pegRNA No:15122457RNATGGATGTsequence of primer binding site of pegRNA No:15452460RNATGGATGTTAsequence of primer binding site of pegRNA No:17752473RNAATGAGGsequence of primer binding site of pegRNA No:22442500RNAATGAGGsequence of primer binding site of pegRNA No:23432501RNAATGAGGAsequence of primer binding site of pegRNA No:23672502RNAATGAGGATsequence of primer binding site of pegRNA No:24542503RNAATGAGGAsequence of primer binding site of pegRNA No:24752504RNAATGAGGsequence of primer binding site of pegRNA No:25722505RNAATGAGGAsequence of primer binding site of pegRNA No:25822506RNAATGAGGATsequence of primer binding site of pegRNA No:25932507RNAATGAGGATAsequence of primer binding site of pegRNA No:26022508RNAATGAGGsequence of primer binding site of pegRNA No:26682509RNAATGAGGAsequence of primer binding site of pegRNA No:26792510RNAATGAGGATsequence of primer binding site of pegRNA No:26892511RNAATGAGGATAsequence of primer binding site of pegRNA No:26992512RNAATGAGGAsequence ofprimer binding site of pegRNA No:27892513RNAATGAGGATAsequence of primer binding site of pegRNA No:28082514RNAATGAGGATsequence of primer binding site of pegRNA No:28872518RNAATGAGGsequence of primer binding site of pegRNA No:29012519RNAATGAGGAsequence of primer binding site of pegRNA No:29122520RNAATGAGGATAsequence of primer binding site of pegRNA No:29342521RNAATGAGGATsequence of primer binding site of pegRNA No:30262524RNAATGAGGAsequence of primer binding site of pegRNA No:30422525RNAATGAGGATAsequence of primer binding site of pegRNA No:30632526RNAATGAGGAsequence of primer binding site of pegRNA No:31592530RNAATGAGGATsequence of primer binding site of pegRNA No:31682531RNAATGAGGATsequence of primer binding site of pegRNA No:32832538RNAATGAGGAsequence of primer binding site of pegRNA No:32932539RNAATGAGGAsequence of primer binding site of pegRNA No:34132543RNAATGAGGATsequence of primer binding site of pegRNA No:34192544RNAATGAGGATAsequence of primer binding site of pegRNANo:34282545RNAATGAGGATAsequence of primer binding site of pegRNA No:36452560RNAATGAGGATAsequence of primer binding site of pegRNA No:33092587RNAGTAATTsequence of primer binding site of pegRNA No:00082597RNAGTAATTsequence of primer binding site of pegRNA No:00182598RNAGTAATTTsequence of primer binding site of pegRNA No:00222599RNAGTAATTTsequence of primer binding site of pegRNA No:00392600RNAGTAATTTGsequence of primer binding site of pegRNA No:00422601RNAGTAATTsequence of primer binding site of pegRNA No:00552602RNAGTAATTTsequence of primer binding site of pegRNA No:00612603RNAGTAATTTGsequence of primer binding site of pegRNA No:00662604RNAGTAATTTGGsequence of primer binding site of pegRNA No:00692605RNAGTAATTTsequence of primer binding site of pegRNA No:00752606RNAGTAATTTGGsequence of primer binding site of pegRNA No:00772607RNAGTAATTsequence of primer binding site of pegRNA No:00842608RNAGTAATTTGsequence of primer binding site of pegRNA No:00952609RNAGTAATTsequence of primer bindingsite of pegRNA No:01202611RNAGTAATTTGsequence of primer binding site of pegRNA No:01342612RNAGTAATTTGGsequence of primer binding site of pegRNA No:01402613RNAGTAATTTGGsequence of primer binding site of pegRNA No:01592616RNAGTAATTsequence of primer binding site of pegRNA No:01692618RNAGTAATTTsequence of primer binding site of pegRNA No:01752619RNAGTAATTTGsequence of primer binding site of pegRNA No:01832620RNAGTAATTsequence of primer binding site of pegRNA No:02242624RNAGTAATTTGsequence of primer binding site of pegRNA No:02392625RNAGTAATTTGGsequence of primer binding site of pegRNA No:02462626RNAGTAATTsequence of primer binding site of pegRNA No:02722630RNAGTAATTTsequence of primer binding site of pegRNA No:02922631RNAGTAATTTGsequence of primer binding site of pegRNA No:03012632RNAGTAATTTGGsequence of primer binding site of pegRNA No:03102633RNAGTAATTTGGsequence of primer binding site of pegRNA No:03472639RNAGTAATTsequence of primer binding site of pegRNA No:03682642RNAGTAATTTsequenceof primer binding site of pegRNA No:03772643RNAGTAATTTGsequence of primer binding site of pegRNA No:03872644RNAGTAATTTGGsequence of primer binding site of pegRNA No:04432650RNAGTAATTTGsequence of primer binding site of pegRNA No:04712651RNAGTAATTsequence of primer binding site of pegRNA No:05622660RNAGTAATTTsequence of primer binding site of pegRNA No:05722661RNAGTAATTTGsequence of primer binding site of pegRNA No:05802662RNAGTAATTTGGsequence of primer binding site of pegRNA No:05892663RNAGTAATTTsequence of primer binding site of pegRNA No:06792670RNAGTAATTTGsequence of primer binding site of pegRNA No:06912671RNAGTAATTTGGsequence of primer binding site of pegRNA No:07012672RNAGTAATTTsequence of primer binding site of pegRNA No:08012680RNAGTAATTTGsequence of primer binding site of pegRNA No:08122681RNAGTAATTTGGsequence of primer binding site of pegRNA No:08202682RNAGTAATTTGsequence of primer binding site of pegRNA No:09342690RNAGTAATTTGGsequence of primer binding site of pegRNANo:09462691RNAGTAATTTGGsequence of primer binding site of pegRNA No:10622696RNAGTTAATsequence of primer binding site of pegRNA No:05592727RNAGTTAATsequence of primer binding site of pegRNA No:06672728RNAGTTAATTsequence of primer binding site of pegRNA No:06772729RNAGTTAATsequence of primer binding site of pegRNA No:07922730RNAGTTAATTTsequence of primer binding site of pegRNA No:08092731RNAGTTAATsequence of primer binding site of pegRNA No:09112732RNAGTTAATTsequence of primer binding site of pegRNA No:09222733RNAGTTAATTTsequence of primer binding site of pegRNA No:09322734RNAGTTAATsequence of primer binding site of pegRNA No:10362736RNAGTTAATTTsequence of primer binding site of pegRNA No:10522737RNAGTTAATTTAsequence of primer binding site of pegRNA No:10612738RNAGTTAATsequence of primer binding site of pegRNA No:11672739RNAGTTAATTsequence of primer binding site of pegRNA No:11752740RNAGTTAATTTsequence of primer binding site of pegRNA No:11822741RNAGTTAATsequence of primer binding siteof pegRNA No:12892745RNAGTTAATTsequence of primer binding site of pegRNA No:12972746RNAGTTAATTTAsequence of primer binding site of pegRNA No:13122747RNAGTTAATTsequence of primer binding site of pegRNA No:13962749RNAGTTAATTTsequence of primer binding site of pegRNA No:14232751RNAGTTAATTsequence of primer binding site of pegRNA No:15102754RNAGTTAATsequence of primer binding site of pegRNA No:15432757RNAGTTAATTTAsequence of primer binding site of pegRNA No:15582758RNAGTTAATTTAsequence of primer binding site of pegRNA No:16302761RNAGTTAATsequence of primer binding site of pegRNA No:16622765RNAGTTAATTsequence of primer binding site of pegRNA No:16672766RNAGTTAATTTsequence of primer binding site of pegRNA No:16712767RNAGTTAATTsequence of primer binding site of pegRNA No:17422771RNAGTTAATTTsequence of primer binding site of pegRNA No:17462772RNAGTTAATsequence of primer binding site of pegRNA No:17652774RNAGTTAATTTAsequence of primer binding site of pegRNA No:17772775RNAGTTAATTTAsequence ofprimer binding site of pegRNA No:18522780RNAGTTAATTsequence of primer binding site of pegRNA No:18532781RNAGTTAATsequence of primer binding site of pegRNA No:18672782RNAGTTAATsequence of primer binding site of pegRNA No:19852789RNAGTTAATTTAsequence of primer binding site of pegRNA No:20032790RNAGTTAATTTsequence of primer binding site of pegRNA No:20862795RNAGTTAATTTAsequence of primer binding site of pegRNA No:20932796RNAGTTAATTTsequence of primer binding site of pegRNA No:21572803RNAGTTAATTTAsequence of primer binding site of pegRNA No:22532809RNAGATAGGsequence of primer binding site of pegRNA No:00162836RNAGATAGGsequence of primer binding site of pegRNA No:00292837RNAGATAGGGsequence of primer binding site of pegRNA No:00352838RNAGATAGGGTsequence of primer binding site of pegRNA No:00452839RNAGATAGGsequence of primer binding site of pegRNA No:00462840RNAGATAGGGsequence of primer binding site of pegRNA No:00572841RNAGATAGGGTAsequence of primer binding site of pegRNANo:00782842RNAGATAGGsequence of primer binding site of pegRNA No:00812843RNAGATAGGGsequence of primer binding site of pegRNA No:00862844RNAGATAGGGTsequence of primer binding site of pegRNA No:00922845RNAGATAGGGTAsequence of prim...

Claims

1. A pegRNA for Prime Editor to correct the c.4957dupA variant of the EYS gene, with the following structure: 5' - [Guide Domain] - [Scaffold] - [Prime Editing Domain] - 3' Here, the scaffold can interact with the prime editor to form a complex, The above guide domain and the above prime editing domain are composed of a selected combination of the following: A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11534 to 11552 and SEQ ID NOs: 12104 to 12122, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3343 to 3482; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11553 to 11571 and SEQ ID NOs: 12123 to 12141, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3483 to 3573; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11572 to 11590 and SEQ ID NOs: 12142 to 12160, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3574 to 3710; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11591 to 11609 and SEQ ID NOs: 12161 to 12179, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3711 to 3829; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11610 to 11628 and SEQ ID NOs: 12180 to 12198, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3830 to 3888; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11629 to 11647 and SEQ ID NOs: 12199 to 12217, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 3889 to 4022; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11648 to 11666 and SEQ ID NOs: 12218 to 12236, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4023 to 4169; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11667 to 11685 and SEQ ID NOs: 12237 to 12255, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4170 to 4309; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11686 to 11704 and SEQ ID NOs: 12256 to 12274, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4310 to 4450; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11705 to 11723 and SEQ ID NOs: 12275 to 12293, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4451 to 4578; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11724 to 11742 and SEQ ID NOs: 12294 to 12312, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4579 to 4608; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11743 to 11761 and SEQ ID NOs: 12313 to 12331, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4609 to 4671; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11762 to 11780 and SEQ ID NOs: 12332 to 12350, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4672 to 4736; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11781 to 11799 and SEQ ID NOs: 12351 to 12369, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4737 to 4878; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11800 to 11818 and SEQ ID NOs: 12370 to 12388, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 4879 to 5024; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11819 to 11837 and SEQ ID NOs: 12389 to 12407, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5025 to 5101; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11838 to 11856 and SEQ ID NOs: 12408 to 12426, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5102 to 5214; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11857 ​​to 11875 and SEQ ID NOs: 12427 to 12445, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5215 to 5311; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11876 to 11894 and SEQ ID NOs: 12446 to 12464, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5312 to 5441; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11895 to 11913 and SEQ ID NOs: 12465 to 12483, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5442 to 5550; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11914 to 11932 and SEQ ID NOs: 12484 to 12502, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5551 to 5681; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11933 to 11951 and SEQ ID NOs: 12503 to 12521, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5682 to 5804; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11952 to 11970 and SEQ ID NOs: 12522 to 12540, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5805 to 5831; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11971 to 11989 and SEQ ID NOs: 12541 to 12559, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5832 to 5923; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 11990 to 12008 and SEQ ID NOs: 12560 to 12578, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5924 to 5966; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 12009 to 12027 and SEQ ID NOs: 12579 to 12597, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5967 to 5993; A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 12028 to 12046 and SEQ ID NOs: 12598 to 12616, and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 5994 to 6040; A guide domain targeting a target sequence consisting of a nucleic acid sequence selected from among SEQ ID NOs: 12047 to 12065 and SEQ ID NOs: 12617 to 12635 and a prime editing domain consisting of a nucleic acid sequence selected from among SEQ ID NOs: 6041 to 6054; and A guide domain targeting a target sequence comprising a nucleic acid sequence selected from among SEQ ID NOs: 12066 to 12103 and a prime editing domain comprising a nucleic acid sequence selected from among SEQ ID NOs: 6055 to 6057.

2. In the first paragraph, the scaffold is a pegRNA composed of a nucleic acid sequence selected from among SEQ ID NO: 11531 to SEQ ID NO: 11533.

3. A prime editor composition for correcting the c.4957dupA variant of the EYS gene, comprising: a prime editor protein, or a nucleic acid encoding said prime editor protein; and The pegRNA of claim 1, or a nucleic acid encoding the pegRNA, Here, the prime editor protein comprises a Cas9 protein derived from Streptococcus pyogenes or a variant thereof, and a reverse transcriptase, The scaffold of the above pegRNA interacts with the above prime editor protein to form a complex.

4. In the third paragraph, the prime editor composition comprises the prime editor protein and the pegRNA, and the prime editor protein and the pegRNA are combined to form a complex.

5. In the third paragraph, the prime editor composition comprises a nucleic acid encoding the prime editor and a nucleic acid encoding the pegRNA.

6. In any one of claims 3 to 5, the prime editor protein is a prime editor composition selected from the following: NRCH-hyPE2max; NRCH-PE2max; NRCH-PE2; and PE2max.

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