Gene therapy for ABCA4

Abstract

Aspects of the present disclosure relate to compositions and methods that can be used to deliver minigenes to subjects. Thus, the present disclosure is based in part on isolated nucleic acids and gene therapy vectors, such as viral (e.g., rAAV) vectors, which contain one or more gene segments encoding therapeutic gene products, such as proteins or peptides (e.g., minigenes). In some embodiments, the present disclosure relates to gene therapy vectors encoding ABCA4 proteins (e.g., gene products of ABCA4 genes) or portions thereof. In some embodiments, the compositions described in the present disclosure can be used to treat diseases associated with ABCA4 gene mutations, such as fundus xanthophytic disease.

Description

[0001] Related Applications

[0002] This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 62 / 836,493, filed on April 19, 2019, entitled “GENETHERAPIES FOR STARGARDT DISEASE (ABCA4)” under 35 U.S.C. §119(e), the entire contents of which are incorporated herein by reference. Background Art

[0003] Stargardt disease is the most common type of autosomal recessive macular degeneration. The disease is caused by mutations in the ABCA4 gene. The length of the human ABCA4 gene is ~7 kb, which exceeds the limit for packaging into conventional adeno-associated virus (AAV) vectors for gene delivery. SUMMARY OF THE INVENTION

[0005] Aspects of the present disclosure relate to compositions and methods for delivering a minigene to a subject. Thus, the present disclosure is based in part on isolated nucleic acids and gene therapy vectors, such as viral (e.g., rAAV) vectors, which contain one or more gene fragments (e.g., minigenes) encoding therapeutic gene products (e.g., proteins or peptides). In some embodiments, the present disclosure relates to gene therapy vectors encoding ABCA4 proteins (e.g., gene products of ABCA4) or portions thereof. In some embodiments, the compositions described in the present disclosure are used to treat diseases associated with ABCA4 gene mutations, such as fundus xanthophytic disease.

[0006] Thus, in some aspects, the present disclosure provides an isolated nucleic acid comprising a transgene encoding an ABCA4 minigene having a sequence as set forth in any one of SEQ ID NOs: 3-8 and 15-19.

[0007] In some aspects, the disclosure provides an isolated nucleic acid comprising a transgene having a nucleic acid sequence encoding an ABCA4 protein, wherein the ABCA4 protein comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9-14 and 20-24.

[0008] In some embodiments, the transgene further comprises a promoter operably linked to the ABCA4 minigene coding sequence. In some embodiments, the promoter is a constitutive promoter, an inducible promoter, or a tissue-specific promoter. In some embodiments, the promoter comprises a chicken beta-actin (CBA) promoter. In some embodiments, the tissue-specific promoter is a photoreceptor-specific promoter. In some embodiments, the photoreceptor-specific promoter comprises a rhodopsin kinase promoter, such as a human GRK promoter.

[0009] In some embodiments, the transgene is flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs). In some embodiments, at least one ITR flanking the transgene is an AAV2 ITR. In some embodiments, at least one ITR flanking the transgene lacks a terminal dissociation site, such as a ΔITR.

[0010] In some aspects, the disclosure provides a vector comprising an isolated nucleic acid as described herein. In some embodiments, the vector is a plasmid DNA, or a closed-ended DNA, or a lipid / DNA nanoparticle, or a viral vector. In some embodiments, the viral vector is an adeno-associated virus (AAV) vector, an adenovirus (Ad) vector, a lentiviral vector, a retroviral vector, or a baculovirus vector.

[0011] In some aspects, the disclosure provides a host cell comprising an isolated nucleic acid or vector as described herein. In some embodiments, the cell is a mammalian (human) cell, a bacterial cell, a yeast cell, or an insect cell.

[0012] In some aspects, the present disclosure provides a recombinant adeno-associated virus (rAAV) comprising: an isolated nucleic acid as described herein; and an AAV capsid protein.

[0013] In some embodiments, the capsid protein is tropic for ocular cells. In some embodiments, the capsid protein is an AAV8 capsid protein.

[0014] In some embodiments, the rAAV is formulated for delivery to the eye. In some embodiments, the rAAV is formulated for delivery to photoreceptor cells or the retinal pigment epithelium (RPE).

[0015] In some aspects, the present disclosure provides a composition comprising an isolated nucleic acid or rAAV as described herein and a pharmaceutically acceptable excipient.

[0016] In some aspects, the present disclosure provides a method of delivering a transgene to a cell, the method comprising administering to the cell an isolated nucleic acid or rAAV described herein.

[0017] In some embodiments, the cell is in a subject. In some embodiments, the subject is a mammalian subject, such as a human subject. In some embodiments, the cell is an eye cell. In some embodiments, the eye cell is a photoreceptor cell or retinal pigmented epithelium (RPE).

[0018] In some aspects, the present disclosure provides a method of treating fundus xanthophyses in a subject in need thereof, the method comprising administering to the subject an isolated nucleic acid or rAAV as described herein.

[0019] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0020] In some embodiments, the subject is characterized by having one or more mutations in the ABCA4 gene. In some embodiments, the subject has one or more mutations resulting in an amino acid substitution selected from G1961E and D2177N corresponding to a wild-type ABCA4 protein (e.g., the amino acid sequence set forth in SEQ ID NO: 2).

[0021] In some embodiments, administration is by injection. In some embodiments, the injection is a subretinal injection or an intravitreal injection or an suprachoroidal injection.

[0022] In some embodiments, the administering is topical administration to the eye of the subject.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a schematic diagram of several embodiments of MiniABCA4 constructs. MG-1, MG-2, MG-3, MG-4, MG-5 and MG-6 having amino acid sequences corresponding to SEQ ID NOs: 9-14 are shown.

[0025] Figure 2 The fluorescence microscopy showed that wild-type ABCA4 knockout mice (Abca KO) and ABCA4 knockout mice injected with miniABCA4-1 (which corresponds to Figure 1 MG-4 construct as described). ZO-1 was used as a cell marker.

[0026] Figure 3is a graph showing quantitative RPE autofluorescence analysis of uninjected and injected ABCA4 knockout mice of different ages. Arrows point to ABCA4 minigene versions with significantly improved autofluorescence. Injections were performed at P10 or P30. Analysis was performed at the age indicated for each minigene. P30 injections showed highly significant improvements compared to P10 injections. In this graph, AB-1 corresponds to MG-1, AB-2 corresponds to MG-2, and AB-5 corresponds to MG-5.

[0027] Figure 4 is a schematic diagram of several embodiments of MiniABCA4 constructs. MG-7, MG-8, MG-9, MG-10, and MG-11 having amino acid sequences corresponding to SEQ ID NOs: 20-24 are shown.

[0028] Figure 5 Yes Display Figure 4 Immunoblot of the expression of MiniABCA4 in HEK cells. Arrows indicate the expected bands. Lipo shows cells transfected with vehicle only. DETAILED DESCRIPTION OF THE INVENTION

[0030] In some aspects, the present disclosure relates to compositions and methods that can be used to treat certain genetic diseases, such as fundus yellow spot disease. The present disclosure is based in part on isolated nucleic acids and gene therapy vectors, such as viral (e.g., rAAV) vectors, which contain one or more gene segments encoding therapeutic gene products, such as MiniABCA4 proteins (e.g., gene products of ABCA4 minigenes).

[0031] "Nucleic acid" sequences refer to DNA or RNA sequences. In some embodiments, the proteins and nucleic acids of the present disclosure are isolated. As used herein, the term "isolated" refers to artificial production. As used herein with respect to nucleic acids, the term "isolated" refers to: (i) amplified in vitro by, for example, polymerase chain reaction (PCR); (ii) produced recombinantly by cloning; (iii) purified, for example, by cleavage and gel separation; or (iv) synthesized, for example, by chemical synthesis. An isolated nucleic acid is a nucleic acid that is amenable to manipulation by recombinant DNA techniques well known in the art. Thus, a nucleotide sequence contained in a vector in which 5' and 3' restriction sites are known, or whose polymerase chain reaction (PCR) primer sequences have been published, is considered isolated, but a nucleic acid sequence that exists in its natural host in its natural state is not. An isolated nucleic acid can be substantially purified, but not necessarily. For example, a nucleic acid isolated within a cloning or expression vector is impure because it may constitute only a small percentage of the material in the cell in which it is located. However, such a nucleic acid is isolated, as the term is used herein, because it is amenable to manipulation by standard techniques known to those of ordinary skill in the art. As used herein with respect to a protein or peptide, the term "isolated" refers to a protein or peptide that has been separated from its natural environment or artificially produced (e.g., by chemical synthesis, by recombinant DNA technology, etc.). In some embodiments, the isolated nucleic acid encodes an ABCA4 protein, such as a MiniABCA4 protein (e.g., a gene product expressed from an ABCA4 gene or a portion thereof such as an ABCA4 minigene).

[0032] In humans, the ABCA4 gene (also known as STGD) encodes an ATP-binding cassette subfamily A (ABC1) member 4 protein that is localized to the outer segment disk edge of rods and cones and can function as an inward-directed flippase. Mutations in the ABCA4 gene have been observed to cause fundus xanthophysema, a form of macular degeneration. In some embodiments, the ABCA4 gene comprises the nucleic acid sequence (SEQ ID NO: 1) shown in NCBI Reference Sequence Accession No. NM_000350.3. In some embodiments, the ABCA4 gene encodes a protein having the amino acid sequence (SEQ ID NO: 2) shown in NCBI Reference Sequence Accession No. NP_000341.2.

[0033] As used herein, "minigene" refers to an isolated nucleic acid sequence encoding a recombinant peptide or protein, wherein one or more non-essential elements of the corresponding gene encoding the naturally occurring peptide or protein have been removed and wherein the peptide or protein encoded by the minigene retains the function of the corresponding naturally occurring peptide or protein. "Therapeutic minigene" refers to a minigene encoding a peptide or protein that can be used to treat genetic diseases, such as dystrophin, dysferlin, factor VIII, amyloid precursor protein (APP), tyrosinase (Tyr), etc. Minigenes are known in the art and are described, for example, by Karpati and Acsadi (1994) Clin Invest Med 17(5):499-509; Plantier et al. (2001) Thromb Haemost.86(2):596-603; and Xiao et al. (2007) World J. Gastroenterol.13(2):244-9. In some embodiments, the minigene does not comprise the sequence of the corresponding naturally occurring peptide or protein.

[0034] In some aspects, the present disclosure relates to isolated nucleic acids encoding ABCA4 minigenes. Typically, an isolated nucleic acid encoding a minigene (e.g., a therapeutic minigene, such as an ABCA4 minigene) is truncated by about 10% to about 99% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 90%, about 99%, etc.) relative to a nucleic acid sequence encoding a corresponding naturally occurring wild-type protein (e.g., SEQ ID NO: 1). The truncation can be continuous (e.g., a single, continuous truncation of an amino acid residue) or discontinuous (e.g., two or more truncations of amino acids, such as truncations of two or more domains separated by one or more peptides). For example, in some embodiments, the minigene encoding the Mini ABCA4 protein is truncated by about 61% to (e.g., comprises about 50% of the nucleic acid sequence) compared to a wild-type ABCA4 gene (e.g., SEQ ID NO: 1). In some embodiments, the ABCA4 minigene comprises (or consists of) a nucleic acid sequence as set forth in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, the ABCA4 minigene encodes a protein (referred to as a MiniABCA4 protein) comprising (or consisting of) an amino acid sequence as set forth in any one of SEQ ID NOs: 9-14 and 20-24. In some embodiments, the nucleic acid encoding the ABCA4 protein (e.g., MiniABCA4 protein) comprises a start codon (e.g., nucleic acid sequence ATG) before the nucleic acid sequence encoding the MiniABCA4 protein. In some embodiments, the nucleic acid sequence encoding the MiniABCA4 protein is codon-optimized.

[0035] The isolated nucleic acid sequence encoding the ABCA4 protein can be operably linked to a promoter. "Promoter" refers to a DNA sequence that is recognized by the synthetic machinery of the cell or introduced synthetic machinery and is required to initiate specific transcription of a gene. The phrases "effectively positioned", "under control" or "under transcriptional control" mean that the promoter is in the correct position and orientation relative to the nucleic acid to control the initiation of RNA polymerase and the expression of the gene. The promoter can be a constitutive promoter, an inducible promoter or a tissue-specific promoter.

[0036] Examples of constitutive promoters include, but are not limited to, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with an RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with a CMV enhancer) [see, e.g., Boshart et al., Cell, 41:521-530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1α promoter [Invitrogen]. In some embodiments, the promoter is the chicken β-actin (CBA) promoter. In some embodiments, the promoter is an enhanced chicken β-actin promoter. In some embodiments, the promoter is the U6 promoter. In some embodiments, the promoter is the chicken β-actin (CBA) promoter.

[0037] Inducible promoters allow for regulation of gene expression and can be regulated by exogenously provided compounds, environmental factors such as temperature or the presence of a particular physiological state, for example, an acute phase, a particular differentiation state of a cell or only in replicating cells. Inducible promoters and inducible systems are available from a variety of commercial sources, including but not limited to Invitrogen, Clontech and Ariad. Many other systems have been described and those skilled in the art can easily select these systems. Examples of inducible promoters regulated by an exogenously provided promoter include the zinc-inducible sheep metallothionine (MT) promoter, the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter, the T7 polymerase promoter system (WO 98 / 10088); the ecdysone insect promoter (No et al., Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)), the tetracycline-repressible system (Gossen et al., Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)), the tetracycline-inducible system (Gossen et al., Science, 268:1766-1769 (1995), see also Harvey et al., Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)), the tetracycline-repressible system (Gossen et al., Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)), the tetracycline-inducible system (Gossen et al., Science ... al., Curr. Opin. Chem. Biol., 2: 512-518 (1998)), RU486 inducible system (Wang et al., Nat. Biotech., 15: 239-243 (1997) and Wang et al., Gene Ther., 4: 432-441 (1997)) and rapamycin inducible system (Magari et al., J. Clin. Invest., 100: 2865-2872 (1997)). Other types of inducible promoters that may be useful in this context are those that are regulated by specific physiological states such as temperature, acute phase, a specific differentiation state of the cell, or only in replicating cells.

[0038] In some embodiments, the regulatory sequence confers tissue-specific gene expression ability. In some cases, the tissue-specific regulatory sequence binds to a tissue-specific transcription factor that induces transcription in a tissue-specific manner. Such tissue-specific regulatory sequences (e.g., promoters, enhancers, etc.) are well known in the art. In some embodiments, the tissue-specific promoter is an eye-specific promoter. Examples of eye-specific promoters include, but are not limited to, retinoschisis protein promoter, K12 promoter, rhodopsin promoter, rod-specific promoter, cone-specific promoter, rhodopsin kinase promoter, GRK1 promoter, inter-photoreceptor retinoid binding protein proximal (IRBP) promoter and opsin promoter (e.g., red opsin promoter, blue opsin promoter, etc.).

[0039] In some embodiments, the promoter is an RNA polymerase III (pol III) promoter. Non-limiting examples of pol III promoters include U6 and H1 promoter sequences. In some embodiments, the promoter is an RNA polymerase II (pol II) promoter. Non-limiting examples of pol II promoters include T7, T3, SP6, RSV, and cytomegalovirus promoter sequences.

[0040] Aspects of the present disclosure relate to gene therapy vectors comprising isolated nucleic acids as described herein. The gene therapy vector can be a viral vector (e.g., a lentiviral vector, an adeno-associated viral vector, an adenovirus (Ad) vector, etc.), a plasmid, a closed-end DNA (e.g., ceDNA), a lipid / DNA nanoparticle, etc. In some embodiments, the gene therapy vector is a viral vector. In some embodiments, the flank of the expression cassette encoding the minigene is one or more viral replication sequences, such as a lentiviral long terminal repeat (LTR) or an adeno-associated virus (AAV) inverted terminal repeat (ITR). In some embodiments, the viral vector is a baculovirus vector.

[0041] The isolated nucleic acid described herein may also include an intron that is desired to be located between the promoter / enhancer sequence and the transgenic gene. In some embodiments, the intron is a synthetic or artificial (e.g., heterologous) intron. Examples of synthetic introns include intron sequences derived from SV-40 (referred to as SV-40T intron sequences) and intron sequences derived from the chicken beta-actin gene. In some embodiments, the transgenic gene described in the present disclosure includes one or more (1, 2, 3, 4, 5 or more) artificial introns. In some embodiments, one or more artificial introns are located between the promoter and the nucleic acid sequence encoding the transgenic gene.

[0042] In some embodiments, rAAV comprises a post-transcriptional response element. As used herein, the term "post-transcriptional response element" refers to a nucleic acid sequence that adopts a tertiary structure that enhances gene expression during transcription. Examples of post-transcriptional regulatory elements include, but are not limited to, a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), a mouse RNA transport element (RTE), a constitutive transport element (CTE) of a monkey type 1 retrovirus (SRV-1), a CTE from Mason-Pfizer monkey virus (MPMV), and a 5' untranslated region (Hsp70 5'UTR) of human heat shock protein 70. In some embodiments, the rAAV vector comprises a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE).

[0043] In some embodiments, the vector further comprises conventional control elements, which are operably linked to the transgenic element in a manner that allows the transgenic element to be transcribed, translated and / or expressed in cells transfected by the vector or infected by the virus produced by the present invention. As used herein, "operably linked" sequences include expression control sequences adjacent to the target gene and expression control sequences that act in trans or at a distance to control the target gene. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; effective RNA processing signals, such as splicing and polyadenylation (polyA) signals; sequences that stabilize cytoplasmic mRNA; sequences that improve translation efficiency (e.g., Kozak consensus sequences); sequences that enhance protein stability; and sequences that enhance secretion of the encoded product when necessary. Many expression control sequences, including natural, constitutive, inducible and / or tissue-specific promoters, are known in the art and can be used.

[0044] Polyadenylation sequences are usually inserted after the transgenic sequence and optionally before the 3'AAV ITR sequence. The rAAV constructs that can be used for the present disclosure can also contain introns that are expected to be located between the promoter / enhancer sequence and the transgenic. A possible intron sequence is derived from SV-40, known as the SV-40T intron sequence. Another vector element that can be used is an internal ribosome entry site (IRES). The IRES sequence is used to produce more than one polypeptide from a single gene transcript. The IRES sequence will be used to produce proteins containing more than one polypeptide chain. The selection of these and other common vector elements is conventional, and many such sequences are available [see, e.g., Sambrook et al., and the references cited therein, e.g., pages 3.183.26 and 16.17 16.27, and Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1989].

[0045] The isolated nucleic acid of the present disclosure can be a recombinant adeno-associated virus (AAV) vector (rAAV vector). In some embodiments, the isolated nucleic acid as described in the present disclosure comprises a region (e.g., a first region) containing a first adeno-associated virus (AAV) inverted terminal repeat (ITR) or a variant thereof. The isolated nucleic acid (e.g., a recombinant AAV vector) can be packaged into a capsid protein and administered to a subject and / or delivered to selected target cells. A "recombinant AAV (rAAV) vector" is generally composed of at least a transgene and its regulatory sequences and 5' and 3' AAV inverted terminal repeats (ITRs). The transgene may include one or more regions encoding one or more proteins (e.g., human ABCA4 or a fragment thereof). The transgene may also include a region encoding, for example, a miRNA binding site and / or an expression control sequence (e.g., a poly-A tail).

[0046] Typically, the length of the ITR sequence is about 145 bp. Preferably, a substantially complete sequence encoding the ITR is used in the molecule, although a certain degree of minor modification of these sequences is allowed. The ability to modify these ITR sequences is within the technical scope of the art. (See, for example, textbooks such as Sambrook et al., "Molecular Cloning. A Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory, New York (1989); and K. Fisher et al., J Virol., 70: 520 532 (1996)). An example of such a molecule used in the present invention is a "cis-acting" plasmid containing a transgene, in which the selected transgene sequence and the associated regulatory elements are flanked by 5' and 3' AAV ITR sequences. AAV ITR sequences can be obtained from any known AAV, including currently identified mammalian AAV types. In some embodiments, the isolated nucleic acid (e.g., rAAV vector) comprises at least one ITR having a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, AAV11, and variants thereof. In some embodiments, the isolated nucleic acid comprises a region (e.g., a first region) encoding an AAV2 ITR.

[0047] In some embodiments, the isolated nucleic acid further comprises a region (e.g., a second region, a third region, a fourth region, etc.) containing a second AAV ITR. In some embodiments, the second AAV ITR has a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, AAV11, and variants thereof. In some embodiments, the second AAV ITR is an AAV2 ITR. In some embodiments, the second ITR is a mutant ITR lacking a functional terminal dissociation site (TRS). The term "lack of a terminal dissociation site" may refer to an AAV ITR comprising a mutation (e.g., a sense mutation, such as a non-synonymous mutation or a missense mutation) that abolishes the function of the terminal dissociation site (TRS) of the ITR, or a truncated AAV ITR (e.g., ΔTRS ITR or ΔITR) lacking a nucleic acid sequence encoding a functional TRS. Without wishing to be bound by any particular theory, rAAV vectors comprising ITRs lacking functional TRSs result in self-complementary rAAV vectors, for example as described by McCarthy (2008) Molecular Therapy 16(10):1648-1656.

[0048] Recombinant adeno-associated virus (rAAV)

[0049] In some aspects, the present disclosure provides an isolated adeno-associated virus (AAV). As used herein with respect to AAV, the term "isolated" refers to an AAV that is artificially produced or obtained. A recombinant method can be used to produce isolated AAV. Such AAV is referred to as "recombinant AAV" in this article. Recombinant AAV (rAAV) preferably has tissue-specific targeting capabilities so that the nuclease and / or transgene of rAAV will be specifically delivered to one or more predetermined tissues. The AAV capsid is an important factor in determining these tissue-specific targeting capabilities. Therefore, rAAV with a capsid suitable for targeted tissues can be selected.

[0050] Methods for obtaining recombinant AAV with desired capsid proteins are well known in the art. (See, e.g., US 2003 / 0138772), the contents of which are incorporated herein by reference in their entirety). Generally, these methods include culturing a host cell containing a nucleic acid sequence encoding an AAV capsid protein; a functional rep gene; a recombinant AAV vector comprising an AAV inverted terminal repeat (ITR) and a transgene; and auxiliary functions sufficient to allow the recombinant AAV vector to be packaged into the AAV capsid protein. In some embodiments, the capsid protein is a structural protein encoded by the cap gene of AAV. AAV contains three capsid proteins: virion proteins 1 to 3 (named VP1, VP2, and VP3), all of which are transcribed from a single cap gene via alternative splicing. In some embodiments, the molecular weights of VP1, VP2, and VP3 are about 87 kDa, about 72 kDa, and about 62 kDa, respectively. In some embodiments, when translated, the capsid protein forms a spherical 60-mer protein shell around the viral genome. In some embodiments, the function of the capsid protein is to protect the viral genome, deliver the genome and interact with the host. In some aspects, the capsid protein delivers the viral genome to the host in a tissue-specific manner.

[0051] In some embodiments, the AAV capsid protein has an AAV serotype selected from the group consisting of AAV2, AAV3, AAV4, AAV5, AAV6, AAV8, AAVrh8, AAV9, and AAV10. In some embodiments, the AAV capsid protein has a serotype derived from a non-human primate, such as an AAVrh8 serotype. In some embodiments, the AAV capsid protein has a serotype that is tropistic to the subject's eye, such as an AAV that transduces the subject's eye cells more effectively than other AAV capsid proteins (e.g., AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAVrh.8, AAVrh.10, AAVrh.39, and AAVrh.43). In some embodiments, the AAV capsid protein has an AAV8 serotype.

[0052] Components cultivated in host cells to package rAAV vectors in AAV capsids can be trans-provided to host cells. Alternatively, any one or more required components (e.g., recombinant AAV vectors, rep sequences, cap sequences and / or auxiliary functions) can be provided by stable host cells, which have been engineered to contain one or more required components using methods known to those skilled in the art. Most suitably, such stable host cells will contain the required components under the control of an inducible promoter. However, the required components can be under the control of a constitutive promoter. In discussing regulatory elements suitable for use with transgenics, examples of suitable inducible and constitutive promoters are provided herein. In another alternative, a selected stable host cell can contain selected components under the control of a constitutive promoter and other selected components under the control of one or more inducible promoters. For example, a stable host cell can be produced, which is derived from 293 cells (which contain E1 auxiliary functions under the control of a constitutive promoter) but contains rep and / or cap proteins under the control of an inducible promoter. Those skilled in the art can produce other stable host cells.

[0053] In some embodiments, the present disclosure relates to a host cell containing a nucleic acid comprising a coding sequence encoding a protein (e.g., MiniABCA4 protein). In some embodiments, the host cell is a mammalian cell (e.g., HEK293 cell) or an insect cell (e.g., SF9 cell). In some embodiments, the present disclosure relates to a composition comprising the above-mentioned host cell. In some embodiments, the composition comprising the above-mentioned host cell further comprises a cryopreservative.

[0054] Any suitable genetic element (vector) can be used to deliver the recombinant AAV vector, rep sequence, cap sequence and auxiliary function required for producing the rAAV of the present disclosure to the packaging host cell. The selected genetic element can be delivered by any suitable method, including those described herein. The method for constructing any embodiment of the present disclosure is known to nucleic acid manipulation technicians, and includes genetic engineering, recombinant engineering and synthetic techniques. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY. Similarly, the method of producing rAAV virions is well known, and the selection of suitable methods is not a limitation of the present disclosure. See, for example, K. Fisher et al., J. Virol., 70: 520-532 (1993) and U.S. Patent No. 5,478,745.

[0055] In some embodiments, recombinant AAV can be produced using a triple transfection method (described in detail in U.S. Patent No. 6,001,650). Typically, recombinant AAV is produced by transfecting host cells with a recombinant AAV vector (including a transgene) to be packaged into AAV particles, an AAV auxiliary function vector, and an accessory function vector. The AAV auxiliary function vector encodes an "AAV auxiliary function" sequence (i.e., rep and cap), which acts in trans for productive AAV replication and encapsidation. Preferably, the AAV auxiliary function vector supports effective AAV vector production without producing any detectable wild-type AAV virions (i.e., AAV virions containing functional rep and cap genes). Non-limiting examples of vectors suitable for use with the present disclosure include pHLP19 described in U.S. Patent No. 6,001,650 and pRep6cap6 vectors described in U.S. Patent No. 6,156,303, the entire contents of which are incorporated herein by reference in their entirety. Accessory function vectors encode nucleotide sequences with non-AAV derived viral and / or cellular functions that AAV depends on for replication (i.e., "accessory functions"). Accessory functions include those required for AAV replication, including but not limited to those involved in activating AAV gene transcription, stage-specific AAV mRNA splicing, AAV DNA replication, cap expression product synthesis, and AAV capsid assembly. Virus-based accessory functions can be derived from any known helper virus, such as adenovirus, herpes virus (except herpes simplex virus type 1), and vaccinia virus.

[0056] In some aspects, the disclosure provides transfected host cells. The term "transfection" is used to refer to the uptake of exogenous DNA by a cell, and a cell has been "transfected" when the exogenous DNA is introduced into the cell membrane. Many transfection techniques are well known in the art. See, for example, Graham et al. (1973) Virology, 52: 456, Sambrook et al. (1989) Molecular Cloning, a laboratory manual, Cold Spring Harbor Laboratories, New York, Davis et al. (1986) Basic Methods in Molecular Biology, Elsevier, and Chu et al. (1981) Gene 13: 197. Such techniques can be used to introduce one or more exogenous nucleic acids, such as nucleotide integration vectors and other nucleic acid molecules, into suitable host cells.

[0057] "Host cell" refers to any cell that contains or is capable of containing a target substance. Typically, the host cell is a mammalian cell. The host cell can be used as a receptor for AAV auxiliary constructs, AAV minigene plasmids, accessory function vectors, or other transfer DNAs associated with recombinant AAV production. The term includes the offspring of the original cell that has been transfected. Therefore, "host cell" as used herein may refer to a cell that has been transfected with an exogenous DNA sequence. It should be understood that the offspring of a single parent cell may not necessarily be exactly the same as the original parent in terms of morphology or genome or total DNA complement due to natural, accidental or intentional mutations.

[0058] As used herein, the term "cell line" refers to a population of cells capable of continuous or prolonged growth and division in vitro. Typically, a cell line is a clonal population derived from a single progenitor cell. It is also known in the art that spontaneous or induced changes in karyotype may occur during storage or transfer of such clonal populations. Thus, cells derived from a reference to a cell line may not be identical to the progenitor cell or culture, and reference to a cell line includes such variants.

[0059] As used herein, the term "recombinant cell" refers to a cell into which an exogenous DNA segment has been introduced (eg, a DNA segment that results in the transcription of a biologically active polypeptide or the production of a biologically active nucleic acid (eg, RNA)).

[0060] As used herein, the term "vector" includes any genetic element, such as a plasmid, a phage, a transposon, a cosmid, a chromosome, an artificial chromosome, a virus, a virion, etc., which is capable of replication when combined with appropriate control elements and which can transfer gene sequences between cells. Thus, the term includes cloning and expression vectors, as well as viral vectors.

[0061] method

[0062] Provided herein is a method for delivering a transgene to an eye (e.g., photoreceptor, such as rod or cone, retinal cell, etc.) tissue or ear of a subject. The method generally comprises administering to the subject an effective amount of rAAV comprising a nucleic acid for expressing a transgene (e.g., MiniABCA4 protein) in the subject. An "effective amount" of rAAV is an amount sufficient to infect a sufficient number of cells of a subject's target tissue. In some embodiments, the target tissue is an eye (e.g., photoreceptor, retina, etc.) tissue. In some embodiments, the transgene is delivered to a photoreceptor cell or retinal pigment epithelium (RPE).

[0063] An effective amount of rAAV can be an amount sufficient to have a therapeutic benefit in a subject, such as improving one or more symptoms of a disease in the subject, such as symptoms of fundus yellow spot disease (e.g., a disease associated with a deletion or mutation in the ABCA4 gene). Examples of mutations in the ABCA4 gene include mutations that result in amino acid substitutions G1961E and D2177N in the ABCA4 protein. The effective amount will depend on a variety of factors, such as the species, age, weight, health status, and ocular tissue to be targeted of the subject, and therefore may vary from subject to subject and tissue to tissue. The effective amount may also depend on the rAAV used.

[0064] In certain embodiments, the effective amount of rAAV is 10 10 , 10 11 , 10 12 , 10 13 or 10 14 In certain embodiments, the effective amount of rAAV is 10 genome copies / kg per subject. 10 , 10 11 , 10 12 , 10 13 , 10 14 or 10 15 genome copies.

[0065] Aspects of the present disclosure relate to methods for treating fundus yellow spot disease in a subject in need thereof. In some embodiments, the subject is a mammal, such as a human, mouse, rat, dog, cat, non-human primate, etc. In some embodiments, the subject is a human.

[0066] As used herein, the term "treating" refers to the application or administration of a composition (e.g., an isolated nucleic acid or rAAV as described herein) to a subject exhibiting one or more signs or symptoms of yellow spot disease (e.g., blurred vision or squinting, inability to see in low light, loss of color vision, one or more mutations in the ABCA4 gene, etc.) for the purpose of curing, healing, alleviating, relieving, altering, rescuing, improving, ameliorging, or affecting the symptoms of the condition, disease, or predisposition to yellow spot disease.

[0067] Alleviating yellow spot disease includes delaying the development or progression of the disease, or reducing the severity of the disease. Alleviating the disease does not necessarily require a curative outcome. As used herein, "delaying" the development of yellow spot disease means postponing, hindering, slowing down, slowing down, stabilizing and / or delaying the progression of the disease. This delay can have different lengths of time, depending on the history of the disease and / or the individual being treated. A method of "delaying" or alleviating the development of a disease or delaying the onset of a disease is a method that reduces the likelihood of one or more symptoms of the disease within a given time frame and / or reduces the extent of the symptoms within a given time frame when compared to not using the method. Such comparisons are typically based on clinical studies using a sufficient number of subjects to produce statistically significant results.

[0068] The "development" or "progression" of a disease refers to the initial manifestation and / or subsequent progression of a disease. The development of a disease can be detected and assessed using standard clinical techniques well known in the art. However, development also refers to progression that may not be detectable. For purposes of this disclosure, development or progression refers to the biological course of symptoms. "Development" includes onset, recurrence, and onset.

[0069] The effective amount can also depend on the mode of administration. For example, in some cases, targeting eye (e.g., photoreceptor, retina, etc.) tissue by intrastromal administration or subcutaneous injection may require a dosage different (e.g., higher or lower) from targeting eye (e.g., photoreceptor, retina, etc.) tissue by another method (e.g., systemic administration, topical administration). In some embodiments, intrastromal injection (IS) has rAAVs of certain serotypes (e.g., AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAVrh.8, AAVrh.10, AAVrh.39, and AAVrh.43) that mediate effective transduction of eye (e.g., cornea, photoreceptor, retina, etc.) cells. Therefore, in some embodiments, injection is intrastromal injection (IS). In some embodiments, administration is by injection, optionally subretinal injection or intravitreal injection. In some embodiments, injection is topical administration (e.g., topical administration to eyes). In some cases, multiple doses of rAAV are administered.

[0070] The rAAV can be delivered to a subject in the form of a composition according to any suitable method known in the art. The rAAV, preferably suspended in a physiologically compatible carrier (i.e., in a composition), can be administered to a subject, i.e., a host animal, such as a human, mouse, rat, cat, dog, sheep, rabbit, horse, cow, goat, pig, guinea pig, hamster, chicken, turkey, or non-human primate (e.g., macaque). In some embodiments, the host animal does not include a human.

[0071] Delivery of rAAV to a mammalian subject can be by, for example, intraocular injection or topical administration (e.g., eye drops). In some embodiments, intraocular injection includes intrastromal injection, subconjunctival injection, or intravitreal injection. In some embodiments, the injection is not topical administration. A combination of administration methods (e.g., topical administration and intrastromal injection) may also be used.

[0072] The compositions of the present disclosure can include rAAV alone, or rAAV in combination with one or more other viruses (e.g., a second rAAV encoding a transgene with one or more different transgenes, such as encoding a different MiniABCA4 protein). In some embodiments, the composition includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different rAAVs, each with one or more different transgenes.

[0073] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. Considering the indications for which rAAV is directed, a person skilled in the art can easily select a suitable carrier. For example, a suitable carrier includes saline, which can be formulated with a variety of buffer solutions (e.g., phosphate buffered saline).

[0074] Other exemplary carriers include sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil and water. The choice of carrier does not constitute a limitation of the present invention.

[0075] Optionally, in addition to rAAV and (one or more) carriers, the compositions of the present disclosure may also contain other pharmaceutical ingredients, such as preservatives or chemical stabilizers. Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerol, phenol and p-chlorophenol. Suitable chemical stabilizers include gelatin and albumin.

[0076] rAAV is administered in sufficient amounts to transfect cells of target tissues (e.g., ocular tissues, such as photoreceptors, retina, etc.) and provide sufficient gene transfer and expression levels without excessive side effects. Examples of pharmaceutically acceptable routes of administration include, but are not limited to, direct delivery to selected organs (e.g., subretinal delivery to the eye), oral, inhalation (including intranasal and intratracheal delivery), intraocular, intravenous, intramuscular, subcutaneous, intradermal, intratumoral, and other parenteral routes of administration. If desired, the routes of administration may be combined.

[0077] The dose of rAAV virions required to achieve a particular "therapeutic effect", for example in units of genome copies per kilogram of body weight (GC / kg), will vary depending on a variety of factors, including but not limited to: the route of administration of the rAAV virions, the gene or RNA expression level required to achieve the therapeutic effect, the specific disease or condition being treated, and the stability of the gene or RNA product. A person skilled in the art can easily determine the dose range of rAAV virions for treating a patient with a particular disease or condition based on the above factors and other factors.

[0078] An effective amount of rAAV is an amount sufficient to target an infected animal, targeting a target tissue. The effective amount will depend primarily on factors such as the subject's species, age, weight, health, and tissue to be targeted, and may therefore vary from animal to animal and tissue to tissue. For example, an effective amount of rAAV is typically about 10 ml to about 100 ml containing about 10 9 Up to 10 16 In some cases, about 10 11 Up to 10 13 A dosage of between 10 and 100 copies of the rAAV genome is appropriate. 9 The rAAV genome copies effectively target ocular tissues (e.g., corneal tissue).

[0079] In some embodiments, when administered to an eye of a subject, the 9 A more concentrated dose of rAAV genome copies is toxic. In some embodiments, an effective amount is produced by multiple doses of rAAV. In some embodiments, one or more immunosuppressants (e.g., corticosteroids, methotrexate, cyclosporine A, mycophenolate mofetil, tacrolimus, rituximab, sirolimus, methylprednisolone, CTLA4Ig, non-depleting CD4 Ab and T cell depleting anti-thymocyte gamma-globulin (ATG), etc.) are administered to the subject before administering rAAV.

[0080] In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once per calendar day (e.g., a 24-hour cycle). In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once per 2, 3, 4, 5, 6, or 7 calendar days. In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once per calendar week (e.g., 7 calendar days). In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once every two weeks (e.g., once during two calendar weeks). In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once per calendar month (e.g., once in 30 calendar days). In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once per six calendar months. In some embodiments, a dose of rAAV is administered to a subject at a frequency of no more than once per calendar year (e.g., 365 days or 366 days in a leap year).

[0081] In some embodiments, the rAAV compositions are formulated to reduce aggregation of AAV particles in the composition, particularly in the presence of high rAAV concentrations (e.g., ~10 13 GC / ml or higher). Suitable methods for reducing aggregation can be used, including, for example, adding surfactants, pH adjustment, salt concentration adjustment, etc. (see, for example, Wright FR, et al., Molecular Therapy (2005) 12, 171-178, the contents of which are incorporated herein by reference.).

[0082] The preparation of pharmaceutically acceptable excipients and vehicle solutions is well known to those skilled in the art, and the development of suitable dosing and treatment regimens for using the specific compositions described herein in various treatment regimens is also well known to those skilled in the art. Typically, these preparations may contain at least about 0.1% or more of the active compound, although the percentage of (one or more) active ingredients may of course vary and may conveniently be between about 1 or 2% to about 70% or 80% or more of the total preparation weight or volume. Naturally, the amount of active compound in each therapeutically useful composition may be prepared in such a way that a suitable dose will be obtained in any given unit dose of the compound. Technicians in the field of preparing such pharmaceutical preparations will consider factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, and other pharmacological considerations, and therefore, various doses and treatment regimens may be desired.

[0083] In some embodiments, rAAV is delivered directly to the target tissue in the form of a suitably formulated pharmaceutical composition disclosed herein, for example, directly to ocular tissue (e.g., tissues such as photoreceptors, retina, etc.). However, in some cases, it may be necessary to deliver rAAV-based therapeutic constructs separately or additionally via another route, such as subcutaneous, intrapancreatic, intranasal, parenteral, intravenous, intramuscular, intrathecal, or orally, intraperitoneally, or by inhalation. In some embodiments, rAAV can be delivered using administration methods as described in U.S. Patent Nos. 5,543,158, 5,641,515, and 5,399,363 (each expressly incorporated herein by reference). In some embodiments, the preferred administration method is by intravitreal injection or subretinal injection.

[0084] The pharmaceutical form suitable for injection includes sterile aqueous solution or dispersion and sterile powder for temporary preparation of sterile injection or dispersion. Dispersion can also be prepared in glycerol, liquid polyethylene glycol and mixture thereof and in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. In many cases, the form is sterile and mobile, reaching the extent of easy injection. It must be stable under manufacturing and storage conditions, and must prevent the contamination of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.), their suitable mixtures and / or vegetable oils. For example, appropriate fluidity can be maintained by using a coating agent such as lecithin, by maintaining the required particle size in the case of a dispersant, and by using a surfactant. Various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. can prevent the effect of microorganisms. In many cases, it is preferred to include isotonic agents, such as sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0085] For example, for the use of injectable aqueous solutions, if necessary, the solution can be appropriately buffered, and the liquid diluent can first be made isotonic with enough saline or glucose. These specific aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, suitable sterile aqueous media can be used. For example, a dosage can be dissolved in 1ml isotonic NaCl solution, and added to 1000ml subcutaneous perfusion fluid (hypodermoclysis fluid) or injected at the infusion site of suggestion, (see, for example, " Remington's Pharmaceutical Sciences ", the 15th edition, pages 1035-1038 and 1570-1580). Depending on the situation of the host, some changes will inevitably occur in the dosage. In any case, the person responsible for administration will determine the appropriate dosage of the individual host.

[0086] Sterile injectable solutions are prepared by incorporating the desired amount of active rAAV into a suitable solvent along with the various other ingredients listed herein (as required) followed by filtered sterilization. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which provide a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution.

[0087] The rAAV compositions disclosed herein can also be formulated into neutral or salt forms. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of proteins) and salts formed with inorganic acids such as hydrochloric acid or phosphoric acid or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Salts formed with free carboxyl groups can also be derived from inorganic bases, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, etc. When formulated, the solution will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The preparation is easy to administer in a variety of dosage forms, such as injectable solutions, drug release capsules, etc.

[0088] As used herein, "carrier" includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients may also be incorporated into the composition. The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce allergic or similar adverse reactions when administered to a host.

[0089] The compositions of the present disclosure can be introduced into suitable host cells using delivery vehicles such as liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles, etc. In particular, the transgene delivered by the rAAV vector can be formulated to be encapsulated in lipid particles, liposomes, vesicles, nanospheres or nanoparticles, etc. for delivery.

[0090] Such preparations may be preferably used for introducing pharmaceutically acceptable preparations of nucleic acids or rAAV constructs disclosed herein. The formation and use of liposomes are generally known to those skilled in the art. Recently, liposomes with improved serum stability and circulation half-life have been developed (U.S. Patent No. 5,741,516). In addition, various methods of liposomes and liposome-like preparations as potential drug carriers have been described (U.S. Patent Nos. 5,567,434; 5,552,157; ​​5,565,213; 5,738,868 and 5,795,587).

[0091] Liposomes have been successfully used in many cell types that are usually resistant to transfection by other programs. In addition, liposomes do not have the DNA length restrictions that are typical of viral delivery systems. Liposomes have been effectively used to introduce genes, drugs, radiotherapeutic agents, viruses, transcription factors, and allosteric effectors into multiple cultured cell lines and animals. In addition, several successful clinical trials examining the effectiveness of liposome-mediated drug delivery have been completed.

[0092] Liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles, also known as multilamellar vesicles (MLVs). MLVs typically have diameters ranging from 25 nm to 4 μm. Ultrasonication of MLVs results in the formation of vesicles with diameters ranging from 200 to Small unilamellar vesicles (SUVs) within the range contain an aqueous solution in the core.

[0093] Alternatively, nanocapsule formulations of rAAV can be used. Nanocapsules can generally capture substances in a stable and reproducible manner. To avoid side effects caused by intracellular polymer overload, such ultrafine particles (about 0.1 μm in size) should be designed using polymers that can be degraded in vivo. Biodegradable polyalkyl cyanoacrylate nanoparticles that meet these requirements are considered. Example

[0094] Example 1: miniABC4 gene constructs MG-1 to MG-6

[0095] This example describes the identification and production of AAV vectors (and rAAV) with one or more domains of ABCA4 (e.g., ABCA4 minigenes and their gene products, "MiniABCA4") that retain function in photoreceptors (e.g., partial ABCA4 function). The expression and stability of miniABCA4 proteins were tested by expressing them as MYC-tagged versions of the protein in cultured HEK293 cells. The versions that showed the best expression and stability were injected into Abca4 cells in vivo. - / - Mice. Viral particles are pseudotyped (e.g., AAV2 / 8) and expression is driven by a promoter that primarily targets photoreceptors. MiniABCA4 constructs are administered using subretinal injections. Figure 1 and SEQ ID NOs: 3-8 show embodiments of MiniABCA4 constructs MG-1 to MG-6. SEQ ID NOs: 9-14 show embodiments of MiniABCA4 proteins of MG-1 to MG-6.

[0096] Reduction of retinal pigment epithelium (RPE) background autofluorescence was used as a surrogate assay to test the efficacy of miniABCA4 candidates. - / - Mice were injected with the Abca4-1(MG-1) construct at 30 days postnatally, and RPE autofluorescence was measured by fluorescence microscopy. RPE cells were stained with the marker ZO-1. Representative data are shown in Figure 2 Compared with wild-type controls, Abca4 - / - Mice showed higher RPE autofluorescence at 488 nM at 4 months of age. Injection of miniABCA4-1 resulted in a significant decrease in autofluorescence at 488 nM, indicating a rescue effect of miniABCA4-1.

[0097] Other ABCA4 minigene constructs were tested using the RPE autofluorescence assay and the results were Figure 3 Quantification of Abca4 - / - Mice were injected with miniABCA4-1 (MG-1), miniABCA4-2 (MG-2), miniABCA4-4 (MG-4), or miniABCA4-5 (MG-5). Injections were performed at postnatal day 10 or 30 (P10 or P30), and RPE autofluorescence was measured at the indicated ages in the figures. Data show that RPE autofluorescence was significantly higher in mice than in mice that did not receive Abca4 injections. - / - Several miniABCA4 constructs significantly reduced RPE autofluorescence compared with mice, and injection at P30 improved RPE autofluorescence better than injection at P10.

[0098] Example 2: miniABC4 gene constructs MG-7 to MG-11

[0099] This example describes additional ABCA4 minigene designs, termed MG-7 to MG-11, and the production of AAV vectors (and rAAV) expressing these ABCA4 minigenes. The expression and stability of the miniABCA4 protein was tested by expressing the miniABCA4 protein as a MYC-tagged version of the protein in cultured HEK293 cells ( Figure 5 ). Tubulin was used as a loading control. Figure 4 and SEQ ID NOs: 15-19 show embodiments of MiniABCA4 constructs MG-7 to MG-11. SEQ ID NOs: 20-24 show embodiments of MiniABCA4 proteins of MG-7 to MG-11.

[0100] sequence

[0101] In some embodiments, the isolated nucleic acid or vector (e.g., rAAV vector) described in the present disclosure comprises or consists of a sequence as shown in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, the isolated nucleic acid or vector (e.g., rAAV vector) described in the present disclosure comprises or consists of a sequence complementary to (e.g., a complement of) a sequence as shown in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, the isolated nucleic acid or vector (e.g., rAAV vector) described in the present disclosure comprises or consists of a sequence that is the reverse complement of a sequence as shown in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, the isolated nucleic acid or vector (e.g., rAAV vector) described in the present disclosure comprises or consists of a portion of a sequence as shown in any one of SEQ ID NOs: 3-8 and 15-19. A portion may comprise at least 25%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of a sequence as shown in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, the nucleic acid sequence described in the present disclosure is a nucleic acid sense strand (e.g., 5' to 3' strand), or in the case of a viral sequence, a positive (+) strand. In some embodiments, the nucleic acid sequence described in the present disclosure is a nucleic acid antisense strand (e.g., 3' to 5' strand), or in the case of a viral sequence, a negative (-) strand.

[0102] Equivalent solution

[0103] Although several embodiments of the present invention have been described and illustrated herein, a person of ordinary skill in the art will readily conceive of various other devices and / or structures for performing the functions described herein and / or obtaining the results described herein and / or one or more advantages described herein, and each of these changes and / or modifications is considered to be within the scope of the present invention. More generally, it will be readily understood by those skilled in the art that all parameters, dimensions, materials, and configurations described herein are exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications for which the present invention teaches. Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein using no more than routine experiments. Therefore, it should be understood that the foregoing embodiments are presented only as examples, and within the scope of the appended claims and their equivalents, the present invention may be implemented in a manner different from that specifically described and claimed. The present invention relates to each individual feature, system, article, material, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, and / or methods is included within the scope of the present invention if such features, systems, articles, materials, and / or methods are not mutually inconsistent.

[0104] Unless explicitly stated to the contrary, the indefinite article "a" or "an" as used herein in the specification and claims should be understood to mean "at least one".

[0105] The phrase "and / or" as used herein in the specification and claims should be understood to mean "one or both" of the elements so combined, i.e., the elements are present together in some cases, and separately in other cases. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified, unless expressly indicated to the contrary. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may refer to A and no B (optionally including elements other than B) in one embodiment; to B and no A (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0106] As used herein in the specification and claims, "or" shall be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., including at least one of a number of elements or a list of elements, but also including more than one, and optionally other unlisted items. Only terms that are clearly indicated to the contrary, such as "only one" or "only one", or "consisting of..." when used in the claims, will refer to the only one element in a number of elements or a list of elements. In general, before exclusive terms, such as "either", "one of", "only one" or "only one", the term "or" used herein shall only be interpreted as indicating an exclusive alternative (i.e., "one or the other, but not both"). "Substantially consisting of..." when used in the claims shall have its ordinary meaning used in the field of patent law.

[0107] As used herein in the specification and claims, with respect to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one element of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B"; or equivalently "at least one of A and / or B") may refer to at least one, optionally including more than one A but no B (and optionally including elements other than B) in one embodiment; to at least one, optionally including more than one B but no A (and optionally including elements other than A) in another embodiment; to at least one, optionally including more than one B but no A (and optionally including elements other than A) in yet another embodiment; and to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0108] In the claims and throughout the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "having," and the like shall be construed as open ended, i.e., meaning including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedure Section 2111.03.

[0109] The use of ordinal terms such as "first", "second", "third" and the like to modify claim elements in the claims does not in itself imply any priority, precedence or order of one claim element relative to another claim element or the temporal order of performance of the actions of a method, but is merely used as a label to distinguish one claim element with a particular name from another element with the same name (but used in ordinal terms) to distinguish the claim elements.

[0110] The terms "about" and "substantially" preceding a numerical value represent ±10% of the stated numerical value. Sequence Listing <110> University of Massachusetts <120> Gene therapy for ABCA4 <130> U0120.70122WO00 <140> Not yet specified <141> Same as above <150> US 62 / 836,493 <151> 2019-04-19 <160> twenty four <170> PatentIn version 3.5 <210> 1 <211> 7328 <212> DNA <213> Homo sapiens <400> 1 ggacacagcg tccggagcca gaggcgctct taacggcgtt tatgtccttt gctgtctgag 60 gggcctcagc tctgaccaat ctggtcttcg tgtggtcatt agcatgggct tcgtgagaca 120 gatacagcttttgctctgga agaactggac cctgcggaaa aggcaaaaga ttcgctttgt 180 ggtggaactc gtgtggcctt tatctttatttctggtcttg atctggttaa ggaatgccaa 240 cccactctac agccatcatg aatgccattt ccccaacaag gcgatgccct cagcaggaat 300 gctgccgtgg ctccaggga tcttctgcaa tgtgaacaat ccctgttttc aaagccccac 360 cccaggagaa tctcctggaa ttgtgtcaaa ctataacaac tccatcttgg caagggtata 420 tcgagattt caagaactcc tcatgaatgc accagagagc cagcaccttg gccgtatttg 480 gacagagcta cacatcttgt cccaattcat ggacaccctc cggactcacc cggagagaat 540 tgcaggaaga ggaatacgaa taaggatat cttgaaagat gaaaacac tgacactatt 600 tctcattaaa aacatcggcc tgtctgactc agtggtctac cttctgatca actctcaagt 660 ccgtccagag cagttcgctc atggagtccc ggacctggcg ctgaaggaca tcgcctgcag 720 cgaggccctc ctggagcgct tcatcatctt cagccagaga cgcggggcaa agacggtgcg 780 ctatgccctg tgctccctct cccagggcac cctacagtgg atagaagaca ctctgtatgc 840 caacgtggac ttcttcaagc tcttccgtgt gcttcccaca ctcctagaca gccgttctca 900 aggtatcaat ctgagatctt ggggaggaat attatctgat atgtcaccaa gaattcaaga 960 gtttatccat cggccgagta tgcaggactt gctgtgggtg accaggcccc tcatgcagaa 1020 tggtggtcca gagaccttta caaagctgat gggcatcctg tctgacctcc tgtgtggcta 1080 ccccgaggga gggtggctctc gggtgctctc cttcaactgg tatgaagaca atataatataa 1140 ggcctttctg gggattgact ccacaaggaa ggatcctatc tattcttatg acaagaac 1200 aacatccttt tgtaatgcat tgatccagag cctggagtca aatcctttaa ccaaaatcgc 1260 ttggagggcg gcaaagcctt tgctgatggg aaaaatcctg tacactcctg attcacctgc 1320 agcacgaagg atactgaaga atgccaactc aactttgaa gaactggaac acgttaggaa 1380 gttggtcaaa gcctgggaag aagtagggcc ccagatctgg tacttctttg aaacagcac 1440 acagatgaac atgatcagag ataccctggg gaacccaaca gtaaaagact ttttgaatag 1500 gcagcttggt gaaaggta ttactgctga agccatccta aacttcctct acaagggccc 1560 tcgggaaagc caggctgacg acatggccaa cttcgactgg agggacatat ttaacatcac 1620 tgatcgcacc ctccgcctgg tcaatcaata cctggagtgc ttggtcctgg ataagtttga 1680 aagctacaat gatgaaactc agctcaccca acgtgccctc tctctactgg aggaaaacat gttctgggcc ggagtggtat tccctgacat gtatccctgg accagctctc taccacccca cgtgaagtat aagatccgaa tggacataga cgtggtggag aaaaccaata agattaaga caggtattgg gattctggtc ccagagctga tcccgtgga gattccggt acatctgggg cgggtttgcc tatctgcagg acatggttga acaggggatc acaaggagcc aggtgcaggc ggaggctcca gttggaatct acctccagca gatgccctac ccctgcttcg tggacgattc tttcatgatc atcctgaacc gctgtttccc tatcttcatg gtgctggcat ggatctactc tgtctccatg actgtgaaga gcatcgtctt ggagaaggag ttgcgactga aggagacctt 2220. gaaaaatcag ggtgtctcca atgcagtgat ttggtgtacc tggttcctgg acagcttctc catcatgtcg atgagcatct tcctcctgac gatattcatc atgcatggaa gatacctaca ttacagcgac ccattcatcc tcttcctgtt cttgttggct ttctccactg ccaccatcat gctgtgcttt ctgctcagca ccttcttctc caaggccagt ctggcagcag cctgtagtgg tgtcatctat ttcaccctct acctgccaca catcctgtgc ttcgcctggc aggaccgcat 2460 gaccgctgag ctgaagaagg ctgtgagctt actgtctccg gtggcatttg gatttggcac 2520 tgagtacctg gttcgctttg aagagcaagg cctggggctg cagtggagca acatcgggaa 2580 cagtcccacg gaaggggacg aattcagctt cctgctgtcc atgcagatga tgctccttga 2640 tgctgctgtc tatggcttac tcgcttggta ccttgatcag gtgtttccag gagactatgg 2700 aaccccactt ccttggtact ttcttctaca agagtcgtat tggcttggcg gtgaagggtg 2760 ttcaaccaga gaaagag ccctggaaaa gaccgagccc ctaacagagg aaacggaga 2820 tccagagcac ccagaaggaa tacacgactc cttctttgaa cgtgagcatc cagggtgggt 2880 tcctggggta tgcgtgaaga atctggtaaa gatttttgag ccctgtggcc ggccagctgt 2940 ggaccgtctg aacatcacct tctacgagaa ccagatcacc gcattcctgg gccacaatgg 3000 agctgggaaa accaccacct tgtccatcct gacgggtctg ttgccaccaa cctctgggac 3060 tgtgctcgtt gggggaaggg acattgaaac cagcctggat gcagtccggc agagccttgg 3120 catgtgtcca cagcacaaca tcctgttcca ccacctcacg gtggctgagc acatgctgtt 3180 ctatgcccag ctgaaaggaa agtcccagga ggaggcccag ctggagatgg aagccatgtt 3240 ggaggacaca ggcctccacc acaagcggaa tgaagaggct caggacctat caggtggcat 3300 gcagagaaag ctgtcggttg ccattgcctt tgtgggagat gccaaggtgg tgattctgga 3360 cgaacccacc tctggggtgg acccttactc gagacgctca atctgggatc tgctcctgaa 3420 gtatcgctca ggcagaacca tcatcatgtc cactcaccac atggacgagg ccgacctcct 3480 tggggaccgc attgccatca ttgcccaggg aaggctctac tgctcaggca ccccactctt 3540 cctgaagaac tgctttggca caggcttgta cttaaccttg gtgcgcaaga tgaaaaacat 3600 ccagagccaa aggaaaggca gtgaggggac ctgcagctgc tcgtctaagg gtttctccac 3660 cacgtgtcca gcccacgtcg atgacctaac tccagaacaa gtcctggatg gggatgtaaa 3720 tgagctgatg gatgtagttc tccaccatgt tccagaggca aagctggtgg agtgcattgg 3780 tcaagaactt atcttccttc ttccaaataa gaacttcaag cacagagcat atgccagcct 3840 tttcagagag ctggaggaga cgctggctga ccttggtctc agcagttttg gaatttctga 3900 cactcccctg gaagagattt ttctgaaggt cacggaggat tctgattcag gacctctgtt 3960 tgcgggtggc gctcagcaga aaagagaaaa cgtcaacccc cgacacccct gcttgggtcc 4020 cagagagaag gctggacaga caccccagga ctccaatgtc tgctccccag gggcgccggc 4080 tgctcaccca gagggccagc ctcccccaga gccagagtgc ccaggcccgc agctcaacac 4140 ggggacacag ctggtcctcc agcatgtgca ggcgctgctg gtcaagagat tccaacacac 4200 catccgcagc cacaaggact tcctggcgca gatcgtgctc ccggctacct ttgtgttttt 4260 ggctctgatg ctttctattg ttatccctcc ttttggcgaa taccccgctt tgacccttca 4320 cccctggata tatgggcagc agtacacctt cttcagcatg gatgaaccag gcagtgagca 4380 gttcacggta cttgcagacg tcctcctgaa taagccaggc tttggcaacc gctgcctgaa 4440 ggaagggtgg cttccggagt acccctgtgg caactcaaca ccctggaaga ctccttctgt 4500 gtccccaaac atcacccagc tgttccagaa gcagaaatgg acacaggtca acccttcacc 4560 atcctgcagg tgcagcacca gggagaagct caccatgctg ccagagtgcc ccgagggtgc 4620 cgggggcctc ccgcccccccc agaacaca gcgcagcacg gaaattctac aagacctgac 4680 ggaggaac atctccgact tcttggtaaa aacgtatcct gctctttaaa gaagcagctt 4740 aaagagcaaa ttctgggtca atgaacagag gtatggagga atttccattg gaggaaagct 4800 cccagtcgtc cccatcacgg gggaagcact tgttgggttt ttaagcgacc ttggccggat 4860 catgaatgtg agcggggggcc ctatcactag agaggcctct aaagaaatac ctgatttcct 4920 4980 cctggtcagc tttctcaatg tggcccacaa cgccatctta cgggccagcc tgcctaagga 5040 caggagcccc gaggagtatg gaatcaccgt cattagccaa cccctgaacc tgaccaagga 5100 gcagctctca gagattacag tgctgaccac ttcagtggat gctgtggttg ccatctgcgt 5160 gattttctcc atgtccttcg tcccagccag ctttgtcctt tatttgatcc aggagcgggt 5220 gaacaaatcc aagcacctcc agtttatcag tggagtgagc cccaccacct actgggtgac 5280 caacttcctc tgggacatca tgaattattc cgtgagtgct gggctggtgg tgggcatctt 5340 catcgggttt cagaagaaag cctacacttc tccagaaaac cttcctgccc ttgtggcact 5400 gctcctgctg tatggatggg cggtcattcc catgatgtac ccagcatcct tcctgtttga 5460 tgtccccagc acagcctatg tggctttatc ttgtgctaat ctgttcatcg gcatcaacag 5520 cagtgctatt accttcatct tggaattatt tgagaataac cggacgctgc tcaggttcaa 5580 cgccgtgctg aggaagctgc tcattgtctt cccccacttc tgcctgggcc ggggcctcat 5640 tgaccttgca ctgagccagg ctgtgacaga tgtctatgcc cggtttggtg aggagcactc 5700 tgcaaatccg ttccactggg acctgattgg gaagaacctg tttgccatgg tggtggaagg 5760 ggtggtgtac ttcctcctga ccctgctggt ccagcgccac ttcttcctct cccaatggat 5820 tgccgagccc actaaggagc ccattgttga tgaagatgat gatgtggctg aagaaagaca 5880 aagaattatt actggtggaa ataaaactga catcttaagg ctacatgaac taaccaagat 5940 ttatccaggc acctccagcc cagcagtgga caggctgtgt gtcggagttc gccctggaga 6000 gtgctttggc ctcctgggag tgaatggtgc cggcaaaaca accacattca agatgctcac 6060 tggggacacc acagtgacct caggggatgc caccgtagca ggcaagagta ttttaaccaa 6120 tatttctgaa gtccatcaaa atatgggcta ctgtcctcag tttgatgcaa ttgatgagct 6180 gctcacagga cgagaacatc tttaccttta tgcccggctt cgaggtgtac cagcagaaga 6240 aatcgaaaag gttgcaaact ggagtattaa gagcctgggc ctgactgtct acgccgactg 6300 cctggctggc acgtacagtg ggggcaacaa gcggaaactc tccacagcca tcgcactcat 6360 tggctgccca ccgctggtgc tgctggatga gcccaccaca gggatggacc cccaggcacg 6420 ccgcatgctg tggaacgtca tcgtgagcat catcagagaa gggagggctg tggtcctcac 6480 atcccacagc atggaagaat gtgaggcact gtgtacccgg ctggccatca tggtaaaggg 6540 cgcctttcga tgtatgggca ccattcagca tctcaagtcc aaatttggag atggctatat 6600 cgtcacaatg aagatcaaat ccccgaagga cgacctgctt cctgacctga accctgtgga 6660 gcagttcttc caggggaact tcccaggcag tgtgcagagg gagaggcact acaacatgct 6720 ccagttccag gtctcctcct cctccctggc gaggatcttc cagctcctcc tctcccacaa 6780 ggacagcctg ctcatcgagg agtactcagt cacacagacc acactggacc aggtgtttgt 6840 aaattttgct aaacagcaga ctgaaagtca tgacctccct ctgcaccctc gagctgctgg 6900 agccagtcga caagcccagg actgatcttt cacaccgctc gttcctgcag ccagaaagga 6960 actctgggca gctggaggcg caggagcctg tgcccatatg gtcatccaaa tggactggcc 7020 agcgtaaatg accccactgc agcagaaaac aaacacacga ggagcatgca gcgaattcag 7080 aaagaggtct ttcagaagga aaccgaaact gacttgctca cctggaacac ctgatggtga 7140 aaccaaacaa atacaaaatc cttctccaga ccccagaact agaaaccccg ggccatccca 7200 ctagcagctt tggcctccat attgctctca tttcaagcag atctgctttt ctgcatgttt 7260 gtctgtgtgt ctgcgttgtg tgtgattttc atggaaaaat aaaatgcaaa tgcactcatc 7320 acaaacta 7328 <210> 2 <211> 2273 <212> PRT <213> Homo sapiens <400> 2 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe Phe Lys Leu Phe Arg Val 245 250 255 Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser 260 265 270 Trp Gly Gly Ile Leu Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile 275 280 285 His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr Arg Pro Leu Met 290 295 300 Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser 305 310 315 320 Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly Gly Ser Arg Val Leu Ser 325 330 335 Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe Leu Gly Ile Asp 340 345 350 Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser 355 360 365 Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu Ser Asn Pro Leu Thr Lys 370 375 380 Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr 385 390 395 400 Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser 405 410 415 Thr Phe Glu Glu Leu Glu His Val Arg Lys Leu Val Lys Ala Trp Glu 420 425 430 Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met 435 440 445 Asn Met Ile Arg Asp Thr Leu Gly Asn Pro Thr Val Lys Asp Phe Leu 450 455 460 Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu Asn 465 470 475 480 Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn 485 490 495 Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr Asp Arg Thr Leu Arg Leu 500 505 510 Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu Ser Tyr 515 520 525 Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu 530 535 540 Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met Tyr Pro Trp Thr 545 550 555 560 Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp 565 570 575 Val Val Glu Lys Thr Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly 580 585 590 Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile Trp Gly Gly Phe 595 600 605 Ala Tyr Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val 610 615 620 Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln Gln Met Pro Tyr Pro 625 630 635 640 Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 645 650 655 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 660 665 670 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 675 680 685 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 690 695 700 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 705 710 715 720 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 725 730 735 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 740 745 750 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 755 760 765 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 770 775 780 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 785 790 795 800 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 805 810 815 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 820 825 830 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 835 840 845 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Phe Pro Gly Asp 850 855 860 Tyr Gly Thr Pro Leu Pro Trp Tyr Phe Leu Leu Gln Glu Ser Tyr Trp 865 870 875 880 Leu Gly Gly Glu Gly Cys Ser Thr Arg Glu Glu Arg Ala Leu Glu Lys 885 890 895 Thr Glu Pro Leu Thr Glu Glu Thr Glu Asp Pro Glu His Pro Glu Gly 900 905 910 Ile His Asp Ser Phe Phe Glu Arg Glu His Pro Gly Trp Val Pro Gly 915 920 925 Val Cys Val Lys Asn Leu Val Lys Ile Phe Glu Pro Cys Gly Arg Pro 930 935 940 Ala Val Asp Arg Leu Asn Ile Thr Phe Tyr Glu Asn Gln Ile Thr Ala 945 950 955 960 Phe Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Ile Leu 965 970 975 Thr Gly Leu Leu Pro Pro Thr Ser Gly Thr Val Leu Val Gly Gly Arg 980 985 990 Asp Ile Glu Thr Ser Leu Asp Ala Val Arg Gln Ser Leu Gly Met Cys 995 1000 1005 Pro Gln His Asn Ile Leu Phe His His Leu Thr Val Ala Glu His 1010 1015 1020 Met Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln Glu Glu Ala 1025 1030 1035 Gln Leu Glu Met Glu Ala Met Leu Glu Asp Thr Gly Leu His His 1040 1045 1050 Lys Arg Asn Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln Arg 1055 1060 1065 Lys Leu Ser Val Ala Ile Ala Phe Val Gly Asp Ala Lys Val Val 1070 1075 1080 Ile Leu Asp Glu Pro Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg 1085 1090 1095 Ser Ile Trp Asp Leu Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile 1100 1105 1110 Ile Met Ser Thr His His Met Asp Glu Ala Asp Leu Leu Gly Asp 1115 1120 1125 Arg Ile Ala Ile Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr 1130 1135 1140 Pro Leu Phe Leu Lys Asn Cys Phe Gly Thr Gly Leu Tyr Leu Thr 1145 1150 1155 Leu Val Arg Lys Met Lys Asn Ile Gln Ser Gln Arg Lys Gly Ser 1160 1165 1170 Glu Gly Thr Cys Ser Cys Ser Ser Lys Gly Phe Ser Thr Thr Cys 1175 1180 1185 Pro Ala His Val Asp Asp Leu Thr Pro Glu Gln Val Leu Asp Gly 1190 1195 1200 Asp Val Asn Glu Leu Met Asp Val Val Leu His His Val Pro Glu 1205 1210 1215 Ala Lys Leu Val Glu Cys Ile Gly Gln Glu Leu Ile Phe Leu Leu 1220 1225 1230 Pro Asn Lys Asn Phe Lys His Arg Ala Tyr Ala Ser Leu Phe Arg 1235 1240 1245 Glu Leu Glu Glu Thr Leu Ala Asp Leu Gly Leu Ser Ser Phe Gly 1250 1255 1260 Ile Ser Asp Thr Pro Leu Glu Glu Ile Phe Leu Lys Val Thr Glu 1265 1270 1275 Asp Ser Asp Ser Gly Pro Leu Phe Ala Gly Gly Ala Gln Gln Lys 1280 1285 1290 Arg Glu Asn Val Asn Pro Arg His Pro Cys Leu Gly Pro Arg Glu 1295 1300 1305 Lys Ala Gly Gln Thr Pro Gln Asp Ser Asn Val Cys Ser Pro Gly 1310 1315 1320 Ala Pro Ala Ala His Pro Glu Gly Gln Pro Pro Pro Glu Pro Glu 1325 1330 1335 Cys Pro Gly Pro Gln Leu Asn Thr Gly Thr Gln Leu Val Leu Gln 1340 1345 1350 His Val Gln Ala Leu Leu Val Lys Arg Phe Gln His Thr Ile Arg 1355 1360 1365 Ser His Lys Asp Phe Leu Ala Gln Ile Val Leu Pro Ala Thr Phe 1370 1375 1380 Val Phe Leu Ala Leu Met Leu Ser Ile Val Ile Pro Pro Phe Gly 1385 1390 1395 Glu Tyr Pro Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln Gln 1400 1405 1410 Tyr Thr Phe Phe Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr 1415 1420 1425 Val Leu Ala Asp Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg 1430 1435 1440 Cys Leu Lys Glu Gly Trp Leu Pro Glu Tyr Pro Cys Gly Asn Ser 1445 1450 1455 Thr Pro Trp Lys Thr Pro Ser Val Ser Pro Asn Ile Thr Gln Leu 1460 1465 1470 Phe Gln Lys Gln Lys Trp Thr Gln Val Asn Pro Ser Pro Ser Cys 1475 1480 1485 Arg Cys Ser Thr Arg Glu Lys Leu Thr Met Leu Pro Glu Cys Pro 1490 1495 1500 Glu Gly Ala Gly Gly Leu Pro Pro Pro Gln Arg Thr Gln Arg Ser 1505 1510 1515 Thr Glu Ile Leu Gln Asp Leu Thr Asp Arg Asn Ile Ser Asp Phe 1520 1525 1530 Leu Val Lys Thr Tyr Pro Ala Leu Ile Arg Ser Ser Leu Lys Ser 1535 1540 1545 Lys Phe Trp Val Asn Glu Gln Arg Tyr Gly Gly Ile Ser Ile Gly 1550 1555 1560 Gly Lys Leu Pro Val Val Pro Ile Thr Gly Glu Ala Leu Val Gly 1565 1570 1575 Phe Leu Ser Asp Leu Gly Arg Ile Met Asn Val Ser Gly Gly Pro 1580 1585 1590 Ile Thr Arg Glu Ala Ser Lys Glu Ile Pro Asp Phe Leu Lys His 1595 1600 1605 Leu Glu Thr Glu Asp Asn Ile Lys Val Trp Phe Asn Asn Lys Gly 1610 1615 1620 Trp His Ala Leu Val Ser Phe Leu Asn Val Ala His Asn Ala Ile 1625 1630 1635 Leu Arg Ala Ser Leu Pro Lys Asp Arg Ser Pro Glu Glu Tyr Gly 1640 1645 1650 Ile Thr Val Ile Ser Gln Pro Leu Asn Leu Thr Lys Glu Gln Leu 1655 1660 1665 Ser Glu Ile Thr Val Leu Thr Thr Ser Val Asp Ala Val Val Ala 1670 1675 1680 Ile Cys Val Ile Phe Ser Met Ser Phe Val Pro Ala Ser Phe Val 1685 1690 1695 Leu Tyr Leu Ile Gln Glu Arg Val Asn Lys Ser Lys His Leu Gln 1700 1705 1710 Phe Ile Ser Gly Val Ser Pro Thr Thr Tyr Trp Val Thr Asn Phe 1715 1720 1725 Leu Trp Asp Ile Met Asn Tyr Ser Val Ser Ala Gly Leu Val Val 1730 1735 1740 Gly Ile Phe Ile Gly Phe Gln Lys Lys Ala Tyr Thr Ser Pro Glu 1745 1750 1755 Asn Leu Pro Ala Leu Val Ala Leu Leu Leu Leu Tyr Gly Trp Ala 1760 1765 1770 Val Ile Pro Met Met Tyr Pro Ala Ser Phe Leu Phe Asp Val Pro 1775 1780 1785 Ser Thr Ala Tyr Val Ala Leu Ser Cys Ala Asn Leu Phe Ile Gly 1790 1795 1800 Ile Asn Ser Ser Ala Ile Thr Phe Ile Leu Glu Leu Phe Glu Asn 1805 1810 1815 Asn Arg Thr Leu Leu Arg Phe Asn Ala Val Leu Arg Lys Leu Leu 1820 1825 1830 Ile Val Phe Pro His Phe Cys Leu Gly Arg Gly Leu Ile Asp Leu 1835 1840 1845 Ala Leu Ser Gln Ala Val Thr Asp Val Tyr Ala Arg Phe Gly Glu 1850 1855 1860 Glu His Ser Ala Asn Pro Phe His Trp Asp Leu Ile Gly Lys Asn 1865 1870 1875 Leu Phe Ala Met Val Val Glu Gly Val Val Tyr Phe Leu Leu Thr 1880 1885 1890 Leu Leu Val Gln Arg His Phe Phe Leu Ser Gln Trp Ile Ala Glu 1895 1900 1905 Pro Thr Lys Glu Pro Ile Val Asp Glu Asp Asp Asp Val Ala Glu 1910 1915 1920 Glu Arg Gln Arg Ile Ile Thr Gly Gly Asn Lys Thr Asp Ile Leu 1925 1930 1935 Arg Leu His Glu Leu Thr Lys Ile Tyr Pro Gly Thr Ser Ser Pro 1940 1945 1950 Ala Val Asp Arg Leu Cys Val Gly Val Arg Pro Gly Glu Cys Phe 1955 1960 1965 Gly Leu Leu Gly Val Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys 1970 1975 1980 Met Leu Thr Gly Asp Thr Thr Val Thr Ser Gly Asp Ala Thr Val 1985 1990 1995 Ala Gly Lys Ser Ile Leu Thr Asn Ile Ser Glu Val His Gln Asn 2000 2005 2010 Met Gly Tyr Cys Pro Gln Phe Asp Ala Ile Asp Glu Leu Leu Thr 2015 2020 2025 Gly Arg Glu His Leu Tyr Leu Tyr Ala Arg Leu Arg Gly Val Pro 2030 2035 2040 Ala Glu Glu Ile Glu Lys Val Ala Asn Trp Ser Ile Lys Ser Leu 2045 2050 2055 Gly Leu Thr Val Tyr Ala Asp Cys Leu Ala Gly Thr Tyr Ser Gly 2060 2065 2070 Gly Asn Lys Arg Lys Leu Ser Thr Ala Ile Ala Leu Ile Gly Cys 2075 2080 2085 Pro Pro Leu Val Leu Leu Asp Glu Pro Thr Thr Gly Met Asp Pro 2090 2095 2100 Gln Ala Arg Arg Met Leu Trp Asn Val Ile Val Ser Ile Ile Arg 2105 2110 2115 Glu Gly Arg Ala Val Val Leu Thr Ser His Ser Met Glu Glu Cys 2120 2125 2130 Glu Ala Leu Cys Thr Arg Leu Ala Ile Met Val Lys Gly Ala Phe 2135 2140 2145 Arg Cys Met Gly Thr Ile Gln His Leu Lys Ser Lys Phe Gly Asp 2150 2155 2160 Gly Tyr Ile Val Thr Met Lys Ile Lys Ser Pro Lys Asp Asp Leu 2165 2170 2175 Leu Pro Asp Leu Asn Pro Val Glu Gln Phe Phe Gln Gly Asn Phe 2180 2185 2190 Pro Gly Ser Val Gln Arg Glu Arg His Tyr Asn Met Leu Gln Phe 2195 2200 2205 Gln Val Ser Ser Ser Ser Leu Ala Arg Ile Phe Gln Leu Leu Leu 2210 2215 2220 Ser His Lys Asp Ser Leu Leu Ile Glu Glu Tyr Ser Val Thr Gln 2225 2230 2235 Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys Gln Gln Thr 2240 2245 2250 Glu Ser His Asp Leu Pro Leu His Pro Arg Ala Ala Gly Ala Ser 2255 2260 2265 Arg Gln Ala Gln Asp 2270 <210> 3 <211> 3816 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 3 atgggcttcg tgagacagat acagcttttg ctctggaga actggaccct gcggaaaagg caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc gctctacagc catcatgaat gccatttccc caacaaggcg atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc atcttggcaa gggtatatcg agttttcaa gaactcctca tgaatgcacc agagagccag caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggagaga atacgaata gggatatctt gaagatga gaaacactga cactatttct cattaaaaac atcggcctgt ctgactcagt ggtctacctt ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 aaggacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagacactc tgtattcttt catgatcatc ctgaaccgct gtttccctat cttcatggtg 780 ctggcatgga tctactctgt ctccatgact gtgaagagca tcgtcttgga gaaggagttg 840 cgactgaagg agaccttgaa aaatcagggt gtctccaatg cagtgatttg gtgtacctgg 900 ttcctggaca gcttctccat catgtcgatg agcatcttcc tcctgacgat attcatcatg 960 catggaagaa tcctacatta cagcgaccca ttcatcctct tcctgttctt gttggctttc 1020 tccactgcca ccatcatgct gtgctttctg ctcagcacct tcttctccaa ggccagtctg 1080 gcagcagcct gtagtggtgt catctatttc accctctacc tgccacacat cctgtgcttc 1140 gcctggcagg accgcatgac cgctgagctg aagaaggctg tgagcttact gtctccggtg 1200 gcatttggat ttggcactga gtacctggtt cgctttgaag agcaaggcct ggggctgcag 1260 tggagcaaca tcgggaacag tcccacggaa ggggacgaat tcagcttcct gctgtccatg 1320 cagatgatgc tccttgatgc tgctgtctat ggcttactcg cttggtacct tgatcaggtg 1380 gtatgcgtga agaatctggt aaagattttt gagccctgtg gccggccagc tgtggaccgt 1440 ctgaacatca ccttctacga gaaccagatc accgcattcc tgggccacaa tggagctggg 1500 aaaaccacca ccttgtccat cctgacgggt ctgttgccac caacctctgg gactgtgctc 1560 gttgggggaa gggacattga aaccagcctg gatgcagtcc ggcagagcct tggcatgtgt 1620 ccacagcaca acatcctgtt ccaccacctc acggtggctg agcacatgct gttctatgcc 1680 cagctgaaag gaaagtccca ggaggaggcc cagctggaga tggaagccat gttggaggac 1740 acaggcctcc accacaagcg gaatgaagag gctcaggacc tatcaggtgg catgcagaga 1800 aagctgtcgg ttgccattgc ctttgtggga gatgccaagg tggtgattct ggacgaaccc 1860 acctctgggg tggaccctta ctcgagacgc tcaatctggg atctgctcct gaagtatcgc 1920 tcaggcagaa ccatcatcat gtccactcac cacatggacg aggccgacct ccttggggac 1980 cgcattgcca tcattgccca gggaaggctc tactgctcag gcaccccact cttcctgaag 2040 aactgctttg gcacaggctt gtacttaacc ttggtgggcg aataccccgc tttgaccctt 2100 cacccctgga tatatgggca gcagtacacc ttcttcagca tggatgaacc aggcagtgag 2160 cagttcacgg tacttgcaga cgtcctcctg ataagccag gctttggcaa ccgctgcctg 2220 aaggaagggt ggctccgga gtaccctgt ggcactca caccctggaa gactccttct 2280 gtgtccccaa acatcaccca gctgttccag aagcagaat ggacacaggt acatcaccca 2340 ccatcctgca ggtgcagcac cagggagaag ctcaccatgc tgccagagtg ccccgaggt 2400 gccggggggcc tcccgccccc ccagagaaca cagcgcagca cggaatttct acagacctg 2460 acggacagga acatctccga cttcttgta aaacgtac ctgcttat aagaagcagc 2520 ttaaagagca aattctgggt caatgaacag aggtaggag gatttccat tggaggaag 2580 ctcccagtcg tcccatcac gggggaagca cttgttggtt tttaagcga ccttggccgg 2640 atcatgaatg tgagcggggg ccctatcact agagaggcct ctaaagaat acctgatttc 2700 cttaaacatc tagaactga agacaacatt aaggtgtggt ttaataca aggctggcat 2760 gccctggtca gctttctcaa tgtgcccac aacgccatct tacggttaag gctacatgaa 2820 ctaaccaaga tttatccagg cacctccagc ccagcagtgg acaggctgtg tgtcggagtt 2880 cgccctggag agtgctttgg cctcctggga gtgaatggtg ccggcaaaac aaccacattc 2940 aagatgctca ctggggacac cacagtgacc tcaggggatg ccaccgtagc aggcaagagt 3000 attttaacca atatttctga agtccatcaa aatatgggct actgtcctca gtttgatgca 3060 attgatgagc tgctcacagg acgagaacat ctttaccttt atgcccggct tcgaggtgta 3120 ccagcagaag aaatcgaaaa ggttgcaaac tggagtatta agagcctggg cctgactgtc 3180 tacgccgact gcctggctgg cacgtacagt gggggcaaca agcggaaact ctccacagcc 3240 atcgcactca ttggctgccc accgctggtg ctgctggatg agcccaccac agggatggac 3300 ccccaggcac gccgcatgct gtggaacgtc atcgtgagca tcatcagaga agggagggct 3360 gtggtcctca catcccacag catggaagaa tgtgaggcac tgtgtacccg gctggccatc 3420 atggtaaagg gcgcctttcg atgtatgggc accattcagc atctcaagtc caaatttgga 3480 gatggctata tcgtcacaat gaagatcaaa tccccgaagg acgacctgct tcctgacctg 3540 aaccctgtgg agcagttctt ccaggggaac ttcccaggca gtgtgcagag ggagaggcac 3600 tacaacatgc tccagttcca ggtctcctcc tcctccctgg cgaggatctt ccagctcctc 3660 ctctcccaca aggacagcct gctcatcgag gagtactcag tcacacagac cacactggac 3720 caggtgtttg taaattttgc taaacagcag actgaaagtc atgacctccc tctgcaccct 3780 cgagctgctg gagccagtcg acaagcccag gactga 3816 <210> 4 <211> 3804 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 4 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc gctctacagc catcatgaat gccatttccc caacaaggcg 180 atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc 240 tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc 300 atcttggcaa gggtatatcg agattttcaa gaactcctca tgaatgcacc agagagccag 360 caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggaaagga atacgaataa gggatatctt gaagataggaa 480 gaacactga cactatttct cattaaaac atcggcctgt ctgactcagt ggtctacctt 540 ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 areacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagaacactc tgtatgtatg cgtgaagaat ctggtaaaaga tttttgagcc ctgtggccgg 780 ccagctgtgg accgtctgaa catcaccttc tacgagaacc agatcaccgc attcctgggc 840 caaatggag ctgggaaac caccaccttg tccatcctga cgggtctgtt gccaccaacc 900 tctgggactg tgctcgttgg gggaagggac attgaaacca gcctggatgc agtccggcag 960 agccttggca tgtgtccaca gcacaacatc ctgttccacc acctcacggt ggctgagcac 1020 atgctgttct atgcccagct gaaggaaag tcccaggagg aggcccagct ggagatggaa 1080 gccatgttgg aggacacagg cctccaccac aagcggaatg aagaggctca ggacctatca 1140 ggtggcatgc agaaagct gtcggttgcc attgcctttg tgggagatgc caaggtggtg 1200 attctggacg aacccacctc tggggtggac ccttactcga gacgctcaat ctgggatctg 1260 ctcctgaagt atcgctcagg cagaaccatc atcatgtcca ctcaccacat ggacgaggcc 1320 gacctccttg gggaccgcat tgccatcatt gcccagggaa ggctctactg ctcaggcacc 1380 ccactcttcc tgaagaactg ctttggcaca ggcttgtact taaccttggt gggcgaatac 1440 cccgctttga cccttcacccc ctggatatat gggcagcagt acaccttctt cagcatggat 1500 gaaccaggca gtgagcagtt cacggtactt gcagacgtcc tcctgaataa gccaggcttt 1560 ggcaaccgct gcctgaagga agggtggctt ccggagtacc cctgtggcaa ctcaacaccc 1620 tggagaactc cttctgtgtc cccaaaacatc acccagctgt tccagaagca gaatggaca 1680 caggtcaacc cttcaccatc ctgcaggtgc agcaccaggg agaagctcac catgctgcca 1740 gagtgccccg agggtgccgg gggcctcccg cccccccaga gaacacagcg cagcacggaa 1800 attctacaag acctgacgga caggaacatc tccgacttct tggtaaaaac gtatcctgct 1860 cttataagaa gcagcttaaa gagcaaattc tgggtcaatg aacagaggta tggaggaatt 1920 tccattggag gaaagctccc agtcgtcccc atcacggggg aagcacttgt tgggttttta 1980 agcgaccttg gccggatcat gaatgtgagc gggggcccta tcactagaga ggcctctaaa 2040 gaaatacctg atttccttaa acatctagaa actgaagaca acattaaggt gtggtttaat 2100 aacaaaggct ggcatgccct ggtcagcttt ctcaatgtgg cccacaacgc catcttacgg 2160 aacttcctct gggacatcat gaattattcc gtgagtgctg ggctggtggt gggcatcttc 2220 atcgggtttc agaagaaagc ctacacttct ccagaaaacc ttcctgccct tgtggcactg 2280 ctcctgctgt atggatgggc ggtcattccc atgatgtacc cagcatcctt cctgtttgat 2340 gtccccagca cagcctatgt ggctttatct tgtgctaatc tgttcatcgg catcaacagc 2400 agtgctatta ccttcatctt ggaattattt gagaataacc ggacgctgct caggttcaac 2460 gccgtgctga ggaagctgct cattgtcttc ccccacttct gcctgggccg gggcctcatt 2520 gaccttgcac tgagccaggc tgtgacagat gtctatgccc ggtttggtga ggagcactct 2580 gcaaatccgt tccactggga cctgattggg aagaacctgt ttgccatggt ggtggaaggg 2640 gtggtgtact tcctcctgac cctgctggtc cagcgccact tcttcctctc ccaatggatt 2700 gccgagccca ctaaggagcc cattgttgat gaagatgatg atgtggctga agaaagacaa 2760 agaattatta ctggtggaaa taaaactgac atcttaaggc tacatgaact aaccaagatt 2820 tatccaggca cctccagccc agcagtggac aggctgtgtg tcggagttcg ccctggagag 2880 tgctttggcc tcctgggagt gaatggtgcc ggcaaaacaa ccacattcaa gatgctcact 2940 ggggacacca cagtgacctc aggggatgcc accgtagcag gcaagagtat tttaaccaat 3000 atttctgaag tccatcaaaa tatgggctac tgtcctcagt ttgatgcaat tgatgagctg 3060 ctcacaggac gagaacatct ttacctttat gcccggcttc gaggtgtacc agcagaagaa 3120 atcgaaaagg ttgcaaactg gagtattaag agcctgggcc tgactgtcta cgccgactgc 3180 ctggctggca cgtacagtgg gggcaacaag cggaaactct ccacagccat cgcactcatt 3240 ggctgcccac cgctggtgct gctggatgag cccaccacag ggatggaccc ccaggcacgc 3300 cgcatgctgt ggaacgtcat cgtgagcatc atcagagaag ggagggctgt ggtcctcaca 3360 tcccacagca tggaagaatg tgaggcactg tgtacccggc tggccatcat ggtaaagggc 3420 gcctttcgat gtatgggcac cattcagcat ctcaagtcca aatttggaga tggctatatc 3480 gtcacaatga agatcaaatc cccgaaggac gacctgcttc ctgacctgaa ccctgtggag 3540 cagttcttcc aggggaactt cccaggcagt gtgcagaggg agaggcacta caacatgctc 3600 cagttccagg tctcctcctc ctccctggcg aggatcttcc agctcctcct ctcccacaag 3660 gacagcctgc tcatcgagga gtactcagtc acacagacca cactggacca ggtgtttgta 3720 aattttgcta aacagcagac tgaaagtcat gacctccctc tgcaccctcg agctgctgga 3780 gccagtcgac aagcccagga ctga 3804 <210> 5 <211> 4062 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 5 atgggcttcg tgagacagat acagcttttg ctctggaga actggaccct gcggaaaagg caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc gctctacagc catcatgaat gccatttccc caacaaggcg atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc atcttggcaa gggtatatcg agttttcaa gaactcctca tgaatgcacc agagagccag caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggagaga atacgaata gggatatctt gaagatga gaaacactga cactatttct cattaaaaac atcggcctgt ctgactcagt ggtctacctt ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 aaggacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagacactc tgtatgccaa cgtggacttc ttcaagctct tccgtgtgct tcccacactc 780 ctagacagcc gttctcaagg tatcaatctg agatcttggg gaggaatatt atctgatatg 840 tcaccaagaa ttcaagagtt tatccatcgg ccgagtatgc aggacttgct gtgggtgacc 900 aggcccctca tgcagaatgg tggtccagag acctttacaa agctgatggg catcctgtct 960 gacctcctgt gtggctaccc cgagggaggt ggctctcggg tgctctcctt caactggtat 1020 gaacaata actataaggc ctttctgggg attgactcca caaggaagga tcctatctat 1080 tcttatgaca gaagaacaac atccttttgt aatgcattga tccagagcct ggagtcaaat 1140 cctttaacca aaatcgcttg gagggcggca aagcctttgc tgatgggaaa aatcctgtac 1200 1260 ctggaacacg ttaggaagtt ggtcaaagcc tgggaagaag tagggcccca gatctggtac 1320 ttctttgaca acagcacaca gatgaacatg atcagagata ccctggggaa cccaacagta 1380 aaagactttt tgaataggca gcttggtgaa gaaggtatta ctgctgaagc catcctaaac 1440 ttcctctaca agggccctcg ggaaagccag gctgacgaca tggccaactt cgactggagg 1500 gacatattta acatcactga tcgcaccctc cgcctggtca atcaatacct ggagtgcttg 1560 gtcctggata agtttgaaag ctacaatgat gaaactcagc tcacccaacg tgccctctct 1620 ctactggagg aaaacatgtt ctgggccgga gtggtattcc ctgacatgta tccctggacc 1680 agctctctac caccccacgt gaagtataag atccgaatgg acatagacgt ggtggagaaa 1740 accaataaga ttaaagacag gtattgggat tctggtccca gagctgatcc cgtggaagat 1800 ttccggtaca tctggggcgg gtttgcctat ctgcaggaca tggttgaaca ggggatcaca 1860 aggagccagg tgcaggcgga ggctccagtt ggaatctacc tccagcagat gccctacccc 1920 tgcttcgtgg acgattcttt catgatcatc ctgaaccgct gtttccctat cttcatggtg 1980 ctggcatgga tctactctgt ctccatgact gtgaagagca tcgtcttgga gaaggagttg 2040 cgactgaagg agaccttgaa aaatcagggt gtctccaatg cagtgatttg gtgtacctgg 2100 ttcctggaca gcttctccat catgtcgatg agcatcttcc tcctgacgat attcatcatg 2160 catggaagaa tcctacatta cagcgaccca ttcatcctct tcctgttctt gttggctttc 2220 tccactgcca ccatcatgct gtgctttctg ctcagcacct tcttctccaa ggccagtctg 2280 gcagcagcct gtagtggtgt catctatttc accctctacc tgccacacat cctgtgcttc 2340 gcctggcagg accgcatgac cgctgagctg aagaaggctg tgagcttact gtctccggtg 2400 gcatttggat ttggcactga gtacctggtt cgctttgaag agcaaggcct ggggctgcag 2460 tggagcaaca tcgggaacag tcccacggaa ggggacgaat tcagcttcct gctgtccatg 2520 cagatgatgc tccttgatgc tgctgtctat ggcttactcg cttggtacct tgatcaggtg 2580 ctaacagagg aaacggagga tccagagcac ccagaaggaa tacacgactc cttctttgaa 2640 cgtgagcatc cagggtgggt tcctggggta tgcgtgaaga atctggtaaa gatttttgag 2700 ccctgtggcc ggccagctgt ggaccgtctg aacatcacct tctacgagaa ccagatcacc 2760 gcattcctgg gccacaatgg agctgggaaa accaccacct tgtccatcct gacgggtctg 2820 ttgccaccaa cctctgggac tgtgctcgtt gggggaaggg acattgaaac cagcctggat 2880 gcaggcgaat accccgcttt gacccttcac ccctggatat atgggcagca gtacaccttc 2940 ttcagcatgg atgaaccagg cagtgagcag ttcacggtac ttgcagacgt cctcctgaat 3000 aagccaggct ttggcaaccg ctgcctgaag gaagggtggc ttccggagta cccctgtggc 3060 aactcaacac cctggaagac tccttctgtg tccccaaaca tcacccagct gttccagaag 3120 cagaatgga cacaggtcaa cccttcacca tcctgcaggt gcagcaccag ggagaagctc 3180 accatgctgc cattaaggct acatgaacta accaagattt atccaggcac ctccagccca 3240 gcagtggaca ggctgtgtgt cggagttcgc cctggagagt gctttggcct cctgggagtg 3300 aatggtgccg gcaaaacaac cacattcaag atgctcactg gggacaccac agtgacctca 3360 ggggatgcca ccgtagcagg caagagtatt ttaaccaata tttctgaagt ccatcaaaat 3420 atgggctact gtcctcagtt tgatgcaatt gatgagctgc tcacaggacg agaacatctt 3480 tacctttatg cccggcttcg aggtgtacca gcaagaaa tcgaaaaggt tgcaaactgg 3540 near you gcctgggcct gactgtctac gccgactgcc tggctggcac gtacagtggg 3600 ggcaacaagc ggaaactctc cacagccatc gcactcattg gctgcccacc gctggtgctg 3660 ctggatgagc ccaccacagg gatggacccc caggcacgcc gcatgctgtg gaacgtcatc 3720 gtgagcatca tcagagaagg gagggctgtg gtcctcacat cccacagcat ggaagaatgt 3780 gaggcactgt gtacccggct ggccatcatg gtaaagggcg cctttcgatg tatgggcacc 3840 attcagcatc tcaagtccaa atttggagat ggctatatcg tcacaatgaa gatcaaatcc 3900 ccgaaggacg acctgcttcc tgacctgaac cctgtggagc agttcttcca ggggaacttc 3960 ccaggcagtg tgcagaggga gaggcactac aacatgctcc agttccaggt ctcctcctcc 4020 tccctggcga ggatcttcca ggtgtttgta aattttgctt ga 4062 <210> 6 <211> 3669 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 6 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc gctctacagc catcatgaat gccatttccc caacaaggcg 180 atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc 240 tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc 300 atcttggcaa gggtatatcg agattttcaa gaactcctca tgaatgcacc agagagccag 360 caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggaagagga atacgaataa gggatatctt gaaagatgaa 480 gaaacactga cactatttct cattaaaaac atcggcctgt ctgactcagt ggtctacctt 540 ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 aaggacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagacactc tgtatgccaa cgtggacttc ttcaagctct tccgtgtgct tcccacactc 780 ctagacagcc gttctcaagg tatcaatctg agatcttggg gaggaatatt atctgatatg 840 tcaccaagaa ttcaagagtt tatccatcgg ccgagtatgc aggacttgct gtgggtgacc 900 aggcccctca tgcagaatgg tggtccagag acctttacaa agctgatggg catcctgtct 960 gacctcctgt gtggctaccc cgagggaggt ggctctcggg tgctctcctt caactggtat 1020 gaacaata actataaggc ctttctgggg attgactcca caaggaagga tcctatctat 1080 tcttatgaca gaagaacaac atccttttgt aatgcattga tccagagcct ggagtcaaat 1140 cctttaacca aaatcgcttg gagggcggca aagcctttgc tgatgggaaa aatcctgtac 1200 1260 ctggaacacg ttaggaagtt ggtcaaagcc tgggaagaag tagggcccca gatctggtac 1320 ttctttgaca acagcacaca gatgaacatg atcagagata ccctggggaa cccaacagta 1380 aaagactttt tgaataggca gcttggtgaa gaaggtatta ctgctgaagc catcctaaac 1440 ttcctctaca agggccctcg ggaaagccag gctgacgaca tggccaactt cgactggagg 1500 gacatattta acatcactga tcgcaccctc cgcctggtca atcaatacct ggagtgcttg 1560 gtcctggata agtttgaaag ctacaatgat gaaactcagc tcacccaacg tgccctctct 1620 ctactggagg aaaacatgtt ctgggccgga gtggtattcc ctgacatgta tccctggacc 1680 agctctctac caccccacgt gaagtataag atccgaatgg acatagacgt ggtggagaaa 1740 accaataaga ttaaagacag gtattgggat tctggtccca gagctgatcc cgtggaagat 1800 ttccggtaca tctggggcgg gtttgcctat ctgcaggaca tggttgaaca ggggatcaca 1860 aggagccagg tgcaggcgga ggctccagtt ggaatctacc tccagcagat gccctacccc 1920 tgcttcgtgg acgattcttt catgatcatc ctgaaccgct gtttccctat cttcatggtg 1980 ctggcatgga tctactctgt ctccatgact gtgaagagca tcgtcttgga gaaggagttg 2040 cgactgaagg agaccttgaa aaatcagggt gtctccaatg cagtgatttg gtgtacctgg 2100 ttcctggaca gcttctccat catgtcgatg agcatcttcc tcctgacgat attcatcatg 2160 catggaagaa tcctacatta cagcgaccca ttcatcctct tcctgttctt gttggctttc 2220 tccactgcca ccatcatgct gtgctttctg ctcagcacct tcttctccaa ggccagtctg 2280 gcagcagcct gtagtggtgt catctatttc accctctacc tgccacacat cctgtgcttc 2340 gcctggcagg accgcatgac cgctgagctg aagaaggctg tgagcttact gtctccggtg 2400 gcatttggat ttggcactga gtacctggtt cgctttgaag agcaaggcct ggggctgcag 2460 tggagcaaca tcgggaacag tcccacggaa ggggacgaat tcagcttcct gctgtccatg 2520 cagatgatgc tccttgatgc tgctgtctat ggcttactcg cttggtacct tgatcaggtg 2580 gtccggcaga gccttggcat gtgtccacag cacaacatcc tgttccacca cctcacggtg 2640 gctgagcaca tgctgttcta tgcccagctg aaaggaaagt cccaggagga ggcccagctg 2700 gagatggaag ccatgttgga ggacacaggc ctccaccaca agcggaatga agaggctcag 2760 gacctatcag gtggcatgca gagaaagctg tcggttgcca ttgcctttgt gggagatgcc 2820 aaggtggtga ttctggacga acccacctct ggggtggacc cttactcgag acgctcaatc 2880 tgggatctgc tcctgaagta tcgctcaggc agaaccatca tcatgtccac tcaccacatg 2940 gacgaggccg acctccttgg ggaccgcatt gccatcattg cccagggaag gctctactgc 3000 tcaggcaccc cactcttcct gaagaactgc tttggcacag gcttgtactt aaccttggtg 3060 ggcgaatacc ccgctttgac ccttcacccc tggatatatg ggcagcagta caccttcttc 3120 agcatggatg aaccaggcag tgagcagttc acggtacttg cagacgtcct cctgaataag 3180 ccaggctttg gcaaccgctg cctgaaggaa gggtggcttc cggagtaccc ctgtggcaac 3240 tcaacaccct ggaagactcc ttctgtgtcc ccaaacatca cccagctgtt ccagaagcag 3300 aaatggacac aggtcaaccc ttcaccatcc tgcaggtgca gcaccaggga gaagctcacc 3360 atgctgccat taaggctaca tgaactaacc aagatttatc caggcacctc cagcccagca 3420 gtggacaggc tgtgtgtcgg agttcgccct ggagagtgct ttggcctcct gggagtgaat 3480 ggtgccggca aaacaaccac attcaagatg ctcactgggg acaccacagt gacctcaggg 3540 gatgccaccg tagcaggcat caaatccccg areacgacc tgcttcctga cctgaaccct 3600 gtggagcagt tcttccaggg gaacttccca ggcagtgtgc agagggaggt gtttgtaaat 3660 tttgcttga 3669 <210> 7 <211> 3069 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 7 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc gctctacagc catcatgaat gccatttccc caacaaggcg 180 atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc 240 tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc 300 atcttggcaa gggtatatcg agattttcaa gaactcctca tgaatgcacc agagagccag 360 caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggaagagga atacgaataa gggatatctt gaaagatgaa 480 gaaacactga cactatttct cattaaaaac atcggcctgt ctgactcagt ggtctacctt 540 ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 aaggacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagacactc tgtattcttt catgatcatc ctgaaccgct gtttccctat cttcatggtg 780 ctggcatgga tctactctgt ctccatgact gtgaagagca tcgtcttgga gaaggagttg 840 cgactgaagg agaccttgaa aaatcagggt gtctccaatg cagtgatttg gtgtacctgg 900 ttcctggaca gcttctccat catgtcgatg agcatcttcc tcctgacgat attcatcatg 960 catggaagaa tcctacatta cagcgaccca ttcatcctct tcctgttctt gttggctttc 1020 tccactgcca ccatcatgct gtgctttctg ctcagcacct tcttctccaa ggccagtctg 1080 gcagcagcct gtagtggtgt catctatttc accctctacc tgccacacat cctgtgcttc 1140 gcctggcagg accgcatgac cgctgagctg aagaaggctg tgagcttact gtctccggtg 1200 gcatttggat ttggcactga gtacctggtt cgctttgaag agcaaggcct ggggctgcag 1260 tggagcaaca tcgggaacag tcccacggaa ggggacgaat tcagcttcct gctgtccatg 1320 cagatgatgc tccttgatgc tgctgtctat ggcttactcg cttggtacct tgatcaggtg 1380 ctaacagagg aaacggagga tccagagcac ccagaaggaa tacacgactc cttctttgaa 1440 cgtgagcatc cagggtgggt tcctggggta tgcgtgaaga atctggtaaa gatttttgag 1500 ccctgtggcc ggccagctgt ggaccgtctg aacatcacct tctacgagaa ccagatcacc 1560 gcattcctgg gccacaatgg agctgggaaa accaccacct tgtccatcct gacgggtctg 1620 ttgccaccaa cctctgggac tgtgctcgtt gggggaaggg acattgaaac cagcctggat 1680 gcacacaagg acttcctggc gcagatcgtg ctcccggcta cctttgtgtt tttggctctg 1740 atgctttcta ttgttatccc tccttttggc gaataccccg ctttgaccct tcacccctgg 1800 atatatgggc agcagtacac cttcttcagc atggatgaac caggcagtga gcagttcacg 1860 gtacttgcag acgtcctcct gaataagcca ggctttggca accgctgcct gaaggaaggg 1920 tggcttccgg agtacccctg tggcaactca acaccctgga agactccttc tgtgtcccca 1980 aacatcaccc agctgttcca gaagcagaaa tggacacagg tcaacccttc accatcctgc 2040 aggtgcagca ccagggagaa gctcaccatg ctgccaaact tcctctggga catcatgaat 2100 tattccgtga gtgctgggct ggtggtgggc atcttcatcg ggtttcagaa gaaagcctac 2160 acttctccag aaaaccttcc tgcccttgtg gcactgctcc tgctgtatgg atgggcggtc 2220 attcccatga tgtacccagc atccttcctg tttgatgtcc ccagcacagc ctatgtggct 2280 ttatcttgtg ctaatctgtt catcggcatc aacagcagtg ctattacctt catcttggaa 2340 ttatttgaga ataaccggac gctgctcagg ttcaacgccg tgctgaggaa gctgctcatt 2400 gtcttccccc acttctgcct gggccggggc ctcattgacc ttgcactgag ccaggctgtg 2460 acagatgtct atgcccggtt tggtgaggag cactctgcaa atccgttcca ctgggacctg 2520 attgggaaga acctgtttgc catggtggtg gaaggggtgg tgtacttcct cctgaccctg 2580 ctggtccagc gccacttctt cctctcccaa tggattgccg agcccactaa ggagcccatt 2640 gttgatgaag atgatgatgt ggctgaagaa agacaaagaa ttattactgg tggaaataaa 2700 actgacatct taaggctaca tgaactaacc aagatttatc caggcacctc cagcccagca 2760 gtggacaggc tgtgtgtcgg agttcgccct ggagagtgct ttggcctcct gggagtgaat 2820 ggtgccggca aaacaaccac attcaagatg ctcactgggg acaccacagt gacctcaggg 2880 gatgccaccg tagcaggcat caaatccccg aaggacgacc tgcttcctga cctgaaccct 2940 gtggagcagt tcttccaggg gaacttccca ggcagtgtgc agagggagag gcactacaac 3000 atgctccagt tccaggtctc ctcctcctcc ctggcgagga tcttccaggt gtttgtaaat 3060 tttgcttga 3069 <210> 8 <211> 4401 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 8 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaaggg ccaacgtgga cttcttcaag ctcttccgtg tgcttcccac actcctagac 180 agccgttctc aaggtatcaa tctgagatct tggggaggaa tattatctga tatgtcacca 240 agaattcaag agtttatcca tcggccgagt atgcaggact tgctgtgggt gaccaggccc 300 ctcatgcaga atggtggtcc agagaccttt acaaagctga tgggcatcct gtctgacctc 360 ctgtgtggct accccgaggg aggtggctct cgggtgctct ccttcaactg gtatgaagac 420 aataactata aggcctttct ggggattgac tccacaagga aggatcctat ctattcttat 480 gacagaagaa caacatcctt ttgtaatgca ttgatccaga gcctggagtc aaatccttta 540 accaaaatcg cttggagggc ggcaaagcct ttgctgatgg gaaaaatcct gtacactcct 600 gattcacctg cagcacgaag gatactgaag aatgccaact caacttttga agaactggaa 660 cacgttagga agttggtcaa agcctgggaa gaagtagggc cccagatctg gtacttcttt 720 gacaacagca cacagatgaa catgatcaga gataccctgg ggaacccaac agtaaaagac 780 tttttgaata ggcagcttgg tgaagaaggt attactgctg aagccatcct aaacttcctc 840 tacaagggcc ctcgggaaag ccaggctgac gacatggcca acttcgactg gagggacata 900 tttaacatca ctgatcgcac cctccgcctg gtcaatcaat acctggagtg cttggtcctg 960 gataagtttg aaagctacaa tgatgaaact cagctcaccc aacgtgccct ctctctactg 1020 gaggaaaaca tgttctgggc cggagtggta ttccctgaca tgtatccctg gaccagctct 1080 ctaccacccc acgtgaagta taagatccga atggacatag acgtggtgga gaaaaccaat 1140 aagattaaag acaggtattg ggattctggt cccagagctg atcccgtgga agatttccgg 1200 tacatctggg gcgggtttgc ctatctgcag gacatggttg aacaggggat cacaaggagc 1260 caggtgcagg cggaggctcc agttggaatc tacctccagc agatgcccta cccctgcttc 1320 gtggacgatt cttcatgat catcctgaac cgctgtttcc ctatcttcat ggtgctggca 1380 tggatctact ctgtctccat gactgtgaag agcatcgtct tggagaagga gttgcgactg 1440 aaggagacct tgaaaaatca gggtgtctcc aatgcagtga tttggtgtac ctggttcctg 1500 gacagcttct ccatcatgtc gatgagcatc ttcctcctga cgatattcat catgcatgga 1560 agaatcctac attacagcga cccattcatc ctcttcctgt tcttgttggc tttctccact 1620 gccaccatca tgctgtgctt tctgctcagc accttcttct ccaaggccag tctggcagca 1680 gcctgtagtg gtgtcatcta tttcaccctc tacctgccac acatcctgtg cttcgcctgg 1740 caggaccgca tgaccgctga gctgaagaag gctgtgagct tactgtctcc ggtggcattt ggatttggca ctgagtacct ggttcgcttt gaagagcaag gcctggggct gcagtggagc aacatcggga acagtcccac ggaaggggac gaattcagct tcctgctgtc catgcagatg atgctccttg atgctgctgt ctatggctta ctcgcttggt accttgatca ggtggtccgg 1980. cagagccttg gcatgtgtcc acagcacaac atcctgttcc accacctcac ggtggctgag cacatgctgt tctatgccca gctgaaagga aagtcccagg aggaggccca gctggagatg gaagccatgt tggaggacac aggcctccac cacaagcgga atgaagaggc tcaggaccta 2220. tcaggtggca tgcagagaaa gctgtcggtt gccattgcct ttgtggggaga tgccaaggtg gtgattctgg acgaacccac ctctggggtg gacccttact cgagacgctc aatctgggat ctgctcctga aggcgctc aggcagaacc atcatcatgt ccactcacca catggacgag gccgacctcc ttggggaccg cattgccatc attgcccagg gaaggctcta ctgctcaggc accccactct tcctgaagaa ctgctttggc acaggcttgt acttaacctt ggtgcgcaag 2460 atgaaaaaca tccagagcca aaggaaaggc agtgaggga cctgcagctg ctcgtctaag 2520 ggtttctcca ccacgtgtcc agcccacgtc gatgacctaa ctccagaaca agtccacaag 2580 gacttcctgg cgcagatcgt gctcccggct acctttgtgt ttttggctct gatgctttct 2640 attgagtgcc ccgagggtgc cgggggcctc ccgcccccccc agaacaca gcgcagcacg 2700 gaaattctac aagacctgac ggaggaac atctccgact tcttggtaaa aacgtatcct 2760 gctctttataa gaagcagctt aaagagcaaa ttctgggtca atgaacagag gtatggagga 2820 atttccattg gagaaagct cccagtcgtc cccatcacgg gggaagcact tgttgggttt 2880 ttaagcgacc ttggccggat catgaatgtg agcggggggcc ctatcactag agaggcctct 2940 aaaagaatac ctgatttcct taaacatcta gaatgaag aacaattaa ggtgtggttt 3000 aataaaag gctggcatgc cctggtcagc tttctcaatg tggcccacaa cgccatctta 3060 cgggccagcc tgcctaagga caggagcccc gagaacttcc tctgggacat catgaattat 3120 tccgtgagtg ctgggctggt ggtgggcatc ttcatcgggt ttcagaagaa agcctacact 3180 tctccagaaa accttcctgc ccttgtggca ctgctcctgc tgtatggatg ggcggtcatt 3240 cccatgatgt acccagcatc cttcctgttt gatgtcccca gcacagccta tgtggcttta 3300 tcttgtgcta atctgttcat cggcatcaac agcagtgcta ttaccttcat cttggaatta 3360 tttgagaata accggacgct gctcaggttc aacgccgtgc tgaggaagct gctcattgtc 3420 ttcccccact tctgcctggg ccggggcctc attgaccttg cactgagcca ggctgtgaca 3480 gatgtctatg cccggtttgg tgaggagcac tctgcaaatc cgttccactg ggacctgatt 3540 gggaagaacc tgtttgccat ggtggtggaa ggggtggtgt acttcctcct gaccctgctg 3600 gtccagcgcc acttcttcct ctcccaatgg attgccgagc ccactaagga gcccattgtt 3660 gatgaagatg atgatgtggc tgaagaaaga caaagaatta ttactggtgg aaataaaact 3720 gacatcttaa agagtatttt aaccaatatt tctgaagtcc atcaaaatat gggctactgt 3780 cctcagtttg atgcaattga tgagctgctc acaggacgag aacatcttta cctttatgcc 3840 cggcttcgag gtgtaccagc agaagaaatc gaaaaggttg caaactggag tattaagagc 3900 ctgggcctga ctgtctacgc cgactgcctg gctggcacgt acagtggggg caacaagcgg 3960 aaactctcca cagccatcgc actcattggc tgcccaccgc tggtgctgct ggatgagccc 4020 accacaggga tggaccccca ggcacgccgc atgctgtgga acgtcatcgt gagcatcatc 4080 agagaaggga gggctgtggt cctcacatcc cacagcatgg aagaatgtga ggcactgtgt 4140 acccggctgg ccatcatggt aaagggcgcc tttcgatgta tgggcaccat tcagcatctc 4200 aagtccaaat ttggagatgg ctatatcgtc acaatgaagc tcctcctctc ccacaaggac 4260 agcctgctca tcgaggagta ctcagtcaca cagaccacac tggaccaggt gtttgtaaat 4320 tttgctaaac agcagactga aagtcatgac ctccctctgc accctcgagc tgctggagcc 4380 agtcgacaag cccaggactg a 4401 <210> 9 <211> 1271 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 9 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 245 250 255 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 260 265 270 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 275 280 285 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 290 295 300 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 305 310 315 320 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 325 330 335 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 340 345 350 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 355 360 365 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 370 375 380 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 385 390 395 400 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 405 410 415 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 420 425 430 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 435 440 445 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Val Cys Val Lys 450 455 460 Asn Leu Val Lys Ile Phe Glu Pro Cys Gly Arg Pro Ala Val Asp Arg 465 470 475 480 Leu Asn Ile Thr Phe Tyr Glu Asn Gln Ile Thr Ala Phe Leu Gly His 485 490 495 Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Ile Leu Thr Gly Leu Leu 500 505 510 Pro Pro Thr Ser Gly Thr Val Leu Val Gly Gly Arg Asp Ile Glu Thr 515 520 525 Ser Leu Asp Ala Val Arg Gln Ser Leu Gly Met Cys Pro Gln His Asn 530 535 540 Ile Leu Phe His His Leu Thr Val Ala Glu His Met Leu Phe Tyr Ala 545 550 555 560 Gln Leu Lys Gly Lys Ser Gln Glu Glu Ala Gln Leu Glu Met Glu Ala 565 570 575 Met Leu Glu Asp Thr Gly Leu His His Lys Arg Asn Glu Glu Ala Gln 580 585 590 Asp Leu Ser Gly Gly Met Gln Arg Lys Leu Ser Val Ala Ile Ala Phe 595 600 605 Val Gly Asp Ala Lys Val Val Ile Leu Asp Glu Pro Thr Ser Gly Val 610 615 620 Asp Pro Tyr Ser Arg Arg Ser Ile Trp Asp Leu Leu Leu Lys Tyr Arg 625 630 635 640 Ser Gly Arg Thr Ile Ile Met Ser Thr His His Met Asp Glu Ala Asp 645 650 655 Leu Leu Gly Asp Arg Ile Ala Ile Ile Ala Gln Gly Arg Leu Tyr Cys 660 665 670 Ser Gly Thr Pro Leu Phe Leu Lys Asn Cys Phe Gly Thr Gly Leu Tyr 675 680 685 Leu Thr Leu Val Gly Glu Tyr Pro Ala Leu Thr Leu His Pro Trp Ile 690 695 700 Tyr Gly Gln Gln Tyr Thr Phe Phe Ser Met Asp Glu Pro Gly Ser Glu 705 710 715 720 Gln Phe Thr Val Leu Ala Asp Val Leu Leu Asn Lys Pro Gly Phe Gly 725 730 735 Asn Arg Cys Leu Lys Glu Gly Trp Leu Pro Glu Tyr Pro Cys Gly Asn 740 745 750 Ser Thr Pro Trp Lys Thr Pro Ser Val Ser Pro Asn Ile Thr Gln Leu 755 760 765 Phe Gln Lys Gln Lys Trp Thr Gln Val Asn Pro Ser Pro Ser Cys Arg 770 775 780 Cys Ser Thr Arg Glu Lys Leu Thr Met Leu Pro Glu Cys Pro Glu Gly 785 790 795 800 Ala Gly Gly Leu Pro Pro Pro Gln Arg Thr Gln Arg Ser Thr Glu Ile 805 810 815 Leu Gln Asp Leu Thr Asp Arg Asn Ile Ser Asp Phe Leu Val Lys Thr 820 825 830 Tyr Pro Ala Leu Ile Arg Ser Ser Leu Lys Ser Lys Phe Trp Val Asn 835 840 845 Glu Gln Arg Tyr Gly Gly Ile Ser Ile Gly Gly Lys Leu Pro Val Val 850 855 860 Pro Ile Thr Gly Glu Ala Leu Val Gly Phe Leu Ser Asp Leu Gly Arg 865 870 875 880 Ile Met Asn Val Ser Gly Gly Pro Ile Thr Arg Glu Ala Ser Lys Glu 885 890 895 Ile Pro Asp Phe Leu Lys His Leu Glu Thr Glu Asp Asn Ile Lys Val 900 905 910 Trp Phe Asn Asn Lys Gly Trp His Ala Leu Val Ser Phe Leu Asn Val 915 920 925 Ala His Asn Ala Ile Leu Arg Leu Arg Leu His Glu Leu Thr Lys Ile 930 935 940 Tyr Pro Gly Thr Ser Ser Pro Ala Val Asp Arg Leu Cys Val Gly Val 945 950 955 960 Arg Pro Gly Glu Cys Phe Gly Leu Leu Gly Val Asn Gly Ala Gly Lys 965 970 975 Thr Thr Thr Phe Lys Met Leu Thr Gly Asp Thr Thr Val Thr Ser Gly 980 985 990 Asp Ala Thr Val Ala Gly Lys Ser Ile Leu Thr Asn Ile Ser Glu Val 995 1000 1005 His Gln Asn Met Gly Tyr Cys Pro Gln Phe Asp Ala Ile Asp Glu 1010 1015 1020 Leu Leu Thr Gly Arg Glu His Leu Tyr Leu Tyr Ala Arg Leu Arg 1025 1030 1035 Gly Val Pro Ala Glu Glu Ile Glu Lys Val Ala Asn Trp Ser Ile 1040 1045 1050 Lys Ser Leu Gly Leu Thr Val Tyr Ala Asp Cys Leu Ala Gly Thr 1055 1060 1065 Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser Thr Ala Ile Ala Leu 1070 1075 1080 Ile Gly Cys Pro Pro Leu Val Leu Leu Asp Glu Pro Thr Thr Gly 1085 1090 1095 Met Asp Pro Gln Ala Arg Arg Met Leu Trp Asn Val Ile Val Ser 1100 1105 1110 Ile Ile Arg Glu Gly Arg Ala Val Val Leu Thr Ser His Ser Met 1115 1120 1125 Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala Ile Met Val Lys 1130 1135 1140 Gly Ala Phe Arg Cys Met Gly Thr Ile Gln His Leu Lys Ser Lys 1145 1150 1155 Phe Gly Asp Gly Tyr Ile Val Thr Met Lys Ile Lys Ser Pro Lys 1160 1165 1170 Asp Asp Leu Leu Pro Asp Leu Asn Pro Val Glu Gln Phe Phe Gln 1175 1180 1185 Gly Asn Phe Pro Gly Ser Val Gln Arg Glu Arg His Tyr Asn Met 1190 1195 1200 Leu Gln Phe Gln Val Ser Ser Ser Ser Leu Ala Arg Ile Phe Gln 1205 1210 1215 Leu Leu Leu Ser His Lys Asp Ser Leu Leu Ile Glu Glu Tyr Ser 1220 1225 1230 Val Thr Gln Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys 1235 1240 1245 Gln Gln Thr Glu Ser His Asp Leu Pro Leu His Pro Arg Ala Ala 1250 1255 1260 Gly Ala Ser Arg Gln Ala Gln Asp 1265 1270 <210> 10 <211> 1267 <212> PRT <213> Artificial Sequence <220> <223> Synthesized multipeptide <400> 10 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Val Cys Val Lys Asn Leu Val Lys Ile Phe Glu 245 250 255 Pro Cys Gly Arg Pro Ala Val Asp Arg Leu Asn Ile Thr Phe Tyr Glu 260 265 270 Asn Gln Ile Thr Ala Phe Leu Gly His Asn Gly Ala Gly Lys Thr Thr 275 280 285 Thr Leu Ser Ile Leu Thr Gly Leu Leu Pro Pro Thr Ser Gly Thr Val 290 295 300 Leu Val Gly Gly Arg Asp Ile Glu Thr Ser Leu Asp Ala Val Arg Gln 305 310 315 320 Ser Leu Gly Met Cys Pro Gln His Asn Ile Leu Phe His His Leu Thr 325 330 335 Val Ala Glu His Met Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln 340 345 350 Glu Glu Ala Gln Leu Glu Met Glu Ala Met Leu Glu Asp Thr Gly Leu 355 360 365 His His Lys Arg Asn Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln 370 375 380 Arg Lys Leu Ser Val Ala Ile Ala Phe Val Gly Asp Ala Lys Val Val 385 390 395 400 Ile Leu Asp Glu Pro Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg Ser 405 410 415 Ile Trp Asp Leu Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile Ile Met 420 425 430 Ser Thr His His Met Asp Glu Ala Asp Leu Leu Gly Asp Arg Ile Ala 435 440 445 Ile Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr Pro Leu Phe Leu 450 455 460 Lys Asn Cys Phe Gly Thr Gly Leu Tyr Leu Thr Leu Val Gly Glu Tyr 465 470 475 480 Pro Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln Gln Tyr Thr Phe 485 490 495 Phe Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr Val Leu Ala Asp 500 505 510 Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg Cys Leu Lys Glu Gly 515 520 525 Trp Leu Pro Glu Tyr Pro Cys Gly Asn Ser Thr Pro Trp Lys Thr Pro 530 535 540 Ser Val Ser Pro Asn Ile Thr Gln Leu Phe Gln Lys Gln Lys Trp Thr 545 550 555 560 Gln Val Asn Pro Ser Pro Ser Cys Arg Cys Ser Thr Arg Glu Lys Leu 565 570 575 Thr Met Leu Pro Glu Cys Pro Glu Gly Ala Gly Gly Leu Pro Pro Pro 580 585 590 Gln Arg Thr Gln Arg Ser Thr Glu Ile Leu Gln Asp Leu Thr Asp Arg 595 600 605 Asn Ile Ser Asp Phe Leu Val Lys Thr Tyr Pro Ala Leu Ile Arg Ser 610 615 620 Ser Leu Lys Ser Lys Phe Trp Val Asn Glu Gln Arg Tyr Gly Gly Ile 625 630 635 640 Ser Ile Gly Gly Lys Leu Pro Val Val Pro Ile Thr Gly Glu Ala Leu 645 650 655 Val Gly Phe Leu Ser Asp Leu Gly Arg Ile Met Asn Val Ser Gly Gly 660 665 670 Pro Ile Thr Arg Glu Ala Ser Lys Glu Ile Pro Asp Phe Leu Lys His 675 680 685 Leu Glu Thr Glu Asp Asn Ile Lys Val Trp Phe Asn Asn Lys Gly Trp 690 695 700 His Ala Leu Val Ser Phe Leu Asn Val Ala His Asn Ala Ile Leu Arg 705 710 715 720 Asn Phe Leu Trp Asp Ile Met Asn Tyr Ser Val Ser Ala Gly Leu Val 725 730 735 Val Gly Ile Phe Ile Gly Phe Gln Lys Lys Ala Tyr Thr Ser Pro Glu 740 745 750 Asn Leu Pro Ala Leu Val Ala Leu Leu Leu Leu Tyr Gly Trp Ala Val 755 760 765 Ile Pro Met Met Tyr Pro Ala Ser Phe Leu Phe Asp Val Pro Ser Thr 770 775 780 Ala Tyr Val Ala Leu Ser Cys Ala Asn Leu Phe Ile Gly Ile Asn Ser 785 790 795 800 Ser Ala Ile Thr Phe Ile Leu Glu Leu Phe Glu Asn Asn Arg Thr Leu 805 810 815 Leu Arg Phe Asn Ala Val Leu Arg Lys Leu Leu Ile Val Phe Pro His 820 825 830 Phe Cys Leu Gly Arg Gly Leu Ile Asp Leu Ala Leu Ser Gln Ala Val 835 840 845 Thr Asp Val Tyr Ala Arg Phe Gly Glu Glu His Ser Ala Asn Pro Phe 850 855 860 His Trp Asp Leu Ile Gly Lys Asn Leu Phe Ala Met Val Val Glu Gly 865 870 875 880 Val Val Tyr Phe Leu Leu Thr Leu Leu Val Gln Arg His Phe Phe Leu 885 890 895 Ser Gln Trp Ile Ala Glu Pro Thr Lys Glu Pro Ile Val Asp Glu Asp 900 905 910 Asp Asp Val Ala Glu Glu Arg Gln Arg Ile Ile Thr Gly Gly Asn Lys 915 920 925 Thr Asp Ile Leu Arg Leu His Glu Leu Thr Lys Ile Tyr Pro Gly Thr 930 935 940 Ser Ser Pro Ala Val Asp Arg Leu Cys Val Gly Val Arg Pro Gly Glu 945 950 955 960 Cys Phe Gly Leu Leu Gly Val Asn Gly Ala Gly Lys Thr Thr Thr Phe 965 970 975 Lys Met Leu Thr Gly Asp Thr Thr Val Thr Ser Gly Asp Ala Thr Val 980 985 990 Ala Gly Lys Ser Ile Leu Thr Asn Ile Ser Glu Val His Gln Asn Met 995 1000 1005 Gly Tyr Cys Pro Gln Phe Asp Ala Ile Asp Glu Leu Leu Thr Gly 1010 1015 1020 Arg Glu His Leu Tyr Leu Tyr Ala Arg Leu Arg Gly Val Pro Ala 1025 1030 1035 Glu Glu Ile Glu Lys Val Ala Asn Trp Ser Ile Lys Ser Leu Gly 1040 1045 1050 Leu Thr Val Tyr Ala Asp Cys Leu Ala Gly Thr Tyr Ser Gly Gly 1055 1060 1065 Asn Lys Arg Lys Leu Ser Thr Ala Ile Ala Leu Ile Gly Cys Pro 1070 1075 1080 Pro Leu Val Leu Leu Asp Glu Pro Thr Thr Gly Met Asp Pro Gln 1085 1090 1095 Ala Arg Arg Met Leu Trp Asn Val Ile Val Ser Ile Ile Arg Glu 1100 1105 1110 Gly Arg Ala Val Val Leu Thr Ser His Ser Met Glu Glu Cys Glu 1115 1120 1125 Ala Leu Cys Thr Arg Leu Ala Ile Met Val Lys Gly Ala Phe Arg 1130 1135 1140 Cys Met Gly Thr Ile Gln His Leu Lys Ser Lys Phe Gly Asp Gly 1145 1150 1155 Tyr Ile Val Thr Met Lys Ile Lys Ser Pro Lys Asp Asp Leu Leu 1160 1165 1170 Pro Asp Leu Asn Pro Val Glu Gln Phe Phe Gln Gly Asn Phe Pro 1175 1180 1185 Gly Ser Val Gln Arg Glu Arg His Tyr Asn Met Leu Gln Phe Gln 1190 1195 1200 Val Ser Ser Ser Ser Leu Ala Arg Ile Phe Gln Leu Leu Leu Ser 1205 1210 1215 His Lys Asp Ser Leu Leu Ile Glu Glu Tyr Ser Val Thr Gln Thr 1220 1225 1230 Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys Gln Gln Thr Glu 1235 1240 1245 Ser His Asp Leu Pro Leu His Pro Arg Ala Ala Gly Ala Ser Arg 1250 1255 1260 Gln Ala Gln Asp 1265 <210> 11 <211> 1353 <212> PRT <213> Artificial Sequence <220> <223> Synthesized multipeptide <400> 11 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe Phe Lys Leu Phe Arg Val 245 250 255 Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser 260 265 270 Trp Gly Gly Ile Leu Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile 275 280 285 His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr Arg Pro Leu Met 290 295 300 Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser 305 310 315 320 Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly Gly Ser Arg Val Leu Ser 325 330 335 Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe Leu Gly Ile Asp 340 345 350 Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser 355 360 365 Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu Ser Asn Pro Leu Thr Lys 370 375 380 Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr 385 390 395 400 Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser 405 410 415 Thr Phe Glu Glu Leu Glu His Val Arg Lys Leu Val Lys Ala Trp Glu 420 425 430 Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met 435 440 445 Asn Met Ile Arg Asp Thr Leu Gly Asn Pro Thr Val Lys Asp Phe Leu 450 455 460 Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu Asn 465 470 475 480 Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn 485 490 495 Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr Asp Arg Thr Leu Arg Leu 500 505 510 Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu Ser Tyr 515 520 525 Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu 530 535 540 Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met Tyr Pro Trp Thr 545 550 555 560 Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp 565 570 575 Val Val Glu Lys Thr Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly 580 585 590 Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile Trp Gly Gly Phe 595 600 605 Ala Tyr Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val 610 615 620 Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln Gln Met Pro Tyr Pro 625 630 635 640 Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 645 650 655 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 660 665 670 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 675 680 685 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 690 695 700 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 705 710 715 720 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 725 730 735 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 740 745 750 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 755 760 765 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 770 775 780 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 785 790 795 800 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 805 810 815 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 820 825 830 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 835 840 845 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Leu Thr Glu Glu 850 855 860 Thr Glu Asp Pro Glu His Pro Glu Gly Ile His Asp Ser Phe Phe Glu 865 870 875 880 Arg Glu His Pro Gly Trp Val Pro Gly Val Cys Val Lys Asn Leu Val 885 890 895 Lys Ile Phe Glu Pro Cys Gly Arg Pro Ala Val Asp Arg Leu Asn Ile 900 905 910 Thr Phe Tyr Glu Asn Gln Ile Thr Ala Phe Leu Gly His Asn Gly Ala 915 920 925 Gly Lys Thr Thr Thr Leu Ser Ile Leu Thr Gly Leu Leu Pro Pro Thr 930 935 940 Ser Gly Thr Val Leu Val Gly Gly Arg Asp Ile Glu Thr Ser Leu Asp 945 950 955 960 Ala Gly Glu Tyr Pro Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln 965 970 975 Gln Tyr Thr Phe Phe Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr 980 985 990 Val Leu Ala Asp Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg Cys 995 1000 1005 Leu Lys Glu Gly Trp Leu Pro Glu Tyr Pro Cys Gly Asn Ser Thr 1010 1015 1020 Pro Trp Lys Thr Pro Ser Val Ser Pro Asn Ile Thr Gln Leu Phe 1025 1030 1035 Gln Lys Gln Lys Trp Thr Gln Val Asn Pro Ser Pro Ser Cys Arg 1040 1045 1050 Cys Ser Thr Arg Glu Lys Leu Thr Met Leu Pro Leu Arg Leu His 1055 1060 1065 Glu Leu Thr Lys Ile Tyr Pro Gly Thr Ser Ser Pro Ala Val Asp 1070 1075 1080 Arg Leu Cys Val Gly Val Arg Pro Gly Glu Cys Phe Gly Leu Leu 1085 1090 1095 Gly Val Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys Met Leu Thr 1100 1105 1110 Gly Asp Thr Thr Val Thr Ser Gly Asp Ala Thr Val Ala Gly Lys 1115 1120 1125 Ser Ile Leu Thr Asn Ile Ser Glu Val His Gln Asn Met Gly Tyr 1130 1135 1140 Cys Pro Gln Phe Asp Ala Ile Asp Glu Leu Leu Thr Gly Arg Glu 1145 1150 1155 His Leu Tyr Leu Tyr Ala Arg Leu Arg Gly Val Pro Ala Glu Glu 1160 1165 1170 Ile Glu Lys Val Ala Asn Trp Ser Ile Lys Ser Leu Gly Leu Thr 1175 1180 1185 Val Tyr Ala Asp Cys Leu Ala Gly Thr Tyr Ser Gly Gly Asn Lys 1190 1195 1200 Arg Lys Leu Ser Thr Ala Ile Ala Leu Ile Gly Cys Pro Pro Leu 1205 1210 1215 Val Leu Leu Asp Glu Pro Thr Thr Gly Met Asp Pro Gln Ala Arg 1220 1225 1230 Arg Met Leu Trp Asn Val Ile Val Ser Ile Ile Arg Glu Gly Arg 1235 1240 1245 Ala Val Val Leu Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu 1250 1255 1260 Cys Thr Arg Leu Ala Ile Met Val Lys Gly Ala Phe Arg Cys Met 1265 1270 1275 Gly Thr Ile Gln His Leu Lys Ser Lys Phe Gly Asp Gly Tyr Ile 1280 1285 1290 Val Thr Met Lys Ile Lys Ser Pro Lys Asp Asp Leu Leu Pro Asp 1295 1300 1305 Leu Asn Pro Val Glu Gln Phe Phe Gln Gly Asn Phe Pro Gly Ser 1310 1315 1320 Val Gln Arg Glu Arg His Tyr Asn Met Leu Gln Phe Gln Val Ser 1325 1330 1335 Ser Ser Ser Leu Ala Arg Ile Phe Gln Val Phe Val Asn Phe Ala 1340 1345 1350 <210> 12 <211> 1222 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 12 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe Phe Lys Leu Phe Arg Val 245 250 255 Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser 260 265 270 Trp Gly Gly Ile Leu Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile 275 280 285 His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr Arg Pro Leu Met 290 295 300 Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser 305 310 315 320 Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly Gly Ser Arg Val Leu Ser 325 330 335 Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe Leu Gly Ile Asp 340 345 350 Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser 355 360 365 Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu Ser Asn Pro Leu Thr Lys 370 375 380 Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr 385 390 395 400 Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser 405 410 415 Thr Phe Glu Glu Leu Glu His Val Arg Lys Leu Val Lys Ala Trp Glu 420 425 430 Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met 435 440 445 Asn Met Ile Arg Asp Thr Leu Gly Asn Pro Thr Val Lys Asp Phe Leu 450 455 460 Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu Asn 465 470 475 480 Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn 485 490 495 Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr Asp Arg Thr Leu Arg Leu 500 505 510 Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu Ser Tyr 515 520 525 Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu 530 535 540 Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met Tyr Pro Trp Thr 545 550 555 560 Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp 565 570 575 Val Val Glu Lys Thr Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly 580 585 590 Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile Trp Gly Gly Phe 595 600 605 Ala Tyr Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val 610 615 620 Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln Gln Met Pro Tyr Pro 625 630 635 640 Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 645 650 655 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 660 665 670 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 675 680 685 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 690 695 700 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 705 710 715 720 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 725 730 735 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 740 745 750 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 755 760 765 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 770 775 780 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 785 790 795 800 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 805 810 815 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 820 825 830 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 835 840 845 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Val Arg Gln Ser 850 855 860 Leu Gly Met Cys Pro Gln His Asn Ile Leu Phe His His Leu Thr Val 865 870 875 880 Ala Glu His Met Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln Glu 885 890 895 Glu Ala Gln Leu Glu Met Glu Ala Met Leu Glu Asp Thr Gly Leu His 900 905 910 His Lys Arg Asn Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln Arg 915 920 925 Lys Leu Ser Val Ala Ile Ala Phe Val Gly Asp Ala Lys Val Val Ile 930 935 940 Leu Asp Glu Pro Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg Ser Ile 945 950 955 960 Trp Asp Leu Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile Ile Met Ser 965 970 975 Thr His His Met Asp Glu Ala Asp Leu Leu Gly Asp Arg Ile Ala Ile 980 985 990 Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr Pro Leu Phe Leu Lys 995 1000 1005 Asn Cys Phe Gly Thr Gly Leu Tyr Leu Thr Leu Val Gly Glu Tyr 1010 1015 1020 Pro Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln Gln Tyr Thr 1025 1030 1035 Phe Phe Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr Val Leu 1040 1045 1050 Ala Asp Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg Cys Leu 1055 1060 1065 Lys Glu Gly Trp Leu Pro Glu Tyr Pro Cys Gly Asn Ser Thr Pro 1070 1075 1080 Trp Lys Thr Pro Ser Val Ser Pro Asn Ile Thr Gln Leu Phe Gln 1085 1090 1095 Lys Gln Lys Trp Thr Gln Val Asn Pro Ser Pro Ser Cys Arg Cys 1100 1105 1110 Ser Thr Arg Glu Lys Leu Thr Met Leu Pro Leu Arg Leu His Glu 1115 1120 1125 Leu Thr Lys Ile Tyr Pro Gly Thr Ser Ser Pro Ala Val Asp Arg 1130 1135 1140 Leu Cys Val Gly Val Arg Pro Gly Glu Cys Phe Gly Leu Leu Gly 1145 1150 1155 Val Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys Met Leu Thr Gly 1160 1165 1170 Asp Thr Thr Val Thr Ser Gly Asp Ala Thr Val Ala Gly Ile Lys 1175 1180 1185 Ser Pro Lys Asp Asp Leu Leu Pro Asp Leu Asn Pro Val Glu Gln 1190 1195 1200 Phe Phe Gln Gly Asn Phe Pro Gly Ser Val Gln Arg Glu Val Phe 1205 1210 1215 Val Asn Phe Ala 1220 <210> 13 <211> 1022 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 13 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 245 250 255 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 260 265 270 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 275 280 285 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 290 295 300 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 305 310 315 320 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 325 330 335 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 340 345 350 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 355 360 365 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 370 375 380 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 385 390 395 400 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 405 410 415 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 420 425 430 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 435 440 445 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Leu Thr Glu Glu 450 455 460 Thr Glu Asp Pro Glu His Pro Glu Gly Ile His Asp Ser Phe Phe Glu 465 470 475 480 Arg Glu His Pro Gly Trp Val Pro Gly Val Cys Val Lys Asn Leu Val 485 490 495 Lys Ile Phe Glu Pro Cys Gly Arg Pro Ala Val Asp Arg Leu Asn Ile 500 505 510 Thr Phe Tyr Glu Asn Gln Ile Thr Ala Phe Leu Gly His Asn Gly Ala 515 520 525 Gly Lys Thr Thr Thr Leu Ser Ile Leu Thr Gly Leu Leu Pro Pro Thr 530 535 540 Ser Gly Thr Val Leu Val Gly Gly Arg Asp Ile Glu Thr Ser Leu Asp 545 550 555 560 Ala His Lys Asp Phe Leu Ala Gln Ile Val Leu Pro Ala Thr Phe Val 565 570 575 Phe Leu Ala Leu Met Leu Ser Ile Val Ile Pro Pro Phe Gly Glu Tyr 580 585 590 Pro Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln Gln Tyr Thr Phe 595 600 605 Phe Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr Val Leu Ala Asp 610 615 620 Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg Cys Leu Lys Glu Gly 625 630 635 640 Trp Leu Pro Glu Tyr Pro Cys Gly Asn Ser Thr Pro Trp Lys Thr Pro 645 650 655 Ser Val Ser Pro Asn Ile Thr Gln Leu Phe Gln Lys Gln Lys Trp Thr 660 665 670 Gln Val Asn Pro Ser Pro Ser Cys Arg Cys Ser Thr Arg Glu Lys Leu 675 680 685 Thr Met Leu Pro Asn Phe Leu Trp Asp Ile Met Asn Tyr Ser Val Ser 690 695 700 Ala Gly Leu Val Val Gly Ile Phe Ile Gly Phe Gln Lys Lys Ala Tyr 705 710 715 720 Thr Ser Pro Glu Asn Leu Pro Ala Leu Val Ala Leu Leu Leu Leu Tyr 725 730 735 Gly Trp Ala Val Ile Pro Met Met Tyr Pro Ala Ser Phe Leu Phe Asp 740 745 750 Val Pro Ser Thr Ala Tyr Val Ala Leu Ser Cys Ala Asn Leu Phe Ile 755 760 765 Gly Ile Asn Ser Ser Ala Ile Thr Phe Ile Leu Glu Leu Phe Glu Asn 770 775 780 Asn Arg Thr Leu Leu Arg Phe Asn Ala Val Leu Arg Lys Leu Leu Ile 785 790 795 800 Val Phe Pro His Phe Cys Leu Gly Arg Gly Leu Ile Asp Leu Ala Leu 805 810 815 Ser Gln Ala Val Thr Asp Val Tyr Ala Arg Phe Gly Glu Glu His Ser 820 825 830 Ala Asn Pro Phe His Trp Asp Leu Ile Gly Lys Asn Leu Phe Ala Met 835 840 845 Val Val Glu Gly Val Val Tyr Phe Leu Leu Thr Leu Leu Val Gln Arg 850 855 860 His Phe Phe Leu Ser Gln Trp Ile Ala Glu Pro Thr Lys Glu Pro Ile 865 870 875 880 Val Asp Glu Asp Asp Asp Val Ala Glu Glu Arg Gln Arg Ile Ile Thr 885 890 895 Gly Gly Asn Lys Thr Asp Ile Leu Arg Leu His Glu Leu Thr Lys Ile 900 905 910 Tyr Pro Gly Thr Ser Ser Pro Ala Val Asp Arg Leu Cys Val Gly Val 915 920 925 Arg Pro Gly Glu Cys Phe Gly Leu Leu Gly Val Asn Gly Ala Gly Lys 930 935 940 Thr Thr Thr Phe Lys Met Leu Thr Gly Asp Thr Thr Val Thr Ser Gly 945 950 955 960 Asp Ala Thr Val Ala Gly Ile Lys Ser Pro Lys Asp Asp Leu Leu Pro 965 970 975 Asp Leu Asn Pro Val Glu Gln Phe Phe Gln Gly Asn Phe Pro Gly Ser 980 985 990 Val Gln Arg Glu Arg His Tyr Asn Met Leu Gln Phe Gln Val Ser Ser 995 1000 1005 Ser Ser Leu Ala Arg Ile Phe Gln Val Phe Val Asn Phe Ala 1010 1015 1020 <210> 14 <211> 1466 <212> PRT <213> Artificial Sequence <220> <223> Synthesized multipeptide <400> 14 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Ala Asn Val Asp Phe 35 40 45 Phe Lys Leu Phe Arg Val Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln 50 55 60 Gly Ile Asn Leu Arg Ser Trp Gly Gly Ile Leu Ser Asp Met Ser Pro 65 70 75 80 Arg Ile Gln Glu Phe Ile His Arg Pro Ser Met Gln Asp Leu Leu Trp 85 90 95 Val Thr Arg Pro Leu Met Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys 100 105 110 Leu Met Gly Ile Leu Ser Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly 115 120 125 Gly Ser Arg Val Leu Ser Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys 130 135 140 Ala Phe Leu Gly Ile Asp Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr 145 150 155 160 Asp Arg Arg Thr Thr Ser Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu 165 170 175 Ser Asn Pro Leu Thr Lys Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu 180 185 190 Met Gly Lys Ile Leu Tyr Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile 195 200 205 Leu Lys Asn Ala Asn Ser Thr Phe Glu Glu Leu Glu His Val Arg Lys 210 215 220 Leu Val Lys Ala Trp Glu Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe 225 230 235 240 Asp Asn Ser Thr Gln Met Asn Met Ile Arg Asp Thr Leu Gly Asn Pro 245 250 255 Thr Val Lys Asp Phe Leu Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr 260 265 270 Ala Glu Ala Ile Leu Asn Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln 275 280 285 Ala Asp Asp Met Ala Asn Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr 290 295 300 Asp Arg Thr Leu Arg Leu Val Asn Gln Tyr Leu Glu Cys Leu Val Leu 305 310 315 320 Asp Lys Phe Glu Ser Tyr Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala 325 330 335 Leu Ser Leu Leu Glu Glu Asn Met Phe Trp Ala Gly Val Val Phe Pro 340 345 350 Asp Met Tyr Pro Trp Thr Ser Ser Leu Pro Pro His Val Lys Tyr Lys 355 360 365 Ile Arg Met Asp Ile Asp Val Val Glu Lys Thr Asn Lys Ile Lys Asp 370 375 380 Arg Tyr Trp Asp Ser Gly Pro Arg Ala Asp Pro Val Glu Asp Phe Arg 385 390 395 400 Tyr Ile Trp Gly Gly Phe Ala Tyr Leu Gln Asp Met Val Glu Gln Gly 405 410 415 Ile Thr Arg Ser Gln Val Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu 420 425 430 Gln Gln Met Pro Tyr Pro Cys Phe Val Asp Asp Ser Phe Met Ile Ile 435 440 445 Leu Asn Arg Cys Phe Pro Ile Phe Met Val Leu Ala Trp Ile Tyr Ser 450 455 460 Val Ser Met Thr Val Lys Ser Ile Val Leu Glu Lys Glu Leu Arg Leu 465 470 475 480 Lys Glu Thr Leu Lys Asn Gln Gly Val Ser Asn Ala Val Ile Trp Cys 485 490 495 Thr Trp Phe Leu Asp Ser Phe Ser Ile Met Ser Met Ser Ile Phe Leu 500 505 510 Leu Thr Ile Phe Ile Met His Gly Arg Ile Leu His Tyr Ser Asp Pro 515 520 525 Phe Ile Leu Phe Leu Phe Leu Leu Ala Phe Ser Thr Ala Thr Ile Met 530 535 540 Leu Cys Phe Leu Leu Ser Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala 545 550 555 560 Ala Cys Ser Gly Val Ile Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu 565 570 575 Cys Phe Ala Trp Gln Asp Arg Met Thr Ala Glu Leu Lys Lys Ala Val 580 585 590 Ser Leu Leu Ser Pro Val Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val 595 600 605 Arg Phe Glu Glu Gln Gly Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn 610 615 620 Ser Pro Thr Glu Gly Asp Glu Phe Ser Phe Leu Leu Ser Met Gln Met 625 630 635 640 Met Leu Leu Asp Ala Ala Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp 645 650 655 Gln Val Val Arg Gln Ser Leu Gly Met Cys Pro Gln His Asn Ile Leu 660 665 670 Phe His His Leu Thr Val Ala Glu His Met Leu Phe Tyr Ala Gln Leu 675 680 685 Lys Gly Lys Ser Gln Glu Glu Ala Gln Leu Glu Met Glu Ala Met Leu 690 695 700 Glu Asp Thr Gly Leu His His Lys Arg Asn Glu Glu Ala Gln Asp Leu 705 710 715 720 Ser Gly Gly Met Gln Arg Lys Leu Ser Val Ala Ile Ala Phe Val Gly 725 730 735 Asp Ala Lys Val Val Ile Leu Asp Glu Pro Thr Ser Gly Val Asp Pro 740 745 750 Tyr Ser Arg Arg Ser Ile Trp Asp Leu Leu Leu Lys Tyr Arg Ser Gly 755 760 765 Arg Thr Ile Ile Met Ser Thr His His Met Asp Glu Ala Asp Leu Leu 770 775 780 Gly Asp Arg Ile Ala Ile Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly 785 790 795 800 Thr Pro Leu Phe Leu Lys Asn Cys Phe Gly Thr Gly Leu Tyr Leu Thr 805 810 815 Leu Val Arg Lys Met Lys Asn Ile Gln Ser Gln Arg Lys Gly Ser Glu 820 825 830 Gly Thr Cys Ser Cys Ser Ser Lys Gly Phe Ser Thr Thr Cys Pro Ala 835 840 845 His Val Asp Asp Leu Thr Pro Glu Gln Val His Lys Asp Phe Leu Ala 850 855 860 Gln Ile Val Leu Pro Ala Thr Phe Val Phe Leu Ala Leu Met Leu Ser 865 870 875 880 Ile Glu Cys Pro Glu Gly Ala Gly Gly Leu Pro Pro Pro Gln Arg Thr 885 890 895 Gln Arg Ser Thr Glu Ile Leu Gln Asp Leu Thr Asp Arg Asn Ile Ser 900 905 910 Asp Phe Leu Val Lys Thr Tyr Pro Ala Leu Ile Arg Ser Ser Leu Lys 915 920 925 Ser Lys Phe Trp Val Asn Glu Gln Arg Tyr Gly Gly Ile Ser Ile Gly 930 935 940 Gly Lys Leu Pro Val Val Pro Ile Thr Gly Glu Ala Leu Val Gly Phe 945 950 955 960 Leu Ser Asp Leu Gly Arg Ile Met Asn Val Ser Gly Gly Pro Ile Thr 965 970 975 Arg Glu Ala Ser Lys Glu Ile Pro Asp Phe Leu Lys His Leu Glu Thr 980 985 990 Glu Asp Asn Ile Lys Val Trp Phe Asn Asn Lys Gly Trp His Ala Leu 995 1000 1005 Val Ser Phe Leu Asn Val Ala His Asn Ala Ile Leu Arg Ala Ser 1010 1015 1020 Leu Pro Lys Asp Arg Ser Pro Glu Asn Phe Leu Trp Asp Ile Met 1025 1030 1035 Asn Tyr Ser Val Ser Ala Gly Leu Val Val Gly Ile Phe Ile Gly 1040 1045 1050 Phe Gln Lys Lys Ala Tyr Thr Ser Pro Glu Asn Leu Pro Ala Leu 1055 1060 1065 Val Ala Leu Leu Leu Leu Tyr Gly Trp Ala Val Ile Pro Met Met 1070 1075 1080 Tyr Pro Ala Ser Phe Leu Phe Asp Val Pro Ser Thr Ala Tyr Val 1085 1090 1095 Ala Leu Ser Cys Ala Asn Leu Phe Ile Gly Ile Asn Ser Ser Ala 1100 1105 1110 Ile Thr Phe Ile Leu Glu Leu Phe Glu Asn Asn Arg Thr Leu Leu 1115 1120 1125 Arg Phe Asn Ala Val Leu Arg Lys Leu Leu Ile Val Phe Pro His 1130 1135 1140 Phe Cys Leu Gly Arg Gly Leu Ile Asp Leu Ala Leu Ser Gln Ala 1145 1150 1155 Val Thr Asp Val Tyr Ala Arg Phe Gly Glu Glu His Ser Ala Asn 1160 1165 1170 Pro Phe His Trp Asp Leu Ile Gly Lys Asn Leu Phe Ala Met Val 1175 1180 1185 Val Glu Gly Val Val Tyr Phe Leu Leu Thr Leu Leu Val Gln Arg 1190 1195 1200 His Phe Phe Leu Ser Gln Trp Ile Ala Glu Pro Thr Lys Glu Pro 1205 1210 1215 Ile Val Asp Glu Asp Asp Asp Val Ala Glu Glu Arg Gln Arg Ile 1220 1225 1230 Ile Thr Gly Gly Asn Lys Thr Asp Ile Leu Lys Ser Ile Leu Thr 1235 1240 1245 Asn Ile Ser Glu Val His Gln Asn Met Gly Tyr Cys Pro Gln Phe 1250 1255 1260 Asp Ala Ile Asp Glu Leu Leu Thr Gly Arg Glu His Leu Tyr Leu 1265 1270 1275 Tyr Ala Arg Leu Arg Gly Val Pro Ala Glu Glu Ile Glu Lys Val 1280 1285 1290 Ala Asn Trp Ser Ile Lys Ser Leu Gly Leu Thr Val Tyr Ala Asp 1295 1300 1305 Cys Leu Ala Gly Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser 1310 1315 1320 Thr Ala Ile Ala Leu Ile Gly Cys Pro Pro Leu Val Leu Leu Asp 1325 1330 1335 Glu Pro Thr Thr Gly Met Asp Pro Gln Ala Arg Arg Met Leu Trp 1340 1345 1350 Asn Val Ile Val Ser Ile Ile Arg Glu Gly Arg Ala Val Val Leu 1355 1360 1365 Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu 1370 1375 1380 Ala Ile Met Val Lys Gly Ala Phe Arg Cys Met Gly Thr Ile Gln 1385 1390 1395 His Leu Lys Ser Lys Phe Gly Asp Gly Tyr Ile Val Thr Met Lys 1400 1405 1410 Leu Leu Leu Ser His Lys Asp Ser Leu Leu Ile Glu Glu Tyr Ser 1415 1420 1425 Val Thr Gln Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys 1430 1435 1440 Gln Gln Thr Glu Ser His Asp Leu Pro Leu His Pro Arg Ala Ala 1445 1450 1455 Gly Ala Ser Arg Gln Ala Gln Asp 1460 1465 <210> 15 <211> 3483 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 15 atgggcttcg tgagacagat acagcttttg ctctggaga actggaccct gcggaaaagg caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc actctacagc catcatgaat gccatttccc caacaaggcg atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc atcttggcaa gggtatatcg agttttcaa gaactcctca tgaatgcacc agagagccag caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggagaga atacgaata gggatatctt gaagatga gaaacactga cactatttct cattaaaaac atcggcctgt ctgactcagt ggtctacctt ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 aaggacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagacactc tgtatgccaa cgtggacttc ttcaagctct tccgtgtgct tcccacactc 780 ctagacagcc gttctcaagg tatcaatctg agatcttggg gaggaatatt atctgatatg 840 tcaccaagaa ttcaagagtt tatccatcgg ccgagtatgc aggacttgct gtgggtgacc 900 aggcccctca tgcagaatgg tggtccagag acctttacaa agctgatggg catcctgtct 960 gacctcctgt gtggctaccc cgagggaggt ggctctcggg tgctctcctt caactggtat 1020 gaacaata actataaggc ctttctgggg attgactcca caaggaagga tcctatctat 1080 tcttatgaca gaagaacaac atccttttgt aatgcattga tccagagcct ggagtcaaat 1140 cctttaacca aaatcgcttg gagggcggca aagcctttgc tgatgggaaa aatcctgtac 1200 1260 ctggaacacg ttaggaagtt ggtcaaagcc tgggaagaag tagggcccca gatctggtac 1320 ttctttgaca acagcacaca gatgaacatg atcagagata ccctggggaa cccaacagta 1380 aaagactttt tgaataggca gcttggtgaa gaaggtatta ctgctgaagc catcctaaac 1440 ttcctctaca agggccctcg ggaaagccag gctgacgaca tggccaactt cgactggagg 1500 gacatattta acatcactga tcgcaccctc cgcctggtca atcaatacct ggagtgcttg 1560 gtcctggata agtttgaaag ctacaatgat gaaactcagc tcacccaacg tgccctctct 1620 ctactggagg aaaacatgtt ctgggccgga gtggtattcc ctgacatgta tccctggacc 1680 agctctctac caccccacgt gaagtataag atccgaatgg acatagacgt ggtggagaaa 1740 accaataaga ttaaagacag gtattgggat tctggtccca gagctgatcc cgtggaagat 1800 ttccggtaca tctggggcgg gtttgcctat ctgcaggaca tggttgaaca ggggatcaca 1860 aggagccagg tgcaggcgga ggctccagtt ggaatctacc tccagcagat gccctacccc 1920 tgcttcgtgg acgattcttt catgatcatc ctgaaccgct gtttccctat cttcatggtg 1980 ctggcatgga tctactctgt ctccatgact gtgaagagca tcgtcttgga gaaggagttg 2040 cgactgaagg agaccttgaa aaatcagggt gtctccaatg cagtgatttg gtgtacctgg 2100 ttcctggaca gcttctccat catgtcgatg agcatcttcc tcctgacgat attcatcatg 2160 catggaagaa tcctacatta cagcgaccca ttcatcctct tcctgttctt gttggctttc 2220 tccactgcca ccatcatgct gtgctttctg ctcagcacct tcttctccaa ggccagtctg 2280 gcagcagcct gtagtggtgt catctatttc accctctacc tgccacacat cctgtgcttc 2340 gcctggcagg accgcatgac cgctgagctg aagaaggctg tgagcttact gtctccggtg 2400 gcatttggat ttggcactga gtacctggtt cgctttgaag agcaaggcct ggggctgcag 2460 tggagcaaca tcgggaacag tcccacggaa ggggacgaat tcagcttcct gctgtccatg 2520 cagatgatgc tccttgatgc tgctgtctat ggcttactcg cttggtacct tgatcaggtg 2580 tttccaggag actatggaac cccacttcct tggtactttc ttctacaaga gtcgtattgg 2640 cttggcggtg aagggtgttc aaccagagaa gaaagagccc tggaaaagac cgagccccta 2700 acagaggaaa cggaggatcc agagcaccca gaaggaatac acgactcctt ctttgaacgt 2760 gagcatccag ggtgggttcc tggggtatgc gtgaagaatc tggtaaagat ttttgagccc 2820 tgtggccggc cagctgtgga ccgtctgaac atcaccttct acgagaacca gatcaccgca 2880 ttcctgggcc acaatggagc tgggaaaacc accaccttgt ccatcctgac gggtctgttg 2940 ccaccaacct ctgggactgt gctcgttggg ggaagggaca ttgaaaccag cctggatgca 3000 gtccggcaga gccttggcat gtgtccacag cacaacatcc tgttccacca cctcacggtg 3060 gctgagcaca tgctgttcta tgcccagctg aaaggaaagt cccaggagga ggcccagctg 3120 gagatggaag ccatgttgga ggacacaggc ctccaccaca agcggaatga agaggctcag 3180 gacctatcag gtggcatgca gagaaagctg tcggttgcca ttgcctttgt gggagatgcc 3240 aaggtggtga ttctggacga acccacctct ggggtggacc cttactcgag acgctcaatc 3300 tgggatctgc tcctgaagta tcgctcaggc agaaccatca tcatgtccac tcaccacatg 3360 gacgaggccg acctccttgg ggaccgcatt gccatcattg cccagggaag gctctactgc 3420 tcaggcaccc cactcttcct gaagaactgc tttggcacag gcttgtactt aaccttggtg 3480 tga 3483 <210> 16 <211> 2754 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 16 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 atcgtgctcc cggctacctt tgtgtttttg gctctgatgc tttctattgt tatccctcct 120 tttggcgaat accccgcttt gacccttcac ccctggatat atgggcagca gtacaccttc 180 ttcagcatgg atgaaccagg cagtgagcag ttcacggtac ttgcagacgt cctcctgaat 240 aagccaggct ttggcaaccg ctgcctgaag gaagggtggc ttccggagta cccctgtggc 300 aactcaacac cctggaagac tccttctgtg tccccaaaca tcacccagct gttccagaag 360 cagaaatgga cacaggtcaa cccttcacca tcctgcaggt gcagcaccag ggagaagctc 420 accatgctgc cagagtgccc cgagggtgcc gggggcctcc cgccccccca gagaacacag 480 cgcagcacgg aaattctaca agacctgacg gacaggaaca tctccgactt cttggtaaaa 540 acgtatcctg ctcttataag aagcagctta aagagcaaat tctgggtcaa tgaacagagg 600 tatggaggaa tttccattgg aggaaagctc ccagtcgtcc ccatcacggg ggaagcactt 660 gttgggtttt taagcgacct tggccggatc atgaatgtga gcgggggccc tatcactaga 720 gaggcctcta aagaaatacc tgatttcctt aaacatctag aaactgaaga caacattaag 780 gtgtggttta ataacaaagg ctggcatgcc ctggtcagct ttctcaatgt ggcccacaac 840 gccatcttac gggccagcct gcctaaggac aggagccccg aggagtatgg aatcaccgtc 900 attagccaac ccctgaacct gaccaaggag cagctctcag agattacagt gctgaccact 960 tcagtggatg ctgtggttgc catctgcgtg attttctcca tgtccttcgt cccagccagc 1020 tttgtccttt atttgatcca ggagcgggtg aacaaatcca agcacctcca gtttatcagt 1080 ggagtgagcc ccaccaccta ctgggtgacc aacttcctct gggacatcat gaattattcc 1140 gtgagtgctg ggctggtggt gggcatcttc atcgggtttc agaagaaagc ctacacttct 1200 ccagaaaacc ttcctgccct tgtggcactg ctcctgctgt atggatgggc ggtcattccc 1260 atgatgtacc cagcatcctt cctgtttgat gtccccagca cagcctatgt ggctttatct 1320 tgtgctaatc tgttcatcgg catcaacagc agtgctatta ccttcatctt ggaattattt 1380 gagaataacc ggacgctgct caggttcaac gccgtgctga ggaagctgct cattgtcttc 1440 ccccacttct gcctgggccg gggcctcatt gaccttgcac tgagccaggc tgtgacagat 1500 gtctatgccc ggtttggtga ggagcactct gcaaatccgt tccactggga cctgattggg 1560 aagaacctgt ttgccatggt ggtggaaggg gtggtgtact tcctcctgac cctgctggtc 1620 cagcgccact tcttcctctc ccaatggatt gccgagccca ctaaggagcc cattgttgat 1680 gaagatgatg atgtggctga agaaagacaa agaattatta ctggtggaaa taaaactgac 1740 atcttaaggc tacatgaact aaccaagatt tatccaggca cctccagccc agcagtggac 1800 aggctgtgtg tcggagttcg ccctggagag tgctttggcc tcctgggagt gaatggtgcc 1860 ggcaaaacaa ccacattcaa gatgctcact ggggacacca cagtgacctc aggggatgcc 1920 accgtagcag gcaagagtat tttaaccaat atttctgaag tccatcaaaa tatgggctac 1980 tgtcctcagt ttgatgcaat tgatgagctg ctcacaggac gagaacatct ttacctttat 2040 gcccggcttc gaggtgtacc agcagaagaa atcgaaaagg ttgcaaactg gagtattaag 2100 agcctgggcc tgactgcta cgccgactgc ctggctggca cgtacagtgg gggcaacaag 2160 cggaaactct ccacagccat cgcactcatt ggctgcccac cgctggtgct gctggatgag 2220 cccaccacag ggatggaccc ccaggcacgc cgcatgctgt ggaacgtcat cgtgagcatc 2280 atcagagaag ggagggctgt ggtcctcaca tcccacagca tggaagaatg tgaggcactg 2340 tgtacccggc tggccatcat ggtaaagggc gcctttcgat gtatgggcac cattcagcat 2400 ctcaagtcca aatttggaga tggctatatc gtcacaatga agatcaaatc cccgaaggac 2460 gacctgcttc ctgacctgaa ccctgtggag cagttcttcc aggggaactt cccaggcagt 2520 gtgcagaggg agaggcacta caacatgctc cagttccagg tctcctcctc ctccctggcg 2580 aggatcttcc agctcctcct ctcccacaag gacagcctgc tcatcgagga gtactcagtc 2640 acacagacca cactggacca ggtgtttgta aattttgcta aacagcagac tgaaagtcat 2700 gacctccctc tgcaccctcg agctgctgga gccagtcgac aagcccagga ctga 2754 <210> 17 <211> 3459 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 17 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc actctacatg ccctacccct gcttcgtgga cgattctttc 180 atgatcatcc tgaaccgctg tttccctatc ttcatggtgc tggcatggat ctactctgtc 240 tccatgactg tgaagagcat cgtcttggag aaggagttgc gactgaagga gaccttgaaa 300 aatcagggtg tctccaatgc agtgatttgg tgtacctggt tcctggacag cttctccatc 360 atgtcgatga gcatcttcct cctgacgata ttcatcatgc atggaagaat cctacattac 420 agcgacccat tcatcctctt cctgttcttg ttggctttct ccactgccac catcatgctg 480 tgctttctgc tcagcacctt cttctccaag gccagtctgg cagcagcctg tagtggtgtc 540 atctatttca ccctctacct gccacacatc ctgtgcttcg cctggcagga ccgcatgacc 600 gctgagctga agaaggctgt gagcttactg tctccggtgg catttggatt tggcactgag 660 tacctggttc gctttgaaga gcaaggcctg gggctgcagt ggagcaacat cgggaacagt 720 cccagggaag gggacgaatt cagcttcctg ctgtccatgc agatgatgct ccttgatgct 780 gctgtctatg gcttactcgc ttggtacctt gatcaggtgt ttccaggaga ctatggaacc 840 ccacttcctt ggtactttct tctacaagag tcgtattggc ttggcggtga agggtgttca 900 accagagaag aaagagccct ggaaaagacc gagcccctaa cagaggaaac ggaggatcca 960 gagcacccag aaagaataca cgactccttc tttgaacgtg agcatccagg gtgggttcct 1020 ggggtatgcg tgaagaatct ggtaaagatt tttgagccct gtggccggcc agctgtggac 1080 cgtctgaaca tcaccttcta cgagaaccag atcaccgcat tcctgggcca caatggagct 1140 gggaaaacca ccaccttgtc catcctgacg ggtctgttgc caccaacctc tgggactgtg 1200 ctcgttgggg gaagggagat tgaaaccagc ctggatgcag tccggcagag ccttggcatg 1260 tgtccacagc acaacatcct gttccaccac ctcacggtgg ctgagcacat gctgttctat 1320 gcccagctga aaggaagtc ccaggaggag gcccagctgg agatggaagc catgttggag 1380 gacacaggcc tccaccacaa gcggaatgaa gaggctcagg acctatcagg tggcatgcag 1440 agaaagctgt cggttgccat tgcctttgtg ggagatgcca aggtggtgat tctggacgaa 1500 cccacctctg gggtggaccc ttactcgaga cgctcaatct gggatctgct cctgaagtat 1560 cgctcaggca gaaccatcat catgtccact caccacatgg acgaggccga cctccttggg 1620 gaccgcattg ccatcattgc ccagggaagg ctctactgct caggcacccc actcttcctg 1680 aagaactgct ttggcacagg cttggacttc ctggcgcaga tcgtgctccc ggctaccttt 1740 gtgtttttgg ctctgatgct ttctattgtt atccctcctt ttggcgaata ccccgctacc 1800 acctactggg tgaccaactt cctctgggac atcatgaatt attccgtgag tgctgggctg 1860 gtggtgggca tcttcatcgg gtttcagaag aaagcctaca cttctccaga aaaccttcct 1920 gcccttgtgg cactgctcct gctgtatgga tgggcggtca ttcccatgat gtacccagca 1980 tccttcctgt ttgatgtccc cagcacagcc tatgtggctt tatcttgtgc taatctgttc 2040 atcggcatca acagcagtgc tattaccttc atcttggaat tatttgagaa taaccggacg 2100 ctgctcaggt tcaacgccgt gctgaggaag ctgctcattg tcttccccca cttctgcctg 2160 ggccggggcc tcattgacct tgcactgagc caggctgtga cagatgtcta tgcccggttt 2220 ggtgaggagc actctgcaaa tccgttccac tgggacctga ttgggaagaa cctgtttgcc 2280 atggtggtgg aaggggtggt gtacttcctc ctgaccctgc tggtccagcg ccacttcttc 2340 ctctcccaat ggattgccga gcccactaag gagcccattg ttgatgaaga tgatgatgtg 2400 gctgaagaaa gacaaagaat tattactggt ggaaataaaa ctgacatctt aaggctacat 2460 gaactaacca agatttatcc aggcacctcc agcccagcag tggacaggct gtgtgtcgga 2520 gttcgccctg gagagtgctt tggcctcctg ggagtgaatg gtgccggcaa aacaaccaca 2580 ttcaagatgc tcactgggga caccacagtg acctcagggg atgccaccgt agcaggcaag 2640 agtattttaa ccaatatttc tgaagtccat caaaatatgg gctactgtcc tcagtttgat 2700 gcaattgatg agctgctcac aggacgagaa catctttacc tttatgcccg gcttcgaggt 2760 gtaccagcag aagaaatcga aaaggttgca aactggagta ttaagagcct gggcctgact 2820 gtctacgccg actgcctggc tggcacgtac agtgggggca acaagcggaa actctccaca 2880 gccatcgcac tcattggctg cccaccgctg gtgctgctgg atgagcccac cacagggatg 2940 gacccccagg cacgccgcat gctgtggaac gtcatcgtga gcatcatcag agaagggagg 3000 gctgtggtcc tcacatccca cagcatggaa gaatgtgagg cactgtgtac ccggctggcc 3060 atcatggtaa agggcgcctt tcgatgtatg ggcaccattc agcatctcaa gtccaaattt 3120 ggagatggct atatcgtcac aatgaagatc aaatccccga aggacgacct gcttcctgac 3180 ctgaaccctg tggagcagtt cttccagggg aacttcccag gcagtgtgca gagggagagg 3240 cactacaaca tgctccagtt ccaggtctcc tcctcctccc tggcgaggat cttccagctc 3300 ctcctctccc acaaggacag cctgctcatc gaggagtact cagtcacaca gaccacactg 3360 gaccaggtgt ttgtaaattt tgctaaacag cagactgaaa gtcatgacct ccctctgcac 3420 cctcgagctg ctggagccag tcgacaagcc caggactga 3459 <210> 18 <211> 3780 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 18 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaaccc actctacagc catcatgaat gccatttccc caacaaggcg 180 atgccctcag caggaatgct gccgtggctc caggggatct tctgcaatgt gaacaatccc 240 tgttttcaaa gccccacccc aggagaatct cctggaattg tgtcaaacta taacaactcc 300 atcttggcaa gggtatatcg agattttcaa gaactcctca tgaatgcacc agagagccag 360 caccttggcc gtatttggac agagctacac atcttgtccc aattcatgga caccctccgg 420 actcacccgg agagaattgc aggaagagga atacgaataa gggatatctt gaaagatgaa 480 gaaacactga cactatttct cattaaaaac atcggcctgt ctgactcagt ggtctacctt 540 ctgatcaact ctcaagtccg tccagagcag ttcgctcatg gagtcccgga cctggcgctg 600 aaggacatcg cctgcagcga ggccctcctg gagcgcttca tcatcttcag ccagagacgc 660 ggggcaaaga cggtgcgcta tgccctgtgc tccctctccc agggcaccct acagtggata 720 gaagacactc tgtatgccaa cgtggacttc ttcaagctct tccgtgtgct tcccacactc 780 ctagacagcc gttctcaagg tatcaatctg agatcttggg gaggaatatt atctgatatg 840 tcaccaagaa ttcaagagtt tatccatcgg ccgagtatgc aggacttgct gtgggtgacc 900 aggcccctca tgcagaatgg tggtccagag acctttacaa agctgatggg catcctgtct 960 gacctcctgt gtggctaccc cgagggaggt ggctctcggg tgctctcctt caactggtat 1020 gaacaata actataaggc ctttctgggg attgactcca caaggaagga tcctatctat 1080 tcttatgaca gaagaacaac atccttttgt aatgcattga tccagagcct ggagtcaaat 1140 cctttaacca aaatcgcttg gagggcggca aagcctttgc tgatgggaaa aatcctgtac 1200 1260 ctggaacacg ttaggaagtt ggtcaaagcc tgggaagaag tagggcccca gatctggtac 1320 ttctttgaca acagcacaca gatgaacatg atcagagata ccctggggaa cccaacagta 1380 aaagactttt tgaataggca gcttggtgaa gaaggtatta ctgctgaagc catcctaaac 1440 ttcctctaca agggccctcg ggaaagccag gctgacgaca tggccaactt cgactggagg 1500 gacatattta acatcactga tcgcaccctc cgcctggtca atcaatacct ggagtgcttg 1560 gtcctggata agtttgaaag ctacaatgat gaaactcagc tcacccaacg tgccctctct 1620 ctactggagg aaaacatgtt ctgggccgga gtggtattcc ctgacatgta tccctggacc 1680 agctctctac caccccacgt gaagtataag atccgaatgg acatagacgt ggtggagaaa 1740 accaataaga ttaaagacag gtattgggat tctggtccca gagctgatcc cgtggaagat 1800 ttccggtaca tctggggcgg gtttgcctat ctgcaggaca tggttgaaca ggggatcaca 1860 aggagccagg tgcaggcgga ggctccagtt ggaatctacc tccagcagat gccctacccc 1920 tgcttcgtgg acgattcttt catgatcatc ctgaaccgct gtttccctat cttcatggtg 1980 ctggcatgga tctactctgt ctccatgact gtgaagagca tcgtcttgga gaaggagttg 2040 cgactgaagg agaccttgaa aaatcagggt gtctccaatg cagtgatttg gtgtacctgg 2100 ttcctggaca gcttctccat catgtcgatg agcatcttcc tcctgacgat attcatcatg 2160 catggaagaa tcctacatta cagcgaccca ttcatcctct tcctgttctt gttggctttc 2220 tccactgcca ccatcatgct gtgctttctg ctcagcacct tcttctccaa ggccagtctg 2280 gcagcagcct gtagtggtgt catctatttc accctctacc tgccacacat cctgtgcttc 2340 gcctggcagg accgcatgac cgctgagctg aagaaggctg tgagcttact gtctccggtg 2400 gcatttggat ttggcactga gtacctggtt cgctttgaag agcaaggcct ggggctgcag 2460 tggagcaaca tcgggaacag tcccacggaa ggggacgaat tcagcttcct gctgtccatg 2520 cagatgatgc tccttgatgc tgctgtctat ggcttactcg cttggtacct tgatcaggtg 2580 gttcctgggg tatgcgtgaa gaatctggta aagatttttg agccctgtgg ccggccagct 2640 gtggaccgtc tgaacatcac cttctacgag aaccagatca ccgcattcct gggccacaat 2700 ggagctggga aaaccaccac cttgtccatc ctgacgggtc tgttgccacc aacctctggg 2760 actgtgctcg ttgggggaag ggacattgaa accagcctgg atgcagtccg gcagagcctt 2820 ggcatgtgtc cacagcacaa catcctgttc cacacctca cggtggctga gcacatgctg ttctatgccc agctgaaagg aaagtcccag gaggaggccc agctggagat ggaagccatg ttggaggaca caggcctcca ccacaagcgg aatgaagagg ctcaggacct atcaggtggc atgcagagaa agctgtcggt tgccattgcc tttgtgggag atgccaaggt ggtgattctg 3060 3120. cctctggggt ggacccttac tcgagacgct caatctggga tctgctcctg aagtatcgct caggcagaac catcatcatg tccactcacc acatggacga ggccgacctc cttggggacc gcattgccat cattgcccag ggaaggctct actgctcagg caccccactc ttcctgaaga actgctttgt gaccaacttc ctctgggaca tcatgaatta ttccgtgagt gctgggctgg tggtgggcat cttcatcggg tttcagaaga aagcctacac ttctccagaa 3360. aaccttcctg cccttgtggc actgctcctg ctgtatggat gggcggtcat tcccatgatg 3420 tacccagcat ccttcctgtt tgatgtcccc agcacagcct atgtggcttt atcttgtgct 3480 aatctgttca tcggcatca cagcagtgct attack tcttggaatt atttgagaat aaccggacgc tgctcaggtt caacgccgtg ctgaggaagc tgctcattgt cttcccccac 3600 ttctgcctgg gccggggcct cattgacctt gcactgagcc aggctgtgac agatgtctat 3660 gcccggtttg gtgaggagca ctctgcaaat ccgttccact gggacctgat tgggaagaac 3720 ctgtttgcca tggtggtgga aggggtggtg tacttcctcc tgaccctgct ggtccagtga 3780 <210> 19 <211> 3498 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 19 atgggcttcg tgagacagat acagcttttg ctctggaaga actggaccct gcggaaaagg 60 caaaagattc gctttgtggt ggaactcgtg tggcctttat ctttatttct ggtcttgatc 120 tggttaagga atgccaacgt ggacgattct ttcatgatca tcctgaaccg ctgtttccct 180 atcttcatgg tgctggcatg gatctactct gtctccatga ctgtgaagag catcgtcttg 240 gagaaggagt tgcgactgaa ggagaccttg aaaaatcagg gtgtctccaa tgcagtgatt 300 tggtgtacct ggttcctgga cagcttctcc atcatgtcga tgagcatctt cctcctgacg 360 atattcatca tgcatggaag aatcctacat tacagcgacc cattcatcct cttcctgttc 420 ttgttggctt tctccactgc caccatcatg ctgtgctttc tgctcagcac cttcttctcc 480 aaggccagtc tggcagcagc ctgtagtggt gtcatctatt tcaccctcta cctgccacac 540 atcctgtgct tcgcctggca ggaccgcatg accgctgagc tgaagaaggc tgtgagctta 600 ctgtctccgg tggcatttgg atttggcact gagtacctgg ttcgctttga agagcaaggc 660 ctggggctgc agtggagcaa catcgggaac agtcccacgg aaggggacga attcagcttc 720 ctgctgtcca tgcagatgat gctccttgat gctgctgtct atggcttact cgcttggtac 780 cttgatcagg tgttcctggc gcagatcgtg ctcccggcta cctttgtgtt tttggctctg 840 atgctttcta ttgttatccc tccttttggc gaataccccg ctttgaccct tcacccctgg 900 atatatgggc agcagtacac cttcttcagc atggatgaac caggcagtga gcagttcacg 960 gtacttgcag acgtcctcct gaataagcca ggctttggca accgctgcct gaaggaaggg 1020 tggcttccgg agtacccctg tggcaactca acaccctgga agactccttc tgtgtcccca 1080 aacatcaccc agctgttcca gaagcagaaa tggacacagg tcaacccttc accatcctgc 1140 aggtgcagca ccagggagaa gctcaccatg ctgccagagt gccccgaggg tgccgggggc 1200 ctcccgcccc cccagagaac acagcgcagc acggaaattc tacaagacct gacggacagg 1260 aacatctccg acttcttggt aaaaacgtat cctgctctta taagaagcag cttaaagagc 1320 1380 gtccccatca cgggggaagc acttgttggg tttttaagcg accttggccg gatcatgaat 1440 gtgagcgggg gccctatcac tagagaggcc tctaaagaaa tacctgattt ccttaaacat 1500 ctagaaactg aagacaacat taaggtgtgg tttaataaca aaggctggca tgccctggtc 1560 agctttctca atgtggccca caacgccatc ttacgggcca gcctgcctaa gcacaggagc 1620 cccgaggat atggaatcac cgtcattagc caacccctga acctgaccaa ggagcagctc 1680 tcagagatta cagtgctgac cacttcagtg gatgctgtgg ttgccatctg cgtgattttc 1740 tccatgtcct tcgtcccagc cagctttgtc ctttatttga tccaggagcg ggtgaacaaa 1800 tccaagcacc tccagtttat cagtggagtg agccccacca cctactgggt gaccaacttc ctctgggaca tcatgaatta ttccgtgagt gctgggctgg tggtgggcat cttcatcggg tttcagaaga aagcctacac ttctccagaa aaccttcctg cccttgtggc actgctcctg ctgtatggat gggcggtcat tcccatgatg tacccagcat ccttcctgtt tgatgtcccc agcacagcct atgtggcttt atcttgtgct aatctgttca tcggcatcaa cagcagtgct attack tcttggaatt attack aaccggacgc tgctcaggtt caacgccgtg ctgaggaagc tgctcattgt cttcccccac ttctgcctgg gccggggcct cattgacctt 2220 gcactgagcc aggctgtgac agatgtctat gcccggtttg gtgaggagca ctctgcaaat ccgttccact gggacctgat tgggaagac ctgtttgcca tggtggtgga aggggtggtg 2340. tacttcctcc tgaccctgct ggtccagcgc cacttctcc tctcccaatg gattgccgag 2400 cccactaagg agcccattgt tgatgaagat gatgatgtgg ctgaagaaag acaaagaatt attactggtg gaataaac tgacatctta aggctacatg aactacca gatttatcca ggcacctcca gcccagcagt ggacaggctg tgtgtcggag ttcgccctgg agagtgcttt 2580 ggcctcctgg gagtgaatgg tgccggcaaa acaaccacat tcaagatgct cactggggac 2640 accacagtga cctcagggga tgccaccgta gcaggcaaga gtattttaac caatatttct 2700 gaagtccatc aaaatatggg ctactgtcct cagtttgatg caattgatga gctgctcaca 2760 ggacgagaac atctttacct ttatgcccgg cttcgaggtg taccagcaga agaaatcgaa 2820 aaggttgcaa actggagtat taagagcctg ggcctgactg tctacgccga ctgcctggct 2880 ggcacgtaca gtgggggcaa caagcggaaa ctctccacag ccatcgcact cattggctgc 2940 ccaccgctgg tgctgctgga tgagcccacc acagggatgg acccccaggc acgccgcatg 3000 ctgtggaacg tcatcgtgag catcatcaga gaagggaggg ctgtggtcct cacatcccac 3060 agcatggaag aatgtgaggc actgtgtacc cggctggcca tcatggtaaa gggcgccttt 3120 cgatgtatgg gcaccattca gcatctcaag tccaaatttg gagatggcta tatcgtcaca 3180 atgaagatca aatccccgaa ggacgacctg cttcctgacc tgaaccctgt ggagcagttc 3240 ttccagggga acttcccagg cagtgtgcag agggagaggc actacaacat gctccagttc 3300 caggtctcct cctcctccct ggcgaggatc ttccagctcc tcctctccca caaggacagc 3360 ctgctcatcg aggagtactc agtcacacag accacactgg accaggtgtt tgtaaatttt 3420 gctaaacagc agactgaaag tcatgacctc cctctgcacc ctcgagctgc tggagccagt 3480 cgacaagccc aggactga 3498 <210> 20 <211> 1160 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 20 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe Phe Lys Leu Phe Arg Val 245 250 255 Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser 260 265 270 Trp Gly Gly Ile Leu Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile 275 280 285 His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr Arg Pro Leu Met 290 295 300 Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser 305 310 315 320 Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly Gly Ser Arg Val Leu Ser 325 330 335 Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe Leu Gly Ile Asp 340 345 350 Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser 355 360 365 Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu Ser Asn Pro Leu Thr Lys 370 375 380 Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr 385 390 395 400 Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser 405 410 415 Thr Phe Glu Glu Leu Glu His Val Arg Lys Leu Val Lys Ala Trp Glu 420 425 430 Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met 435 440 445 Asn Met Ile Arg Asp Thr Leu Gly Asn Pro Thr Val Lys Asp Phe Leu 450 455 460 Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu Asn 465 470 475 480 Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn 485 490 495 Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr Asp Arg Thr Leu Arg Leu 500 505 510 Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu Ser Tyr 515 520 525 Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu 530 535 540 Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met Tyr Pro Trp Thr 545 550 555 560 Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp 565 570 575 Val Val Glu Lys Thr Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly 580 585 590 Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile Trp Gly Gly Phe 595 600 605 Ala Tyr Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val 610 615 620 Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln Gln Met Pro Tyr Pro 625 630 635 640 Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 645 650 655 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 660 665 670 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 675 680 685 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 690 695 700 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 705 710 715 720 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 725 730 735 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 740 745 750 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 755 760 765 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 770 775 780 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 785 790 795 800 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 805 810 815 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 820 825 830 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 835 840 845 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Phe Pro Gly Asp 850 855 860 Tyr Gly Thr Pro Leu Pro Trp Tyr Phe Leu Leu Gln Glu Ser Tyr Trp 865 870 875 880 Leu Gly Gly Glu Gly Cys Ser Thr Arg Glu Glu Arg Ala Leu Glu Lys 885 890 895 Thr Glu Pro Leu Thr Glu Glu Thr Glu Asp Pro Glu His Pro Glu Gly 900 905 910 Ile His Asp Ser Phe Phe Glu Arg Glu His Pro Gly Trp Val Pro Gly 915 920 925 Val Cys Val Lys Asn Leu Val Lys Ile Phe Glu Pro Cys Gly Arg Pro 930 935 940 Ala Val Asp Arg Leu Asn Ile Thr Phe Tyr Glu Asn Gln Ile Thr Ala 945 950 955 960 Phe Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Ile Leu 965 970 975 Thr Gly Leu Leu Pro Pro Thr Ser Gly Thr Val Leu Val Gly Gly Arg 980 985 990 Asp Ile Glu Thr Ser Leu Asp Ala Val Arg Gln Ser Leu Gly Met Cys 995 1000 1005 Pro Gln His Asn Ile Leu Phe His His Leu Thr Val Ala Glu His 1010 1015 1020 Met Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln Glu Glu Ala 1025 1030 1035 Gln Leu Glu Met Glu Ala Met Leu Glu Asp Thr Gly Leu His His 1040 1045 1050 Lys Arg Asn Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln Arg 1055 1060 1065 Lys Leu Ser Val Ala Ile Ala Phe Val Gly Asp Ala Lys Val Val 1070 1075 1080 Ile Leu Asp Glu Pro Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg 1085 1090 1095 Ser Ile Trp Asp Leu Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile 1100 1105 1110 Ile Met Ser Thr His His Met Asp Glu Ala Asp Leu Leu Gly Asp 1115 1120 1125 Arg Ile Ala Ile Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr 1130 1135 1140 Pro Leu Phe Leu Lys Asn Cys Phe Gly Thr Gly Leu Tyr Leu Thr 1145 1150 1155 Leu Val 1160 <210> 21 <211> 917 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 21 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Ile Val Leu Pro Ala Thr Phe Val Phe Leu Ala Leu 20 25 30 Met Leu Ser Ile Val Ile Pro Pro Phe Gly Glu Tyr Pro Ala Leu Thr 35 40 45 Leu His Pro Trp Ile Tyr Gly Gln Gln Tyr Thr Phe Phe Ser Met Asp 50 55 60 Glu Pro Gly Ser Glu Gln Phe Thr Val Leu Ala Asp Val Leu Leu Asn 65 70 75 80 Lys Pro Gly Phe Gly Asn Arg Cys Leu Lys Glu Gly Trp Leu Pro Glu 85 90 95 Tyr Pro Cys Gly Asn Ser Thr Pro Trp Lys Thr Pro Ser Val Ser Pro 100 105 110 Asn Ile Thr Gln Leu Phe Gln Lys Gln Lys Trp Thr Gln Val Asn Pro 115 120 125 Ser Pro Ser Cys Arg Cys Ser Thr Arg Glu Lys Leu Thr Met Leu Pro 130 135 140 Glu Cys Pro Glu Gly Ala Gly Gly Leu Pro Pro Pro Gln Arg Thr Gln 145 150 155 160 Arg Ser Thr Glu Ile Leu Gln Asp Leu Thr Asp Arg Asn Ile Ser Asp 165 170 175 Phe Leu Val Lys Thr Tyr Pro Ala Leu Ile Arg Ser Ser Leu Lys Ser 180 185 190 Lys Phe Trp Val Asn Glu Gln Arg Tyr Gly Gly Ile Ser Ile Gly Gly 195 200 205 Lys Leu Pro Val Val Pro Ile Thr Gly Glu Ala Leu Val Gly Phe Leu 210 215 220 Ser Asp Leu Gly Arg Ile Met Asn Val Ser Gly Gly Pro Ile Thr Arg 225 230 235 240 Glu Ala Ser Lys Glu Ile Pro Asp Phe Leu Lys His Leu Glu Thr Glu 245 250 255 Asp Asn Ile Lys Val Trp Phe Asn Asn Lys Gly Trp His Ala Leu Val 260 265 270 Ser Phe Leu Asn Val Ala His Asn Ala Ile Leu Arg Ala Ser Leu Pro 275 280 285 Lys Asp Arg Ser Pro Glu Glu Tyr Gly Ile Thr Val Ile Ser Gln Pro 290 295 300 Leu Asn Leu Thr Lys Glu Gln Leu Ser Glu Ile Thr Val Leu Thr Thr 305 310 315 320 Ser Val Asp Ala Val Val Ala Ile Cys Val Ile Phe Ser Met Ser Phe 325 330 335 Val Pro Ala Ser Phe Val Leu Tyr Leu Ile Gln Glu Arg Val Asn Lys 340 345 350 Ser Lys His Leu Gln Phe Ile Ser Gly Val Ser Pro Thr Thr Tyr Trp 355 360 365 Val Thr Asn Phe Leu Trp Asp Ile Met Asn Tyr Ser Val Ser Ala Gly 370 375 380 Leu Val Val Gly Ile Phe Ile Gly Phe Gln Lys Lys Ala Tyr Thr Ser 385 390 395 400 Pro Glu Asn Leu Pro Ala Leu Val Ala Leu Leu Leu Leu Tyr Gly Trp 405 410 415 Ala Val Ile Pro Met Met Tyr Pro Ala Ser Phe Leu Phe Asp Val Pro 420 425 430 Ser Thr Ala Tyr Val Ala Leu Ser Cys Ala Asn Leu Phe Ile Gly Ile 435 440 445 Asn Ser Ser Ala Ile Thr Phe Ile Leu Glu Leu Phe Glu Asn Asn Arg 450 455 460 Thr Leu Leu Arg Phe Asn Ala Val Leu Arg Lys Leu Leu Ile Val Phe 465 470 475 480 Pro His Phe Cys Leu Gly Arg Gly Leu Ile Asp Leu Ala Leu Ser Gln 485 490 495 Ala Val Thr Asp Val Tyr Ala Arg Phe Gly Glu Glu His Ser Ala Asn 500 505 510 Pro Phe His Trp Asp Leu Ile Gly Lys Asn Leu Phe Ala Met Val Val 515 520 525 Glu Gly Val Val Tyr Phe Leu Leu Thr Leu Leu Val Gln Arg His Phe 530 535 540 Phe Leu Ser Gln Trp Ile Ala Glu Pro Thr Lys Glu Pro Ile Val Asp 545 550 555 560 Glu Asp Asp Asp Val Ala Glu Glu Arg Gln Arg Ile Ile Thr Gly Gly 565 570 575 Asn Lys Thr Asp Ile Leu Arg Leu His Glu Leu Thr Lys Ile Tyr Pro 580 585 590 Gly Thr Ser Ser Pro Ala Val Asp Arg Leu Cys Val Gly Val Arg Pro 595 600 605 Gly Glu Cys Phe Gly Leu Leu Gly Val Asn Gly Ala Gly Lys Thr Thr 610 615 620 Thr Phe Lys Met Leu Thr Gly Asp Thr Thr Val Thr Ser Gly Asp Ala 625 630 635 640 Thr Val Ala Gly Lys Ser Ile Leu Thr Asn Ile Ser Glu Val His Gln 645 650 655 Asn Met Gly Tyr Cys Pro Gln Phe Asp Ala Ile Asp Glu Leu Leu Thr 660 665 670 Gly Arg Glu His Leu Tyr Leu Tyr Ala Arg Leu Arg Gly Val Pro Ala 675 680 685 Glu Glu Ile Glu Lys Val Ala Asn Trp Ser Ile Lys Ser Leu Gly Leu 690 695 700 Thr Val Tyr Ala Asp Cys Leu Ala Gly Thr Tyr Ser Gly Gly Asn Lys 705 710 715 720 Arg Lys Leu Ser Thr Ala Ile Ala Leu Ile Gly Cys Pro Pro Leu Val 725 730 735 Leu Leu Asp Glu Pro Thr Thr Gly Met Asp Pro Gln Ala Arg Arg Met 740 745 750 Leu Trp Asn Val Ile Val Ser Ile Ile Arg Glu Gly Arg Ala Val Val 755 760 765 Leu Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu 770 775 780 Ala Ile Met Val Lys Gly Ala Phe Arg Cys Met Gly Thr Ile Gln His 785 790 795 800 Leu Lys Ser Lys Phe Gly Asp Gly Tyr Ile Val Thr Met Lys Ile Lys 805 810 815 Ser Pro Lys Asp Asp Leu Leu Pro Asp Leu Asn Pro Val Glu Gln Phe 820 825 830 Phe Gln Gly Asn Phe Pro Gly Ser Val Gln Arg Glu Arg His Tyr Asn 835 840 845 Met Leu Gln Phe Gln Val Ser Ser Ser Ser Leu Ala Arg Ile Phe Gln 850 855 860 Leu Leu Leu Ser His Lys Asp Ser Leu Leu Ile Glu Glu Tyr Ser Val 865 870 875 880 Thr Gln Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys Gln Gln 885 890 895 Thr Glu Ser His Asp Leu Pro Leu His Pro Arg Ala Ala Gly Ala Ser 900 905 910 Arg Gln Ala Gln Asp 915 <210> 22 <211> 1152 <212> PRT <213> Artificial Sequence <220> <223> Synthesized multiple peptides <400> 22 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Met Pro Tyr Pro Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu 50 55 60 Asn Arg Cys Phe Pro Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val 65 70 75 80 Ser Met Thr Val Lys Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys 85 90 95 Glu Thr Leu Lys Asn Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr 100 105 110 Trp Phe Leu Asp Ser Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu 115 120 125 Thr Ile Phe Ile Met His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe 130 135 140 Ile Leu Phe Leu Phe Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu 145 150 155 160 Cys Phe Leu Leu Ser Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala 165 170 175 Cys Ser Gly Val Ile Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys 180 185 190 Phe Ala Trp Gln Asp Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser 195 200 205 Leu Leu Ser Pro Val Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg 210 215 220 Phe Glu Glu Gln Gly Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser 225 230 235 240 Pro Thr Glu Gly Asp Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met 245 250 255 Leu Leu Asp Ala Ala Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln 260 265 270 Val Phe Pro Gly Asp Tyr Gly Thr Pro Leu Pro Trp Tyr Phe Leu Leu 275 280 285 Gln Glu Ser Tyr Trp Leu Gly Gly Glu Gly Cys Ser Thr Arg Glu Glu 290 295 300 Arg Ala Leu Glu Lys Thr Glu Pro Leu Thr Glu Glu Thr Glu Asp Pro 305 310 315 320 Glu His Pro Glu Gly Ile His Asp Ser Phe Phe Glu Arg Glu His Pro 325 330 335 Gly Trp Val Pro Gly Val Cys Val Lys Asn Leu Val Lys Ile Phe Glu 340 345 350 Pro Cys Gly Arg Pro Ala Val Asp Arg Leu Asn Ile Thr Phe Tyr Glu 355 360 365 Asn Gln Ile Thr Ala Phe Leu Gly His Asn Gly Ala Gly Lys Thr Thr 370 375 380 Thr Leu Ser Ile Leu Thr Gly Leu Leu Pro Pro Thr Ser Gly Thr Val 385 390 395 400 Leu Val Gly Gly Arg Asp Ile Glu Thr Ser Leu Asp Ala Val Arg Gln 405 410 415 Ser Leu Gly Met Cys Pro Gln His Asn Ile Leu Phe His His Leu Thr 420 425 430 Val Ala Glu His Met Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln 435 440 445 Glu Glu Ala Gln Leu Glu Met Glu Ala Met Leu Glu Asp Thr Gly Leu 450 455 460 His His Lys Arg Asn Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln 465 470 475 480 Arg Lys Leu Ser Val Ala Ile Ala Phe Val Gly Asp Ala Lys Val Val 485 490 495 Ile Leu Asp Glu Pro Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg Ser 500 505 510 Ile Trp Asp Leu Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile Ile Met 515 520 525 Ser Thr His His Met Asp Glu Ala Asp Leu Leu Gly Asp Arg Ile Ala 530 535 540 Ile Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr Pro Leu Phe Leu 545 550 555 560 Lys Asn Cys Phe Gly Thr Gly Leu Asp Phe Leu Ala Gln Ile Val Leu 565 570 575 Pro Ala Thr Phe Val Phe Leu Ala Leu Met Leu Ser Ile Val Ile Pro 580 585 590 Pro Phe Gly Glu Tyr Pro Ala Thr Thr Tyr Trp Val Thr Asn Phe Leu 595 600 605 Trp Asp Ile Met Asn Tyr Ser Val Ser Ala Gly Leu Val Val Gly Ile 610 615 620 Phe Ile Gly Phe Gln Lys Lys Ala Tyr Thr Ser Pro Glu Asn Leu Pro 625 630 635 640 Ala Leu Val Ala Leu Leu Leu Leu Tyr Gly Trp Ala Val Ile Pro Met 645 650 655 Met Tyr Pro Ala Ser Phe Leu Phe Asp Val Pro Ser Thr Ala Tyr Val 660 665 670 Ala Leu Ser Cys Ala Asn Leu Phe Ile Gly Ile Asn Ser Ser Ala Ile 675 680 685 Thr Phe Ile Leu Glu Leu Phe Glu Asn Asn Arg Thr Leu Leu Arg Phe 690 695 700 Asn Ala Val Leu Arg Lys Leu Leu Ile Val Phe Pro His Phe Cys Leu 705 710 715 720 Gly Arg Gly Leu Ile Asp Leu Ala Leu Ser Gln Ala Val Thr Asp Val 725 730 735 Tyr Ala Arg Phe Gly Glu Glu His Ser Ala Asn Pro Phe His Trp Asp 740 745 750 Leu Ile Gly Lys Asn Leu Phe Ala Met Val Val Glu Gly Val Val Tyr 755 760 765 Phe Leu Leu Thr Leu Leu Val Gln Arg His Phe Phe Leu Ser Gln Trp 770 775 780 Ile Ala Glu Pro Thr Lys Glu Pro Ile Val Asp Glu Asp Asp Asp Val 785 790 795 800 Ala Glu Glu Arg Gln Arg Ile Ile Thr Gly Gly Asn Lys Thr Asp Ile 805 810 815 Leu Arg Leu His Glu Leu Thr Lys Ile Tyr Pro Gly Thr Ser Ser Pro 820 825 830 Ala Val Asp Arg Leu Cys Val Gly Val Arg Pro Gly Glu Cys Phe Gly 835 840 845 Leu Leu Gly Val Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys Met Leu 850 855 860 Thr Gly Asp Thr Thr Val Thr Ser Gly Asp Ala Thr Val Ala Gly Lys 865 870 875 880 Ser Ile Leu Thr Asn Ile Ser Glu Val His Gln Asn Met Gly Tyr Cys 885 890 895 Pro Gln Phe Asp Ala Ile Asp Glu Leu Leu Thr Gly Arg Glu His Leu 900 905 910 Tyr Leu Tyr Ala Arg Leu Arg Gly Val Pro Ala Glu Glu Ile Glu Lys 915 920 925 Val Ala Asn Trp Ser Ile Lys Ser Leu Gly Leu Thr Val Tyr Ala Asp 930 935 940 Cys Leu Ala Gly Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser Thr 945 950 955 960 Ala Ile Ala Leu Ile Gly Cys Pro Pro Leu Val Leu Leu Asp Glu Pro 965 970 975 Thr Thr Gly Met Asp Pro Gln Ala Arg Arg Met Leu Trp Asn Val Ile 980 985 990 Val Ser Ile Ile Arg Glu Gly Arg Ala Val Val Leu Thr Ser His Ser 995 1000 1005 Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala Ile Met Val 1010 1015 1020 Lys Gly Ala Phe Arg Cys Met Gly Thr Ile Gln His Leu Lys Ser 1025 1030 1035 Lys Phe Gly Asp Gly Tyr Ile Val Thr Met Lys Ile Lys Ser Pro 1040 1045 1050 Lys Asp Asp Leu Leu Pro Asp Leu Asn Pro Val Glu Gln Phe Phe 1055 1060 1065 Gln Gly Asn Phe Pro Gly Ser Val Gln Arg Glu Arg His Tyr Asn 1070 1075 1080 Met Leu Gln Phe Gln Val Ser Ser Ser Ser Leu Ala Arg Ile Phe 1085 1090 1095 Gln Leu Leu Leu Ser His Lys Asp Ser Leu Leu Ile Glu Glu Tyr 1100 1105 1110 Ser Val Thr Gln Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala 1115 1120 1125 Lys Gln Gln Thr Glu Ser His Asp Leu Pro Leu His Pro Arg Ala 1130 1135 1140 Ala Gly Ala Ser Arg Gln Ala Gln Asp 1145 1150 <210> 23 <211> 1259 <212> PRT <213> Artificial Sequence <220> <223> Synthesized multiple peptides <400> 23 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu 35 40 45 Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50 55 60 Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro 65 70 75 80 Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn 85 90 95 Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100 105 110 Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu 115 120 125 Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu 130 135 140 Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu 145 150 155 160 Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser 165 170 175 Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala 180 185 190 His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200 205 Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr 210 215 220 Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile 225 230 235 240 Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe Phe Lys Leu Phe Arg Val 245 250 255 Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser 260 265 270 Trp Gly Gly Ile Leu Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile 275 280 285 His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr Arg Pro Leu Met 290 295 300 Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser 305 310 315 320 Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly Gly Ser Arg Val Leu Ser 325 330 335 Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe Leu Gly Ile Asp 340 345 350 Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser 355 360 365 Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu Ser Asn Pro Leu Thr Lys 370 375 380 Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr 385 390 395 400 Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser 405 410 415 Thr Phe Glu Glu Leu Glu His Val Arg Lys Leu Val Lys Ala Trp Glu 420 425 430 Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met 435 440 445 Asn Met Ile Arg Asp Thr Leu Gly Asn Pro Thr Val Lys Asp Phe Leu 450 455 460 Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu Asn 465 470 475 480 Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn 485 490 495 Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr Asp Arg Thr Leu Arg Leu 500 505 510 Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu Ser Tyr 515 520 525 Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu 530 535 540 Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met Tyr Pro Trp Thr 545 550 555 560 Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp 565 570 575 Val Val Glu Lys Thr Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly 580 585 590 Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile Trp Gly Gly Phe 595 600 605 Ala Tyr Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val 610 615 620 Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln Gln Met Pro Tyr Pro 625 630 635 640 Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro 645 650 655 Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 660 665 670 Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn 675 680 685 Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 690 695 700 Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met 705 710 715 720 His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe 725 730 735 Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 740 745 750 Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile 755 760 765 Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 770 775 780 Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val 785 790 795 800 Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly 805 810 815 Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp 820 825 830 Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala 835 840 845 Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Val Pro Gly Val 850 855 860 Cys Val Lys Asn Leu Val Lys Ile Phe Glu Pro Cys Gly Arg Pro Ala 865 870 875 880 Val Asp Arg Leu Asn Ile Thr Phe Tyr Glu Asn Gln Ile Thr Ala Phe 885 890 895 Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Ile Leu Thr 900 905 910 Gly Leu Leu Pro Pro Thr Ser Gly Thr Val Leu Val Gly Gly Arg Asp 915 920 925 Ile Glu Thr Ser Leu Asp Ala Val Arg Gln Ser Leu Gly Met Cys Pro 930 935 940 Gln His Asn Ile Leu Phe His His Leu Thr Val Ala Glu His Met Leu 945 950 955 960 Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln Glu Glu Ala Gln Leu Glu 965 970 975 Met Glu Ala Met Leu Glu Asp Thr Gly Leu His His Lys Arg Asn Glu 980 985 990 Glu Ala Gln Asp Leu Ser Gly Gly Met Gln Arg Lys Leu Ser Val Ala 995 1000 1005 Ile Ala Phe Val Gly Asp Ala Lys Val Val Ile Leu Asp Glu Pro 1010 1015 1020 Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg Ser Ile Trp Asp Leu 1025 1030 1035 Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile Ile Met Ser Thr His 1040 1045 1050 His Met Asp Glu Ala Asp Leu Leu Gly Asp Arg Ile Ala Ile Ile 1055 1060 1065 Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr Pro Leu Phe Leu Lys 1070 1075 1080 Asn Cys Phe Val Thr Asn Phe Leu Trp Asp Ile Met Asn Tyr Ser 1085 1090 1095 Val Ser Ala Gly Leu Val Val Gly Ile Phe Ile Gly Phe Gln Lys 1100 1105 1110 Lys Ala Tyr Thr Ser Pro Glu Asn Leu Pro Ala Leu Val Ala Leu 1115 1120 1125 Leo Leo Leo Tyr Gly Trp Ala Val Ile Pro Met Met Tyr Pro Ala 1130 1135 1140 Ser Phe Leu Phe Asp Val Pro Ser Thr Ala Tyr Val Ala Leu Ser 1145 1150 1155 Cys Ala Asn Leu Phe Ile Gly Ile Asn Ser Ser Ala Ile Thr Phe 1160 1165 1170 Ile Leu Glu Leu Phe Glu Asn Asn Arg Thr Leu Leu Arg Phe Asn 1175 1180 1185 Ala Val Leu Arg Lys Leu Leu Ile Val Phe Pro His Phe Cys Leu 1190 1195 1200 Gly Arg Gly Leu Ile Asp Leu Ala Leu Ser Gln Ala Val Thr Asp 1205 1210 1215 Val Tyr Ala Arg Phe Gly Glu Glu His Ser Ala Asn Pro Phe His 1220 1225 1230 Trp Asp Leu Ile Gly Lys Asn Leu Phe Ala Met Val Val Glu Gly 1235 1240 1245 Val Val Tyr Phe Leu Leu Thr Leu Leu Val Gln 1250 1255 <210> 24 <211> 1165 <212> PRT <213> Artificial Sequence <220> <223> Synthesized multiple peptides <400> 24 Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr 1 5 10 15 Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20 25 30 Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Val Asp 35 40 45 Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro Ile Phe Met Val 50 55 60 Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys Ser Ile Val Leu 65 70 75 80 Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn Gln Gly Val Ser 85 90 95 Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser Phe Ser Ile Met 100 105 110 Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met His Gly Arg Ile 115 120 125 Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe Leu Leu Ala Phe 130 135 140 Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser Thr Phe Phe Ser 145 150 155 160 Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile Tyr Phe Thr Leu 165 170 175 Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp Arg Met Thr Ala 180 185 190 Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val Ala Phe Gly Phe 195 200 205 Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly Leu Gly Leu Gln 210 215 220 Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp Glu Phe Ser Phe 225 230 235 240 Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala Val Tyr Gly Leu 245 250 255 Leu Ala Trp Tyr Leu Asp Gln Val Phe Leu Ala Gln Ile Val Leu Pro 260 265 270 Ala Thr Phe Val Phe Leu Ala Leu Met Leu Ser Ile Val Ile Pro Pro 275 280 285 Phe Gly Glu Tyr Pro Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln 290 295 300 Gln Tyr Thr Phe Phe Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr 305 310 315 320 Val Leu Ala Asp Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg Cys 325 330 335 Leu Lys Glu Gly Trp Leu Pro Glu Tyr Pro Cys Gly Asn Ser Thr Pro 340 345 350 Trp Lys Thr Pro Ser Val Ser Pro Asn Ile Thr Gln Leu Phe Gln Lys 355 360 365 Gln Lys Trp Thr Gln Val Asn Pro Ser Pro Ser Cys Arg Cys Ser Thr 370 375 380 Arg Glu Lys Leu Thr Met Leu Pro Glu Cys Pro Glu Gly Ala Gly Gly 385 390 395 400 Leu Pro Pro Pro Gln Arg Thr Gln Arg Ser Thr Glu Ile Leu Gln Asp 405 410 415 Leu Thr Asp Arg Asn Ile Ser Asp Phe Leu Val Lys Thr Tyr Pro Ala 420 425 430 Leu Ile Arg Ser Ser Leu Lys Ser Lys Phe Trp Val Asn Glu Gln Arg 435 440 445 Tyr Gly Gly Ile Ser Ile Gly Gly Lys Leu Pro Val Val Pro Ile Thr 450 455 460 Gly Glu Ala Leu Val Gly Phe Leu Ser Asp Leu Gly Arg Ile Met Asn 465 470 475 480 Val Ser Gly Gly Pro Ile Thr Arg Glu Ala Ser Lys Glu Ile Pro Asp 485 490 495 Phe Leu Lys His Leu Glu Thr Glu Asp Asn Ile Lys Val Trp Phe Asn 500 505 510 Asn Lys Gly Trp His Ala Leu Val Ser Phe Leu Asn Val Ala His Asn 515 520 525 Ala Ile Leu Arg Ala Ser Leu Pro Lys Asp Arg Ser Pro Glu Glu Tyr 530 535 540 Gly Ile Thr Val Ile Ser Gln Pro Leu Asn Leu Thr Lys Glu Gln Leu 545 550 555 560 Ser Glu Ile Thr Val Leu Thr Thr Ser Val Asp Ala Val Val Ala Ile 565 570 575 Cys Val Ile Phe Ser Met Ser Phe Val Pro Ala Ser Phe Val Leu Tyr 580 585 590 Leu Ile Gln Glu Arg Val Asn Lys Ser Lys His Leu Gln Phe Ile Ser 595 600 605 Gly Val Ser Pro Thr Thr Tyr Trp Val Thr Asn Phe Leu Trp Asp Ile 610 615 620 Met Asn Tyr Ser Val Ser Ala Gly Leu Val Val Gly Ile Phe Ile Gly 625 630 635 640 Phe Gln Lys Lys Ala Tyr Thr Ser Pro Glu Asn Leu Pro Ala Leu Val 645 650 655 Ala Leu Leu Leu Leu Tyr Gly Trp Ala Val Ile Pro Met Met Tyr Pro 660 665 670 Ala Ser Phe Leu Phe Asp Val Pro Ser Thr Ala Tyr Val Ala Leu Ser 675 680 685 Cys Ala Asn Leu Phe Ile Gly Ile Asn Ser Ser Ala Ile Thr Phe Ile 690 695 700 Leu Glu Leu Phe Glu Asn Asn Arg Thr Leu Leu Arg Phe Asn Ala Val 705 710 715 720 Leu Arg Lys Leu Leu Ile Val Phe Pro His Phe Cys Leu Gly Arg Gly 725 730 735 Leu Ile Asp Leu Ala Leu Ser Gln Ala Val Thr Asp Val Tyr Ala Arg 740 745 750 Phe Gly Glu Glu His Ser Ala Asn Pro Phe His Trp Asp Leu Ile Gly 755 760 765 Lys Asn Leu Phe Ala Met Val Val Glu Gly Val Val Tyr Phe Leu Leu 770 775 780 Thr Leu Leu Val Gln Arg His Phe Phe Leu Ser Gln Trp Ile Ala Glu 785 790 795 800 Pro Thr Lys Glu Pro Ile Val Asp Glu Asp Asp Asp Val Ala Glu Glu 805 810 815 Arg Gln Arg Ile Ile Thr Gly Gly Asn Lys Thr Asp Ile Leu Arg Leu 820 825 830 His Glu Leu Thr Lys Ile Tyr Pro Gly Thr Ser Ser Pro Ala Val Asp 835 840 845 Arg Leu Cys Val Gly Val Arg Pro Gly Glu Cys Phe Gly Leu Leu Gly 850 855 860 Val Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys Met Leu Thr Gly Asp 865 870 875 880 Thr Thr Val Thr Ser Gly Asp Ala Thr Val Ala Gly Lys Ser Ile Leu 885 890 895 Thr Asn Ile Ser Glu Val His Gln Asn Met Gly Tyr Cys Pro Gln Phe 900 905 910 Asp Ala Ile Asp Glu Leu Leu Thr Gly Arg Glu His Leu Tyr Leu Tyr 915 920 925 Ala Arg Leu Arg Gly Val Pro Ala Glu Glu Ile Glu Lys Val Ala Asn 930 935 940 Trp Ser Ile Lys Ser Leu Gly Leu Thr Val Tyr Ala Asp Cys Leu Ala 945 950 955 960 Gly Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser Thr Ala Ile Ala 965 970 975 Leu Ile Gly Cys Pro Pro Leu Val Leu Leu Asp Glu Pro Thr Thr Gly 980 985 990 Met Asp Pro Gln Ala Arg Arg Met Leu Trp Asn Val Ile Val Ser Ile 995 1000 1005 Ile Arg Glu Gly Arg Ala Val Val Leu Thr Ser His Ser Met Glu 1010 1015 1020 Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala Ile Met Val Lys Gly 1025 1030 1035 Ala Phe Arg Cys Met Gly Thr Ile Gln His Leu Lys Ser Lys Phe 1040 1045 1050 Gly Asp Gly Tyr Ile Val Thr Met Lys Ile Lys Ser Pro Lys Asp 1055 1060 1065 Asp Leu Leu Pro Asp Leu Asn Pro Val Glu Gln Phe Phe Gln Gly 1070 1075 1080 Asn Phe Pro Gly Ser Val Gln Arg Glu Arg His Tyr Asn Met Leu 1085 1090 1095 Gln Phe Gln Val Ser Ser Ser Ser Leu Ala Arg Ile Phe Gln Leu 1100 1105 1110 Leu Leu Ser His Lys Asp Ser Leu Leu Ile Glu Glu Tyr Ser Val 1115 1120 1125 Thr Gln Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys Gln 1130 1135 1140 Gln Thr Glu Ser His Asp Leu Pro Leu His Pro Arg Ala Ala Gly 1145 1150 1155 Ala Ser Arg Gln Ala Gln Asp 1160 1165

Claims

1. An isolated nucleic acid comprising a transgene encoding an ABCA4 minigene consisting of the sequence shown in SEQ ID NO:

3.

2. The isolated nucleic acid of claim 1, wherein the transgene further comprises a promoter operably linked to the ABCA4 minigene sequence.

3. The isolated nucleic acid of claim 2, wherein the promoter is a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

4. The isolated nucleic acid of claim 3, wherein the tissue-specific promoter is a photoreceptor-specific promoter.

5. The isolated nucleic acid of claim 1, wherein the transgene is flanked by adeno-associated virus inverted terminal repeats (ITRs).

6. The isolated nucleic acid of claim 5, wherein at least one ITR is an AAV2 ITR.

7. The isolated nucleic acid of claim 5 or 6, wherein at least one ITR lacks a terminal dissociation site.

8. An isolated nucleic acid comprising a transgene encoding an ABCA4 protein, wherein the ABCA4 protein consists of the amino acid sequence shown in SEQ ID NO:

9.

9. The isolated nucleic acid of claim 8, wherein the transgene further comprises a promoter operably linked to the nucleic acid sequence encoding the ABCA4 protein.

10. The isolated nucleic acid of claim 9, wherein the promoter is a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

11. The isolated nucleic acid of claim 10, wherein the tissue-specific promoter is a photoreceptor-specific promoter.

12. The isolated nucleic acid of claim 8, wherein the transgene is flanked by adeno-associated virus inverted terminal repeats (ITRs).

13. The isolated nucleic acid of claim 12, wherein at least one ITR is an AAV2 ITR.

14. The isolated nucleic acid of claim 12 or 13, wherein at least one ITR lacks a terminal dissociation site.

15. A vector comprising the isolated nucleic acid of any one of claims 1 to 14.

16. The vector according to claim 15, wherein the vector is a plasmid DNA, a blocked-end DNA, a lipid nanoparticle or a viral vector.

17. The vector according to claim 16, wherein the viral vector is an adeno-associated viral vector, an adenoviral vector, a lentiviral vector, a retroviral vector or a baculoviral vector.

18. A host cell comprising the isolated nucleic acid of any one of claims 1 to 14 or the vector of any one of claims 15 to 17.

19. The host cell of claim 18, wherein the cell is a mammalian cell, a bacterial cell, a yeast cell or an insect cell.

20. The host cell of claim 18, wherein the cell is a human cell.

21. A recombinant adeno-associated virus (rAAV), comprising: (i) the isolated nucleic acid of any one of claims 1 to 14; and (ii) AAV capsid protein.

22. The rAAV of claim 21, wherein the capsid protein is tropic for ocular cells.

23. The rAAV of claim 21 or 22, wherein the capsid protein is an AAV8 capsid protein.

24. The rAAV of claim 21 or 22, wherein the rAAV is formulated for delivery to the eye.

25. The rAAV of claim 24, wherein the rAAV is formulated for delivery to photoreceptor cells or the retinal pigment epithelium.

26. A composition comprising the isolated nucleic acid of any one of claims 1 to 14 or the rAAV of any one of claims 21 to 25, and a pharmaceutically acceptable excipient.

27. Use of the isolated nucleic acid of any one of claims 1 to 14 or the rAAV of any one of claims 21 to 25 in the preparation of an agent for delivering a transgene to a cell.

28. The use of claim 27, wherein the cell is in a subject.

29. The use of claim 28, wherein the cell is in a mammalian subject.

30. The use of claim 27, wherein the cell is in a human subject.

31. Use according to any one of claims 27 to 30, wherein the cell is an ocular cell.

32. The use according to claim 31, wherein the ocular cell is a photoreceptor cell or retinal pigment epithelium.

33. Use of the isolated nucleic acid of any one of claims 1 to 14 or the rAAV of any one of claims 21 to 25 in the preparation of a medicament for treating fundus xanthophyma in a subject in need thereof.

34. The use according to claim 33, wherein the subject is a mammal.

35. The use according to claim 33, wherein the subject is a human.

36. Use according to any one of claims 33 to 35, wherein the subject is characterised by having one or more mutations in the ABCA4 gene.

37. The use according to any one of claims 33 to 35, wherein the medicament is administered by injection.

38. The use according to claim 37, wherein the injection is a subretinal injection, an intravitreal injection, or a suprachoroidal injection.

39. The use according to any one of claims 33 to 35, wherein the medicament is administered topically to the eye of a subject.

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