Dumbbell-shaped DNA vectors

Abstract

The invention refers to a dumbbell-shaped DNA vector comprising a transcriptional promoter, a sequence for expressing an RNA, and a transcriptional terminator The sequence for expressing an RNA may be selected from the group consisting of an ornithine transcarbamylase, a phenylalanine hydroxylase (PAH), and a viral antigen.

Description

[0001] DUMBBELL-SHAPED DNA VECTORS

[0002] Field of the Invention

[0003] This invention relates to dumbbell-shaped DNA vectors, for example, for the use of treating ornithine transcarbamylase deficiency (OTC) or phenylketonuria (PKU) or for a genetic vaccination using SARS-CoV-2.

[0004] Background of the invention

[0005] In the field of genetic engineering and biomedicine, the development of efficient and safe methods for delivering genetic material into cells is crucial for various applications, such as gene therapy, vaccine development, and genetic research. Traditional methods of delivering DNA vectors, such as viral vectors and plasmids, have limitations including immunogenicity, limited cargo capacity, and potential safety concerns linked to the risk of genomic integration.

[0006] Dumbbell-shaped DNA vectors represent a significant innovation in the field of non-viral gene delivery systems. These vectors are designed to overcome the shortcomings of conventional delivery methods by providing a structure that enhances stability, cellular uptake, nuclear targeting, and expression of the delivered genetic material.

[0007] The dumbbell-shaped DNA vectors consist of a central double-stranded DNA segment which forms a B-form DNA helix flanked by two single-stranded DNA loops, resembling the shape of a dumbbell. Dumbbell-shaped DNA vectors are also referred to as dumbbells, doggybones, closed-ended DNA (ceDNA), or hairpin (hp)DNA. Advanced dumbbell-shaped DNA vectors, also referred to as SPRING DNA, additionally harbour internal loops in the double-stranded DNA segment which are typically positioned close to the ends of the double-stranded DNA segment. These internal loops can be symmetric loops, with equal numbers of unpaired nucleotides or abasic positions bulging out opposite to each other, or these can be asymmetric loops with unequal numbers of unpaired nucleotides or abasic positions bulging out opposite to each other.

[0008] This unique design of dumbbell-shaped vectors offers several advantages:

[0009] 1 . Enhanced Stability: The closed circular structure of the dumbbell prevents enzymatic degradation and enhances stability in various biological environments, such as serum and cytoplasm.

[0010] 2. Efficient Cellular Uptake: The compact size and unique shape of the dumbbell facilitate efficient cellular uptake through mechanisms such as endocytosis and direct penetration through the cell membrane. 3. Facilitated Nuclear Targeting: The unique rod-shaped structure with a hydrodynamic diameter of only 5 nm perpendicular to the helix axis facilitates nuclear entry via the nuclear pore complex.

[0011] 4. Improved Transgene Expression: Once inside the nucleus, the dumbbell-shaped vector efficiently expresses its cargo DNA, allowing for robust transgene expression without eliciting significant immune responses or cytotoxicity.

[0012] 5. Safety: Non-viral vectors reduce the risk of immunogenicity and insertional mutagenesis associated with viral vectors.

[0013] 6. Versatility: Can deliver a wide range of genetic payloads, including large genes and regulatory sequences.

[0014] 7. Scalability: Production of dumbbell-shaped DNA vectors can be scaled up using standard molecular biology techniques, facilitating clinical translation and commercialization.

[0015] By addressing key limitations of traditional vector systems, dumbbell-shaped DNA vectors combine enhanced stability and efficacy, specificity, with improved safety profiles and low cost manufacturing, making them promising candidates for biomedical applications in the field of genetic engineering, gene therapy, and genetic vaccination.

[0016] Ornithine transcarbamylase (OTC) deficiency is a genetic disorder that affects the urea cycle, leading to the accumulation of toxic ammonia in the blood. Gene therapy offers a promising approach to treat OTC deficiency by delivering functional copies of the OTC gene into the patient's cells. This therapy aims to restore the deficient enzyme activity, thereby reducing ammonia levels and preventing associated neurological damage. Gene therapy holds potential as a future treatment option for OTC deficiency.

[0017] Gene therapy for phenylketonuria (PKU) aims to correct the underlying genetic defect that leads to the deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is responsible for metabolizing phenylalanine, an amino acid found in many foods. In PKU, the inability to metabolize phenylalanine results in its accumulation in the body, causing neurological damage if left untreated. By restoring PAH enzyme activity, gene therapy aims to reduce phenylalanine levels to normal or near-normal levels in individuals with PKU.

[0018] The current treatments for both, OTC deficiency and PKU, involves a combination of dietary management, medications, and sometimes liver transplantations.

[0019] Brief Description of the Invention In a first aspect, the invention refers to a dumbbell-shaped DNA vector (also referred to as SPRING DNA) for expressing a gene of part of a gene. In an embodiment, the dumbbellshaped DNA vector comprises

[0020] - a transcriptional promoter,

[0021] - a sequence for expressing an RNA, and

[0022] - a transcriptional terminator.

[0023] In an embodiment of the dumbbell-shaped DNA vector, the sequence for expressing an RNA is selected from the group consisting of

[0024] - an ornithine transcarbamylase, in particular a human ornithine transcarbamylase,

[0025] - a phenylalanine hydroxylase (PAH), and

[0026] - a viral antigen, in particular a SARS-CoV-2 spike protein.

[0027] In an embodiment of the dumbbell-shaped DNA vector, the transcriptional promoter is selected from the group consisting of a CMV promoter and a hAAT promoter.

[0028] In an embodiment of the dumbbell-shaped DNA vector, the transcriptional terminator is selected from the group consisting of a SV40 polyadenylation signal and a BGH polyadenylation signal.

[0029] In an embodiment of the dumbbell-shaped DNA vector, it comprises a DNA nuclear import signal, in particular an SV40 enhancer sequence. The DNA nuclear import signal can be located upstream or downstream of the gene to be delivered, i.e. typically next to either of the loops.

[0030] In an embodiment of the dumbbell-shaped DNA vector, the RNA that is expressed from the sequence comprises an RNA nuclear export signal at a 5’ untranslated region.

[0031] In an embodiment of the dumbbell-shaped DNA vector, the RNA nuclear export signal is selected from the group consisting of a Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), a human hepatitis B virus post-transcriptional regulatory element (PRE), or a type D retroviral constitutive transport element (CTE).

[0032] In an embodiment of the dumbbell-shaped DNA vector, the sequence for expressing an RNA comprises a spliceable intron, in particular a beta-globin mini-intron.

[0033] In an embodiment of the dumbbell-shaped DNA vector, the sequence for expressing an RNA is a trans-splicing RNA. In an embodiment of the dumbbell-shaped DNA vector, the trans-splicing RNA comprises at least once splice site and at least one binding domain specific for at least a part of the gene, in particular wherein the gene is specifically expressed in liver cells or is specifically expressed in a population of professional antigen presenting cells.

[0034] In a second aspect, the invention refers to a cell containing a dumbbell-shaped DNA vector as described above and herein.

[0035] In a third aspect, the invention refers to a vector containing a dumbbell-shaped DNA vector as described above and herein.

[0036] In a third aspect, the invention refers to a method of transfecting or targeting a cell, optionally comprising the use of a dumbbell-shaped vector as described above and herein, in particular comprising topical application, intranasal application, alveolar application, systemic application, oral application, intravenous injection, intramuscular injection, subcutaneous application, cutaneous application, intraperitoneal application, or portal vein injection. In an embodiment of the method, the cell is selected from the group consisting of a liver cell, and an antigen presenting cell.

[0037] In a fourth aspect, the invention refers to a method of treating ornithine transcarbamylase deficiency, optionally comprising targeting, transfecting, lipofection, transducing, electroporating, nucleofecting or transforming a liver cell with a dumbbell-shaped DNA vector as described above and herein ex vivo or in vivo, wherein the sequence for expressing an RNA is an ornithine transcarbamylase, in particular a human ornithine transcarbamylase.

[0038] In a fifth aspect, the invention refers to a method of treating phenylketonuria, optionally comprising targeting, transfecting, lipofection, electroporating or nucleofecting a liver cell with a dumbbell-shaped DNA vector as described above and herein ex vivo or in vivo, wherein the sequence for expressing an RNA is a phenylalanine hydroxylase, in particular a human phenylalanine hydroxylase.

[0039] In a sixth aspect, the invention refers to a method of vaccinating against a viral disease, optionally comprising targeting, transfecting, lipofection, electroporating or nucleofecting antigen presenting cells with a dumbbell-shaped DNA vector as described above and herein ex vivo or in vivo wherein the sequence for expressing an RNA is a viral antigen, in particular a SARS-CoV-2 spike protein. In an embodiment of the method, the viral disease is SARS- CoV-2 and the sequence for expressing an RNA is a SARS-CoV-2 spike protein. In another aspect, the invention refers to a method of manufacturing the dumbbell-shaped DNA vector as described above and herein, wherein a chemically modified primer is used in the polymerase chain reaction (PCR). In particular, for dumbbell manufacture, the sequences or gene of interest are PCR-amplified using chemically modified primers. In addition to the 3’ primer binding site, these primers harbour a gap, an abasic position which is a tetrahydrofuran- based mimic of one purine or pyridinic abasic site and which forces the DNA polymerase to stop primer extension during PCR. The 5’ ends are phosphorylated with the 5’ terminal positions to be self-complementary capable of refolding and pre-shaping the dumbbells’ loops. PCR with these primers produces products with refolding 5’ overhangs whereby the 5’ phosphates are positioned next to the 3’ OH groups ready for ligation. Subsequently, ligation yields covalently closed DNA with the characteristic mismatches close to the ends. SPRING DNA can be purified by exonuclease treatment and / or chromatography.

[0040] In a seventh aspect, the invention refers to a medicament comprising a dumbbell-shaped DNA vector as described above and herein

[0041] In an eighth aspect, the invention refers to a pharmaceutical composition, in particular for use in the treatment of an ornithine transcarbamylase deficiency, phenylketonuria or a viral disease, comprising said dumbbell-shaped DNA vector as described above and herein.

[0042] Detailed Description of the Invention

[0043] This invention provides genetic non-viral dumbbell-shaped DNA vectors (SPRING DNA) for gene therapy of OTC deficiency and PKU.

[0044] The gene therapy vectors of this invention allow for high stability in vitro and in vivo, best possible delivery into the nuclei of cells of the liver and for maximal and long-lasting expression of ornithine transcarbamylase (OTC) or phenylalanine hydroxylase (PAH). These vectors can be delivered using preferred carriers and modes of application.

[0045] The principle of genetic vaccination relies on the concept to deliver nucleic acids (DNA or RNA) coding for an antigen (viral or tumor antigen) into antigen-presenting cells (APCs) of the individual to be vaccinated. Expression and presentation of the antigen by the APCs then triggers humoral and cellular immune responses. RNA recently revolutionized the vaccine, but it is unstable and needs to be protected by chemical modification and / or a carrier, requires the help of a carrier systems (typically lipid-based nanoparticles (LNPs) or nanoparticles) for delivery, needs to be delivered repeatedly, is immunogenic and needs to be chemically modified (e.g. pseudouridine), and is temperature sensitive requiring cold chain supply for transportation and storage. DNA on the other hand is cheaper, and more table in vitro and in vivo with no cold chain requirement. But as opposed to RNA, DNA has to be delivered into the nuclei of target cells.

[0046] This invention describes in certain embodiments the use of dumbbell-shaped DNA vectors (SPRING DNA) for genetic vaccination and vaccination against SARS-CoV-2.

[0047] The vaccine vectors of this invention were designed for high stability in vitro and in vivo, best possible eventually even carrier-free delivery into target cells and their nuclei, and for maximal and long-lasting expression of the SARS-CoV-2 spike protein either in all APCs or for selective expression in professional APCs only. These vectors are being delivered i.m. either naked or using preferred carriers.

[0048] Cell type-specificity of gene expression is crucial requirement for many gene therapeutic applications. It can be achieved either by targeted delivery, by using cell type-specific promoters, or by employing the RNA trans-splicing technology.

[0049] Spliceosome-meditated RNA trans-splicing involves the targeted modification of mRNA transcripts within cells. This technique utilizes a modified RNA molecule, called a trans- splicing RNA, which contains a binding domain that recognizes a specific target pre-mRNA sequence. It further contains a splicing domain to recruit the spliceosome and a coding domain coding for the sequence of interest to be expressed. Upon recognition of the pre-mRNA target in the cellular nucleus, the trans-splicing RNA molecule facilitates the replacement or addition of a specific sequence into the target mRNA, resulting in the production of a hybrid or chimeric mRNA molecule which subsequently can be exported into the cytoplasm and translated into a protein. In an off-target cell, the trans-splicing RNA does not find a pre-mRNA target, trans- splicing does not occur, and the coding domain of the trans-splicing RNA cannot be expressed. Cell type-specificity of gene expression can be achieved by engineering the trans- splicing RNA to target pre-mRNA sequences that are specific to certain cell types. That is, specificity is achieved by designing the trans-splicing RNA molecule to recognize and interact with unique sequences or motifs which are present in the pre-mRNA of the target cell type but which are absent in off-target cells. The target cell can be any cell of an eukaryotic organisms including a human body for which unique pre-mRNA sequences are known. For example, a liver cell-specific pre-mRNA has to be selected as target to specifically express a transgene in liver cells, a brain cell-specific pre-mRNA has to be selected as target to specifically express a transgene in brain cells, a cancer cell-specific pre-mRNA has to be selected as target to specifically express a transgene in cancer cells, or a spliceable viral RNA has to be selected as target to specifically express a transgene in a virus infected cell. To specifically express an antigen in professional APCs or distinct subpopulations thereof, the trans-splicing RNA needs to be engineered to specifically recognise pre-mRNA targets which are specifically expressed in professional APCs or distinct subpopulations of APCs including macrophages, dendritic cells, B cells, and Langerhans cells.

[0050] The advantages of RNA trans-splicing include a high level of precision as it allows for precise manipulation of gene expression in specific cell types without affecting other cell types, high flexibility, as it is can target a wide range of genes and cellular processes by designing trans- splicing RNAs specific to different pre-mRNA sequences, and safety as it interferes with the cellular transcriptome but not with the genome.

[0051] According to one aspect of the invention, a dumbbell-shaped DNA vector is provided wherein said vector may comprise at least one or a combination of the following features: i) one or more linear or hairpin-shaped transcription cassettes each comprising a nucleotide sequence encoding a nucleic acid molecule to be expressed (a sequence for expressing an RNA); ii) operably linked to said transcription cassette a transcription promoter nucleotide sequence (a transcriptional promoter); iii) operably linked to said transcription cassette a transcriptional terminator nucleotide sequence (a transcriptional terminator); iv) operably linked to said transcription cassette, optionally, a spliceable intron; v) operably linked to said transcription cassette, optionally, a nucleotide sequence comprising a post-transcriptional regulatory element or a constitutive nuclear transport element; vi) a nucleotide sequence comprising a DNA nuclear targeting sequence; vii) optionally, a sequence comprising a branch point (BP), a polypyrimidine tract, and a splice acceptor sequence; and / or viii) optionally, a nucleotide sequence comprising a sequence with homology to a part of a mammalian genome that can serve as template for the transcription of an antisense RNA complementary to a part of a mammalian precursor messenger RNA (pre-mRNA); and / or ix) optionally, a nucleotide sequence that can enter the mitochondria of mammalian cells.

[0052] In a preferred embodiment of the invention, said transcription cassette expresses a human enzyme involved in metabolism, for example, ornithine transcarbamylase or phenylalanine hydroxylase. In a preferred embodiment of this invention, the aid transcription cassette expresses the human or murine ornithine transcarbamylase (hOTC or mOTC) to treat OTC deficiency comprising the nucleotide sequences as set forth below: (OTC Vector Sequences).

[0053] In a preferred embodiment of this invention, said transcription cassette expresses the human or murine phenylalanine hydroxylase (hPAH or mPAH) to treat phenylketonuria comprising the nucleotide sequences as set forth below: (PKU Vector Sequences).

[0054] In a preferred embodiment of this invention, said transcription cassette expresses a viral antigen for vaccination against a virus causing a viral diseases.

[0055] In a preferred embodiment of this invention, said transcription cassette expresses the SARS- CoV-2 spike protein for vaccination against Covid-19 comprising the nucleotide sequences as set forth below (under SARS-CoV-2 Vector Sequences).

[0056] In a preferred embodiment of this invention, said transcription cassette expresses the SARS- CoV-2 spike protein for vaccination against Covid-19 comprising the nucleotide sequences as set forth under SARS-CoV-2_Vector Sequences specifically in one or more types of professional antigen presenting cells including macrophages, dendritic cells, B cells, and Langerhans cells.

[0057] In a further preferred embodiment of the invention, said vector comprises at least one internal loop domain. Preferably, said loop domain comprises an abasic site or nucleotide mismatch. In a preferred embodiment of the invention, said abasic site comprises one or more internal loops.

[0058] In a preferred embodiment of the invention, said abasic site comprises one or more apurinic and / or apyrimidinic abasic sites.

[0059] In a preferred embodiment of the invention, said nucleotide mismatch comprises a tetrahydrofuran-based mimic of an abasic site.

[0060] In a preferred embodiment of the invention, said post-transcriptional regulatory element is the WPRE (SEQ ID NO 1 ).

[0061] In a preferred embodiment of the invention, said vector nucleic acid molecule as set forth in i)-ix) above is single stranded or double stranded nucleic acid.

[0062] In a preferred embodiment of the invention, said mammalian genome is human.

[0063] In a preferred embodiment of the invention, said expressed nucleic acid molecule is a therapeutic nucleic acid molecule. In a preferred embodiment of the invention, said therapeutic nucleic acid molecule is a pre- mRNA or mRNA.

[0064] In a preferred embodiment of the invention, sequence and RNA secondary structure of said pre-mRNA or mRNA have any of the following features or any combination of the following features: i) predicted miRNA binding sites are inactivated by sequence changes employing usage of alternative codons in the coding sequence; ii) predicted splice donor and acceptor sites, except those which were artificially introduced, are inactivated by sequence changes employing usage of alternative codons in the coding sequence; iii) coding sequences are codon-optimised to accommodate usage of transfer RNAs (tRNAs) with highest abundance in human or murine cells, respectively. iv) predicted RNA secondary structures are thermodynamically destabilised in the 5’ untranslated region (5’UTR) and around the translational start codon. That may achieved by sequence changes employing usage of alternative codons in the coding sequence. The Kozak sequence is preferably preserved. v) the natural 3’ untranslated regions (3’UTRs) is replaced by the Woodchuck hepatitis B virus post-transcriptional regulatory element (WPRE). During this replacement, the active WPRE structure, i.e. the structure found in the natural viral sequence context, is preserved by selecting suitable linker sequences. vi) a spliceable intron is inserted between the first G in position 3 and the G / A in position 4 of any C / AAGG / A sequence motif (C or A in position 1 , A in position 2, G in position 3, G or A in position 4).

[0065] In another preferred embodiment of the invention, said pre-mRNA or mRNA is designed as a trans-splicing RNA comprising the coding sequence, a splicing sequence, and an antisense RNA sequence complementary to a part of a cellular pre-mRNA target sequence that is specifically expressed in the intended target cell or cells.

[0066] In an alternative preferred embodiment of the invention, said therapeutic nucleic acid is a small hairpin RNA (shRNA).

[0067] In an alternative preferred embodiment of the invention ,said therapeutic nucleic acid molecule is an antisense RNA antisense miRNA. In a further preferred embodiment of the invention, said therapeutic nucleic acid molecule is a primary or precursor microRNA (pri-miRNA or pre- miRNA). In a further preferred embodiment of the invention said therapeutic nucleic acid molecule is a trans-splicing RNA. In a further preferred embodiment of the invention said therapeutic nucleic acid molecule is a guide RNA, single-guide RNA, crRNA, or tracrRNA. In a further preferred embodiment of the invention said transcription promoter is derived from an RNA polymerase II promoter. In a preferred embodiment of the invention said RNA polymerase II promoter is a CMV promoter and comprises a nucleotide sequence as set forth in SEQ ID NO: 2.

[0068] In a preferred embodiment of the invention said RNA polymerase II promoter is the human alpha 1 -antitrypsin (hAAT) promoter and comprises a nucleotide sequence as set forth in SEQ ID NO: 3. In a preferred embodiment of the invention said RNA polymerase II promoter is the GAG promoter and comprises a nucleotide sequence as set forth in SEQ ID NO: 4. In a further preferred embodiment of the invention, said transcription promoter is derived from an RNA polymerase III promoter.

[0069] In a preferred embodiment of the invention, said RNA polymerase III promoter is a U6 promoter and comprises a nucleotide sequences as set forth in SEQ ID NO: 5. In an alternative preferred embodiment of the invention, said RNA polymerase III promoter is a H1 promoter comprising a nucleotide sequence as set forth in SEQ ID NO: 6. In an alternative preferred embodiment of the invention said RNA polymerase III promoter is a minimal H1 (mH1 ) promoter comprising a nucleotide sequence as set forth in SEQ ID NO: 7.

[0070] In a preferred embodiment of the invention said transcription terminator nucleotide sequence is a RNA polymerase II or RNA polymerase III termination sequence.

[0071] In a preferred embodiment of the invention said RNA polymerase II termination sequence is the Simian virus 40 (SV40) polyadenylation sequence as set forth in SEQ ID NO: 8.

[0072] In a preferred embodiment of the invention said RNA polymerase II termination sequence is the bovine growth hormone polyadenylation (BGH) sequence as set forth in SEQ ID NO: 9.

[0073] In a preferred embodiment of the invention said RNA polymerase III termination sequence comprises one or more motifs comprising the nucleotide sequence TTTTT. In a preferred embodiment of the invention said DNA nuclear targeting sequence comprises the nucleotide sequence set forth in SEQ ID NO: 10.

[0074] In a further preferred embodiment of the invention said intron comprises the nucleotide sequence set forth in SEQ ID NO: 11 .

[0075] In a preferred embodiment of the invention, wherein said nucleotide sequence with homology to a part of a mammalian genome is implemented into the double-stranded DNA part of the dumbbell vector. In an alternative preferred embodiment of the invention said nucleotide sequence with homology to a part of a mammalian genome comprises a single-stranded loop of the dumbbell vector.

[0076] According to a further aspect of the invention there is provided a pharmaceutical composition comprising a dumbbell-shaped vector according to the invention.

[0077] The dumbbell-shaped vector compositions of the present invention are administered in pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers and supplementary therapeutic agents’. Such preparations may include components used to form liposomal nanoparticles (LNPs) including an ionizable cationic lipid, a phospholipid, cholesterol, and PEG. Supplementary therapeutic agents can include agents functioning as adjuvants for vaccination purposes. The dumbbell shaped vector compositions of the invention can be administered by any conventional route, including injection or by gradual infusion over time. The administration may be, for example, intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, transdermal, oral, topical, intratracheal, nasal, intravaginal, trans-epithelial or by portal vein injection. Alternatively, the dumbbell-shaped vector or vector composition of this invention is delivered by physical methods including but not limited to liquid jet-injection, microinjection, microneedles, powder particle injection, gold particle injection, gene gun, electroporation or hydrodynamic injection.

[0078] The dumbbell-shaped vector compositions of the invention are administered in effective amounts. An “effective amount” is that amount of the dumbbell-shaped vector that alone, or together with further doses, produces the desired response. In the case of treating a disease, the desired response is inhibiting the progression of the disease. This may involve only slowing the progression of the disease temporarily, although more preferably, it involves halting the progression of the disease permanently. This can be monitored by routine methods. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons. The dumbbell-shaped vector compositions used in the foregoing methods preferably are sterile and contain an effective amount of dumbbell-shaped vector according to the invention for producing the desired response in a unit of weight or volume suitable for administration to a patient. The doses of vector administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Other protocols for the administration of vector compositions will be known to one of ordinary skill in the art, in which the dose amount, schedule of injections, sites of injections, mode of administration and the like vary from the foregoing. The administration of compositions to mammals other than humans, (e.g. for testing purposes or veterinary therapeutic purposes), is carried out under substantially the same conditions as described above. A subject, as used herein, is a mammal, preferably a human, and including a nonhuman primate, cow, horse, pig, sheep, goat, dog, cat or rodent.

[0079] When administered, the dumbbell-shaped vector compositions of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptable compositions. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active agent. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents’ (e.g. those typically used in the treatment of the specific disease indication). When used in medicine, the salts should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically- acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically- acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

[0080] The pharmaceutical compositions containing dumbbell-shaped vectors according to the invention may contain suitable buffering agents, including: acetic acid in a salt; citric acid in a salt; boric acid in a salt; and phosphoric acid in a salt. The pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal. The dumbbell-shaped vector compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a vector which constitutes one or more accessory ingredients. Compositions containing vectors according to the invention may be administered as aerosols and inhaled. Compositions suitable for parenteral administration conveniently comprise a sterile aqueous or non-aqueous preparation of the vectors, which is preferably isotonic with the blood of the recipient. This preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 , 3-butanediol. Among the acceptable solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Carrier formulation suitable for oral, subcutaneous, intravenous, intramuscular, etc. administrations can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

[0081] In an alternative embodiment of the invention, said pharmaceutical composition is a DNA vaccine composition comprising an adjuvant and / or carrier.

[0082] Preferred features of each aspect of the invention may be as described in connection with any of the other aspects of the invention.

[0083] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0084] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprises”, or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. , to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

[0085] All references, including any patent or patent application, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Further, no admission is made that any of the prior art constitutes part of the common general knowledge in the art. Other features of the present invention will become apparent from the following examples. Generally speaking, the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including the accompanying claims and drawings). Thus, features, integers, characteristics, compounds, or chemical moieties described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. Moreover, unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.

[0086] Specific Embodiments and Examples

[0087] Therapeutic Proteins and Peptides

[0088] The invention refers to dumbbell-shape vectors comprising nucleic acids encoding pharmaceutical proteins, in particular Ornithine Transcarbamylase (OTO), and Phenylalanine Hydroxylase (PAH).

[0089] DNA Vaccines / Adjuvants

[0090] The invention encompasses dumbbell-shaped vectors encoding antigenic polypeptides or proteins in the immunisation against diseases and pathogenic organisms including the SARS- CV-2 spike protein (S) and Nucleocapsid protein (N), the Measles Virus Hemagglutinin (H) and Fusion protein (F), the Mumps Virus Hemagglutinin-neuraminidase (HN) and Fusion protein (F), the Rubella Virus Envelope glycoprotein E1 and Envelope glycoprotein E2, the Varicella-Zoster Virus (VZV) Glycoprotein E (gE) and Glycoprotein I (gl), the Hepatitis A Virus antigen (HAV antigen), the Hepatitis B Virus surface antigen (HBsAg), the Human Papillomavirus (HPV) Virus-like particles (VLPs) composed of L1 capsid protein, the Poliovirus capsid proteins (VP1 , VP2, VP3), the Rotavirus VP6 protein, the Yellow Fever Virus Envelope protein (E), the Dengue Virus Envelope protein (E) and Pre-membrane protein (prM), the Japanese Encephalitis Virus Envelope protein (E), the Zika Virus Envelope protein (E), the Ebola Virus Glycoprotein (GP), the Rabies Virus Glycoprotein (G), and the Human Immunodeficiency Virus (HIV) Envelope glycoproteins gp 120 and gp41 .

[0091] Typically DNA vaccines comprising dumbbell-shaped vectors include adjuvants and / or carriers to augment immune response to encoded antigens.

[0092] Adjuvants (immune potentiators or immunomodulators) have been used for decades to improve the immune response to vaccine antigens. The incorporation of adjuvants into vaccine formulations is aimed at enhancing, accelerating and prolonging the specific immune response to vaccine antigens. Advantages of adjuvants include the enhancement of the immunogenicity of weaker antigens, the reduction of the antigen amount needed for a successful immunisation, the reduction of the frequency of booster immunisations needed and an improved immune response in elderly and immunocompromised vaccines. Selectively, adjuvants can also be employed to optimise a desired immune response, e.g. with respect to immunoglobulin classes and induction of cytotoxic or helper T lymphocyte responses. In addition, certain adjuvants can be used to promote antibody responses at mucosal surfaces. Aluminium hydroxide and aluminium or calcium phosphate has been used routinely in human vaccines. More recently, antigens incorporated into IRIV's (immunostimulating reconstituted influenza virosomes) and vaccines containing the emulsion-based adjuvant MF59 have been licensed in countries. Adjuvants can be classified according to their source, mechanism of action and physical or chemical properties. The most commonly described adjuvant classes are gel-type, microbial, oilemulsion and emulsifier-based, particulate, synthetic and cytokines. More than one adjuvant may be present in the final vaccine product. They may be combined together with a single antigen or all antigens present in the vaccine, or each adjuvant may be combined with one particular antigen. The origin and nature of the adjuvants currently being used or developed is highly diverse. For example, aluminium based adjuvants consist of simple inorganic compounds, PLG is a polymeric carbohydrate, virosomes can be derived from disparate viral particles, MDP is derived from bacterial cell walls; saponins are of plant origin, squalene is derived from shark liver and recombinant endogenous immunomodulators are derived from recombinant bacterial, yeast or mammalian cells.

[0093] There are several adjuvants licensed for veterinary vaccines, such as mineral oil emulsions that are too reactive for human use. Similarly, complete Freund's adjuvant, although being one of the most powerful adjuvants known, is not suitable for human use.

[0094] The term carrier is construed in the following manner. A carrier is an immunogenic molecule which, when bound to a second molecule augments immune responses to the latter. Some antigens are not intrinsically immunogenic yet may be capable of generating antibody responses when associated with a foreign protein molecule such as keyhole-limpet haemocyanin or tetanus toxoid. Such antigens contain B-cell epitopes but no T cell epitopes. The protein moiety of such a conjugate (the “carrier” protein) provides T-cell epitopes which stimulate helper T-cells that in turn stimulate antigen-specific B-cells to differentiate into plasma cells and produce antibody against the antigen.

[0095] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, means “including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps. “Consisting essentially” means having the essential integers but including integers which do not materially affect the function of the essential integers.

[0096] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Figures

[0097] Figure 1. Dumbbell-shaped DNA (herein also referred to as SPRING DNA) is manufactured enzymatically using a PCR-based process. For SPRING DNA manufacture, the sequences or gene of interest are PCR-amplified using chemically modified primers. In addition to the 3’ primer binding site, these primers harbour a gap, an abasic position which is a tetrahydrofuran-based mimic of one purine or pyridinic abasic site and which forces the DNA polymerase to stop primer extension during PGR. The 5’ ends are phosphorylated with the 5’ terminal positions to be self-complementary capable refolding and pre-shaping the dumbbells’ loops. PGR with these primers produces products with refolding 5’ overhangs whereby the 5’ phosphates are positioned next to the 3’ OH groups ready for ligation. Subsequently, ligation yields covalently closed SPRING DNA with the characteristic mismatches close to the ends. SPRING DNA can be purified by exonuclease treatment and / or chromatography.

[0098] Figure 2. Dumbbell-shaped DNA vectors are more thermostable stable compared with plasmid or minicircle DNA with SPRING DNA being the most stable dumbbell-shaped DNA vector, a, Different vectors including a plasmid, a minicircle DNA, two commercial dumbbell-shaped vectors and the dumbbell-shaped vectors (SPRING DNA) were stored in TE buffer in the fridge (untreated - UT), at 37 °C, or at 50 °C for 1 month and analysed using 1 % agarose gel electrophoresis (gel image). All vectors except SPRING DNA exhibit disintegration as indicated by alternative isoforms popping up or increasing in abundance at the higher temperatures. After incubation, all samples but the minicircle DNA, were also treated with an exonuclease, analysed using 1% agarose gel electrophoresis, and band intensities of the intact uncompromised vector DNA were quantified imaged (bar diagram). Dumbbell vectors exhibit a higher integrity compared with the plasmid and SPRING DNA appears to be the most stable dumbbell-shaped DNA. b, Integrity of vectors after incubation at 50 °C for 3 months. Different vectors including a plasmid, a minicircle DNA, two commercial dumbbell-shaped vectors and the dumbbell-shaped vectors (SPRING DNA) were stored in TE buffer at 50 °C for 1 day, 1 week, 1 month, and some for 3 months and analysed using 1% agarose gel electrophoresis, and band intensities of the intact uncompromised vector DNA were quantified using imaged (bar diagram). All vectors except SPRING DNA exhibit disintegration after 1 week. After 3 months, plasmid DNA was completely disintegrated and minincircle DNA to 50%. SPRING DNA virtually did not show any disintegration after 3 months, c, SPRING and plasmid DNA were stored in TE buffer at room temperature for 1 year. After 1 year, analytical agarose gel electrophoreses did not show any disintegration of SPRING DNA but plasmid DNA was disintegrated to 50%. Figure 3. Advanced dumbbell-shaped DNA (SPRING DNA) triggers long-lasting gene expression in murine liver after i.v. injection using liver-specific LNPs. BALB / c mice of 8-12 months age were injected i.v. with luciferase expressing SPRING or plasmid DNA formulated with the liver-specific liver delivery reagent VFS2202 from Thermo Fischer, a, Monitoring luciferase expression in the alive mice indicated long-lasting (up to ~1 year, ongoing) luciferase expression in the murine livers, b, While SPRING DNA expression was found to be very specific for the murine livers, plasmid expression was more prominent in the spleen and also detected in the lungs.

[0099] Figure 4. Advanced dumbbell-shaped DNA (SPRING DNA) triggers long-lasting gene expression in murine hindlimb muscles when injected i.m. as naked (unformulated) DNA. BALB / c mice of 8-12 months age were injected i.m. with luciferase expressing naked SPRING or naked plasmid DNA. a, Monitoring luciferase expression in the alive mice indicated SPRING DNA but plasmid DNA triggers long-lasting (up to 200 days) luciferase expression in the injected hindlimb muscles, b, SRIND DNA expression was found to be specific for the injected hindlimb muscles with no vector copies detected in other organs after 1 week or in the liver after 1 or 3 months. Luciferase activity was exclusively detected in the injected muscles.

[0100] Figure 5. Naked (non-conjugated) or LNP-formulated advanced dumbbell-shaped DNA (SPRING DNA) is virtually not immunogenic following intravenous (i.v.) tail vein injection in mice. BALB / c mice of 8-12 months age were injected i.v. with luciferase expressing naked or LNP-formulated SPRING DNA or plasmid DNA and Cytokine responses were monitored 4 and 24 hours after injection. SPRING DNA shows only little or not sensed by the murine innate immune system.

[0101] Figure 6. Delivery and expression of OTC expressing advanced dumbbell-shaped DNA (SPRING DNA) in the liver of wildtype mice. Single-dose i.v. injection of human OTC (hOTC) expressing advanced dumbbell-shaped DNA (SPRING DNA) lipid nanoparticle formulation triggers hOTC expression in 15-20% of hepatocytes.

[0102] Figure 7. Rescue of OTC RNAi knockdown phenotype in wildtype mice. Single-dose i.v. injection of human OTC (hOTC) expressing advanced dumbbell-shaped DNA (SPRING DNA) lipid nanoparticle formulation rescues siRNA triggered murine OTC (mOTC) knockdown phenotype in the liver of wildtype mice to 54% and elevates OTC plasma activity ~250-fold over the untreated control.

[0103] Figure 8. Complete rescue of OTC phenotype in OTC knockout mice. Single-dose i.v. injection of human OTC (hOTC) expressing dumbbell-shaped DNA (SPRING DNA) lipid nanoparticle formulation completely rescues OTC knockout phenotype in the liver of OTC KO- mice establishing an OTC plasma activity which is 5-fold above the activity in wildtype mice.

[0104] Figure 9. Complete rescue of PAH expression in RNAi knockdown mice. A single-dose i.v. injection of human PAH (hPAH) expressing advanced dumbbell DNA (SPRING DNA) lipid nanoparticle formulation elevates PAH mRNA levels in the liver of wildtype mice about 45- fold. A single-dose i.v. injection of a PAH targeting siRNA knocked down the mPAH mRNA levels in the liver virtually by 100%. A single-dose i.v. injection of the hPAH expressing SPRING DNA lipid nanoparticle formulation completely rescued siRNA triggered mPAH knockdown in wildtype mice establishing PAH mRNA levels that are 35-fold higher than those found in the livers of untreated control mice.

[0105] Figure 10. Genetic vaccination using dumbbell-shaped DNA (SPRING DNA). SARS-CoV- 2 spike protein expressing dumbbell-shaped DNA (SPRING DNA) triggers significant antibody & T cell responses against SARS-CoV-2. Intramuscular injection (naked or LNP-formulated) of SARS-CoV-2 spike expressing SPRING DNA in BALB / c mice triggered significant levels of spike protein-specific antibodies comparable with those triggered by the only approved DNA (plasmid) based vaccine ZyCoV-D which requires needle-free jet injection but at lower doses. Intracellular cytokine staining at week 7 (4 weeks post-boost) demonstrated induction of IFN- gamma in both CD4+ CD8+ T-cells. The T-cell response triggered by the SPRING vaccine was long-lasting and at similar / higher levels compared with that triggered by alternative DNA vaccine platforms.

[0106] Sequences

[0107] SEQ ID NO 1 : WPRE

[0108] AATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCT

[0109] TTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCT

[0110] TTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTT

[0111] GTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGC

[0112] ATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGC

[0113] GGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGA

[0114] CAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCC

[0115] ACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACC

[0116] TTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCA

[0117] GACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGC

[0118] SEQ ID NO 2: CMV promoter

[0119] CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTG

[0120] ACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATG

[0121] GGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTA

[0122] CGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGAC

[0123] CTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGAT

[0124] GCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGT

[0125] CTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAA

[0126] ATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGT

[0127] CTATATAAGCAGAGCT

[0128] SEQ ID NO 3: hAAT promoter

[0129] GATCTTGCTACCAGTGGAACAGCCACTAAGGATTCTGCAGTGAGAGCAGAGGGCCAGCTAA

[0130] GTGGTACTCTCCCAGAGACTGTCTGACTCACGCCACCCCCTCCACCTTGGACACAGGACGC

[0131] TGTGGTTTCTGAGCCAGGTACAATGACTCCTTTCGGTAAGTGCAGTGGAAGCTGTACACTG

[0132] CCCAGGCAAAGCGTCCGGGCAGCGTAGGCGGGCGACTCAGATCCCAGCCAGTGGACTTA

[0133] GCCCCTGTTTGCTCCTCCGATAACTGGGGTGACCTTGGTTAATATTCACCAGCAGCCTCCC

[0134] CCGTTGCCCCTCTGGATCCACTGCTTAAATACGGACGAGGACAGGGCCCTGTCTCCTCAGC

[0135] TTCAGGCACCACCACTGACCTGGGACAGTGAAT

[0136] SEQ ID NO 4: GAG promoter

[0137] GGCATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCAT

[0138] ATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGA

[0139] CCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCC

[0140] ATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTAT

[0141] CATATGCCAAGTCCGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATG

[0142] CCCAGTACATGACCTTACGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCT

[0143] ATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCC

[0144] CACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGG

[0145] GGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAG

[0146] GCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGC

[0147] GAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCG

[0148] SEQ ID NO 5: U6 promoter GAGGGCCTATTTCCCATGATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGAT AATTGGAATTAATTTGACTGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTA ATAATTTCTTGGGTAGTTTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTACC

[0149] GTAACTTGAAAGTATTTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGAC

[0150] SEQ ID NO 6: H1 promoter

[0151] GAACGCTGACGTCATCAACCCGCTCCAAGGAATCGCGGGCCCAGTGTCACTAGGCGGGAA CACCCAGCGCGCGTGCGCCCTGGCAGGAAGATGGCTGTGAGGGACAGGGGAGTGGCGCC CTGCAAATATTTGCATGTCGCTATGTGTTCTGGGAAATCACCATAAACGTGAAATGTCTTTG

[0152] GATTTGGGAATCTTATAAGTTCTGTATGAGACCACTCTTTCCC

[0153] SEQ ID NO 7: mH1 promoter

[0154] ATATTTGCATGTCGCTATGTGTTCTGGGAAATCACCATAAACGTGAAATGTCTTTGGATTTGG

[0155] GAATCTTATAAGTTCTGTATGAGACCACTCTTTCCC

[0156] SEQ ID NO 8: SV40 polyA

[0157] AACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATA AAGCATTTTTTTCACTGC

[0158] SEQ ID NO 9: BGH polyA

[0159] AATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCA

[0160] SEQ ID NO 10: dNLS

[0161] CGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGTTAGGGGCGGGATGGGCGGAGTTAG GGGCGGGACTATGGTTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGG GAGCCTGGGGACTTTCCACACCTGGTTGCTGACTAATTGAGATGCATGCTTTGCATACTTCT

[0162] GCCTGCTGGGGAGCCTGGGGACTTTCCACACCCTAACTGACACACATTCCACAGC

[0163] SEQ ID NO 11 : Mini-intron

[0164] GTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGAC AGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTT CTCTCCACAG

[0165] SEQ ID NO 12: SV40 enhancer

[0166] CGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGTTAGGGGCGGGATGGGCGGAGTTAG GGGCGGGACTATGGTTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGG GAGCCTGGGGACTTTCCACACCTGGTTGCTGACTAATTGAGATGCATGCTTTGCATACTTCT

[0167] GCCTGCTGGGGAGCCTGGGGACTTTCCACACCCTAACTGACACACATTCCACAGC

[0168] Additional Sequences

[0169] A. PTC Vector Sequences

[0170] OTC-D

[0171] All the vectors have the DNA, RNA and protein sequences in the document

[0172] Legend for DNA sequences:

[0173] Stem Loop Primers

[0174] Nuclear Localization Signal (NLS)

[0175] Intron

[0176] • WPRE

[0177] • m Leader sequence (needed to deliver hOTC gene in vivo in mice)

[0178] Legend for RNA sequences:

[0179] • WPRE

[0180] • m Leader sequence (needed to deliver hOTC gene in vivo in mice)

[0181] Legend for protein sequences

[0182] • m Leader sequence (needed to deliver hOTC gene in vivo in mice)

[0183] 1 . db38 a. 1.1 DNA sequence of db38 (SEQ ID NO 12) b. 1.2 RNA sequence of db38 (SEQ ID NO 13) c. 1 .3 Protein sequence of db38 (SEQ ID NO 14)

[0184] 2. db39 a. 2.1 DNA sequence of db39 (SEQ ID NO 15) b. 2.2 RNA sequence of db39 (SEQ ID NO 13) c. 2.3 Protein sequence of db39 (SEQ ID NO 14)

[0185] 3. db40 a. 3.1 DNA sequence of db40 (SEQ ID NO 15) b. 3.2 RNA sequence of db40 (SEQ ID NO 16) c. 3.3 Protein sequence of db40 (SEQ ID NO 17)

[0186] 4. db41 a. 4.1 DNA sequence of db41 (SEQ ID NO 18) b. 4.2 RNA sequence of db41 (SEQ ID NO 19) c. 4.3 Protein sequence of db41 (SEQ ID NO 20)

[0187] 5. db42 a. 5.1 DNA sequence of db42 (SEQ ID NO 21 ) b. 5.2 RNA sequence of db42 (SEQ ID NO 22) c. 5.3 Protein sequence of db42 (SEQ ID NO 23)

[0188] 6. db43 a. 6.1 DNA sequence of db43 (SEQ ID NO 24) b. 6.2 RNA sequence of db43 (SEQ ID NO 25) c. 6.3 Protein sequence of db43 (SEQ ID NO 26)

[0189] 7. db44 a. 7.1 DNA sequence of db44 (SEQ ID NO 27) b. 7.2 RNA sequence of db44 (SEQ ID NO 28) c. 7.3 Protein sequence of db44 (SEQ ID NO 29)

[0190] 8. db45 a. 8.1 DNA sequence of db45 (SEQ ID NO 30) b. 8.2 RNA sequence of db45 (SEQ ID NO 31 ) c. 8.3 Protein sequence of db45 (SEQ ID NO 32)

[0191] 9. db74 a. 9.1 DNA sequence of db74 (SEQ ID NO 33) b. 9.2 RNA sequence of db74 (SEQ ID NO 34) c. 9.3 Protein sequence of db74 (SEQ ID NO 35)

[0192] 10. db80 a. 10.1 DNA sequence of db80 (SEQ ID NO 36) b. 10.2 RNA sequence of db80 (SEQ ID NO 37) c. 10.3 Protein sequence of db80 (SEQ ID NO 38)

[0193] 11. db101 a. 11.1 DNA sequence of db101 (SEQ ID NO 39) b. 11.2 RNA sequence of db101 (SEQ ID NO 40) c. 1 1 .3 Protein sequence of db101 (SEQ ID NO 41 )

[0194] 1 . db38

[0195] Name: inactive CMV-hOTC-WT

[0196] 1 .1 DNA sequence of db38

[0197] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT

[0198] TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA

[0199] TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA

[0200] ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0201] AACTGACACACATTCCACAGCACTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG

[0202] TTCATAGCCCATATATGGAGTTCCGATTTATACGCTCGTTAGAGATCACCAGGAGGCGGAAG

[0203] AAGCTAGTCGTTTAACACTAGTGTTATGCCCCGTGAGCCCAACAGGGCGGCAATTGATTGG

[0204] AAGTCGGCATTCCAGCAACTGAGTCTTATTTAAGTGAGATTATCAACAGGCGGGATAATCCT

[0205] TATAATTATCAGAAGACTATAACAGGCGTATGGCCGCCATGTAGTACCCTGTAAGTGGTGTG

[0206] CAAACCCAATGACATAGCTCGAGCGGGCTACGACCCTGGTGGATAAACCAAATTTGGAACC

[0207] GCAGTTTGAGGACAACATCGGCTGACTCCCCCGGATTTCTCGGATTTGCTGAATTATCAGTC

[0208] AGGGCGCCCTACGTACGCTCGCATTAAAGGGTTCTACGAACTATTGTCCGCGGTCCCGTGG

[0209] CCTTTCCTGCGGCCGGATATCATGCGGCCACTGAGCACCACTTCGAGAGGGGTAGCCACA

[0210] GTCGCCAACTTTTCCAGTTATTGCTTCTTATAATTATGTCGTATTCTCCCCCATCTTCAGATC

[0211] GAGCTAGCGAATTCatgctgtttaatctgaggatcctgttaaacaatgcagcttttagaaatggtcacaacttcatggttcgaaatt ttcggtgtggacaaccactacaaaataaagtgcagctgaagggccgtgaccttctcactctaaaaaactttaccggagaagaaattaa atatatgctatggctatcagcagatctgaaatttaggataaaacagaaaggagagtatttgcctttattgcaagggaagtccttaggcatg atttttgagaaaagaagtactcgaacaagattgtctacagaaacaggctttgcacttctgggaggacatccttgttttcttaccacacaaga tattcatttgggtgtgaatgaaagtctcacggacacggcccgtgtattgtctagcatggcagatgcagtattggctcgagtgtataaacaat cagatttggacaccctggctaaagaagcatccatcccaattatcaatgggctgtcagatttgtaccatcctatccagatcctggctgattac cicacgclccagGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTT GTCGAGACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACT TreCCTTTCTCTCCACAGgaacactatagctctctgaaaggtcttaccctcagctggatcggggatgggaacaatatcctgc actccatcatgatgagcgcagcgaaattcggaatgcaccttcaggcagctactccaaagggttatgagccggatgctagtgtaaccaa gttggcagagcagtatgccaaagagaatggtaccaagctgttgctgacaaatgatccattggaagcagcgcatggaggcaatgtatta attacagacacttggataagcatgggacaagaagaggagaagaaaaagcggctccaggctttccaaggttaccaggttacaatgaa gactgctaaagttgctgcctctgactggacatttttacactgcttgcccagaaagccagaagaagtggatgatgaagtcttttattctcctcg atcactagtgttcccagaggcagaaaacagaaagtggacaatcatggctgtcatggtgtccctgctgacagattactcacctcagctcc agaagcctaaattttgaACCGGTctcgagGGATCCGTGAAATTTGTGATGCTATTGCAACATGTTAAGA AAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAA GATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGC CTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTT GCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTG TTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGA CTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTG CTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGAC GTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGC TACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTG CGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCT CCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTG CGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCC AAGTAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTA CTTAAGCCCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCTTATAATG GTTACAAATAAAGCAATAGCATCACAAATTTCAGAAATAAAGCATTTTTTTCACTGCattctagttgt ggt:tgtccaaac:ca:caa:gta:c:gaagacaatagcaggca:gc:gggAAGGtGaJgBTTTcaiGAGGTGAAGGGAT AGAGCCCACCGGATC

[0212] 1 .2 RNA sequence of db38

[0213] UCAGAUCGAGCUAGCGAAUUCAUGCUGUUUAAUCUGAGGAUCCUGUUAAACAAUGCAGC UUUUAGAAAUGGUCACAACUUCAUGGUUCGAAAUUUUCGGUGUGGACAACCACUACAAAA UAAAGUGCAGCUGAAGGGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAU UAAAUAUAUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUA UUUGCCUUUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAA CAAGAUUGUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACC ACACAAGAUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUC UAGCAUGGCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGG CUAAAGAAGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGA UCCUGGCUGAUUACCUCACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUC AGCUGGAUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUU CGGAAUGCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCA AGUUGGCAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCA UUGGAAGCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACA AGAAGAGGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGA CUGCUAAAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAA GAAGUGGAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAA CAGAAAGUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGC UCCAGAAGCCUAAAUUUUGAACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUAUUG CAACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAU UACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUG UGGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUU UCUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGU CAGGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGGGC AUUGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCAC GGCGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGC ACUGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCU GUGUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUCAA UCCAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUU CGCCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGUUUCGC CUCGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGGAU UCCACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAGGA CCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUAAG CCCUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUU ACAAAU AAAGCAAU AGCAUCACAAAUU UCACAAAU AAAGCAU UU U UU UCACUGC

[0214] 1 .3 Protein sequence of db38

[0215] MLFNLRILLNNAAFRNGHNFMVRNFRCGQPLQNKVQLKGRDLLTLKNFTGEEIKYMLWLSADLK FRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTAR VLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIGD GNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNVL ITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSLV FPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0216] 2. db39

[0217] Name: CMV-hOTC-WT

[0218] 2.1 DNA sequence of db39 gcgttgacattgattattgactagtcgatggagcggagaatgggcggaactgggcggagttaggggcgggatgggcggagtt aggggcgggactatggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccaca cctggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccacaccctaactgaca cacattccacagcactagttagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataactta cggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagg gactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcccccta ttgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag tcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccacccc attgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatcGCTAGCGAATTCatgctgtttaatct gaggatcctgttaaacaatgcagcttttagaaatggtcacaacttcatggttcgaaattttcggtgtggacaaccactacaaaataaagtg cagctgaagggccgtgaccttctcactctaaaaaactttaccggagaagaaattaaatatatgctatggctatcagcagatctgaaattta ggataaaacagaaaggagagtatttgcctttattgcaagggaagtccttaggcatgatttttgagaaaagaagtactcgaacaagattgt ctacagaaacaggctttgcacttctgggaggacatccttgttttcttaccacacaagatattcatttgggtgtgaatgaaagtctcacggac acggcccgtgtattgtctagcatggcagatgcagtattggctcgagtgtataaacaatcagatttggacaccctggctaaagaagcatcc atcccaattatcaatgggctgtcagatttgtaccatcctatccagatcctggctgattacctcacgctccagGTAAGTATCAAGGT TACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTG CGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGgaacac tatagctctctgaaaggtcttaccctcagctggatcggggatgggaacaatatcctgcactccatcatgatgagcgcagcgaaattcgg aatgcaccttcaggcagctactccaaagggttatgagccggatgctagtgtaaccaagttggcagagcagtatgccaaagagaatggt accaagctgttgctgacaaatgatccattggaagcagcgcatggaggcaatgtattaattacagacacttggataagcatgggacaag aag ag g ag aag aaaaag eg gctccag gctttccaag g ttaccag g ttacaatg aag aetgetaaag ttgctgcctctg actg gacattt ttacactgcttgcccagaaagccagaagaagtggatgatgaagtcttttattctcctcgatcactagtgttcccagaggcagaaaacaga aagtggacaatcatggctgtcatggtgtccctgctgacagattactcacctcagctccagaagcctaaattttgaACCGGTctcgag GGATCCGTGAAATTTGTGATGCTATTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCT GTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTAT

[0219] GTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCC

[0220] CGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTG

[0221] TGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACT

[0222] GGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTA

[0223] TTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGT

[0224] TGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGC

[0225] CTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAAT

[0226] CCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGC

[0227] CTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTCGG

[0228] CGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCATGGATTCCACCGT

[0229] GAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGTAAGGACCTTTGGACTC

[0230] CTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGGTAATTA

[0231] GGTGGTGTAGCGGCCGCaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttcacaaataa

[0232] 2.2 RNA sequence of db39

[0233] UCAGAUCGCUAGCGAAUUCAUGCUGUUUAAUCUGAGGAUCCUGUUAAACAAUGCAGCUU

[0234] UUAGAAAUGGUCACAACUUCAUGGUUCGAAAUUUUCGGUGUGGACAACCACUACAAAAUA

[0235] AAGUGCAGCUGAAGGGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUUA

[0236] AAUAUAUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUAUU

[0237] UGCCUUUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACA

[0238] AGAUUGUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCAC

[0239] ACAAGAUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUA

[0240] GCAUGGCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGGCU

[0241] AAAGAAGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGAUC

[0242] CUGGCUGAUUACCUCACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAG

[0243] CUGGAUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCG

[0244] GAAUGCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAG

[0245] UUGGCAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUU

[0246] GGAAGCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAG

[0247] AAGAGGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACU

[0248] GCUAAAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAAGA

[0249] AGUGGAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAACA

[0250] GAAAGUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUC

[0251] CAGAAGCCUAAAUUUUGAACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUAUUGCA

[0252] ACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUA

[0253] CAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUG

[0254] GAUACGCUGCUUUAAUGCCIIUUGUAIJCAUGCUAUUGCUUCCCGUAUGGCUUIJCAUUUUC

[0255] UCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCA

[0256] GGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGGGCAU

[0257] UGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGG

[0258] CGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCAC

[0259] UGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGU

[0260] GUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUC

[0261] CAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCG

[0262] CCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGU U U CGCC U

[0263] CGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGGAUUC

[0264] CACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAGGACC

[0265] UUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUAAGCC CUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUAC AAAU AAAGCAAU AGCAUC ACAAAU U U CACAAAU AAAGCAU U U U U U UCACUGC

[0266] 2.3 Protein sequence of db39

[0267] MLFNLRILLNNAAFRNGHNFMVRNFRCGQPLQNKVQLKGRDLLTLKNFTGEEIKYMLWLSADLK FRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTAR

[0268] VLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIGD GNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNVL ITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSLV FPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0269] 3. db40

[0270] Name: CMV-hOTC-opt 1

[0271] 3.1 DNA sequence of db40

[0272] > gcgttgacattgattattgactagtcgatggagcggagaatgggcggaactgggcggagttaggggcgggatgggcggagtt aggggcgggactatggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccaca cctggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccacaccctaactgaca cacattccacagcactagttagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataactta cggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagg gactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcccccta ttgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag tcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccacccc attgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatcGCTAGCAATCAAAT ATT ATTA TTATCATACCAACAGACTCAGAGAGAACCCGCCACCATGCTGTTTAATCTGAGGATCCTGTT

[0273] AAACAATGCAGCTTTTAGAAATGGTCACAACTTCATGGTTCGAAATTTTCGGTGTGGACAAC CACTACAAAACAAAGTGCAGCTGAAGGGCCGTGACCTTCTCACTCTAAAAAACTTTACCGGA GAAGAAATTAAATATATGCTATGGCTATCAGCAGATCTAAAATTCAGGATAAAACAGAAAGGA GAGTATTTGCCTTTATTGCAAGGGAAGTCCTTAGGCATGATTTTTGAGAAAAGAAGTACTCG AACAAGATTGTCTACAGAAACAGGCTTTGCACTTCTGGGAGGACATCCTTGTTTTCTTACCA CACAAGATATTCATTTGGGTGTGAATGAAAGTCTCACGGACACGGCCCGTGTATTGTCTAGC ATGGCAGATGCAGTATTGGCTCGTGTGTATAAACAATCAGATTTGGACACCCTGGCTAAAGA AGCATCCATCCCAATTATCAATGGGCTGTCAGATTTGTACCATCCTATCCAAATCCTGGCTG

[0274] ATTACC1CACGCTCCAGGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAA CTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGA CATCCACTTTGCCT7TCTCTCCACAGGAACACTATAGCTCTCTGAAAGGTCTTACCCTCAGC TGGATCGGGGATGGGAACAATATCCTGCACTCCATCATGATGAGCGCAGCGAAATTCGGAA TGCACCTTCAGGCAGCTACTCCAAAGGGTTATGAGCCGGATGCTAGTGTAACCAAGTTGGC AGAGCAGTATGCCAAAGAGAATGGTACCAAGCTGTTGCTGACAAATGATCCATTGGAAGCA GCGCATGGAGGCAATGTATTAATTACAGACACTTGGATAAGCATGGGACAAGAAGAGGAGA AGAAAAAGCGGCTCCAGGCTTTCCAAGGTTACCAGGTTACAATGAAGACTGCTAAAGTTGCT

[0275] GCCTCTGACTGGACATTTTTACATTGCTTGCCCAGAAAGCCAGAAGAAGTGGATGATGAAGT CTTTTATTCTCCACGATCACTAGTGTTCCCAGAGGCAGAAAACAGAAAGTGGACAATCATGG CTGTCATGGTGTCCCTGCTGACAGATTACTCACCTCAGCTCCAGAAGCCTAAATTTTGACTC GAGGGATCCGTGAAATTTGTGTTGCTATTGCAACATGTTAAGAAAATTTCCCGTTATTTGCAC TCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAAC TATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCT TCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAG TTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCA

[0276] CTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCC TATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCT

[0277] GTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTC

[0278] GCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCA

[0279] ATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTC

[0280] GCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTC

[0281] GGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCATGGATTCCACC

[0282] GTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGCAAGGACCTTTGGA

[0283] CTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGGCA

[0284] ATTAGGTGGTGTAGCGGCCGCaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttcaca aataaagcatttttttcactgcattctagttg tgg tttg tccaaactcatcaatg tatctg aagacaatagcag gcatgctg g g AAG GTCa tpWBBAC®

[0285] 3.2 RNA sequence of db40

[0286] UCAGAUCGCUAGCAAUCAAAUAUUAUUAUUAUCAUACCAACAGACUCAGAGAGAACCCGC

[0287] CACCAUGCUGUUUAAUCUGAGGAUCCUGUUAAACAAUGCAGCUUUUAGAAAUGGUCACAA

[0288] CUUCAUGGUUCGAAAUUUUCGGUGUGGACAACCACUACAAAACAAAGUGCAGCUGAAGG

[0289] GCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUUAAAUAUAUGCUAUGGC

[0290] UAUCAGCAGAUCUAAAAUUCAGGAUAAAACAGAAAGGAGAGUAUUUGCCUUUAUUGCAAG

[0291] GGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUUGUCUACAGAAA

[0292] CAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCACACAAGAUAUUCAUUUG

[0293] GGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUAGCAUGGCAGAUGCAGU

[0294] AUUGGCUCGUGUGUAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGAAGCAUCCAUCC

[0295] CAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAAAUCCUGGCUGAUUACCUCA

[0296] CGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGGAUCGGGGAUGGG

[0297] AACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAUGCACCUUCAGGCA

[0298] GCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGGCAGAGCAGUAUGC

[0299] CAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAAGCAGCGCAUGGAG

[0300] GCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAGAAGAGGAGAAGAAAAAGC

[0301] GGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACUGCUAAAGUUGCUGCCUCU

[0302] GACUGGACAUUUUUACAUUGCUUGCCCAGAAAGCCAGAAGAAGUGGAUGAUGAAGUCUU

[0303] UUAUUCUCCACGAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAAGUGGACAAUCAUGGC

[0304] UGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUCCAGAAGCCUAAAUUUUGAC

[0305] UCGAGGGAUCCGUGAAAUUUGUGUUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUAU

[0306] UUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACUGG

[0307] UAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUGU

[0308] AUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUUG

[0309] CUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACUG

[0310] UGUUUGCUGACGCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUCC

[0311] GGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUUG

[0312] CCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGGG

[0313] GAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGGG

[0314] ACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCCU

[0315] GCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAUC

[0316] UCCCUUUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGGU

[0317] CUUCACCUGUGCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAUG

[0318] CAAAUCGUCAACUUGGCAUGCCAAGCAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAAU

[0319] UAUUAACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCGGCAAUUAGGUGGUGUAGCGGC

[0320] CGCAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUC

[0321] ACAAAUAAAGCAUUUUUUUCACUGC

[0322] 3.3 Protein sequence of db40 MLFNLRILLNNAAFRNGHNFMVRNFRCGQPLQNKVQLKGRDLLTLKNFTGEEIKYMLWLSADLK

[0323] FRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTAR

[0324] VLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIGD

[0325] GNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNVL

[0326] ITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSLV

[0327] FPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0328] 4. db41

[0329] Name: CMV-hOTC-opt 2

[0330] 4.1 DNA sequence of db41

[0331] >

[0332] ATCGAGafgTTTTcatCTGGAGAGTGTTGGCGATGTACGGGCCAGATATAC

[0333] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT

[0334] TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA

[0335] TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA

[0336] ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0337] AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG

[0338] TTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGA

[0339] CCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAA

[0340] TAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTA

[0341] CATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG

[0342] CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTA

[0343] TTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC

[0344] GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGG

[0345] CACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGG

[0346] GCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGAT

[0347] CGCTAGCAATCAAATATTATTATTATCATACCAACAGACTCAGG7AAGTATCA4GG7TACAAG

[0348] ACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTC

[0349] TGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGAGAGAACCCG

[0350] CCACCATGCTGTTTAATCTGAGGATCCTGTTAAACAATGCAGCTTTTAGAAATGGTCACAACT

[0351] TCATGGTTCGAAATTTTCGGTGTGGACAACCACTACAAAACAAAGTGCAGCTGAAGGGCCG

[0352] TGACCTTCTCACTCTAAAAAACTTTACCGGAGAAGAAATTAAATATATGCTATGGCTATCAGC

[0353] AGATCTAAAATTCAGGATAAAACAGAAAGGAGAGTATTTGCCTTTATTGCAAGGGAAGTCCT

[0354] TAGGCATGATTTTTGAGAAAAGAAGTACTCGAACAAGATTGTCTACAGAAACAGGCTTTGCA

[0355] CTTCTGGGAGGACATCCTTGTTTTCTTACCACACAAGATATTCATTTGGGTGTGAATGAAAGT

[0356] CTCACGGACACGGCCCGTGTATTGTCTAGCATGGCAGATGCAGTATTGGCTCGTGTGTATA

[0357] AACAATCAGATTTGGACACCCTGGCTAAAGAAGCATCCATCCCAATTATCAATGGGCTGTCA

[0358] GATTTGTACCATCCTATCCAAATCCTGGCTGATTACCTCACGCTCCAGGAACACTATAGCTC

[0359] TCTGAAAGGTCTTACCCTCAGCTGGATCGGGGATGGGAACAATATCCTGCACTCCATCATG

[0360] ATGAGCGCAGCGAAATTCGGAATGCACCTTCAGGCAGCTACTCCAAAGGGTTATGAGCCGG

[0361] ATGCTAGTGTAACCAAGTTGGCAGAGCAGTATGCCAAAGAGAATGGTACCAAGCTGTTGCT

[0362] GACAAATGATCCATTGGAAGCAGCGCATGGAGGCAATGTATTAATTACAGACACTTGGATAA

[0363] GCATGGGACAAGAAGAGGAGAAGAAAAAGCGGCTCCAGGCTTTCCAAGGTTACCAGGTTAC

[0364] AATGAAGACTGCTAAAGTTGCTGCCTCTGACTGGACATTTTTACATTGCTTGCCCAGAAAGC

[0365] CAGAAGAAGTGGATGATGAAGTCTTTTATTCTCCACGATCACTAGTGTTCCCAGAGGCAGAA

[0366] AACAGAAAGTGGACAATCATGGCTGTCATGGTGTCCCTGCTGACAGATTACTCACCTCAGCT

[0367] CCAGAAGCCTAAATTTTGACTCGAGGGATCCGTGAAATTTGTGTTGCTATTGCAACATGTTA

[0368] AGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTG

[0369] AAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAA

[0370] TGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCT

[0371] GGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCAC

[0372] TGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCC

[0373] GGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCC GCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGC

[0374] TGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTT

[0375] CTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGC

[0376] TCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCC

[0377] GCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGA

[0378] CTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCA

[0379] TGCCAAGCAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAG

[0380] GGTTACTTAAGCCCTGCGGCAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCTT

[0381] ATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCa ttctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctgggOMiiiiiHiHBMiBlOi

[0382] 4.2 RNA sequence of db41

[0383] UCAGAUCGCUAGCAAUCAAAUAUUAUUAUUAUCAUACCAACAGACUCAGAGAGAACCCGC

[0384] CACCAUGCUGUUUAAUCUGAGGAUCCUGUUAAACAAUGCAGCUUUUAGAAAUGGUCACAA

[0385] CUUCAUGGUUCGAAAUUUUCGGUGUGGACAACCACUACAAAACAAAGUGCAGCUGAAGG

[0386] GCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUUAAAUAUAUGCUAUGGC

[0387] UAUCAGCAGAUCUAAAAUUCAGGAUAAAACAGAAAGGAGAGUAUUUGCCUUUAUUGCAAG

[0388] GGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUUGUCUACAGAAA

[0389] CAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCACACAAGAUAUUCAUUUG

[0390] GGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUAGCAUGGCAGAUGCAGU

[0391] AUUGGCUCGUGUGUAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGAAGCAUCCAUCC

[0392] CAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAAAUCCUGGCUGAUUACCUCA

[0393] CGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGGAUCGGGGAUGGG

[0394] AACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAUGCACCUUCAGGCA

[0395] GCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGGCAGAGCAGUAUGC

[0396] CAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAAGCAGCGCAUGGAG

[0397] GCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAGAAGAGGAGAAGAAAAAGC

[0398] GGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACUGCUAAAGUUGCUGCCUCU

[0399] GACUGGACAUUUUUACAUUGCUUGCCCAGAAAGCCAGAAGAAGUGGAUGAUGAAGUCUU

[0400] UUAUUCUCCACGAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAAGUGGACAAUCAUGGC

[0401] UGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUCCAGAAGCCUAAAUUUUGAC

[0402] UCGAGGGAUCCGUGAAAUUUGUGUUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUAU

[0403] UUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACUGG

[0404] UAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUGU

[0405] AUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUUG

[0406] CUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACUG

[0407] UGUUUGCUGACGCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUCC

[0408] GGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUUG

[0409] CCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGGG

[0410] GAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGGG

[0411] ACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCCU

[0412] GCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAUC

[0413] UCCCUUUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGGU

[0414] CUUCACCUGUGCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAUG

[0415] CAAAUCGUCAACUUGGCAUGCCAAGCAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAAU

[0416] UAUUAACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCGGCAAUUAGGUGGUGUAGCGGC

[0417] CGCAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUC

[0418] ACAAAUAAAGCAUUUUUUUCACUGC

[0419] 4.3 Protein sequence of db41 MLFNLRILLNNAAFRNGHNFMVRNFRCGQPLQNKVQLKGRDLLTLKNFTGEEIKYMLWLSADLK FRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTAR VLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIGD GNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNVL ITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSLV FPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0420] 5. db42

[0421] Name: inactive CMV-mLeader-hOTC-WT

[0422] 5.1 DNA sequence of db42

[0423] >

[0424] ATCCAGafgTTTTcatCTGGAGACTCTTCGCGATGTACGGGCCAGATATAC

[0425] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT AACTGACACACATTCCACAGCACTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG TTCATAGCCCATATATGGAGTTCCGATTTATACGCTCGTTAGAGATCACCAGGAGGCGGAAG AAGCTAGTCGTTTAACACTAGTGTTATGCCCCGTGAGCCCAACAGGGCGGCAATTGATTGG AAGTCGGCATTCCAGCAACTGAGTCTTATTTAAGTGAGATTATCAACAGGCGGGATAATCCT TATAATTATCAGAAGACTATAACAGGCGTATGGCCGCCATGTAGTACCCTGTAAGTGGTGTG CAAACCCAATGACATAGCTCGAGCGGGCTACGACCCTGGTGGATAAACCAAATTTGGAACC GCAGTTTGAGGACAACATCGGCTGACTCCCCCGGATTTCTCGGATTTGCTGAATTATCAGTC AGGGCGCCCTACGTACGCTCGCATTAAAGGGTTCTACGAACTATTGTCCGCGGTCCCGTGG CCTTTCCTGCGGCCGGATATCATGCGGCCACTGAGCACCACTTCGAGAGGGGTAGCCACA GTCGCCAACTTTTCCAGTTATTGCTTCTTATAATTATGTCGTATTCTCCCCCATCTTCAGATC GAG CT AGCG AATT Catactatctaatttaaaaatcctactcaacaatacaactcttaqaaaqgatcacacttctataatt caacatttttaqtqtaaaaaaccaatccaaaatcaaatacaactaaaaaaccataaccttctcactctaaaaaactttaccaaaaa agaaattaaatatatgctatggctatcagcagatctgaaatttaggataaaacagaaaggagagtatttgcctttattgcaagggaagtc cttaggcatgatttttgagaaaagaagtactcgaacaagattgtctacagaaacaggctttgcacttctgggaggacatccttgttttcttac cacacaagatattcatttgggtgtgaatgaaagtctcacggacacggcccgtgtattgtctagcatggcagatgcagtattggctcgagtg tataaacaatcagatttg gacaccctg gctaaag aag catccatcccaattatcaatg g gctg tcag atttgtaccatcctatccag atcct ggctgattacctcacgctccagGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACT GGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGAC ATCCACT7TGCC7TTCTCTCCACAGgaacactatagctctctgaaaggtcttaccctcagctggatcggggatgggaac aatatcctgcactccatcatgatgagcgcagcgaaattcggaatgcaccttcaggcagctactccaaagggttatgagccggatgctag tgtaaccaagttggcagagcagtatgccaaagagaatggtaccaagctgttgctgacaaatgatccattggaagcagcgcatggagg caatgtattaattacagacacttggataagcatgggacaagaagaggagaagaaaaagcggctccaggctttccaaggttaccaggt tacaatgaagactgctaaagttgctgcctctgactggacatttttacactgcttgcccagaaagccagaagaagtggatgatgaagtctttt attctcctcgatcactagtgttcccagaggcagaaaacagaaagtggacaatcatggctgtcatggtgtccctgctgacagattactcac ctcagctccagaagcctaaattttgaACCGGTctcgagGGATCCGTGAAATTTGTGATGCTATTGCAACATG

[0426] TTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTG TGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTT AATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCC TGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCA CTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTC CGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCC CGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAG CTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCT TCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGG CTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGC CGCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAG ACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGC ATGCCAAGTAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGA

[0427] GGGTTACTTAAGCCCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCT

[0428] TATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGC attc:agttgtggt:tg:ccaaactcatcaatgta:ctgaagacaa:agcaggcatgctgggAAGGTCifgYWWca:GAGG4GA

[0429] AGGCATAGAGGCCAGGGGATC

[0430] 5.2 RNA sequence of db42

[0431] UCAGAUCGAGCUAGCGAAUUCAUGCUGUCUAAUUUGAGGAUCCUGCUCAACAAUGCAGC

[0432] UCUUAGAAAGGGUCACACUUCUGUGGUUCGACAUUUUUGGUGUGGGAAGCCAGUCCAAA

[0433] GUCAAGUGCAGCUGAAGGGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAA

[0434] AUUAAAUAUAUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAG

[0435] UAUUUGCCUUUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCG

[0436] AACAAGAUUGUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUA

[0437] CCACACAAGAUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUG

[0438] UCUAGCAUGGCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCU

[0439] GGCUAAAGAAGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCA

[0440] GAUCCUGGCUGAUUACCUCACGCUCCAGAACACUAUAGCUCUCUGAAAGGUCUUACCCU

[0441] CAGCUGGAUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAU

[0442] UCGGAAUGCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACC

[0443] AAGUUGGCAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCC

[0444] AUUGGAAGCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGAC

[0445] AAGAAGAGGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGA

[0446] CUGCUAAAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAA

[0447] GAAGUGGAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAA

[0448] CAGAAAGUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGC

[0449] UCCAGAAGCCUAAAUUUUGAACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUAUUG

[0450] CAACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAU

[0451] UACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUG

[0452] UGGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUU

[0453] UCUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGU

[0454] CAGGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGGGC

[0455] AUUGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCAC

[0456] GGCGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGC

[0457] ACUGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCU

[0458] GUGUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUCAA

[0459] UCCAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUU

[0460] CGCCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGUUUCGC

[0461] CUCGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGGAU

[0462] UCCACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAGGA

[0463] CCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUAAG CCCUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUU ACAAAU AAAGCAAU AGCAUCACAAAUU UCACAAAU AAAGCAU UU U UU UCACUGC

[0464] 5.3 Protein sequence of db42

[0465] MLSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKN FTG E E IKYM LWLS ADL

[0466] KFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTA

[0467] RVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIG

[0468] DGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNV LITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSL VFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0469] 6. db43 Name: CMV-mLeader-hOTC-WT

[0470] 6.1 DNA sequence of db43

[0471] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0472] AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG TTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGA CCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAA TAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTA CATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTA TTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGG CACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGG GCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGAT

[0473] CGCTAGCGAATTCatactatctaatttaaaaatcctactcaacaatacaactcttaaaaaaaatcacacttctataattc qacatttttqqtqtqqqaaqccaqtccaaaatcaaqtacaqctqaaaaaccqtaaccttctcactctaaaaaactttaccaaaaaa gaaattaaatatatgctatggctatcagcagatctgaaatttaggataaaacagaaaggagagtatttgcctttattgcaagggaagtcct taggcatgatttttgagaaaagaagtactcgaacaagattgtctacagaaacaggctttgcacttctgggaggacatccttgttttcttacc acacaagatattcatttgggtgtgaatgaaagtctcacggacacggcccgtgtattgtctagcatggcagatgcagtattggctcgagtgt ataaacaatcagatttggacaccctggctaaagaagcatccatcccaattatcaatgggctgtcagatttgtaccatcctatccagatcct ggctgattacctcacgctccagGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACT GGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGAC ATCCAC'nTGCCTTTCTCTCCACAGgaacactatagctctctgaaaggtcttaccctcagctggatcggggatgggaac aatatcctgcactccatcatgatgagcgcagcgaaattcggaatgcaccttcaggcagctactccaaagggttatgagccggatgctag tgtaaccaagttggcagagcagtatgccaaagagaatggtaccaagctgttgctgacaaatgatccattggaagcagcgcatggagg caatgtattaattacagacacttggataagcatgggacaagaagaggagaagaaaaagcggctccaggctttccaaggttaccaggt tacaatgaagactgctaaagttgctgcctctgactggacatttttacactgcttgcccagaaagccagaagaagtggatgatgaagtctttt attctcctcgatcactagtgttcccagaggcagaaaacagaaagtggacaatcatggctgtcatggtgtccctgctgacagattactcac ctcagctccagaagcctaaattttgaACCGGTctcgagGGATCCGTGAAATTTGTGATGCTATTGCAACATG TTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTG

[0474] TGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTT AATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCC TGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCA CTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTC CGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCC CGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAG CTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCT TCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGG CTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGC CGCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAG ACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGC ATGCCAAGTAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGA GGGTTACTTAAGCCCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCT TATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGC attctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctggg

[0475] 6.2 RNA sequence of db43 UCAGAUCGCUAGCGAAUUCAUGCUGUCUAAUUUGAGGAUCCUGCUCAACAAUGCAGCUC UUAGAAAGGGUCACACUUCUGUGGUUCGACAUUUUUGGUGUGGGAAGCCAGUCCAAAGU CAAGUGCAGCUGAAGGGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUU AAAUAUAUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUAU UUGCCUUUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAAC AAGAUUGUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCA CACAAGAUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCU AGCAUGGCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGGC UAAAGAAGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGAU

[0476] CCUGGCUGAUUACCUCACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCA GCUGGAUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUC GGAAUGCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAA GUUGGCAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAU UGGAAGCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAA GAAGAGGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGAC UGCUAAAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAAG AAGUGGAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAAC AGAAAGUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCU

[0477] CCAGAAGCCUAAAUUUUGAACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUAUUGC AACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUU ACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGU GGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUU CUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCA GGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGGGCAU UGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGG CGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCAC UGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGU

[0478] GUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUC CAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCG CCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGU U U CGCC U CGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGGAUUC CACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAGGACC UUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUAAGCC CUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUAC AAAU AAAGCAAU AGCAUC ACAAAU U U CACAAAU AAAGCAU U U U U U UCACUGC

[0479] 6.3 Protein sequence of db43

[0480] MLSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKN FTG E E IKYM LWLS ADL

[0481] KFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTA RVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIG DGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNV LITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSL VFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0482] 7. db44

[0483] Name: CMV-mLeader-hOTC-opt 1

[0484] 7.1 DNA sequence of db44

[0485] > gcgttgacattgattattgactagtcgatggagcggagaatgggcggaactgggcggagttaggggcgggatgggcggagtt aggggcgggactatggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccaca cctggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccacaccctaactgaca cacattccacagcactagttagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataactta cggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagg gactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcccccta ttgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag tcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccacccc attgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatcGCTAGCAATCAAAT ATT ATTA

[0486] TTATCATACCAACAGACTCAGAGAGAACCCGCCACCatqctatctaatttaaaaatcctactcaacaatgc TactcttaaaaaaaqtcacacttctatqattcaacatttttaqtqtqgaaaaccaatccaaaatcaaGTGCAGCTGAAG GGCCGTGACCTTCTCACTCTAAAAAACTTTACCGGAGAAGAAATTAAATATATGCTATGGCT ATCAGCAGATCTAAAATTCAGGATAAAACAGAAAGGAGAGTATTTGCCTTTATTGCAAGGGA AGTCCTTAGGCATGATTTTTGAGAAAAGAAGTACTCGAACAAGATTGTCTACAGAAACAGGC TTTGCACTTCTGGGAGGACATCCTTGTTTTCTTACCACACAAGATATTCATTTGGGTGTGAAT GAAAGTCTCACGGACACGGCCCGTGTATTGTCTAGCATGGCAGATGCAGTATTGGCTCGTG

[0487] TGTATAAACAATCAGATTTGGACACCCTGGCTAAAGAAGCATCCATCCCAATTATCAATGGG CTGTCAGATTTGTACCATCCTATCCAAATCCTGGCTGATTACCTCACGCTCCAGGTAAGTAT

[0488] CAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGA CTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACA GGAACACTATAGCTCTCTGAAAGGTCTTACCCTCAGCTGGATCGGGGATGGGAACAATATC CTGCACTCCATCATGATGAGCGCAGCGAAATTCGGAATGCACCTTCAGGCAGCTACTCCAA

[0489] AGGGTTATGAGCCGGATGCTAGTGTAACCAAGTTGGCAGAGCAGTATGCCAAAGAGAATGG TACCAAGCTGTTGCTGACAAATGATCCATTGGAAGCAGCGCATGGAGGCAATGTATTAATTA CAGACACTTGGATAAGCATGGGACAAGAAGAGGAGAAGAAAAAGCGGCTCCAGGCTTTCCA AGGTTACCAGGTTACAATGAAGACTGCTAAAGTTGCTGCCTCTGACTGGACATTTTTACATT

[0490] GCTTGCCCAGAAAGCCAGAAGAAGTGGATGATGAAGTCTTTTATTCTCCACGATCACTAGTG TTCCCAGAGGCAGAAAACAGAAAGTGGACAATCATGGCTGTCATGGTGTCCCTGCTGACAG ATTACTCACCTCAGCTCCAGAAGCCTAAATTTTGACTCGAGGGATCCGTGAAATTTGTGTTG CTATTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTG GATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGT GGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCC TCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACG

[0491] TGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCAC CTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATC

[0492] GCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTG GTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTC TGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCG CGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCG GATCTCCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTG GTCTTCACCTGTGCAGACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGC AAATCGTCAACTTGGCATGCCAAGCAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATT

[0493] AACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGGCAATTAGGTGGTGTAGCGGCCGCaact tgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttcacaaataaagcatttttttcactgcattctagttgtggtttgtc caaactcatcaatg:atctgaagacaatagcaggcatgc:gggAAGGt®tg^fTTcaiGAG<STGA®(S<SMAGAG

[0494] CCGAGGGCATG

[0495] 7.2 RNA sequence of db44

[0496] UCAGAUCGCUAGCAAUCAAAUAUUAUUAUUAUCAUACCAACAGACUCAGAGAGAACCCGC CACCAUGCUGUCUAAUUUGAGGAUCCUGCUCAACAAUGCUGCUCUUAGAAAGGGUCACA CUUCUGUGGUUCGACAUUUUUGGUGUGGGAAGCCAGUCCAAAGUCAAGUGCAGCUGAAG

[0497] GGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUUAAAUAUAUGCUAUGG CUAUCAGCAGAUCUAAAAUUCAGGAUAAAACAGAAAGGAGAGUAUUUGCCUUUAUUGCAA GGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUUGUCUACAGAA ACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCACACAAGAUAUUCAUUU GGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUAGCAUGGCAGAUGCAG UAUUGGCUCGUGUGUAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGAAGCAUCCAUC CCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAAAUCCUGGCUGAUUACCU CACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGGAUCGGGGAUG GGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAUGCACCUUCAG GCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGGCAGAGCAGUA

[0498] UGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAAGCAGCGCAUG GAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAGAAGAGGAGAAGAAAA AGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACUGCUAAAGUUGCUGCC UCUGACUGGACAUUUUUACAUUGCUUGCCCAGAAAGCCAGAAGAAGUGGAUGAUGAAGU CUUUUAUUCUCCACGAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAAGUGGACAAUCAU GGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUCCAGAAGCCUAAAUUUU

[0499] GACUCGAGGGAUCCGUGAAAUUUGUGUUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGU UAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACU GGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAALIGCCUUU GUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGU UGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCAC

[0500] UGUGUUUGCUGACGCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUU CCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUU GCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGG GGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGG GACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCC UGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAU

[0501] CUCCCUUUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGG UCUUCACCUGUGCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAU GCAAAUCGUCAACUUGGCAUGCCAAGCAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAA UUAUUAACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCGGCAAUUAGGUGGUGUAGCGG CCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUU CACAAAUAAAGCAUUUUUUUCACUGC

[0502] 7.3 Protein sequence of db44

[0503] MLSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKNFTG E E IKYM LWLSADL

[0504] KFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTA RVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIG DGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNV LITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSL VFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0505] 8. db45

[0506] Name: CMV-mLeader-hOTC-opt 2

[0507] 8.1 DNA sequence of db45

[0508] > gcgttgacattgattattgactagtcgatggagcggagaatgggcggaactgggcggagttaggggcgggatgggcggagtt aggggcgggactatggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccaca cctggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccacaccctaactgaca cacattccacagcactagttagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataactta cggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagg gactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcccccta ttgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag tcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccacccc attgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcagagctGGTTTAGTGAACCGTCAGATCGCTAGCAATCAAA TATTATTATTATCATACCAACAGACTCAGG77L4GL47’CA4GG7TACAAGACAGG7’7'TAAGGAG ACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATT GGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGAGAGAACCGGGCAGGatactatclaatla aqqatcctqctcaacaatqcTqctcttaqaaaqqqtcacacttctqtqqttcqacatttttqqtqtqqqaaqccaqtccaaagt caaGTGCAGCTGAAGGGCCGTGACCTTCTCACTCTAAAAAACTTTACCGGAGAAGAAATTAA ATATATGCTATGGCTATCAGCAGATCTAAAATTCAGGATAAAACAGAAAGGAGAGTATTTGC CTTTATTGCAAGGGAAGTCCTTAGGCATGATTTTTGAGAAAAGAAGTACTCGAACAAGATTG TCTACAGAAACAGGCTTTGCACTTCTGGGAGGACATCCTTGTTTTCTTACCACACAAGATATT CATTTGGGTGTGAATGAAAGTCTCACGGACACGGCCCGTGTATTGTCTAGCATGGCAGATG

[0509] CAGTATTGGCTCGTGTGTATAAACAATCAGATTTGGACACCCTGGCTAAAGAAGCATCCATC CCAATTATCAATGGGCTGTCAGATTTGTACCATCCTATCCAAATCCTGGCTGATTACCTCAC GCTCCAGGAACACTATAGCTCTCTGAAAGGTCTTACCCTCAGCTGGATCGGGGATGGGAAC AATATCCTGCACTCCATCATGATGAGCGCAGCGAAATTCGGAATGCACCTTCAGGCAGCTA CTCCAAAGGGTTATGAGCCGGATGCTAGTGTAACCAAGTTGGCAGAGCAGTATGCCAAAGA

[0510] GAATGGTACCAAGCTGTTGCTGACAAATGATCCATTGGAAGCAGCGCATGGAGGCAATGTA TTAATTACAGACACTTGGATAAGCATGGGACAAGAAGAGGAGAAGAAAAAGCGGCTCCAGG CTTTCCAAGGTTACCAGGTTACAATGAAGACTGCTAAAGTTGCTGCCTCTGACTGGACATTT TTACATTGCTTGCCCAGAAAGCCAGAAGAAGTGGATGATGAAGTCTTTTATTCTCCACGATC ACTAGTGTTCCCAGAGGCAGAAAACAGAAAGTGGACAATCATGGCTGTCATGGTGTCCCTG

[0511] CTGACAGATTACTCACCTCAGCTCCAGAAGCCTAAATTTTGACTCGAGGGATCCGTGAAATT TGTGTTGCTATTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCA ACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTAC GCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCAT TTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCA

[0512] GGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTG CCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGA ACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAA TTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACC TGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTC

[0513] CTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGA CGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTGTTTCGCGTCGGCGTCCGGTCCGTG TTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCT GGCATGCAAATCGTCAACTTGGCATGCCAAGCAAGGACCTTTGGACTCCTTATATAAAAGAT CAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGGCAATTAGGTGGTGTAGCG

[0514] GCCGCaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttcacaaataaagcatttttttcactgcattct agf.gtggf.tg'.ccaaactcatcaatgta'.ctgaagacaa'.agcaggcatgctgggAAGG^CzrgTT^catGACGWGAAG CCATAGAGCCCACCGCATC

[0515] 8.2 RNA sequence of db45

[0516] UCAGAUCGCUAGCAAUCAAAUAUUAUUAUUAUCAUACCAACAGACUCAGAUGCUGUCUAA UUUGAGGAUCCUGCUCAACAAUGCUGCUCUUAGAAAGGGUCACACUUCUGUGGUUCGAC AUUUUUGGUGUGGGAAGCCAGUCCAAAGUCAAGUGCAGCUGAAGGGCCGUGACCUUCUC ACUCUAAAAAACUUUACCGGAGAAGAAAUUAAAUAUAUGCUAUGGCUAUCAGCAGAUCUA AAAUUCAGGAUAAAACAGAAAGGAGAGUAUUUGCCUUUAUUGCAAGGGAAGUCCUUAGGC

[0517] AUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUUGUCUACAGAAACAGGCUUUGCACUU CUGGGAGGACAUCCUUGUUUUCUUACCACACAAGAUAUUCAUUUGGGUGUGAAUGAAAG UCUCACGGACACGGCCCGUGUAUUGUCUAGCAUGGCAGAUGCAGUAUUGGCUCGUGUG UAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGAAGCAUCCAUCCCAAUUAUCAAUGGG CUGUCAGAUUUGUACCAUCCUAUCCAAAUCCUGGCUGAUUACCUCACGCUCCAGGAACA

[0518] CUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGGAUCGGGGAUGGGAACAAUAUCCUGC ACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAUGCACCUUCAGGCAGCUACUCCAAAG GGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGGCAGAGCAGUAUGCCAAAGAGAAUGG UACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAAGCAGCGCAUGGAGGCAAUGUAUUAA UUACAGACACUUGGAUAAGCAUGGGACAAGAAGAGGAGAAGAAAAAGCGGCUCCAGGCU

[0519] UUCCAAGGUUACCAGGUUACAAUGAAGACUGCUAAAGUUGCUGCCUCUGACUGGACAUU UUUACAUUGCUUGCCCAGAAAGCCAGAAGAAGUGGAUGAUGAAGUCUUUUAUUCUCCAC GAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAAGUGGACAAUCAUGGCUGUCAUGGUG UCCCUGCUGACAGAUUACUCACCUCAGCUCCAGAAGCCUAAAUUUUGACUCGAGGGAUC CGUGAAAUUUGUGUUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUG UUCCUGUUAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACU AUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUU GCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUA

[0520] UGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGAC GCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGC UUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGG ACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGU CCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUG CUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCU CUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGG CCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGGUGUUCACCUGU

[0521] GCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCA ACUUGGCAUGCCAAGCAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAA AUGGGAGGAGGGUUACUUAAGCCCUGCGGCAAUUAGGUGGUGUAGCGGCCGCAACUUG UUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAG CAUUUUUUUCACUGC

[0522] 8.3 Protein sequence of db45

[0523] MLSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKN FTG E E IKYM LWLS ADL

[0524] KFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTA RVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIG

[0525] DGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNV LITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSL VFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0526] 9. db74

[0527] Name: CMV-eGFP-P2A-mLeader-hOTC-WT-3xFLAG

[0528] 9.1 DNA sequence of db74

[0529] ATQCAG^gnTT^tQTGGAGAGTCTTaGCGATGTAQQGGCCAGATATAO gcgttgacattgattattgactagtcgatggagcggagaatgggcggaactgggcggagttaggggcgggatgggcggagtt aggggcgggactatggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccaca cctggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccacaccctaactgaca cacattccacagcactagttagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataactta cggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagg gactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcccccta ttgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag tcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccacccc attgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatcgCTAGCGCTACCGGTCGCCA CCATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTG

[0530] GACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCAC CTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCC CACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACAT GAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCAT CTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACAC CCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGG GCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAG AACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTC GCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAAC CACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATG GTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAG TCCGGCCGGACTCAGATCTCGAGCTCAAGCTTcGGAAGCGGAGCTACTAACTTCAGCCTGC T G AAGCAGGCTGGAG ACGTGGAGG AG AACCCTGGGCCT ctatctaatttaaaaatcctactcaacaata caactcttaqaaaaaatcacacttctataattcaacatttttaatataaqaaaccaatccaaaatcaaatgcaactaaaaaacc gtgaccttctcactctaaaaaactttaccggagaagaaattaaatatatgctatggctatcagcagatctgaaatttaggataaaacaga aaggagagtatttgcctttattgcaagggaagtccttaggcatgatttttgagaaaagaagtactcgaacaagattgtctacagaaacag gctttgcacttctgggaggacatccttgttttcttaccacacaagatattcatttgggtgtgaatgaaagtctcacggacacggcccgtgtatt gtctagcatggcagatgcagtattggctcgagtgtataaacaatcagatttggacaccctggctaaagaagcatccatcccaattatcaa tgggctgtcagatttgtaccatcctatccagatcctggctgattacctcacgctccagGTAAGTAT'CAAGGTTACAAGACA GGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCTGA TAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGgaacactaXagcXcXcigaa aggtcttaccctcagctggatcggggatgggaacaatatcctgcactccatcatgatgagcgcagcgaaattcggaatgcaccttcagg cagctactccaaagggttatgagccggatgctagtgtaaccaagttggcagagcagtatgccaaagagaatggtaccaagctgttgct gacaaatgatccattggaagcagcgcatggaggcaatgtattaattacagacacttggataagcatgggacaagaagaggagaag aaaaagcggctccaggctttccaaggttaccaggttacaatgaagactgctaaagttgctgcctctgactggacatttttacactgcttgcc cagaaagccagaagaagtggatgatgaagtcttttattctcctcgatcactagtgttcccagaggcagaaaacagaaagtggacaatc atggctgtcatggtgtccctgctgacagattactcacctcagctccagaagcctaaatttGACTACAAGGACCACGACGGT GACTACAAGGACCACGACATCGACTACAAGGACGACGACGACAAGtgatgataaGGTACCGCG GGCCCGGGATCCACCGGATCTAGATAACTGATCATAATCAGCCATACCACATTTGTAGAGG TTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAA

[0531] TTGTTGTTGTTGCggccgcaacttgtttattgcxagcttataatggttacaaataaagcaatagcatcacaaatttcacaaataa agcatttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctgggOBBiM^O TTcatGACCTGAAGCCATAGAGCCCACCGCATO

[0532] 9.2 RNA sequence of db74

[0533] UCAGAUCGCUAGCGCUACCGGUCGCCACCAUGGUGAGCAAGGGCGAGGAGCUGUUCAC CGGGGUGGUGCCCAUCCUGGUCGAGCUGGACGGCGACGUAAACGGCCACAAGUUCAGC GUGUCCGGCGAGGGCGAGGGCGAUGCCACCUACGGCAAGCUGACCCUGAAGUUCAUCU GCACCACCGGCAAGCUGCCCGUGCCCUGGCCCACCCUCGUGACCACCCUGACCUACGGC GUGCAGUGCUUCAGCCGCUACCCCGACCACAUGAAGCAGCACGACUUCUUCAAGUCCGC CAUGCCCGAAGGCUACGUCCAGGAGCGCACCAUCUUCUUCAAGGACGACGGCAACUACA AGACCCGCGCCGAGGUGAAGUUCGAGGGCGACACCCUGGUGAACCGCAUCGAGCUGAA GGGCAUCGACUUCAAGGAGGACGGCAACAUCCUGGGGCACAAGCUGGAGUACAACUACA ACAGCCACAACGUCUAUAUCAUGGCCGACAAGCAGAAGAACGGCAUCAAGGUGAACUUCA AGAUCCGCCACAACAUCGAGGACGGCAGCGUGCAGCUCGCCGACCACUACCAGCAGAAC ACCCCCAUCGGCGACGGCCCCGUGCUGCUGCCCGACAACCACUACCUGAGCACCCAGUC CGCCCUGAGCAAAGACCCCAACGAGAAGCGCGAUCACAUGGUCCUGCUGGAGUUCGUGA CCGCCGCCGGGAUCACUCUCGGCAUGGACGAGCUGUACAAGUCCGGCCGGACUCAGAU CUCGAGCUCAAGCUUCGGAAGCGGAGCUACUAACUUCAGCCUGCUGAAGCAGGCUGGAG ACGUGGAGGAGAACCCUGGGCCUCUGUCUAAUUUGAGGAUCCUGCUCAACAAUGCAGCU CUUAGAAAGGGUCACACUUCUGUGGUUCGACAUUUUUGGUGUGGGAAGCCAGUCCAAAG UCAAGUGCAGCUGAAGGGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAU UAAAUAUAUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUA UUUGCCUUUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAA CAAGAUUGUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACC ACACAAGAUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUC UAGCAUGGCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGG CUAAAGAAGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGA UCCUGGCUGAUUACCUCACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUC AGCUGGAUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUU CGGAAUGCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCA AGUUGGCAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCA UUGGAAGCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACA AGAAGAGGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGA CUGCUAAAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAA GAAGUGGAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAA CAGAAAGUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGC UCCAGAAGCCUAAAUUUGACUACAAGGACCACGACGGUGACUACAAGGACCACGACAUCG ACUACAAGGACGACGACGACAAGUGAUGAUAAGGUACCGCGGGCCCGGGAUCCACCGGA UCUAGAUAACUGAUCAUAAUCAGCCAUACCACAUUUGUAGAGGUUUUACUUGCUUUAAAA AACCUCCCACACCUCCCCCUGAACCUGAAACAUAAAAUGAAUGCAAUUGUUGUUGUUGCG GCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUU UCACAAAUAAAGCAUUUUUUUCACUGC

[0534] 9.3 Protein sequence of db74

[0535] GFP

[0536] MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTL TYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGI DFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPV LLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYK mLeader-hOTC-FLAG

[0537] LSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKNFTGEEIKYMLWLSADLKF RIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTARVL SSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIGDGN NILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNVLITD TWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSLVFPE AENRKWTIMAVMVSLLTDYSPQLQKPKFDYKDHDGDYKDHDIDYKDDDDK

[0538] 10. db80

[0539] Name: hAAT-mLeader-hOTC-WT

[0540] 10.1 DNA sequence of db80

[0541] > > > > > >

[0542] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGC GGAGTTAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAA TTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACA CCTGGTTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGC CTGGGGACTTTCCACACCCTAACTGACACACATTCCACAGCaCTAGTTAGTTATTAA

[0543] Taggctcagaggcacacaggagtttctgggctcaccctgcccccttccaacccctcagttcccatcctccagcagctgtttgt gtgctgcctctgaagtccacactgaacaaacttcagcctactcatgtccctaaaatgggcaaacattgcaagcagcaaaca gcaaacacacagccctccctgcctgctgaccttggagctggggcagaggtcagagacctctctgggcccatgccacctcc aacatccactcgaccccttggaatttcggtggagaggagcagaggttgtcctggcgtggtttaggtagtgtgagaggggtac ccggggatcttgctaccagtggaacagccactaaggattctgcagtgagagcagagggccagctaagtggtactctccca gagactgtctgactcacgccaccccctccaccttggacacaggacgctgtggtttctgagccaggtacaatgactcctttcgg taagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcagcgtaggcgggcgactcagatcccagccagtg gacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccagcagcctcccccgttgcccctctggatcc actgcttaaatacggacgaggacagggccctgtctcctcagcttcaggcaccaccactgacctgggacagtgaatGCTA GCGAATTCatactatctaatttaaaaatcctactcaacaatacaactcttaaaaaaaatcacacttctgtaattc qacatttttaatataaaaaaccaatccaaaatcaaatacaactaaaqqaccataaccttctcactctaaaaaactttacc ggagaagaaattaaatatatgctatggctatcagcagatctgaaatttaggataaaacagaaaggagagtatttgcctttatt gcaagggaagtccttaggcatgatttttgagaaaagaagtactcgaacaagattgtctacagaaacaggctttgcacttctg ggaggacatccttgttttcttaccacacaagatattcatttgggtgtgaatgaaagtctcacggacacggcccgtgtattgtcta gcatggcagatgcagtattggctcgagtgtataaacaatcagatttggacaccctggctaaagaagcatccatcccaattat caatgggctgtcagatttgtaccatcctatccagatcctggctgattacctcacgctccagGTAAGTATCAAGGTTA CAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTC TTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCA CAGgaacactatagctctctgaaaggtcttaccctcagctggatcggggatgggaacaatatcctgcactccatcatgatg agcgcagcgaaattcggaatgcaccttcaggcagctactccaaagggttatgagccggatgctagtgtaaccaagttggc agagcagtatgccaaagagaatggtaccaagctgttgctgacaaatgatccattggaagcagcgcatggaggcaatgtat taattacagacacttggataagcatgggacaagaagaggagaagaaaaagcggctccaggctttccaaggttaccaggt tacaatgaagactgctaaagttgctgcctctgactggacatttttacactgcttgcccagaaagccagaagaagtggatgatg aagtcttttattctcctcgatcactagtgttcccagaggcagaaaacagaaagtggacaatcatggctgtcatggtgtccctgct gacagattactcacctcagctccagaagcctaaattttg aACCGGT CT CGAGGGATCCGTGAAATTTGT GATGCTATTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAAT CAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTC CTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCG TATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAG TTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAAC CCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTT TCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTG GACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTG ACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTC CTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGC TGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATC TCCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTG GTCTTCACCTGTGCAGACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGG CATGCAAATCGTCAACTTGGCATGCCAAGTAAGGACCTTTGGACTCCTTATATAAAA GATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGGTAATTAGGTGG TGTAGCGGCCGCAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGC AT CACAAATTT CACAAAT AAAGCATTTTTTT CACT GCattctagttgtggtttgtccaaactcatcaatgt atctg aagacaatagcag g catgctg g g AAG GTCatgTTTT cafGACCTGAAGCCAT AGAGCCCAC CGCAT

[0544] 10.2 RNA sequence of db80

[0545] UCAGAUCCCAGCCAGUGGACUUAGCCCCUGUUUGCUCCUCCGAUAACUGGGGUGACCUU

[0546] GGUUAAUAUUCACCAGCAGCCUCCCCCGUUGCCCCUCUGGAUCCACUGCUUAAAUACGG

[0547] ACGAGGACAGGGCCCUGUCUCCUCAGCUUCAGGCACCACCACUGACCUGGGACAGUGAA

[0548] UGCUAGCGAAUUCAUGCUGUCUAAUUUGAGGAUCCUGCUCAACAAUGCAGCUCUUAGAA

[0549] AGGGUCACACUUCUGUGGUUCGACAUUUUUGGUGUGGGAAGCCAGUCCAAAGUCAAGUG

[0550] CAGCUGAAGGGCCGUGACCUUCUCACUCUAAAAAACUUUACCGGAGAAGAAAUUAAAUAU

[0551] AUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUAUUUGCCU

[0552] UUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUU

[0553] GUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCACACAAG

[0554] AUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUAGCAUG

[0555] GCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGA

[0556] AGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGAUCCUGG

[0557] CUGAUUACCUCACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGG

[0558] AUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAU

[0559] GCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGG

[0560] CAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAA

[0561] GCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAGAAGA GGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACUGCUA AAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAAGAAGUG GAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAA GUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUCCAGA AGCCUAAAUUUUGAACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUAUUGCAACAU GUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUACAAA AUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUA CGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCU CCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAA CGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGGGCAUUGCCA CCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAA CUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCACUGACA

[0562] AUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGC CACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCG GACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUC GCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCG UCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGGAUUCCACCG UGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAGGACCUUUGG ACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCG GUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUA AAGCAAU AGCAUC ACAAAU U U CACAAAU AAAGCAU U U U U U UCAC UGC

[0563] 10.3 Protein sequence of db80

[0564] MLSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKN FTG E E IKYM LWLS ADL

[0565] KFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTA RVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIG

[0566] DGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNV LITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSL VFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF

[0567] 11. db101

[0568] Name: hAAT-eGFP-P2A-mLeader-hOTC-WT-FLAG

[0569] 11.1 DNA sequence of db101

[0570] >

[0571] ATCCAGatgTTTTcatCTGGABACTGTTCGOGATGTACGGGqGAGATATAC

[0572] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0573] AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATaggctcagaggcacacaggagtttctgggctcac cctgcccccttccaacccctcagttcccatcctccagcagctgtttgtgtgctgcctctgaagtccacactgaacaaacttcagcctactcat gtccctaaaatgggcaaacattgcaagcagcaaacagcaaacacacagccctccctgcctgctgaccttggagctggggcagaggt cagagacctctctgggcccatgccacctccaacatccactcgaccccttggaatttcggtggagaggagcagaggttgtcctggcgtgg tttaggtagtgtgagaggggtacccggggatcttgctaccagtggaacagccactaaggattctgcagtgagagcagagggccagct aagtggtactctcccagagactgtctgactcacgccaccccctccaccttggacacaggacgctgtggtttctgagccaggtacaatga ctcctttcggtaagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcagcgtaggcgggcgactcagatcccagccagt ggacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccagcagcctcccccgttgcccctctggatccactgctt aaatacggacgaggacagggccctgtctcctcagcttcaggcaccaccactgacctgggacagtgaatGCTAGCGCTACCG GTCGCCACCATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTC GAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGA

[0574] TGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCC CTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGA CCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCG CACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGG CGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACAT CCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAG CAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTG CAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCC GACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGAT CACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTG TACAAGTCCGGCCGGACTCAGATCTCGAGCTCAAGCTTcGGAAGCGGAGCTACTAACTTCA GCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGGCCTctatctaatttaaaaatcctgct caacaatacaactcttaaaaaaaatcacacttctataattcaacatttttaatataaaaaaccaatccaaaatcaaatacaact gaagggccgtgaccttctcactctaaaaaactttaccggagaagaaattaaatatatgctatggctatcagcagatctgaaatttaggat aaaacagaaaggagagtatttgcctttattgcaagggaagtccttaggcatgatttttgagaaaagaagtactcgaacaagattgtctac agaaacaggctttgcacttctgggaggacatccttgttttcttaccacacaagatattcatttgggtgtgaatgaaagtctcacggacacgg cccgtgtattgtctagcatggcagatgcagtattggctcgagtgtataaacaatcagatttggacaccctggctaaagaagcatccatcc caattatcaatgggctgtcagatttgtaccatcctatccagatcctggctgattacctcacgctccagGTAAGTATCAAGGTTAC

[0575] AAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTGCGT TTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGgaacaclaiag ctctctgaaaggtcttaccctcagctggatcggggatgggaacaatatcctgcactccatcatgatgagcgcagcgaaattcggaatgc accttcaggcagctactccaaagggttatgagccggatgctagtgtaaccaagttggcagagcagtatgccaaagagaatggtacca agctgttgctgacaaatgatccattggaagcagcgcatggaggcaatgtattaattacagacacttggataagcatgggacaagaaga ggagaagaaaaagcggctccaggctttccaaggttaccaggttacaatgaagactgctaaagttgctgcctctgactggacatttttaca ctgcttgcccagaaagccagaagaagtggatgatgaagtcttttattctcctcgatcactagtgttcccagaggcagaaaacagaaagt ggacaatcatggctgtcatggtgtccctgctgacagattactcacctcagctccagaagcctaaatttGACTACAAGGACCAC GACGGTGACTACAAGGACCACGACATCGACTACAAGGACGACGACGACAAGtgatgataaGGT ACCGCGGGCCCGGGATCCACCGGATCTAGATAACTGATCATAATCAGCCATACCACATTTG TAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGA ATGCAATTGTTGTTGTTGCggccgcaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttca caaataaagcatttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctgggMiiM

[0576] 11 .2 RNA sequence of db101

[0577] UCAGAUCCCAGCCAGUGGACUUAGCCCCUGUUUGCUCCUCCGAUAACUGGGGUGACCUU

[0578] GGUUAAUAUUCACCAGCAGCCUCCCCCGUUGCCCCUCUGGAUCCACUGCUUAAAUACGG

[0579] ACGAGGACAGGGCCCUGUCUCCUCAGCUUCAGGCACCACCACUGACCUGGGACAGUGAA

[0580] UGCUAGCGCUACCGGUCGCCACCAUGGUGAGCAAGGGCGAGGAGCUGUUCACCGGGGU

[0581] GGUGCCCAUCCUGGUCGAGCUGGACGGCGACGUAAACGGCCACAAGUUCAGCGUGUCC

[0582] GGCGAGGGCGAGGGCGAUGCCACCUACGGCAAGCUGACCCUGAAGUUCAUCUGCACCAC

[0583] CGGCAAGCUGCCCGUGCCCUGGCCCACCCUCGUGACCACCCUGACCUACGGCGUGCAG

[0584] UGCUUCAGCCGCUACCCCGACCACAUGAAGCAGCACGACUUCUUCAAGUCCGCCAUGCC

[0585] CGAAGGCUACGUCCAGGAGCGCACCAUCUUCUUCAAGGACGACGGCAACUACAAGACCC

[0586] GCGCCGAGGUGAAGUUCGAGGGCGACACCCUGGUGAACCGCAUCGAGCUGAAGGGCAU

[0587] CGACUUCAAGGAGGACGGCAACAUCCUGGGGCACAAGCUGGAGUACAACUACAACAGCC

[0588] ACAACGUCUAUAUCAUGGCCGACAAGCAGAAGAACGGCAUCAAGGUGAACUUCAAGAUCC

[0589] GCCACAACAUCGAGGACGGCAGCGUGCAGCUCGCCGACCACUACCAGCAGAACACCCCC

[0590] AUCGGCGACGGCCCCGUGCUGCUGCCCGACAACCACUACCUGAGCACCCAGUCCGCCCU

[0591] GAGCAAAGACCCCAACGAGAAGCGCGAUCACAUGGUCCUGCUGGAGUUCGUGACCGCCG

[0592] CCGGGAUCACUCUCGGCAUGGACGAGCUGUACAAGUCCGGCCGGACUCAGAUCUCGAGC

[0593] UCAAGCUUCGGAAGCGGAGCUACUAACUUCAGCCUGCUGAAGCAGGCUGGAGACGUGGA

[0594] GGAGAACCCUGGGCCUCUGUCUAAUUUGAGGAUCCUGCUCAACAAUGCAGCUCUUAGAA

[0595] AGGGUCACACUUCUGUGGUUCGACAUUUUUGGUGUGGGAAGCCAGUCCAAAGUCAAGUG CAGCUGAAGGGCCGUGACCUUCLICACIICUAAAAAACUUIIACCGGAGAAGAAAUUAAAUAU

[0596] AUGCUAUGGCUAUCAGCAGAUCUGAAAUUUAGGAUAAAACAGAAAGGAGAGUAUUUGCCU

[0597] UUAUUGCAAGGGAAGUCCUUAGGCAUGAUUUUUGAGAAAAGAAGUACUCGAACAAGAUU

[0598] GUCUACAGAAACAGGCUUUGCACUUCUGGGAGGACAUCCUUGUUUUCUUACCACACAAG

[0599] AUAUUCAUUUGGGUGUGAAUGAAAGUCUCACGGACACGGCCCGUGUAUUGUCUAGCAUG

[0600] GCAGAUGCAGUAUUGGCUCGAGUGUAUAAACAAUCAGAUUUGGACACCCUGGCUAAAGA

[0601] AGCAUCCAUCCCAAUUAUCAAUGGGCUGUCAGAUUUGUACCAUCCUAUCCAGAUCCUGG

[0602] CUGAUUACCUCACGCUCCAGGAACACUAUAGCUCUCUGAAAGGUCUUACCCUCAGCUGG

[0603] AUCGGGGAUGGGAACAAUAUCCUGCACUCCAUCAUGAUGAGCGCAGCGAAAUUCGGAAU

[0604] GCACCUUCAGGCAGCUACUCCAAAGGGUUAUGAGCCGGAUGCUAGUGUAACCAAGUUGG

[0605] CAGAGCAGUAUGCCAAAGAGAAUGGUACCAAGCUGUUGCUGACAAAUGAUCCAUUGGAA

[0606] GCAGCGCAUGGAGGCAAUGUAUUAAUUACAGACACUUGGAUAAGCAUGGGACAAGAAGA

[0607] GGAGAAGAAAAAGCGGCUCCAGGCUUUCCAAGGUUACCAGGUUACAAUGAAGACUGCUA

[0608] AAGUUGCUGCCUCUGACUGGACAUUUUUACACUGCUUGCCCAGAAAGCCAGAAGAAGUG

[0609] GAUGAUGAAGUCUUUUAUUCUCCUCGAUCACUAGUGUUCCCAGAGGCAGAAAACAGAAA

[0610] GUGGACAAUCAUGGCUGUCAUGGUGUCCCUGCUGACAGAUUACUCACCUCAGCUCCAGA

[0611] AGCCUAAAUUUGACUACAAGGACCACGACGGUGACUACAAGGACCACGACAUCGACUACA

[0612] AGGACGACGACGACAAGUGAUGAUAAGGUACCGCGGGCCCGGGAUCCACCGGAUCUAGA

[0613] UAACUGAUCAUAAUCAGCCAUACCACAUUUGUAGAGGUUUUACUUGCUUUAAAAAACCUC

[0614] CCACACCUCCCCCUGAACCUGAAACAUAAAAUGAAUGCAAUUGUUGUUGUUGCGGCCGC

[0615] AACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACA

[0616] AAUAAAGCAUUUUUUUCACUGC

[0617] 11 .3 Protein sequence of db101

[0618] GFP

[0619] MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTL

[0620] TYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGI

[0621] DFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPV

[0622] LLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYK— mLeader-hOTC-FLAG

[0623] LSNLRILLNNAALRKGHTSVVRHFWCGKPVQSQVQLKGRDLLTLKNFTGEEIKYMLWLSADLKF

[0624] RIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGVNESLTDTARVL

[0625] SSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQEHYSSLKGLTLSWIGDGN

[0626] NILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKENGTKLLLTNDPLEAAHGGNVLITD

[0627] TWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTFLHCLPRKPEEVDDEVFYSPRSLVFPE

[0628] AENRKWTIMAVMVSLLTDYSPQLQKPKFDYKDHDGDYKDHDIDYKDDDDK

[0629] B, PAH Vector Sequences

[0630] Sequences for disclosure submission

[0631] All the vectors have the DNA, RNA and protein sequences in the document

[0632] Legend for DNA sequences:

[0633] • Nuclear Localization Signal (NLS)

[0634] • Intron

[0635] • WPRE Legend for RNA sequences:

[0636] • WPRE

[0637] 1 . db46 a. 1.1 DNA sequence of db46 (SEQ ID NO 41 ) b. 1 .2 RNA sequence of db46 (SEQ ID NO 42) c. 1 .3 Protein sequence of db46 (SEQ ID NO 43)

[0638] 2. db47 a. 2.1 DNA sequence of db47 (SEQ ID NO 44) b. 2.2 RNA sequence of db47 (SEQ ID NO 45) c. 2.3 Protein sequence of db47 (SEQ ID NO 46)

[0639] 3. db48 a. 3.1 DNA sequence of db48 (SEQ ID NO 47) b. 3.2 RNA sequence of db48 (SEQ ID NO 48) c. 3.3 Protein sequence of db48 (SEQ ID NO 49)

[0640] 4. db49 a. 4.1 DNA sequence of db49 (SEQ ID NO 50) b. 4.2 RNA sequence of db49 (SEQ ID NO 51 ) c. 4.3 Protein sequence of db49 (SEQ ID NO 52)

[0641] 5. db81 a. 5.1 DNA sequence of db81 (SEQ ID NO 53) b. 5.2 RNA sequence of db81 (SEQ ID NO 54) c. 5.3 Protein sequence of db81 (SEQ ID NO 55)

[0642] 6. db87 a. 6.1 DNA sequence of db87 (SEQ ID NO 56) b. 6.2 RNA sequence of db87 (SEQ ID NO 57) c. 6.3 Protein sequence of db87 (SEQ ID NO 58)

[0643] 7. db102 a. 7.1 DNA sequence of db102 (SEQ ID NO 59) b. 7.2 RNA sequence of db102 (SEQ ID NO 60) c. 7.3 Protein sequence of db102 (SEQ ID NO 61 )

[0644] 1 . db46

[0645] Name: inactive CMV-hPAH-WT

[0646] 1 .1 DNA sequence of db46 TTCATAGCCCATATATGGAGTTCCGATTTATACGCTCGTTAGAGATCACCAGGAGGCGGAAG AAGCTAGTCGTTTAACACTAGTGTTATGCCCCGTGAGCCCAACAGGGCGGCAATTGATTGG AAGTCGGCATTCCAGCAACTGAGTCTTATTTAAGTGAGATTATCAACAGGCGGGATAATCCT TATAATTATCAGAAGACTATAACAGGCGTATGGCCGCCATGTAGTACCCTGTAAGTGGTGTG CAAACCCAATGACATAGCTCGAGCGGGCTACGACCCTGGTGGATAAACCAAATTTGGAACC GCAGTTTGAGGACAACATCGGCTGACTCCCCCGGATTTCTCGGATTTGCTGAATTATCAGTC AGGGCGCCCTACGTACGCTCGCATTAAAGGGTTCTACGAACTATTGTCCGCGGTCCCGTGG CCTTTCCTGCGGCCGGATATCATGCGGCCACTGAGCACCACTTCGAGAGGGGTAGCCACA GTCGCCAACTTTTCCAGTTATTGCTTCTTATAATTATGTCGTATTCTCCCCCATCTTCAGATC GAGCTAGCGAATTCatgtccactgcggtcctggaaaacccaggcttgggcaggaaactctctgactttggacagGTAAGT ATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGAC GACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCA CAGgaaacaagctatattgaagacaactgcaatcaaaatggtgccatatcactgatcttctcactcaaagaagaagttggtgcattgg ccaaagtattgcgcttatttgaggagaatgatgtaaacctgacccacattgaatctagaccttctcgtttaaagaaagatgagtatgaatttt tcacccatttggataaacgtagcctgcctgctctgacaaacatcatcaagatcttgaggcatgacattggtgccactgtccatgagctttca cgagataagaagaaagacacagtgccctggttcccaagaaccattcaagagctggacagatttgccaatcagattctcagctatgga gcggaactggatgctgaccaccctggttttaaagatcctgtgtaccgtgcaagacggaagcagtttgctgacattgcctacaactaccgc catgggcagcccatccctcgagtggaatacatggaggaagaaaagaaaacatggggcacagtgttcaagactctgaagtccttgtat aaaacccatgcttgctatgagtacaatcacatttttccacttcttgaaaagtactgtggcttccatgaagataacattccccagctggaaga cgtttctcagttcctgcagacttgcactggtttccgcctccgacctgtggctggcctgctttcctctcgggatttcttgggtggcctggccttccg agtcttccactgcacacagtacatcagacatggatccaagcccatgtatacccccgaacctgacatctgccatgagctgttgggacatgt gcccttgttttcagatcgcagctttgcccagttttcccaggaaattggccttgcctctctgggtgcacctgatgaatacattgaaaagctcgc cacaatttactggtttactgtggagtttgggctctgcaaacaaggagactccataaaggcatatggtgctgggctcctgtcatcctttggtga attacagtactgcttatcagagaagccaaagcttctccccctggagctggagaagacagccatccaaaattacactgtcacggagttcc agcccctctattacgtggcagagagttttaatgatgccaaggagaaagtaaggaactttgctgccacaatacctcggcccttctcagttcg ctacgacccatacacccaaaggattgaggtcttggacaatacccagcagcttaagattttggctgattccattaacagtgaaattggaat cctttgcagtgccctccagaaaataaagtaactcgag ACCGGT CTCG AGGG AT CCGT G AAATTTGTG AT GOT A TTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGAT TACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGA TACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCC TTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGG CGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGT CAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCG

[0647] CCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGT TGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCG CGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGC CTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCT CCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTC ACCTGTGCAGACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATC GTCAACTTGGCATGCCAAGTAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTA AATGGGAGGAGGGTTACTTAAGCCCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTT TATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTT TTTTCACTGCattctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctgggAAGGTCatgTTT

[0648] 1 .2 RNA sequence of db46

[0649] UCAGAUCGAGCUAGCGAAUUCAUGUCCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAG

[0650] GAAACUCUCUGACUUUGGACAGGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGG

[0651] UGCCAUAUCACUGAUCUUCUCACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGC

[0652] GCUUAUUUGAGGAGAAUGAUGUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAA

[0653] AGAAAGAUGAGUAUGAAUUUUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAA ACAUCAUCAAGAUCUUGAGGCAUGACAUUGGUGCCACUGUCCAUGAGCUUUCACGAGAU

[0654] AAGAAGAAAGACACAGUGCCCUGGUUCCCAAGAACCAUUCAAGAGCUGGACAGAUUUGCC

[0655] AAUCAGAUUCUCAGCUAUGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAAGAUCC

[0656] UGUGUACCGUGCAAGACGGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGC

[0657] AGCCCAUCCCUCGAGUGGAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUC

[0658] AAGACUCUGAAGUCCUUGUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCA

[0659] CUUCUUGAAAAGUACUGUGGCUUCCAUGAAGAUAACAUUCCCCAGCUGGAAGACGUUUC

[0660] UCAGUUCCUGCAGACUUGCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCC

[0661] UCUCGGGAUUUCUUGGGUGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAG

[0662] ACAUGGAUCCAAGCCCAUGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGAC

[0663] AUGUGCCCUUGUUUUCAGAUCGCAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCC

[0664] UCUCUGGGUGCACCUGAUGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGU

[0665] GGAGUUUGGGCUCUGCAAACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGU

[0666] CAUCCUUUGGUGAAUUACAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAG

[0667] CUGGAGAAGACAGCCAUCCAAAAUUACACUGUCACGGAGUUCCAGCCCCUCUAUUACGU

[0668] GGCAGAGAGUUUUAAUGAUGCCAAGGAGAAAGUAAGGAACUUUGCUGCCACAAUACCUC

[0669] GGCCCUUCUCAGUUCGCUACGACCCAUACACCCAAAGGAUUGAGGUCUUGGACAAUACC

[0670] CAGCAGCUUAAGAUUUUGGCUGAUUCCAUUAACAGUGAAAUUGGAAUCCUUUGCAGUGC

[0671] CCUCCAGAAAAUAAAGUAACUCGAGACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGC

[0672] UAUUGCAACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUC

[0673] UGGAUUACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACG

[0674] CUAUGUGGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUU

[0675] CAUUUUCUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCG

[0676] UUGUCAGGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUG

[0677] GGGCAUUGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUG

[0678] CCACGGCGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUU

[0679] GGGCACUGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUC

[0680] GCCUGUGUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCC

[0681] UCAAUCCAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCG

[0682] UCUUCGCCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGU U

[0683] UCGCCUCGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAU

[0684] GGAUUCCACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUA

[0685] AGGACCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACU

[0686] UAAGCCCUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAU

[0687] GGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCAUUUUUUUCACUGC

[0688] 1 .3 Protein sequence of db46

[0689] MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIE

[0690] SRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFA

[0691] NQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKS

[0692] LYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFR

[0693] VFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWF

[0694] TVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESF

[0695] NDAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIK

[0696] 2. db47

[0697] Name: CMV-hPAH-WT

[0698] 2.1 DNA sequence of db47 TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG TTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGA CCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAA TAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTA CATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTA TTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGG CACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGG GCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGAT CGGTAGCGAATTCatgtccactgcggtcctggaaaacccaggcttgggcaggaaactctctgactttggacagGTAAGTA TCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACG ACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCAC AGgaaacaagctatattgaagacaactgcaatcaaaatggtgccatatcactgatcttctcactcaaagaagaagttggtgcattggc caaagtattgcgcttatttgaggagaatgatgtaaacctgacccacattgaatctagaccttctcgtttaaagaaagatgagtatgaattttt cacccatttggataaacgtagcctgcctgctctgacaaacatcatcaagatcttgaggcatgacattggtgccactgtccatgagctttca cgagataagaagaaagacacagtgccctggttcccaagaaccattcaagagctggacagatttgccaatcagattctcagctatgga gcggaactggatgctgaccaccctggttttaaagatcctgtgtaccgtgcaagacggaagcagtttgctgacattgcctacaactaccgc catgggcagcccatccctcgagtggaatacatggaggaagaaaagaaaacatggggcacagtgttcaagactctgaagtccttgtat aaaacccatgcttgctatgagtacaatcacatttttccacttcttgaaaagtactgtggcttccatgaagataacattccccagctggaaga cgtttctcagttcctgcagacttgcactggtttccgcctccgacctgtggctggcctgctttcctctcgggatttcttgggtggcctggccttccg agtcttccactgcacacagtacatcagacatggatccaagcccatgtatacccccgaacctgacatctgccatgagctgttgggacatgt gcccttgttttcagatcgcagctttgcccagttttcccaggaaattggccttgcctctctgggtgcacctgatgaatacattgaaaagctcgc cacaatttactggtttactgtggagtttgggctctgcaaacaaggagactccataaaggcatatggtgctgggctcctgtcatcctttggtga attacagtactgcttatcagagaagccaaagcttctccccctggagctggagaagacagccatccaaaattacactgtcacggagttcc agcccctctattacgtggcagagagttttaatgatgccaaggagaaagtaaggaactttgctgccacaatacctcggcccttctcagttcg ctacgacccatacacccaaaggattgaggtcttggacaatacccagcagcttaagattttggctgattccattaacagtgaaattggaat cctttgcagtgccctccagaaaataaagtaactcgag ACCGGT CTCG AGGG AT CCGT G AAATTTGTG AT GOT A TTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGAT TACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGA TACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCC

[0699] TTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGG CGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGT CAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCG CCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGT TGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCG CGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGC CTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCT CCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTC ACCTGTGCAGACTTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATC GTCAACTTGGCATGCCAAGTAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTA AATGGGAGGAGGGTTACTTAAGCCCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTT TATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTT TTTTCACTGCat'.ctagt'.gtggtttg'.ccaaactcatcaatg'.atctgaagacaa'.agcaggcatgctgggAAGGTGalgTTT TcaSGACCTGAAGCCATAGAGCCCACCGCATC

[0700] 2.2 RNA sequence of db47

[0701] UCAGAUCGCUAGCGAAUUCAUGUCCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGA

[0702] AACUCUCUGACUUUGGACAGGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGUG

[0703] CCAUAUCACUGAUCUUCUCACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGC UUAUUUGAGGAGAAUGAUGUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAG

[0704] AAAGAUGAGUAUGAAUUUUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAAC

[0705] AUCAUCAAGAUCUUGAGGCAUGACAUUGGUGCCACUGUCCAUGAGCUUUCACGAGAUAA

[0706] GAAGAAAGACACAGUGCCCUGGUUCCCAAGAACCAUUCAAGAGCUGGACAGAUUUGCCAA

[0707] UCAGAUUCUCAGCUAUGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAAGAUCCUG

[0708] UGUACCGUGCAAGACGGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGCAG

[0709] CCCAUCCCUCGAGUGGAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAA

[0710] GACUCUGAAGUCCUUGUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCACU

[0711] UCUUGAAAAGUACUGUGGCUUCCAUGAAGAUAACAUUCCCCAGCUGGAAGACGUUUCUC

[0712] AGUUCCUGCAGACUUGCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCCUC

[0713] UCGGGAUUUCUUGGGUGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAGAC

[0714] AUGGAUCCAAGCCCAUGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGACAU

[0715] GUGCCCUUGUUUUCAGAUCGCAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCCUC

[0716] UCUGGGUGCACCUGAUGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGUGG

[0717] AGUUUGGGCUCUGCAAACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGUCA

[0718] UCCUUUGGUGAAUUACAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAGCU

[0719] GGAGAAGACAGCCAUCCAAAAUUACACUGUCACGGAGUUCCAGCCCCUCUAUUACGUGG

[0720] CAGAGAGUUUUAAUGAUGCCAAGGAGAAAGUAAGGAACUUUGCUGCCACAAUACCUCGG

[0721] CCCUUCUCAGUUCGCUACGACCCAUACACCCAAAGGAUUGAGGUCUUGGACAAUACCCA

[0722] GCAGCUUAAGAUUUUGGCUGAUUCCAUUAACAGUGAAAUUGGAAUCCUUUGCAGUGCCC

[0723] UCCAGAAAAUAAAGUAACUCGAGACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUA

[0724] UUGCAACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUG

[0725] GAUUACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUA

[0726] UGUGGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAU

[0727] UUUCUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUU

[0728] GUCAGGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGG

[0729] GCAUUGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCC

[0730] ACGGCGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGG

[0731] GCACUGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGC

[0732] CUGUGUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUC

[0733] AAUCCAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUC UUCGCCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCC U G U U U C

[0734] GCCUCGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGG

[0735] AUUCCACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAG

[0736] GACCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUA AGCCCUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGG UUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCAUUUUUUUCACUGC

[0737] 2.3 Protein sequence of db47

[0738] MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIE

[0739] SRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFA

[0740] NQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKS

[0741] LYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFR

[0742] VFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWF

[0743] TVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESF

[0744] NDAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIK

[0745] 3. db48

[0746] Name: CMV-hPAH-opt 1

[0747] 3.1 DNA sequence of db48

[0748] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG TTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGA CCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAA TAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTA CATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTA TTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGG CACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGG GCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGAT CGCTAGCAATCAAATATTATTATTATCATACCAACAGACTCAGAGAGAACCCGCCACCATGT CCACTGCGGTCCTGGAAAACCCAGGCTTGGGCAGGAAACTCTCTGACTTTGGTCAGG77WG TATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGA CGACTCTTGCGTTTCTGA TAGGCACCTA TTGGTCTTACTGACA TCCACTTTGCCTTTCTCTCC AC AGGAAACAAGCT AT ATTGAAG AC AACTGCAATCAAAATGGAGCC AT ATCACTGATCTTCT CACTCAAAGAAGAAGTTGGTGCATTGGCCAAAGTATTGCGCTTATTTGAGGAAAATGATGTA AACCTGACCCACATTGAATCTAGACCTTCTCGTTTAAAAAAAGATGAGTATGAATTTTTCACA CATTTGGATAAACGTAGCCTGCCTGCTCTGACAAACATCATCAAGATCTTGAGGCATGACAT TGGAGCCACTGTCCATGAGCTTTCACGAGATAAGAAGAAAGACACAGTGCCCTGGTTCCCA AGAACCATTCAAGAGCTAGACAGATTTGCCAATCAGATTCTCAGCTATGGAGCGGAACTGG ATGCTGACCACCCTGGTTTTAAGGATCCTGTGTACCGTGCAAGACGGAAGCAGTTTGCTGA CATTGCCTACAACTACCGCCATGGGCAGCCCATCCCTCGTGTGGAATACATGGAGGAAGAA AAGAAAACATGGGGCACAGTGTTCAAGACTCTGAAGTCCTTGTATAAAACCCATGCTTGCTA TGAGTACAATCACATTTTTCCACTTCTTGAAAAATACTGTGGCTTCCATGAAGATAACATTCC CCAGCTAGAAGACGTTTCTCAGTTCCTGCAAACTTGCACTGGTTTCCGCCTCCGACCTGTG GCTGGCCTGCTTTCCTCTCGGGATTTCTTGGGTGGCCTGGCCTTCCGAGTCTTCCACTGCA CACAGTACATCAGACATGGATCCAAGCCCATGTATACCCCCGAACCTGACATCTGCCATGA GCTGTTGGGACATGTGCCCTTGTTTTCTGATCGAAGCTTTGCCCAGTTTTCCCAGGAAATTG GCCTTGCCTCTCTGGGTGCTCCTGATGAATACATTGAAAAGCTCGCCACAATTTACTGGTTT ACTGTGGAGTTTGGGCTCTGCAAACAAGGAGACTCCATAAAGGCATATGGTGCTGGGCTCC TGTCATCCTTTGGTGAATTACAGTACTGCTTATCAGAGAAGCCAAAGCTTCTCCCCCTGGAG CTAGAGAAGACAGCCATCCAAAATTACACTGTCACGGAGTTCCAGCCCCTCTATTACGTGG CAGAGAGTTTTAATGATGCCAAGGAAAAAGTTAGGAACTTTGCTGCCACAATACCTCGGCCC TTCTCTGTTCGCTACGACCCATACACACAAAGGATTGAGGTCTTGGACAATACCCAACAGCT TAAGATTTTGGCTGATTCCATTAACAGCGAAATTGGAATCCTTTGTAGTGCCCTCCAGAAAAT TAAGTAACTCGAGGGATCCGTGAAATTTGTGTTGCTATTGCAACATGTTAAGAAAATTTCCC GTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTG GTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATC ATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTC TTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGA CGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCT TTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACA GGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTT CCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCC CTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTC

[0749] TTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCC

[0750] TGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCA

[0751] TGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGCAAG GACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGC

[0752] CCTGCGGCAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCTTATAATGGTTACAA

[0753] ATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCattctagttgtggtttgtccaa actcatcaatgtatctgaagacaatagcaggcatgctgggAWWWt^aOeCT®»AW^®e

[0754] AGGGCATG

[0755] 3.2 RNA sequence of db48

[0756] UCAGAUCGCUAGCAAUCAAAUAUUAUUAUUAUCAUACCAACAGACUCAGAGAGAACCCGC

[0757] CACCAUGUCCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUCUCUGACUUUG

[0758] GUCAGGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGAGCCAUAUCACUGAUCU

[0759] UCUCACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUUUGAGGAAAAU

[0760] GAUGUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAAAAAGAUGAGUAUGAA

[0761] UUUUUCACACAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAUCAAGAUCUUG

[0762] AGGCAUGACAUUGGAGCCACUGUCCAUGAGCUUUCACGAGAUAAGAAGAAAGACACAGU

[0763] GCCCUGGUUCCCAAGAACCAUUCAAGAGCUAGACAGAUUUGCCAAUCAGAUUCUCAGCUA

[0764] UGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAGGAUCCUGUGUACCGUGCAAGAC

[0765] GGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGCAGCCCAUCCCUCGUGUG

[0766] GAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAAGACUCUGAAGUCCUU

[0767] GUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCACUUCUUGAAAAAUACUG

[0768] UGGCUUCCAUGAAGAUAACAUUCCCCAGCUAGAAGACGUUUCUCAGUUCCUGCAAACUU

[0769] GCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCCUCUCGGGAUUUCUUGGG

[0770] UGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAGACAUGGAUCCAAGCCCA

[0771] UGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGACAUGUGCCCUUGUUUUCU

[0772] GAUCGAAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCCUCUCUGGGUGCUCCUGA

[0773] UGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGUGGAGUUUGGGCUCUGCA

[0774] AACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGUCAUCCUUUGGUGAAUUA

[0775] CAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAGCUAGAGAAGACAGCCAU

[0776] CCAAAAUUACACUGUCACGGAGUUCCAGCCCCUCUAUUACGUGGCAGAGAGUUUUAAUG

[0777] AUGCCAAGGAAAAAGUUAGGAACUUUGCUGCCACAAUACCUCGGCCCUUCUCUGUUCGC

[0778] UACGACCCAUACACACAAAGGAUUGAGGUCUUGGACAAUACCCAACAGCUUAAGAUUUUG

[0779] GCUGAUUCCAUUAACAGCGAAAUUGGAAUCCUUUGUAGUGCCCUCCAGAAAAUUAAGUAA

[0780] CUCGAGGGAUCCGUGAAAUUUGUGUUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUA

[0781] UUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACUG

[0782] GUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUG

[0783] UAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUU

[0784] GCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACU

[0785] GUGUUUGCUGACGCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUC

[0786] CGGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUU

[0787] GCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGG

[0788] GGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGG

[0789] GACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCC

[0790] UGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAU

[0791] CUCCCUUUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGG

[0792] UCUUCACCUGUGCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAU

[0793] GCAAAUCGUCAACUUGGCAUGCCAAGCAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAA

[0794] UUAUUAACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCGGCAAUUAGGUGGUGUAGCGG

[0795] CCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUU

[0796] CACAAAUAAAGCAUUUUUUUCACUGC

[0797] 3.3 Protein sequence of db48

[0798] MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIE

[0799] SRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFA

[0800] NQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKS LYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFR

[0801] VFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWF

[0802] TVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESF

[0803] NDAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIK

[0804] 4. db49

[0805] Name: CMV-hPAH-opt 2

[0806] 4.1 DNA sequence of db49

[0807] ATCCAGatgTTTTcatCTGGAGAGTCTTGGCGATGTACGGGCCAGATATAC

[0808] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT

[0809] TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA

[0810] TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA

[0811] ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0812] AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATAGTAATCAATTACGGGGTCATTAG

[0813] TTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGA

[0814] CCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAA

[0815] TAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTA

[0816] CATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG

[0817] CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTA

[0818] TTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGC

[0819] GGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGG

[0820] CACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGG

[0821] GCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGAT

[0822] CGCTAGCAATCAAATATTATTATTATCATACCAACAGACTCAGGTAAGTATC / WGG7TACAAG

[0823] ACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTC

[0824] TGATAGGCAGCTATTGGTCTTAGTG AC ATCCACTTTGCGTTTCTCTCC ACAGAG AG AACCGG

[0825] CCACCATGTCCACTGCGGTCCTGGAAAACCCAGGCTTGGGCAGGAAACTCTCTGACTTTGG

[0826] TCAGGAAACAAGCTATATTGAAGACAACTGCAATCAAAATGGAGCCATATCACTGATCTTCT

[0827] CACTCAAAGAAGAAGTTGGTGCATTGGCCAAAGTATTGCGCTTATTTGAGGAAAATGATGTA

[0828] AACCTGACCCACATTGAATCTAGACCTTCTCGTTTAAAAAAAGATGAGTATGAATTTTTCACA

[0829] CATTTGGATAAACGTAGCCTGCCTGCTCTGACAAACATCATCAAGATCTTGAGGCATGACAT

[0830] TGGAGCCACTGTCCATGAGCTTTCACGAGATAAGAAGAAAGACACAGTGCCCTGGTTCCCA

[0831] AGAACCATTCAAGAGCTAGACAGATTTGCCAATCAGATTCTCAGCTATGGAGCGGAACTGG

[0832] ATGCTGACCACCCTGGTTTTAAGGATCCTGTGTACCGTGCAAGACGGAAGCAGTTTGCTGA

[0833] CATTGCCTACAACTACCGCCATGGGCAGCCCATCCCTCGTGTGGAATACATGGAGGAAGAA

[0834] AAGAAAACATGGGGCACAGTGTTCAAGACTCTGAAGTCCTTGTATAAAACCCATGCTTGCTA

[0835] TGAGTACAATCACATTTTTCCACTTCTTGAAAAATACTGTGGCTTCCATGAAGATAACATTCC

[0836] CCAGCTAGAAGACGTTTCTCAGTTCCTGCAAACTTGCACTGGTTTCCGCCTCCGACCTGTG

[0837] GCTGGCCTGCTTTCCTCTCGGGATTTCTTGGGTGGCCTGGCCTTCCGAGTCTTCCACTGCA

[0838] CACAGTACATCAGACATGGATCCAAGCCCATGTATACCCCCGAACCTGACATCTGCCATGA

[0839] GCTGTTGGGACATGTGCCCTTGTTTTCTGATCGAAGCTTTGCCCAGTTTTCCCAGGAAATTG

[0840] GCCTTGCCTCTCTGGGTGCTCCTGATGAATACATTGAAAAGCTCGCCACAATTTACTGGTTT

[0841] ACTGTGGAGTTTGGGCTCTGCAAACAAGGAGACTCCATAAAGGCATATGGTGCTGGGCTCC

[0842] TGTCATCCTTTGGTGAATTACAGTACTGCTTATCAGAGAAGCCAAAGCTTCTCCCCCTGGAG

[0843] CTAGAGAAGACAGCCATCCAAAATTACACTGTCACGGAGTTCCAGCCCCTCTATTACGTGG

[0844] CAGAGAGTTTTAATGATGCCAAGGAAAAAGTTAGGAACTTTGCTGCCACAATACCTCGGCCC

[0845] TTCTCTGTTCGCTACGACCCATACACACAAAGGATTGAGGTCTTGGACAATACCCAACAGCT

[0846] TAAGATTTTGGCTGATTCCATTAACAGCGAAATTGGAATCCTTTGTAGTGCCCTCCAGAAAAT

[0847] TAAGTAACTCGAGGGATCCGTGAAATTTGTGTTGCTATTGCAACATGTTAAGAAAATTTCCC

[0848] GTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTG

[0849] GTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATC

[0850] ATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTC TTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGA CGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCT TTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACA GGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTT

[0851] CCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCC

[0852] CTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTC

[0853] TTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCC TGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCA TGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGTAAG GACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGC

[0854] CCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCTTATAATGGTTACAA

[0855] ATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCattctagttgtggtttgtccaa actcatcaatgtatctgaagacaatagcaggcatgctgggAAGQTGatgTTTTcatGAGCTGAAGOOATAQAGOOC ACCGCATC

[0856] 4.2 RNA sequence of db49

[0857] UCAGAUCGCUAGCAAUCAAAUAUUAUUAUUAUCAUACCAACAGACUCAGAUGUCCACUGC

[0858] GGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUCUCUGACUUUGGUCAGGAAACAAGCU

[0859] AUAUUGAAGACAACUGCAAUCAAAAUGGAGCCAUAUCACUGAUCUUCUCACUCAAAGAAG

[0860] AAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUUUGAGGAAAAUGAUGUAAACCUGACC

[0861] CACAUUGAAUCUAGACCUUCUCGUUUAAAAAAAGAUGAGUAUGAAUUUUUCACACAUUUG

[0862] GAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAUCAAGAUCUUGAGGCAUGACAUUGG

[0863] AGCCACUGUCCAUGAGCUUUCACGAGAUAAGAAGAAAGACACAGUGCCCUGGUUCCCAA

[0864] GAACCAUUCAAGAGCUAGACAGAUUUGCCAAUCAGAUUCUCAGCUAUGGAGCGGAACUG

[0865] GAUGCUGACCACCCUGGUUUUAAGGAUCCUGUGUACCGUGCAAGACGGAAGCAGUUUGC

[0866] UGACAUUGCCUACAACUACCGCCAUGGGCAGCCCAUCCCUCGUGUGGAAUACAUGGAGG

[0867] AAGAAAAGAAAACAUGGGGCACAGUGUUCAAGACUCUGAAGUCCUUGUAUAAAACCCAUG

[0868] CUUGCUAUGAGUACAAUCACAUUUUUCCACUUCUUGAAAAAUACUGUGGCUUCCAUGAAG

[0869] AUAACAUUCCCCAGCUAGAAGACGUUUCUCAGUUCCUGCAAACUUGCACUGGUUUCCGC

[0870] CUCCGACCUGUGGCUGGCCUGCUUUCCUCUCGGGAUUUCUUGGGUGGCCUGGCCUUCC

[0871] GAGUCUUCCACUGCACACAGUACAUCAGACAUGGAUCCAAGCCCAUGUAUACCCCCGAAC

[0872] CUGACAUCUGCCAUGAGCUGUUGGGACAUGUGCCCUUGUUUUCUGAUCGAAGCUUUGCC

[0873] CAGUUUUCCCAGGAAAUUGGCCUUGCCUCUCUGGGUGCUCCUGAUGAAUACAUUGAAAA

[0874] GCUCGCCACAAUUUACUGGUUUACUGUGGAGUUUGGGCUCUGCAAACAAGGAGACUCCA

[0875] UAAAGGCAUAUGGUGCUGGGCUCCUGUCAUCCUUUGGUGAAUUACAGUACUGCUUAUCA

[0876] GAGAAGCCAAAGCUUCUCCCCCUGGAGCUAGAGAAGACAGCCAUCCAAAAUUACACUGUC

[0877] ACGGAGUUCCAGCCCCUCUAUUACGUGGCAGAGAGUUUUAAUGAUGCCAAGGAAAAAGU

[0878] UAGGAACUUUGCUGCCACAAUACCUCGGCCCUUCUCUGUUCGCUACGACCCAUACACAC

[0879] AAAGGAUUGAGGUCUUGGACAAUACCCAACAGCUUAAGAUUUUGGCUGAUUCCAUUAACA

[0880] GCGAAAUUGGAAUCCUUUGUAGUGCCCUCCAGAAAAUUAAGUAACUCGAGGGAUCCGUG

[0881] AAAUUUGUGUUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCC

[0882] UGUUAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGU

[0883] UGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUU

[0884] CCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAG

[0885] GAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAA

[0886] CCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUU

[0887] CCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCLIUGCCCGCUGCIJGGACA

[0888] GGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCU

[0889] UUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUA

[0890] CGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUG

[0891] CGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCG CCLJCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCA GACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACU UGGCAUGCCAAGUAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUG GGAGGAGGGUUACUUAAGCCCUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUU AUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCAU UUUUUUCACUGC

[0892] 4.3 Protein sequence of db49

[0893] MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIE SRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFA NQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKS LYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFR VFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWF TVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESF NDAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIK

[0894] 5. db81

[0895] Name: hAAT-hPAH-WT

[0896] 5.1 DNA sequence of db81

[0897] ATCCAGatgTTTTcatCTGGAGACTCTTCGQGATGTACGGQGGAGATATAG

[0898] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0899] AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATaggctcagaggcacacaggagtttctgggctcac cctgcccccttccaacccctcagttcccatcctccagcagctgtttgtgtgctgcctctgaagtccacactgaacaaacttcagcctactcat gtccctaaaatgggcaaacattgcaagcagcaaacagcaaacacacagccctccctgcctgctgaccttggagctggggcagaggt cagagacctctctgggcccatgccacctccaacatccactcgaccccttggaatttcggtggagaggagcagaggttgtcctggcgtgg tttaggtagtgtgagaggggtacccggggatcttgctaccagtggaacagccactaaggattctgcagtgagagcagagggccagct aagtggtactctcccagagactgtctgactcacgccaccccctccaccttggacacaggacgctgtggtttctgagccaggtacaatga ctcctttcggtaagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcagcgtaggcgggcgactcagatcccagccagt ggacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccagcagcctcccccgttgcccctctggatccactgctt aaatacggacgaggacagggccctgtctcctcagcttcaggcaccaccactgacctgggacagtgaatGCTAGCGAATTCat gtccactgcggtcctggaaaacccaggcttgggcaggaaactctctgactttggacagGTAAGTATCAAGGTTACAAGA CAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCT GATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCACAGgaaacaagc aiaiig aagacaactgcaatcaaaatggtgccatatcactgatcttctcactcaaagaagaagttggtgcattggccaaagtattgcgcttatttga ggagaatgatgtaaacctgacccacattgaatctagaccttctcgtttaaagaaagatgagtatgaatttttcacccatttggataaacgta gcctgcctgctctgacaaacatcatcaagatcttgaggcatgacattggtgccactgtccatgagctttcacgagataagaagaaagac acagtgccctggttcccaagaaccattcaagagctggacagatttgccaatcagattctcagctatggagcggaactggatgctgacca ccctggttttaaagatcctgtgtaccgtgcaagacggaagcagtttgctgacattgcctacaactaccgccatgggcagcccatccctcg agtggaatacatggaggaagaaaagaaaacatggggcacagtgttcaagactctgaagtccttgtataaaacccatgcttgctatgag tacaatcacatttttccacttcttgaaaagtactgtggcttccatgaagataacattccccagctggaagacgtttctcagttcctgcagactt gcactggtttccgcctccgacctgtggctggcctgctttcctctcgggatttcttgggtggcctggccttccgagtcttccactgcacacagta catcagacatggatccaagcccatgtatacccccgaacctgacatctgccatgagctgttgggacatgtgcccttgttttcagatcgcagc tttgcccagttttcccaggaaattggccttgcctctctgggtgcacctgatgaatacattgaaaagctcgccacaatttactggtttactgtgg agtttgggctctgcaaacaaggagactccataaaggcatatggtgctgggctcctgtcatcctttggtgaattacagtactgcttatcagag aagccaaagcttctccccctggagctggagaagacagccatccaaaattacactgtcacggagttccagcccctctattacgtggcag agagttttaatgatgccaaggagaaagtaaggaactttgctgccacaatacctcggcccttctcagttcgctacgacccatacacccaa aggattgaggtcttggacaatacccagcagcttaagattttggctgattccattaacagtgaaattggaatcctttgcagtgccctccagaa aataaagtaactcgagACCGGTCTCGAGGGATCCGTGAAATTTGTGATGCTATTGCAACATGTTAA GAAAATTTCCCGTTATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGA AAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAAT GCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTG GTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACT

[0900] GTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCG GGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCG CTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCT GACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTC

[0901] TGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCT

[0902] CTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCG

[0903] CCTCCCCGCCTGTTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGAC TTGCGAACCATGGATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCAT GCCAAGTAAGGACCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGG GTTACTTAAGCCCTGCGGTAATTAGGTGGTGTAGCGGCCGCAACTTGTTTATTGCAGCTTAT

[0904] AATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCattct agt'.gtggUg'.ccaaactcatcaatgta'.ctgaagacaa'.agcaggcatgctgggAAGGTGjEgWTTcaiGAGGTGAAG GGOAGAGGGGAGGiGAI^

[0905] 5.2 RNA sequence of db81

[0906] UCAGAUCCCAGCCAGUGGACUUAGCCCCUGUUUGCUCCUCCGAUAACUGGGGUGACCUU

[0907] GGUUAAUAUUCACCAGCAGCCUCCCCCGUUGCCCCUCUGGAUCCACUGCUUAAAUACGG ACGAGGACAGGGCCCUGUCUCCUCAGCUUCAGGCACCACCACUGACCUGGGACAGUGAA UGCUAGCGAAUUCAUGUCCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUCU CUGACUUUGGACAGGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGUGCCAUAU

[0908] CACUGAUCUUCUCACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUUU GAGGAGAAUGAUGUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAGAAAGAU GAGUAUGAAUUUUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAUC AAGAUCUUGAGGCAUGACAUUGGUGCCACUGUCCAUGAGCUUUCACGAGAUAAGAAGAA

[0909] AGACACAGUGCCCUGGUUCCCAAGAACCAUUCAAGAGCUGGACAGAUUUGCCAAUCAGA UUCUCAGCUAUGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAAGAUCCUGUGUAC CGUGCAAGACGGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGCAGCCCAU CCCUCGAGUGGAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAAGACUC

[0910] UGAAGUCCUUGUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCACUUCUUG

[0911] AAAAGUACUGUGGCUUCCAUGAAGAUAACAUUCCCCAGCUGGAAGACGUUUCUCAGUUC

[0912] CUGCAGACUUGCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCCUCUCGGG AUUUCUUGGGUGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAGACAUGGA UCCAAGCCCAUGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGACAUGUGCC CUUGUUUUCAGAUCGCAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCCUCUCUGG

[0913] GUGCACCUGAUGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGUGGAGUUU GGGCUCUGCAAACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGUCAUCCUU UGGUGAAUUACAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAGCUGGAGA AGACAGCCAUCCAAAAUUACACUGUCACGGAGUUCCAGCCCCUCUAUUACGUGGCAGAG

[0914] AGUUUUAAUGAUGCCAAGGAGAAAGUAAGGAACUUUGCUGCCACAAUACCUCGGCCCUU

[0915] CUCAGUUCGCUACGACCCAUACACCCAAAGGAUUGAGGUCUUGGACAAUACCCAGCAGC

[0916] UUAAGAUUUUGGCUGAUUCCAUUAACAGUGAAAUUGGAAUCCUUUGCAGUGCCCUCCAG

[0917] AAAAUAAAGUAACUCGAGACCGGUCUCGAGGGAUCCGUGAAAUUUGUGAUGCUAUUGCA ACAUGUUAAGAAAAUUUCCCGUUAUUUGCACUCUGUUCCUGUUAAUCAACCUCUGGAUUA CAAAAUUUGUGAAAGAUUGACUGGUAUUCUUAACUAUGUUGCUCCUUUUACGCUAUGUG GAUACGCUGCUUUAAUGCCUUUGUAUCAUGCUAUUGCUUCCCGUAUGGCUUUCAUUUUC

[0918] UCCUCCUUGUAUAAAUCCUGGUUGCUGUCUCUUUAUGAGGAGUUGUGGCCCGUUGUCA GGCAACGUGGCGUGGUGUGCACUGUGUUUGCUGACGCAACCCCCACUGGUUGGGGCAU UGCCACCACCUGUCAGCUCCUUUCCGGGACUUUCGCUUUCCCCCUCCCUAUUGCCACGG CGGAACUCAUCGCCGCCUGCCUUGCCCGCUGCUGGACAGGGGCUCGGCUGUUGGGCAC UGACAAUUCCGUGGUGUUGUCGGGGAAGCUGACGUCCUUUCCAUGGCUGCUCGCCUGU GUUGCCACCUGGAUUCUGCGCGGGACGUCCUUCUGCUACGUCCCUUCGGCCCUCAAUC CAGCGGACCUUCCUUCCCGCGGCCUGCUGCCGGCUCUGCGGCCUCUUCCGCGUCUUCG

[0919] CCUUCGCCCUCAGACGAGUCGGAUCUCCCUUUGGGCCGCCUCCCCGCCUGU U U CGCC U CGGCGUCCGGUCCGUGUUGCUUGGUCUUCACCUGUGCAGACUUGCGAACCAUGGAUUC

[0920] CACCGUGAACUUUGUCUCCUGGCAUGCAAAUCGUCAACUUGGCAUGCCAAGUAAGGACC

[0921] UUUGGACUCCUUAUAUAAAAGAUCAAUUAUUAACUAAAUGGGAGGAGGGUUACUUAAGCC CUGCGGUAAUUAGGUGGUGUAGCGGCCGCAACUUGUUUAUUGCAGCUUAUAAUGGUUAC AAAU AAAGCAAU AGCAUC ACAAAU U U CACAAAU AAAGCAU U U U U U UCACUGC

[0922] 5.3 Protein sequence of db81

[0923] MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIE SRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFA

[0924] NQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKS LYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFR VFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWF

[0925] TVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESF NDAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIK

[0926] 6. db87

[0927] Name: CMV-eGFP-P2A-hPAH-WT-3xFLAG

[0928] 6.1 DNA sequence of db87 gcgttgacattgattattgactagtcgatggagcggagaatgggcggaactgggcggagttaggggcgggatgggcggagtt aggggcgggactatggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccaca cctggttgctgactaattgagatgcatgctttgcatacttctgcctgctggggagcctggggactttccacaccctaactgaca cacattccacagcactagttagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataactta cggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagg gactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgcccccta ttgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattag tcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccacccc attgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggc ggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatcgCTAGCGCTACCGGTCGCCA CCATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTG GACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCAC CTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCC CACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACAT GAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCAT CTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACAC CCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGG GCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAG AACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTC GCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAAC CACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATG GTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAG TCCGGCCGGACTCAGATCTCGAGCTCaGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGC AGGCTGGAGACGTGGAGGAGAACCCTGGGCCTtccactgcggtcctggaaaacccaggcttgggcaggaaa cXctclgacmggacaqGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGG CTTGTCGAGACAGAGACGACTCTTGCGTTTCTGA TAGGCACCTA TTGGTCTTACTGACA TCC AC7TTGCCT7TCTCTCCACAGgaaacaagctatattgaagacaactgcaatcaaaatggtgccatatcactgatcttctca ctcaaagaagaagttggtgcattggccaaagtattgcgcttatttgaggagaatgatgtaaacctgacccacattgaatctagaccttctc gtttaaagaaagatgagtatgaatttttcacccatttggataaacgtagcctgcctgctctgacaaacatcatcaagatcttgaggcatgac attggtgccactgtccatgagctttcacgagataagaagaaagacacagtgccctggttcccaagaaccattcaagagctggacagat ttgccaatcagattctcagctatggagcggaactggatgctgaccaccctggttttaaagatcctgtgtaccgtgcaagacggaagcagt ttgctgacattgcctacaactaccgccatgggcagcccatccctcgagtggaatacatggaggaagaaaagaaaacatggggcaca gtgttcaagactctgaagtccttgtataaaacccatgcttgctatgagtacaatcacatttttccacttcttgaaaagtactgtggcttccatga agataacattccccagctggaagacgtttctcagttcctgcagacttgcactggtttccgcctccgacctgtggctggcctgctttcctctcg ggatttcttgggtggcctggccttccgagtcttccactgcacacagtacatcagacatggatccaagcccatgtatacccccgaacctga catctgccatgagctgttgggacatgtgcccttgttttcagatcgcagctttgcccagttttcccaggaaattggccttgcctctctgggtgca cctgatgaatacattgaaaagctcgccacaatttactggtttactgtggagtttgggctctgcaaacaaggagactccataaaggcatatg gtgctgggctcctgtcatcctttggtgaattacagtactgcttatcagagaagccaaagcttctccccctggagctggagaagacagccat ccaaaattacactgtcacggagttccagcccctctattacgtggcagagagttttaatgatgccaaggagaaagtaaggaactttgctgc cacaatacctcggcccttctcagttcgctacgacccatacacccaaaggattgaggtcttggacaatacccagcagcttaagattttggct gattccattaacagtgaaattggaatcctttgcagtgccctccagaaaataaagGACTACAAGGACCACGACGGTGAC TACAAGGACCACGACATCGACTACAAGGACGACGACGACAAGtaataaTGCAGGTACCGCGG GCCCGGGATCCACCGGATCTAGATAACTGATCATAATCAGCCATACCACATTTGTAGAGGTT TTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATT GTTGTTGTTGCggccgcaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttcacaaataaagca ttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctggg

[0929] 6.2 RNA sequence of db87

[0930] UCAGAUCGCUAGCGCUACCGGUCGCCACCAUGGUGAGCAAGGGCGAGGAGCUGUUCAC

[0931] CGGGGUGGUGCCCAUCCUGGUCGAGCUGGACGGCGACGUAAACGGCCACAAGUUCAGC

[0932] GUGUCCGGCGAGGGCGAGGGCGAUGCCACCUACGGCAAGCUGACCCUGAAGUUCAUCU

[0933] GCACCACCGGCAAGCUGCCCGUGCCCUGGCCCACCCUCGUGACCACCCUGACCUACGGC

[0934] GUGCAGUGCUUCAGCCGCUACCCCGACCACAUGAAGCAGCACGACUUCUUCAAGUCCGC

[0935] CAUGCCCGAAGGCUACGUCCAGGAGCGCACCAUCUUCUUCAAGGACGACGGCAACUACA

[0936] AGACCCGCGCCGAGGUGAAGUUCGAGGGCGACACCCUGGUGAACCGCAUCGAGCUGAA

[0937] GGGCAUCGACUUCAAGGAGGACGGCAACAUCCUGGGGCACAAGCUGGAGUACAACUACA

[0938] ACAGCCACAACGUCUAUAUCAUGGCCGACAAGCAGAAGAACGGCAUCAAGGUGAACUUCA

[0939] AGAUCCGCCACAACAUCGAGGACGGCAGCGUGCAGCUCGCCGACCACUACCAGCAGAAC

[0940] ACCCCCAUCGGCGACGGCCCCGUGCUGCUGCCCGACAACCACUACCUGAGCACCCAGUC

[0941] CGCCCUGAGCAAAGACCCCAACGAGAAGCGCGAUCACAUGGUCCUGCUGGAGUUCGUGA

[0942] CCGCCGCCGGGAUCACUCUCGGCAUGGACGAGCUGUACAAGUCCGGCCGGACUCAGAU

[0943] CUCGAGCUCAGGAAGCGGAGCUACUAACUUCAGCCUGCUGAAGCAGGCUGGAGACGUGG

[0944] AGGAGAACCCUGGGCCUUCCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUC

[0945] UCUGACUUUGGACAGGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGUGCCAUA

[0946] UCACUGAUCUUCUCACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUU

[0947] UGAGGAGAAUGAUGUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAGAAAGA

[0948] UGAGUAUGAAUUUUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAU

[0949] CAAGAUCUUGAGGCAUGACAUUGGUGCCACUGUCCAUGAGCUUUCACGAGAUAAGAAGA

[0950] AAGACACAGUGCCCUGGUUCCCAAGAACCAUUCAAGAGCUGGACAGAUUUGCCAAUCAGA

[0951] UUCUCAGCUAUGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAAGAUCCUGUGUAC

[0952] CGUGCAAGACGGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGCAGCCCAU

[0953] CCCUCGAGUGGAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAAGACUC

[0954] UGAAGUCCUUGUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCACUUCUUG

[0955] AAAAGUACUGUGGCUUCCAUGAAGAUAACAUUCCCCAGCUGGAAGACGUUUCUCAGUUC

[0956] CUGCAGACUUGCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCCUCUCGGG

[0957] AUUUCUUGGGUGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAGACAUGGA

[0958] UCCAAGCCCAUGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGACAUGUGCC CUUGUUUUCAGAUCGCAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCCUCUCUGG GUGCACCUGAUGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGUGGAGUUU GGGCUCUGCAAACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGUCAUCCUU UGGUGAAUUACAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAGCUGGAGA AGACAGCCAUCCAAAAUUACACUGUCACGGAGUUCCAGCCCCUCUAUUACGUGGCAGAG AGUUUUAAUGAUGCCAAGGAGAAAGUAAGGAACUUUGCUGCCACAAUACCUCGGCCCUU CUCAGUUCGCUACGACCCAUACACCCAAAGGAUUGAGGUCUUGGACAAUACCCAGCAGC UUAAGAUUUUGGCUGAUUCCAUUAACAGUGAAAUUGGAAUCCUUUGCAGUGCCCUCCAG AAAAUAAAGGACUACAAGGACCACGACGGUGACUACAAGGACCACGACAUCGACUACAAG GACGACGACGACAAGUAAUAAUGCAGGUACCGCGGGCCCGGGAUCCACCGGAUCUAGAU AACUGAUCAUAAUCAGCCAUACCACAUUUGUAGAGGUUUUACUUGCUUUAAAAAACCUCC

[0959] CACACCUCCCCCUGAACCUGAAACAUAAAAUGAAUGCAAUUGUUGUUGUUGCGGCCGCAA CUUGUUUAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAA UAAAGCAUUUUUUUCACUGC

[0960] 6.3 Protein sequence of db87 eGFP

[0961] MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTL TYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGI DFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPV LLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYK hPAH

[0962] STAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIES RPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFAN QILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKSL

[0963] YKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFRV FHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWFT VEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESFN DAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIKDYKDHDGD YKDHDIDYKDDDDK

[0964] 7. db102

[0965] Name: hAAT-eGFP-P2A-hPAH-WT-3xFLAG

[0966] 7.1 DNA sequence of db102

[0967] > > > > > >

[0968] GCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACTGGGCGGAGT TAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAATTGAGATGCA TGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGGTTGCTGACTA ATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCCT

[0969] AACTGACACACATTCCACAGCaCTAGTTAGTTATTAATaggctcagaggcacacaggagtttctgggctcac cctgcccccttccaacccctcagttcccatcctccagcagctgtttgtgtgctgcctctgaagtccacactgaacaaacttcagcctactcat gtccctaaaatgggcaaacattgcaagcagcaaacagcaaacacacagccctccctgcctgctgaccttggagctggggcagaggt cagagacctctctgggcccatgccacctccaacatccactcgaccccttggaatttcggtggagaggagcagaggttgtcctggcgtgg tttaggtagtgtgagaggggtacccggggatcttgctaccagtggaacagccactaaggattctgcagtgagagcagagggccagct aagtggtactctcccagagactgtctgactcacgccaccccctccaccttggacacaggacgctgtggtttctgagccaggtacaatga ctcctttcggtaagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcagcgtaggcgggcgactcagatcccagccagt ggacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccagcagcctcccccgttgcccctctggatccactgctt aaatacggacgaggacagggccctgtctcctcagcttcaggcaccaccactgacctgggacagtgaatGCTAGCGCTACCG GTCGCCACCATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTC GAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGA TGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCC CTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGA CCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCG CACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGG CGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACAT CCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAG CAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTG CAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCC GACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGAT CACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTG TACAAGTCCGGCCGGACTCAGATCTCGAGCTCaGGAAGCGGAGCTACTAACTTCAGCCTGC TGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGGCCTtccactgcggtcctggaaaacccaggcttggg caggaaacicWgacmggacagGTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAA CTGGGCTTGTCGAGACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGA CATCCACTTTGCCTTTCTCTCCACAGgaaacaagctatattgaagacaactgcaatcaaaatggtgccatatcactg atcttctcactcaaagaagaagttggtgcattggccaaagtattgcgcttatttgaggagaatgatgtaaacctgacccacattgaatcta gaccttctcgtttaaagaaagatgagtatgaatttttcacccatttggataaacgtagcctgcctgctctgacaaacatcatcaagatcttga ggcatgacattggtgccactgtccatgagctttcacgagataagaagaaagacacagtgccctggttcccaagaaccattcaagagct ggacagatttgccaatcagattctcagctatggagcggaactggatgctgaccaccctggttttaaagatcctgtgtaccgtgcaagacg gaagcagtttgctgacattgcctacaactaccgccatgggcagcccatccctcgagtggaatacatggaggaagaaaagaaaacat ggggcacagtgttcaagactctgaagtccttgtataaaacccatgcttgctatgagtacaatcacatttttccacttcttgaaaagtactgtg gcttccatgaagataacattccccagctggaagacgtttctcagttcctgcagacttgcactggtttccgcctccgacctgtggctggcctg ctttcctctcgggatttcttgggtggcctggccttccgagtcttccactgcacacagtacatcagacatggatccaagcccatgtatacccc cgaacctgacatctgccatgagctgttgggacatgtgcccttgttttcagatcgcagctttgcccagttttcccaggaaattggccttgcctct ctgggtgcacctgatgaatacattgaaaagctcgccacaatttactggtttactgtggagtttgggctctgcaaacaaggagactccataa aggcatatggtgctgggctcctgtcatcctttggtgaattacagtactgcttatcagagaagccaaagcttctccccctggagctggagaa gacagccatccaaaattacactgtcacggagttccagcccctctattacgtggcagagagttttaatgatgccaaggagaaagtaagg aactttgctgccacaatacctcggcccttctcagttcgctacgacccatacacccaaaggattgaggtcttggacaatacccagcagctt aagattttggctgattccattaacagtgaaattggaatcctttgcagtgccctccagaaaataaagGACTACAAGGACCACGA CGGTGACTACAAGGACCACGACATCGACTACAAGGACGACGACGACAAGtaataaTGCAGGT ACCGCGGGCCCGGGATCCACCGGATCTAGATAACTGATCATAATCAGCCATACCACATTTG TAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGA ATGCAATTGTTGTTGTTGCggccgcaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttca caaataaagcatttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatctgaagacaatagcaggcatgctgggMMl

[0970] 7.2 RNA sequence of db 102

[0971] UCAGAUCCCAGCCAGUGGACUUAGCCCCUGUUUGCUCCUCCGAUAACUGGGGUGACCUU GGUUAAUAUUCACCAGCAGCCUCCCCCGUUGCCCCUCUGGAUCCACUGCUUAAAUACGG ACGAGGACAGGGCCCUGUCUCCUCAGCUUCAGGCACCACCACUGACCUGGGACAGUGAA UGCUAGCGCUACCGGUCGCCACCAUGGUGAGCAAGGGCGAGGAGCUGUUCACCGGGGU GGUGCCCAUCCUGGUCGAGCUGGACGGCGACGUAAACGGCCACAAGUUCAGCGUGUCC GGCGAGGGCGAGGGCGAUGCCACCUACGGCAAGCUGACCCUGAAGUUCAUCUGCACCAC CGGCAAGCUGCCCGUGCCCUGGCCCACCCUCGUGACCACCCUGACCUACGGCGUGCAG UGCUUCAGCCGCUACCCCGACCACAUGAAGCAGCACGACUUCUUCAAGUCCGCCAUGCC CGAAGGCUACGUCCAGGAGCGCACCAUCUUCUUCAAGGACGACGGCAACUACAAGACCC GCGCCGAGGUGAAGUUCGAGGGCGACACCCUGGUGAACCGCAUCGAGCUGAAGGGCAU CGACUUCAAGGAGGACGGCAACAUCCUGGGGCACAAGCUGGAGUACAACUACAACAGCC ACAACGUCUAUAUCAUGGCCGACAAGCAGAAGAACGGCAUCAAGGUGAACUUCAAGAUCC GCCACAACAUCGAGGACGGCAGCGUGCAGCUCGCCGACCACUACCAGCAGAACACCCCC AUCGGCGACGGCCCCGUGCUGCUGCCCGACAACCACUACCUGAGCACCCAGUCCGCCCU GAGCAAAGACCCCAACGAGAAGCGCGAUCACAUGGUCCUGCUGGAGUUCGUGACCGCCG CCGGGAUCACUCUCGGCAUGGACGAGCUGUACAAGUCCGGCCGGACUCAGAUCUCGAGC UCAGGAAGCGGAGCUACUAACUUCAGCCUGCUGAAGCAGGCUGGAGACGUGGAGGAGAA

[0972] CCCUGGGCCUUCCACUGCGGUCCUGGAAAACCCAGGCUUGGGCAGGAAACUCUCUGACU

[0973] UUGGACAGGAAACAAGCUAUAUUGAAGACAACUGCAAUCAAAAUGGUGCCAUAUCACUGA

[0974] UCUUCUCACUCAAAGAAGAAGUUGGUGCAUUGGCCAAAGUAUUGCGCUUAUUUGAGGAG

[0975] AAUGAUGUAAACCUGACCCACAUUGAAUCUAGACCUUCUCGUUUAAAGAAAGAUGAGUAU

[0976] GAAUUUUUCACCCAUUUGGAUAAACGUAGCCUGCCUGCUCUGACAAACAUCAUCAAGAUC

[0977] UUGAGGCAUGACAUUGGUGCCACUGUCCAUGAGCUUUCACGAGAUAAGAAGAAAGACAC

[0978] AGUGCCCUGGUUCCCAAGAACCAUUCAAGAGCUGGACAGAUUUGCCAAUCAGAUUCUCA

[0979] GCUAUGGAGCGGAACUGGAUGCUGACCACCCUGGUUUUAAAGAUCCUGUGUACCGUGCA

[0980] AGACGGAAGCAGUUUGCUGACAUUGCCUACAACUACCGCCAUGGGCAGCCCAUCCCUCG

[0981] AGUGGAAUACAUGGAGGAAGAAAAGAAAACAUGGGGCACAGUGUUCAAGACUCUGAAGU

[0982] CCUUGUAUAAAACCCAUGCUUGCUAUGAGUACAAUCACAUUUUUCCACUUCUUGAAAAGU

[0983] ACUGUGGCUUCCAUGAAGAUAACAUUCCCCAGCUGGAAGACGUUUCUCAGUUCCUGCAG

[0984] ACUUGCACUGGUUUCCGCCUCCGACCUGUGGCUGGCCUGCUUUCCUCUCGGGAUUUCU

[0985] UGGGUGGCCUGGCCUUCCGAGUCUUCCACUGCACACAGUACAUCAGACAUGGAUCCAAG

[0986] CCCAUGUAUACCCCCGAACCUGACAUCUGCCAUGAGCUGUUGGGACAUGUGCCCUUGUU

[0987] UUCAGAUCGCAGCUUUGCCCAGUUUUCCCAGGAAAUUGGCCUUGCCUCUCUGGGUGCAC

[0988] CUGAUGAAUACAUUGAAAAGCUCGCCACAAUUUACUGGUUUACUGUGGAGUUUGGGCUC

[0989] UGCAAACAAGGAGACUCCAUAAAGGCAUAUGGUGCUGGGCUCCUGUCAUCCUUUGGUGA

[0990] AUUACAGUACUGCUUAUCAGAGAAGCCAAAGCUUCUCCCCCUGGAGCUGGAGAAGACAG

[0991] CCAUCCAAAAUUACACUGUCACGGAGUUCCAGCCCCUCUAUUACGUGGCAGAGAGUUUU

[0992] AAUGAUGCCAAGGAGAAAGUAAGGAACUUUGCUGCCACAAUACCUCGGCCCUUCUCAGU

[0993] UCGCUACGACCCAUACACCCAAAGGAUUGAGGUCUUGGACAAUACCCAGCAGCUUAAGAU

[0994] UUUGGCUGAUUCCAUUAACAGUGAAAUUGGAAUCCUUUGCAGUGCCCUCCAGAAAAUAAA

[0995] GGACUACAAGGACCACGACGGUGACUACAAGGACCACGACAUCGACUACAAGGACGACG

[0996] ACGACAAGUAAUAAUGCAGGUACCGCGGGCCCGGGAUCCACCGGAUCUAGAUAACUGAU

[0997] CAUAAUCAGCCAUACCACAUUUGUAGAGGUUUUACUUGCUUUAAAAAACCUCCCACACCU

[0998] CCCCCUGAACCUGAAACAUAAAAUGAAUGCAAUUGUUGUUGUUGCGGCCGCAACUUGUU

[0999] UAUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCA

[1000] UUUUUUUCACUGC

[1001] 7.3 Protein sequence of db102 eGFP

[1002] MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTL

[1003] TYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGI

[1004] DFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPV

[1005] LLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYK hPAH

[1006] STAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDVNLTHIES

[1007] RPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPWFPRTIQELDRFAN

[1008] QILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYMEEEKKTWGTVFKTLKSL

[1009] YKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGFRLRPVAGLLSSRDFLGGLAFRV

[1010] FHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFAQFSQEIGLASLGAPDEYIEKLATIYWFT

[1011] VEFGLCKQGDSIKAYGAGLLSSFGELQYCLSEKPKLLPLELEKTAIQNYTVTEFQPLYYVAESFN

[1012] DAKEKVRNFAATIPRPFSVRYDPYTQRIEVLDNTQQLKILADSINSEIGILCSALQKIKDYKDHDGD

[1013] YKDHDIDYKDDDDK

[1014] C. SARS-CoV-2 (Vaccine) Vector Sequences

[1015] Vaccine Sequences All the vectors have the DNA, RNA and protein sequences in the document

[1016] Legend for DNA sequences:

[1017] • Nuclear Localization Signal (NLS)

[1018] • Splicing Domain

[1019] • Binding Domain

[1020] • T7 promoter

[1021] • Intron

[1022] • WPRE

[1023] Legend for RNA sequences:

[1024] • Binding Domain

[1025] • Splicing Domain

[1026] • WPRE

[1027] Legend for protein sequences

[1028] • Leader sequence

[1029] 1. db11 a. 1 .1 DNA sequence of db11 (SEQ ID NO 62) b. 1 .2 RNA sequence of db11 (SEQ ID NO 63) c. 1 .3 Protein sequence of db1 1 (SEQ ID NO 64)

[1030] 2. RNA12 a. 2.1 DNA sequence of RNA12 (SEQ ID NO 65) b. 2.2 Protein sequence of RNA12 (SEQ ID NO

[1031] 66) c. 2.3 Protein sequence of RNA12 (SEQ ID NO

[1032] 67)

[1033] 3. db13 a. 3.1 DNA sequence of db13 (SEQ ID NO 68) b. 3.2 RNA sequence of db13 (SEQ ID NO 69) c. 3.3 Protein sequence of db13 (SEQ ID NO 70)

[1034] 4. db14 a. 4.1 DNA sequence of db14 (SEQ ID NO 71 ) b. 4.2 RNA sequence of db14 (SEQ ID NO 72) c. 4.3 Protein sequence of db14 (SEQ ID NO 73)

[1035] 5. db15 a. 5.1 DNA sequence of db15 (SEQ ID NO 74) b. 5.2 RNA sequence of db15 (SEQ ID NO 75) c. 5.3 Protein sequence of db15 (SEQ ID NO 76)

[1036] 1. db11 Name: NIAID product 1 db-inactive RNA BioNTech

[1037] 1.1 DNA sequence of db11

[1038] CCAGATATACGCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACT

[1039] GGGCGGAGTTAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAAT TGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGG

[1040] TTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTT

[1041] TCCACACCCTAACTGACACACATTCCACAGCACTAGTTAGTTATTAATAGTAATCAATTACG

[1042] GGGTCATTAGTTCATAGCCCATATATGGAGTTCCGATTTATACGCTCGTTAGAGATCACCAG GAGGCGGAAGAAGCTAGTCGTTTAACACTAGTGTTATGCCCCGTGAGCCCAACAGGGCGG

[1043] CAATTGATTGGAAGTCGGCATTCCAGCAACTGAGTCTTATTTAAGTGAGATTATCAACAGGC GGGATAATCCTTATAATTATCAGAAGACTATAACAGGCGTATGGCCGCCATGTAGTACCCTG

[1044] TAAGTGGTGTGCAAACCCAATGACATAGCTCGAGCGGGCTACGACCCTGGTGGATAAACCA AATTTGGAACCGCAGTTTGAGGACAACATCGGCTGACTCCCCCGGATTTCTCGGATTTGCT GAATTATCAGTCAGGGCGCCCTACGTACGCTCGCATTAAAGGGTTCTACGAACTATTGTCC GCGGTCCCGTGGCCTTTCCTGCGGCCGGATATCATGCGGCCACTGAGCACCACTTCGAGA

[1045] GGGGTAGCCACAGTCGCCAACTTTTCCAGTTATTGCTTCTTATAATTATGTCGTATTCTCCCC CATCTTCAGATCGAGAATAAACTAGTATTCTTCTGGTCCCCACAGACTCAGAGAGAACCCGC CACCATGTTCGTGTTCCTGGTGCTGCTGCCTCTGGTGTCCAGCCAGTGTGTGAACCTGACC ACCAGAACACAGCTGCCTCCAGCCTACACCAACAGCTTTACCAGAGGCGTGTACTACCCCG ACAAGGTGTTCAGATCCAGCGTGCTGCACTCTACCCAGGACCTGTTCCTGCCTTTCTTCAG

[1046] CAACGTGACCTGGTTCCACGCCATCCACGTGTCCGGCACCAATGGCACCAAGAGATTCGAC AACCCCGTGCTGCCCTTCAACGACGGGGTGTACTTTGCCAGCACCGAGAAGTCCAACATCA TCAGAGGCTGGATCTTCGGCACCACACTGGACAGCAAGACCCAGAGCCTGCTGATCGTGA ACAACGCCACCAACGTGGTCATCAAAGTGTGCGAGTTCCAGTTCTGCAACGACCCCTTCCT GGGCGTCTACTACCACAAGAACAACAAGAGCTGGATGGAAAGCGAGTTCCGGGTGTACAG

[1047] CAGCGCCAACAACTGCACCTTCGAGTACGTGTCCCAGCCTTTCCTGATGGACCTGGAAGGC AAGCAGGGCAACTTCAAGAACCTGCGCGAGTTCGTGTTTAAGAACATCGACGGCTACTTCA AGATCTACAGCAAGCACACCCCTATCAACCTCGTGCGGGATCTGCCTCAGGGCTTCTCTGC

[1048] TCTGGAACCCCTGGTGGATCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACTGCTG GCCCTGCACAGAAGCTACCTGACACCTGGCGATAGCAGCAGCGGATGGACAGCTGGTGCC

[1049] GCCGCTTACTATGTGGGCTACCTGCAGCCTAGAACCTTCCTGCTGAAGTACAACGAGAACG GCACCATCACCGACGCCGTGGATTGTGCTCTGGATCCTCTGAGCGAGACAAAGTGCACCCT GAAGTCCTTCACCGTGGAAAAGGGCATCTACCAGACCAGCAACTTCCGGGTGCAGCCCAC CGAATCCATCGTGCGGTTCCCCAATATCACCAATCTGTGCCCCTTCGGCGAGGTGTTCAAT GCCACCAGATTCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCAGCAATTGCGTGGCC

[1050] GACTACTCCGTGCTGTACAACTCCGCCAGCTTCAGCACCTTCAAGTGCTACGGCGTGTCCC CTACCAAGCTGAACGACCTGTGCTTCACAAACGTGTACGCCGACAGCTTCGTGATCCGGGG AGATGAAGTGCGGCAGATTGCCCCTGGACAGACAGGCAAGATCGCCGACTACAACTACAA

[1051] GCTGCCCGACGACTTCACCGGCTGTGTGATTGCCTGGAACAGCAACAACCTGGACTCCAAA GTCGGCGGCAACTACAATTACCTGTACCGGCTGTTCCGGAAGTCCAATCTGAAGCCCTTCG AGCGGGACATCTCCACCGAGATCTATCAGGCCGGCAGCACCCCTTGTAACGGCGTGGAAG GCTTCAACTGCTACTTCCCACTGCAGTCCTACGGCTTTCAGCCCACAAATGGCGTGGGCTA

[1052] TCAGCCCTACAGAGTGGTGGTGCTGAGCTTCGAACTGCTGCATGCCCCTGCCACAGTGTGC GGCCCTAAGAAAAGCACCAATCTCGTGAAGAACAAATGCGTGAACTTCAACTTCAACGGCC TGACCGGCACCGGCGTGCTGACAGAGAGCAACAAGAAGTTCCTGCCATTCCAGCAGTTTG GCCGGGATATCGCCGATACCACAGACGCCGTTAGAGATCCCCAGACACTGGAAATCCTGG

[1053] ACATCACCCCTTGCAGCTTCGGCGGAGTGTCTGTGATCACCCCTGGCACCAACACCAGCAA TCAG GTAAGTA TCAAGGTTACAAGACAGGTTTAAGGAGACCAA TAGAAACTGGGCTTGTCGA GACAGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCC nTCTCTCCACAGGTGGCAGTGCTGTACCAGGACGTGAACTGTACCGAAGTGCCCGTGGCC ATTCACGCCGATCAGCTGACACCTACATGGCGGGTGTACTCCACCGGCAGCAATGTGTTTC AGACCAGAGCCGGCTGTCTGATCGGAGCCGAGCACGTGAACAATAGCTACGAGTGCGACA

[1054] TCCCCATCGGCGCTGGAATCTGCGCCAGCTACCAGACACAGACAAACAGCCCTCGGAGAG

[1055] CCAGAAGCGTGGCCAGCCAGAGCATCATTGCCTACACAATGTCTCTGGGCGCCGAGAACA

[1056] GCGTGGCCTACTCCAACAACTCTATCGCTATCCCCACCAACTTCACCATCAGCGTGACCAC

[1057] AGAGATCCTGCCTGTGTCCATGACCAAGACCAGCGTGGACTGCACCATGTACATCTGCGGC

[1058] GATTCCACCGAGTGCTCCAACCTGCTGCTGCAGTACGGCAGCTTCTGCACCCAGCTGAATA

[1059] GAGCCCTGACAGGGATCGCCGTGGAACAGGACAAGAACACCCAAGAGGTGTTCGCCCAAG

[1060] TGAAGCAGATCTACAAGACCCCTCCTATCAAGGACTTCGGCGGCTTCAATTTCAGCCAGATT

[1061] CTGCCCGATCCTAGCAAGCCCAGCAAGCGGAGCTTCATCGAGGACCTGCTGTTCAACAAAG

[1062] TGACACTGGCCGACGCCGGCTTCATCAAGCAGTATGGCGATTGTCTGGGCGACATTGCCG

[1063] CCAGGGATCTGATTTGCGCCCAGAAGTTTAACGGACTGACAGTGCTGCCTCCTCTGCTGAC

[1064] CGATGAGATGATCGCCCAGTACACATCTGCCCTGCTGGCCGGCACAATCACAAGCGGCTG

[1065] GACATTTGGAGCAGGCGCCGCTCTGCAGATCCCCTTTGCTATGCAGATGGCCTACCGGTTC

[1066] AACGGCATCGGAGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGT

[1067] TCAACAGCGCCATCGGCAAGATCCAGGACAGCCTGAGCAGCACAGCAAGCGCCCTGGGAA

[1068] AGCTGCAGGACGTGGTCAACCAGAATGCCCAGGCACTGAACACCCTGGTCAAGCAGCTGT

[1069] CCTCCAACTTCGGCGCCATCAGCTCTGTGCTGAACGATATCCTGAGCAGACTGGACCCTCC

[1070] TGAGGCCGAGGTGCAGATCGACAGACTGATCACAGGCAGACTGCAGAGCCTCCAGACATA

[1071] CGTGACCCAGCAGCTGATCAGAGCCGCCGAGATTAGAGCCTCTGCCAATCTGGCCGCCAC

[1072] CAAGATGTCTGAGTGTGTGCTGGGCCAGAGCAAGAGAGTGGACTTTTGCGGCAAGGGCTA

[1073] CCACCTGATGAGCTTCCCTCAGTCTGCCCCTCACGGCGTGGTGTTTCTGCACGTGACATAT

[1074] GTGCCCGCTCAAGAGAAGAATTTCACCACCGCTCCAGCCATCTGCCACGACGGCAAAGCC

[1075] CACTTTCCTAGAGAAGGCGTGTTCGTGTCCAACGGCACCCATTGGTTCGTGACACAGCGGA

[1076] ACTTCTACGAGCCCCAGATCATCACCACCGACAACACCTTCGTGTCTGGCAACTGCGACGT

[1077] CGTGATCGGCATTGTGAACAATACCGTGTACGACCCTCTGCAGCCCGAGCTGGACAGCTTC

[1078] AAAGAGGAACTGGACAAGTACTTTAAGAACCACACAAGCCCCGACGTGGACCTGGGCGATA

[1079] TCAGCGGAATCAATGCCAGCGTCGTGAACATCCAGAAAGAGATCGACCGGCTGAACGAGG

[1080] TGGCCAAGAATCTGAACGAGAGCCTGATCGACCTGCAAGAACTGGGGAAGTACGAGCAGT

[1081] ACATCAAGTGGCCCTGGTACATCTGGCTGGGCTTTATCGCCGGACTGATTGCCATCGTGAT

[1082] GGTCACAATCATGCTGTGTTGCATGACCAGCTGCTGTAGCTGCCTGAAGGGCTGTTGTAGC

[1083] TGTGGCAGCTGCTGCAAGTTCGACGAGGACGATTCTGAGCCCGTGCTGAAGGGCGTGAAA

[1084] CTGCACTACACATGATGAGTGAAATTTGTGATGCTATTGCAACATGTTAAGAAAATTTCCCGT

[1085] TATTTGCACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGT

[1086] ATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCAT

[1087] GCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTT

[1088] TATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACG

[1089] CAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTT

[1090] CCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGG

[1091] GGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCA

[1092] TGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTT

[1093] CGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTC

[1094] CGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTG

[1095] TTTCGCCTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCATG

[1096] GATTCCACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGTAAGGA

[1097] CCTTTGGACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCC

[1098] TGCGGTAATTAGGTGGTGTAAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATA

[1099] GCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACT

[1100] CATCAATGTATCTGAAGACAATAGCAGGCATGCTGGGiiiiiiiiHiiiiHiWiiiiii

[1101] ATAGAGCGCAGCGGATG

[1102] 1 .2 RNA sequence of db11 No RNA

[1103] 1 .3 Protein sequence of db11

[1104] No protein

[1105] 2. RNA12

[1106] Name: NIAID product 2_IVT_BioNTech RNA

[1107] 2.1 DNA sequence of RNA12

[1108] CTAATACGAGTCAGTATAGAGAATAAACTAGTATTCTTCTGGTCCCCACAGACTCAGAGAGA

[1109] ACCCGCCACCATGTTCGTGTTCCTGGTGCTGCTGCCTCTGGTGTCCAGCCAGTGTGTGAAC

[1110] CTGACCACCAGAACACAGCTGCCTCCAGCCTACACCAACAGCTTTACCAGAGGCGTGTACT

[1111] ACCCCGACAAGGTGTTCAGATCCAGCGTGCTGCACTCTACCCAGGACCTGTTCCTGCCTTT

[1112] CTTCAGCAACGTGACCTGGTTCCACGCCATCCACGTGTCCGGCACCAATGGCACCAAGAGA

[1113] TTCGACAACCCCGTGCTGCCCTTCAACGACGGGGTGTACTTTGCCAGCACCGAGAAGTCCA

[1114] ACATCATCAGAGGCTGGATCTTCGGCACCACACTGGACAGCAAGACCCAGAGCCTGCTGAT

[1115] CGTGAACAACGCCACCAACGTGGTCATCAAAGTGTGCGAGTTCCAGTTCTGCAACGACCCC

[1116] TTCCTGGGCGTCTACTACCACAAGAACAACAAGAGCTGGATGGAAAGCGAGTTCCGGGTGT

[1117] ACAGCAGCGCCAACAACTGCACCTTCGAGTACGTGTCCCAGCCTTTCCTGATGGACCTGGA

[1118] AGGCAAGCAGGGCAACTTCAAGAACCTGCGCGAGTTCGTGTTTAAGAACATCGACGGCTAC

[1119] TTCAAGATCTACAGCAAGCACACCCCTATCAACCTCGTGCGGGATCTGCCTCAGGGCTTCT

[1120] CTGCTCTGGAACCCCTGGTGGATCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACT

[1121] GCTGGCCCTGCACAGAAGCTACCTGACACCTGGCGATAGCAGCAGCGGATGGACAGCTGG

[1122] TGCCGCCGCTTACTATGTGGGCTACCTGCAGCCTAGAACCTTCCTGCTGAAGTACAACGAG

[1123] AACGGCACCATCACCGACGCCGTGGATTGTGCTCTGGATCCTCTGAGCGAGACAAAGTGCA

[1124] CCCTGAAGTCCTTCACCGTGGAAAAGGGCATCTACCAGACCAGCAACTTCCGGGTGCAGCC

[1125] CACCGAATCCATCGTGCGGTTCCCCAATATCACCAATCTGTGCCCCTTCGGCGAGGTGTTC

[1126] AATGCCACCAGATTCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCAGCAATTGCGTGG

[1127] CCGACTACTCCGTGCTGTACAACTCCGCCAGCTTCAGCACCTTCAAGTGCTACGGCGTGTC

[1128] CCCTACCAAGCTGAACGACCTGTGCTTCACAAACGTGTACGCCGACAGCTTCGTGATCCGG

[1129] GGAGATGAAGTGCGGCAGATTGCCCCTGGACAGACAGGCAAGATCGCCGACTACAACTAC

[1130] AAGCTGCCCGACGACTTCACCGGCTGTGTGATTGCCTGGAACAGCAACAACCTGGACTCCA

[1131] AAGTCGGCGGCAACTACAATTACCTGTACCGGCTGTTCCGGAAGTCCAATCTGAAGCCCTT

[1132] CGAGCGGGACATCTCCACCGAGATCTATCAGGCCGGCAGCACCCCTTGTAACGGCGTGGA

[1133] AGGCTTCAACTGCTACTTCCCACTGCAGTCCTACGGCTTTCAGCCCACAAATGGCGTGGGC

[1134] TATCAGCCCTACAGAGTGGTGGTGCTGAGCTTCGAACTGCTGCATGCCCCTGCCACAGTGT

[1135] GCGGCCCTAAGAAAAGCACCAATCTCGTGAAGAACAAATGCGTGAACTTCAACTTCAACGG

[1136] CCTGACCGGCACCGGCGTGCTGACAGAGAGCAACAAGAAGTTCCTGCCATTCCAGCAGTTT

[1137] GGCCGGGATATCGCCGATACCACAGACGCCGTTAGAGATCCCCAGACACTGGAAATCCTG

[1138] GACATCACCCCTTGCAGCTTCGGCGGAGTGTCTGTGATCACCCCTGGCACCAACACCAGCA

[1139] ATCAGGTGGCAGTGCTGTACCAGGACGTGAACTGTACCGAAGTGCCCGTGGCCATTCACG

[1140] CCGATCAGCTGACACCTACATGGCGGGTGTACTCCACCGGCAGCAATGTGTTTCAGACCAG

[1141] AGCCGGCTGTCTGATCGGAGCCGAGCACGTGAACAATAGCTACGAGTGCGACATCCCCAT

[1142] CGGCGCTGGAATCTGCGCCAGCTACCAGACACAGACAAACAGCCCTCGGAGAGCCAGAAG

[1143] CGTGGCCAGCCAGAGCATCATTGCCTACACAATGTCTCTGGGCGCCGAGAACAGCGTGGC

[1144] CTACTCCAACAACTCTATCGCTATCCCCACCAACTTCACCATCAGCGTGACCACAGAGATCC

[1145] TGCCTGTGTCCATGACCAAGACCAGCGTGGACTGCACCATGTACATCTGCGGCGATTCCAC

[1146] CGAGTGCTCCAACCTGCTGCTGCAGTACGGCAGCTTCTGCACCCAGCTGAATAGAGCCCTG

[1147] ACAGGGATCGCCGTGGAACAGGACAAGAACACCCAAGAGGTGTTCGCCCAAGTGAAGCAG

[1148] ATCTACAAGACCCCTCCTATCAAGGACTTCGGCGGCTTCAATTTCAGCCAGATTCTGCCCGA

[1149] TCCTAGCAAGCCCAGCAAGCGGAGCTTCATCGAGGACCTGCTGTTCAACAAAGTGACACTG GCCGACGCCGGCTTCATCAAGCAGTATGGCGATTGTCTGGGCGACATTGCCGCCAGGGAT

[1150] CTGATTTGCGCCCAGAAGTTTAACGGACTGACAGTGCTGCCTCCTCTGCTGACCGATGAGA

[1151] TGATCGCCCAGTACACATCTGCCCTGCTGGCCGGCACAATCACAAGCGGCTGGACATTTGG

[1152] AGCAGGCGCCGCTCTGCAGATCCCCTTTGCTATGCAGATGGCCTACCGGTTCAACGGCATC

[1153] GGAGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACAGCG

[1154] CCATCGGCAAGATCCAGGACAGCCTGAGCAGCACAGCAAGCGCCCTGGGAAAGCTGCAGG

[1155] ACGTGGTCAACCAGAATGCCCAGGCACTGAACACCCTGGTCAAGCAGCTGTCCTCCAACTT

[1156] CGGCGCCATCAGCTCTGTGCTGAACGATATCCTGAGCAGACTGGACCCTCCTGAGGCCGA

[1157] GGTGCAGATCGACAGACTGATCACAGGCAGACTGCAGAGCCTCCAGACATACGTGACCCA

[1158] GCAGCTGATCAGAGCCGCCGAGATTAGAGCCTCTGCCAATCTGGCCGCCACCAAGATGTCT

[1159] GAGTGTGTGCTGGGCCAGAGCAAGAGAGTGGACTTTTGCGGCAAGGGCTACCACCTGATG

[1160] AGCTTCCCTCAGTCTGCCCCTCACGGCGTGGTGTTTCTGCACGTGACATATGTGCCCGCTC

[1161] AAGAGAAGAATTTCACCACCGCTCCAGCCATCTGCCACGACGGCAAAGCCCACTTTCCTAG

[1162] AGAAGGCGTGTTCGTGTCCAACGGCACCCATTGGTTCGTGACACAGCGGAACTTCTACGAG

[1163] CCCCAGATCATCACCACCGACAACACCTTCGTGTCTGGCAACTGCGACGTCGTGATCGGCA

[1164] TTGTGAACAATACCGTGTACGACCCTCTGCAGCCCGAGCTGGACAGCTTCAAAGAGGAACT

[1165] GGACAAGTACTTTAAGAACCACACAAGCCCCGACGTGGACCTGGGCGATATCAGCGGAATC

[1166] AATGCCAGCGTCGTGAACATCCAGAAAGAGATCGACCGGCTGAACGAGGTGGCCAAGAAT

[1167] CTGAACGAGAGCCTGATCGACCTGCAAGAACTGGGGAAGTACGAGCAGTACATCAAGTGG

[1168] CCCTGGTACATCTGGCTGGGCTTTATCGCCGGACTGATTGCCATCGTGATGGTCACAATCA

[1169] TGCTGTGTTGCATGACCAGCTGCTGTAGCTGCCTGAAGGGCTGTTGTAGCTGTGGCAGCTG

[1170] CTGCAAGTTCGACGAGGACGATTCTGAGCCCGTGCTGAAGGGCGTGAAACTGCACTACACA

[1171] TGATGACTCGAGCTGGTACTGCATGCACGCAATGCTAGCTGCCCCTTTCCCGTCCTGGGTA

[1172] CCCCGAGTCTCCCCCGACCTCGGGTCCCAGGTATGCTCCCACCTCCACCTGCCCCACTCA

[1173] CCACCTCTGCTAGTTCCAGACACCTCCCAAGCACGCAGCAATGCAGCTCAAAACGCTTAGC

[1174] CTAGCCACACCCCCACGGGAAACAGCAGTGATTAACCTTTAGCAATAAACGAAAGTTTAACT

[1175] AAGCTATACTAACCCCAGGGTTGGTCAATTTCGTGCCAGCCACACCCTGGAGCTAGCAAAA

[1176] AAAAAAAAAAAAAAAAAAAAAAAAAAGCATATCTAG

[1177] 2.2 RNA sequence of RNA12

[1178] GAGAAUAAACUAGUAUUCUUCUGGUCCCCACAGACUCAGAGAGAACCCGCCACCAUGUUC

[1179] GUGUUCCUGGUGCUGCUGCCUCUGGUGUCCAGCCAGUGUGUGAACCUGACCACCAGAA

[1180] CACAGCUGCCUCCAGCCUACACCAACAGCUUUACCAGAGGCGUGUACUACCCCGACAAG

[1181] GUGUUCAGAUCCAGCGUGCUGCACUCUACCCAGGACCUGUUCCUGCCUUUCUUCAGCAA

[1182] CGUGACCUGGUUCCACGCCAUCCACGUGUCCGGCACCAAUGGCACCAAGAGAUUCGACA

[1183] ACCCCGUGCUGCCCUUCAACGACGGGGUGUACUUUGCCAGCACCGAGAAGUCCAACAUC

[1184] AUCAGAGGCUGGAUCUUCGGCACCACACUGGACAGCAAGACCCAGAGCCUGCUGAUCGU

[1185] GAACAACGCCACCAACGUGGUCAUCAAAGUGUGCGAGUUCCAGUUCUGCAACGACCCCU

[1186] UCCUGGGCGUCUACUACCACAAGAACAACAAGAGCUGGAUGGAAAGCGAGUUCCGGGUG

[1187] UACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGUCCCAGCCUUUCCUGAUGGACCU

[1188] GGAAGGCAAGCAGGGCAACUUCAAGAACCUGCGCGAGUUCGUGUUUAAGAACAUCGACG

[1189] GCUACUUCAAGAUCUACAGCAAGCACACCCCUAUCAACCUCGUGCGGGAUCUGCCUCAG

[1190] GGCUUCUCUGCUCUGGAACCCCUGGUGGAUCUGCCCAUCGGCAUCAACAUCACCCGGUU

[1191] UCAGACACUGCUGGCCCUGCACAGAAGCUACCUGACACCUGGCGAUAGCAGCAGCGGAU

[1192] GGACAGCUGGUGCCGCCGCUUACUAUGUGGGCUACCUGCAGCCUAGAACCUUCCUGCU

[1193] GAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGAUUGUGCUCUGGAUCCUCUGA

[1194] GCGAGACAAAGUGCACCCUGAAGUCCUUCACCGUGGAAAAGGGCAUCUACCAGACCAGC

[1195] AACUUCCGGGUGCAGCCCACCGAAUCCAUCGUGCGGUUCCCCAAUAUCACCAAUCUGUG

[1196] CCCCUUCGGCGAGGUGUUCAAUGCCACCAGAUUCGCCUCUGUGUACGCCUGGAACCGGA

[1197] AGCGGAUCAGCAAUUGCGUGGCCGACUACUCCGUGCUGUACAACUCCGCCAGCUUCAGC

[1198] ACCUUCAAGUGCUACGGCGUGUCCCCUACCAAGCUGAACGACCUGUGCUUCACAAACGU GUACGCCGACAGCUUCGUGAUCCGGGGAGAUGAAGUGCGGCAGAUUGCCCCUGGACAG

[1199] ACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGUGUGAU

[1200] UGCCUGGAACAGCAACAACCUGGACUCCAAAGUCGGCGGCAACUACAAUUACCUGUACC

[1201] GGCUGUUCCGGAAGUCCAAUCUGAAGCCCUUCGAGCGGGACAUCUCCACCGAGAUCUAU

[1202] CAGGCCGGCAGCACCCCUUGUAACGGCGUGGAAGGCUUCAACUGCUACUUCCCACUGCA

[1203] GUCCUACGGCUUUCAGCCCACAAAUGGCGUGGGCUAUCAGCCCUACAGAGUGGUGGUG

[1204] CUGAGCUUCGAACUGCUGCAUGCCCCUGCCACAGUGUGCGGCCCUAAGAAAAGCACCAA

[1205] UCUCGUGAAGAACAAAUGCGUGAACUUCAACUUCAACGGCCUGACCGGCACCGGCGUGC

[1206] UGACAGAGAGCAACAAGAAGUUCCUGCCAUUCCAGCAGUUUGGCCGGGAUAUCGCCGAU

[1207] ACCACAGACGCCGUUAGAGAUCCCCAGACACUGGAAAUCCUGGACAUCACCCCUUGCAG

[1208] CUUCGGCGGAGUGUCUGUGAUCACCCCUGGCACCAACACCAGCAAUCAGGUGGCAGUGC

[1209] UGUACCAGGACGUGAACUGUACCGAAGUGCCCGUGGCCAUUCACGCCGAUCAGCUGACA

[1210] CCUACAUGGCGGGUGUACUCCACCGGCAGCAAUGUGUUUCAGACCAGAGCCGGCUGUCU

[1211] GAUCGGAGCCGAGCACGUGAACAAUAGCUACGAGUGCGACAUCCCCAUCGGCGCUGGAA

[1212] UCUGCGCCAGCUACCAGACACAGACAAACAGCCCUCGGAGAGCCAGAAGCGUGGCCAGC

[1213] CAGAGCAUCAUUGCCUACACAAUGUCUCUGGGCGCCGAGAACAGCGUGGCCUACUCCAA

[1214] CAACUCUAUCGCUAUCCCCACCAACUUCACCAUCAGCGUGACCACAGAGAUCCUGCCUGU

[1215] GUCCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCUGCGGCGAUUCCACCGAGU

[1216] GCUCCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCCAGCUGAAUAGAGCCCUGACA

[1217] GGGAUCGCCGUGGAACAGGACAAGAACACCCAAGAGGUGUUCGCCCAAGUGAAGCAGAU

[1218] CUACAAGACCCCUCCUAUCAAGGACUUCGGCGGCUUCAAUUUCAGCCAGAUUCUGCCCG

[1219] AUCCUAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUGCUGUUCAACAAAGUGACA

[1220] CUGGCCGACGCCGGCUUCAUCAAGCAGUAUGGCGAUUGUCUGGGCGACAUUGCCGCCA

[1221] GGGAUCUGAUUUGCGCCCAGAAGUUUAACGGACUGACAGUGCUGCCUCCUCUGCUGACC

[1222] GAUGAGAUGAUCGCCCAGUACACAUCUGCCCUGCUGGCCGGCACAAUCACAAGCGGCUG

[1223] GACAUUUGGAGCAGGCGCCGCUCUGCAGAUCCCCUUUGCUAUGCAGAUGGCCUACCGG

[1224] UUCAACGGCAUCGGAGUGACCCAGAAUGUGCUGUACGAGAACCAGAAGCUGAUCGCCAA

[1225] CCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGCAGCACAGCAAGCGCCC

[1226] UGGGAAAGCUGCAGGACGUGGUCAACCAGAAUGCCCAGGCACUGAACACCCUGGUCAAG

[1227] CAGCUGUCCUCCAACUUCGGCGCCAUCAGCUCUGUGCUGAACGAUAUCCUGAGCAGACU

[1228] GGACCCUCCUGAGGCCGAGGUGCAGAUCGACAGACUGAUCACAGGCAGACUGCAGAGCC

[1229] UCCAGACAUACGUGACCCAGCAGCUGAUCAGAGCCGCCGAGAUUAGAGCCUCUGCCAAU

[1230] CUGGCCGCCACCAAGAUGUCUGAGUGUGUGCUGGGCCAGAGCAAGAGAGUGGACUUUU

[1231] GCGGCAAGGGCUACCACCUGAUGAGCUUCCCUCAGUCUGCCCCUCACGGCGUGGUGUU

[1232] UCUGCACGUGACAUAUGUGCCCGCUCAAGAGAAGAAUUUCACCACCGCUCCAGCCAUCU

[1233] GCCACGACGGCAAAGCCCACUUUCCUAGAGAAGGCGUGUUCGUGUCCAACGGCACCCAU

[1234] UGGUUCGUGACACAGCGGAACUUCUACGAGCCCCAGAUCAUCACCACCGACAACACCUU

[1235] CGUGUCUGGCAACUGCGACGUCGUGAUCGGCAUUGUGAACAAUACCGUGUACGACCCUC

[1236] UGCAGCCCGAGCUGGACAGCUUCAAAGAGGAACUGGACAAGUACUUUAAGAACCACACAA

[1237] GCCCCGACGUGGACCUGGGCGAUAUCAGCGGAAUCAAUGCCAGCGUCGUGAACAUCCAG

[1238] AAAGAGAUCGACCGGCUGAACGAGGUGGCCAAGAAUCUGAACGAGAGCCUGAUCGACCU

[1239] GCAAGAACUGGGGAAGUACGAGCAGUACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCU

[1240] UUAUCGCCGGACUGAUUGCCAUCGUGAUGGUCACAAUCAUGCUGUGUUGCAUGACCAGC

[1241] UGCUGUAGCUGCCUGAAGGGCUGUUGUAGCUGUGGCAGCUGCUGCAAGUUCGACGAGG

[1242] ACGAUUCUGAGCCCGUGCUGAAGGGCGUGAAACUGCACUACACAUGAUGACUCGAGCUG

[1243] GUACUGCAUGCACGCAAUGCUAGCUGCCCCUUUCCCGUCCUGGGUACCCCGAGUCUCCC

[1244] CCGACCUCGGGUCCCAGGUAUGCUCCCACCUCCACCUGCCCCACUCACCACCUCUGCUA

[1245] GUUCCAGACACCUCCCAAGCACGCAGCAAUGCAGCUCAAAACGCUUAGCCUAGCCACACC

[1246] CCCACGGGAAACAGCAGUGAUUAACCUUUAGCAAUAAACGAAAGUUUAACUAAGCUAUAC

[1247] UAACCCCAGGGUUGGUCAAUUUCGUGCCAGCCACACCCUGGAGCUAGCAAAAAAAAAAAA

[1248] AAAAAAAAAAAAAAAAAAGCAUAUCUAG 2.3 Protein sequence of RNA12

[1249] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTW

[1250] FHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKV

[1251] CEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREF

[1252] VFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWT

[1253] AGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTE

[1254] SIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLND

[1255] LCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLY

[1256] RLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFEL

[1257] LHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQT

[1258] LEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTR

[1259] AGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSI

[1260] AIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNT

[1261] QEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDI

[1262] AARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGI

[1263] GVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAIS

[1264] SVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRV

[1265] DFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWF

[1266] VTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDI

[1267] SGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCC

[1268] MTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT**

[1269] 3. db13

[1270] Name: NIAID product 3_db_active_BioNTech RNA

[1271] 3.1 DNA sequence of db13

[1272] >

[1273] ATCCAGatgTTTTcatCTGGAGACTCTTCGCGATGTACGGGCCAGATATAC

[1274] CCAGATATACGCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACT

[1275] GGGCGGAGTTAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAAT

[1276] TGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGG

[1277] TTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTT

[1278] TCCACACCCTAACTGACACACATTCCACAGCACTAGTTAGTTATTAATAGTAATCAATTACG

[1279] GGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCC

[1280] GCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATA

[1281] GTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCA

[1282] CTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTA

[1283] AATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTAC

[1284] ATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCG

[1285] TGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGT

[1286] TTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGAC

[1287] GCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAA

[1288] CCGTCAGATCGAGAATAAACTAGTATTCTTCTGGTCCCCACAGACTCAGAGAGAACCCGCC

[1289] ACCATGTTCGTGTTCCTGGTGCTGCTGCCTCTGGTGTCCAGCCAGTGTGTGAACCTGACCA

[1290] CCAGAACACAGCTGCCTCCAGCCTACACCAACAGCTTTACCAGAGGCGTGTACTACCCCGA

[1291] CAAGGTGTTCAGATCCAGCGTGCTGCACTCTACCCAGGACCTGTTCCTGCCTTTCTTCAGC

[1292] AACGTGACCTGGTTCCACGCCATCCACGTGTCCGGCACCAATGGCACCAAGAGATTCGACA

[1293] ACCCCGTGCTGCCCTTCAACGACGGGGTGTACTTTGCCAGCACCGAGAAGTCCAACATCAT

[1294] CAGAGGCTGGATCTTCGGCACCACACTGGACAGCAAGACCCAGAGCCTGCTGATCGTGAA

[1295] CAACGCCACCAACGTGGTCATCAAAGTGTGCGAGTTCCAGTTCTGCAACGACCCCTTCCTG

[1296] GGCGTCTACTACCACAAGAACAACAAGAGCTGGATGGAAAGCGAGTTCCGGGTGTACAGCA GCGCCAACAACTGCACCTTCGAGTACGTGTCCCAGCCTTTCCTGATGGACCTGGAAGGCAA

[1297] GCAGGGCAACTTCAAGAACCTGCGCGAGTTCGTGTTTAAGAACATCGACGGCTACTTCAAG

[1298] ATCTACAGCAAGCACACCCCTATCAACCTCGTGCGGGATCTGCCTCAGGGCTTCTCTGCTC

[1299] TGGAACCCCTGGTGGATCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGC

[1300] CCTGCACAGAAGCTACCTGACACCTGGCGATAGCAGCAGCGGATGGACAGCTGGTGCCGC

[1301] CGCTTACTATGTGGGCTACCTGCAGCCTAGAACCTTCCTGCTGAAGTACAACGAGAACGGC

[1302] ACCATCACCGACGCCGTGGATTGTGCTCTGGATCCTCTGAGCGAGACAAAGTGCACCCTGA

[1303] AGTCCTTCACCGTGGAAAAGGGCATCTACCAGACCAGCAACTTCCGGGTGCAGCCCACCG

[1304] AATCCATCGTGCGGTTCCCCAATATCACCAATCTGTGCCCCTTCGGCGAGGTGTTCAATGC

[1305] CACCAGATTCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCAGCAATTGCGTGGCCGA

[1306] CTACTCCGTGCTGTACAACTCCGCCAGCTTCAGCACCTTCAAGTGCTACGGCGTGTCCCCT

[1307] ACCAAGCTGAACGACCTGTGCTTCACAAACGTGTACGCCGACAGCTTCGTGATCCGGGGAG

[1308] ATGAAGTGCGGCAGATTGCCCCTGGACAGACAGGCAAGATCGCCGACTACAACTACAAGCT

[1309] GCCCGACGACTTCACCGGCTGTGTGATTGCCTGGAACAGCAACAACCTGGACTCCAAAGTC

[1310] GGCGGCAACTACAATTACCTGTACCGGCTGTTCCGGAAGTCCAATCTGAAGCCCTTCGAGC

[1311] GGGACATCTCCACCGAGATCTATCAGGCCGGCAGCACCCCTTGTAACGGCGTGGAAGGCT

[1312] TCAACTGCTACTTCCCACTGCAGTCCTACGGCTTTCAGCCCACAAATGGCGTGGGCTATCA

[1313] GCCCTACAGAGTGGTGGTGCTGAGCTTCGAACTGCTGCATGCCCCTGCCACAGTGTGCGG

[1314] CCCTAAGAAAAGCACCAATCTCGTGAAGAACAAATGCGTGAACTTCAACTTCAACGGCCTGA

[1315] CCGGCACCGGCGTGCTGACAGAGAGCAACAAGAAGTTCCTGCCATTCCAGCAGTTTGGCC

[1316] GGGATATCGCCGATACCACAGACGCCGTTAGAGATCCCCAGACACTGGAAATCCTGGACAT

[1317] CACCCCTTGCAGCTTCGGCGGAGTGTCTGTGATCACCCCTGGCACCAACACCAGCAATCAG

[1318] GTAAGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGAC

[1319] AGAGACGACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTT

[1320] CTCTCCACAGGTGGCAGTGCTGTACCAGGACGTGAACTGTACCGAAGTGCCCGTGGCCATT

[1321] CACGCCGATCAGCTGACACCTACATGGCGGGTGTACTCCACCGGCAGCAATGTGTTTCAGA

[1322] CCAGAGCCGGCTGTCTGATCGGAGCCGAGCACGTGAACAATAGCTACGAGTGCGACATCC

[1323] CCATCGGCGCTGGAATCTGCGCCAGCTACCAGACACAGACAAACAGCCCTCGGAGAGCCA

[1324] GAAGCGTGGCCAGCCAGAGCATCATTGCCTACACAATGTCTCTGGGCGCCGAGAACAGCG

[1325] TGGCCTACTCCAACAACTCTATCGCTATCCCCACCAACTTCACCATCAGCGTGACCACAGAG

[1326] ATCCTGCCTGTGTCCATGACCAAGACCAGCGTGGACTGCACCATGTACATCTGCGGCGATT

[1327] CCACCGAGTGCTCCAACCTGCTGCTGCAGTACGGCAGCTTCTGCACCCAGCTGAATAGAGC

[1328] CCTGACAGGGATCGCCGTGGAACAGGACAAGAACACCCAAGAGGTGTTCGCCCAAGTGAA

[1329] GCAGATCTACAAGACCCCTCCTATCAAGGACTTCGGCGGCTTCAATTTCAGCCAGATTCTGC

[1330] CCGATCCTAGCAAGCCCAGCAAGCGGAGCTTCATCGAGGACCTGCTGTTCAACAAAGTGAC

[1331] ACTGGCCGACGCCGGCTTCATCAAGCAGTATGGCGATTGTCTGGGCGACATTGCCGCCAG

[1332] GGATCTGATTTGCGCCCAGAAGTTTAACGGACTGACAGTGCTGCCTCCTCTGCTGACCGAT

[1333] GAGATGATCGCCCAGTACACATCTGCCCTGCTGGCCGGCACAATCACAAGCGGCTGGACA

[1334] TTTGGAGCAGGCGCCGCTCTGCAGATCCCCTTTGCTATGCAGATGGCCTACCGGTTCAACG

[1335] GCATCGGAGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAA

[1336] CAGCGCCATCGGCAAGATCCAGGACAGCCTGAGCAGCACAGCAAGCGCCCTGGGAAAGCT

[1337] GCAGGACGTGGTCAACCAGAATGCCCAGGCACTGAACACCCTGGTCAAGCAGCTGTCCTC

[1338] CAACTTCGGCGCCATCAGCTCTGTGCTGAACGATATCCTGAGCAGACTGGACCCTCCTGAG

[1339] GCCGAGGTGCAGATCGACAGACTGATCACAGGCAGACTGCAGAGCCTCCAGACATACGTG

[1340] ACCCAGCAGCTGATCAGAGCCGCCGAGATTAGAGCCTCTGCCAATCTGGCCGCCACCAAG

[1341] ATGTCTGAGTGTGTGCTGGGCCAGAGCAAGAGAGTGGACTTTTGCGGCAAGGGCTACCAC

[1342] CTGATGAGCTTCCCTCAGTCTGCCCCTCACGGCGTGGTGTTTCTGCACGTGACATATGTGC

[1343] CCGCTCAAGAGAAGAATTTCACCACCGCTCCAGCCATCTGCCACGACGGCAAAGCCCACTT

[1344] TCCTAGAGAAGGCGTGTTCGTGTCCAACGGCACCCATTGGTTCGTGACACAGCGGAACTTC

[1345] TACGAGCCCCAGATCATCACCACCGACAACACCTTCGTGTCTGGCAACTGCGACGTCGTGA

[1346] TCGGCATTGTGAACAATACCGTGTACGACCCTCTGCAGCCCGAGCTGGACAGCTTCAAAGA

[1347] GGAACTGGACAAGTACTTTAAGAACCACACAAGCCCCGACGTGGACCTGGGCGATATCAGC

[1348] GGAATCAATGCCAGCGTCGTGAACATCCAGAAAGAGATCGACCGGCTGAACGAGGTGGCC AAGAATCTGAACGAGAGCCTGATCGACCTGCAAGAACTGGGGAAGTACGAGCAGTACATCA

[1349] AGTGGCCCTGGTACATCTGGCTGGGCTTTATCGCCGGACTGATTGCCATCGTGATGGTCAC

[1350] AATCATGCTGTGTTGCATGACCAGCTGCTGTAGCTGCCTGAAGGGCTGTTGTAGCTGTGGC

[1351] AGCTGCTGCAAGTTCGACGAGGACGATTCTGAGCCCGTGCTGAAGGGCGTGAAACTGCAC

[1352] TACACATGATGAGTGAAATTTGTGATGCTATTGCAACATGTTAAGAAAATTTCCCGTTATTTG

[1353] CACTCTGTTCCTGTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTT

[1354] AACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATT

[1355] GCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAG

[1356] GAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACC

[1357] CCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCC

[1358] TCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTC

[1359] GGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCT

[1360] GCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCC

[1361] CTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGT

[1362] CTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTGTTTCGC

[1363] CTCGGCGTCCGGTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCATGGATTCC

[1364] ACCGTGAACTTTGTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGTAAGGACCTTTG

[1365] GACTCCTTATATAAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGG

[1366] TAATTAGGTGGTGTAAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATC

[1367] ACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCA

[1368] ATGTATCTGAAGACAATAGCAGGCATGCTGGGAAGGSipTT®yi^ACCTGAl@^CATAGA

[1369] GCCCACCGGATC

[1370] 3.2 RNA sequence of db13

[1371] UCAGAUCGAGAAUAAACUAGUAUUCUUCUGGUCCCCACAGACUCAGAGAGAACCCGCCAC

[1372] CAUGUUCGUGUUCCUGGUGCUGCUGCCUCUGGUGUCCAGCCAGUGUGUGAACCUGACC

[1373] ACCAGAACACAGCUGCCUCCAGCCUACACCAACAGCUUUACCAGAGGCGUGUACUACCCC

[1374] GACAAGGUGUUCAGAUCCAGCGUGCUGCACUCUACCCAGGACCUGUUCCUGCCUUUCUU

[1375] CAGCAACGUGACCUGGUUCCACGCCAUCCACGUGUCCGGCACCAAUGGCACCAAGAGAU

[1376] UCGACAACCCCGUGCUGCCCUUCAACGACGGGGUGUACUUUGCCAGCACCGAGAAGUCC

[1377] AACAUCAUCAGAGGCUGGAUCUUCGGCACCACACUGGACAGCAAGACCCAGAGCCUGCU

[1378] GAUCGUGAACAACGCCACCAACGUGGUCAUCAAAGUGUGCGAGUUCCAGUUCUGCAACG

[1379] ACCCCUUCCUGGGCGUCUACUACCACAAGAACAACAAGAGCUGGAUGGAAAGCGAGUUC

[1380] CGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAGUACGUGUCCCAGCCUUUCCUGAU

[1381] GGACCUGGAAGGCAAGCAGGGCAACUUCAAGAACCUGCGCGAGUUCGUGUUUAAGAACA

[1382] UCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCUAUCAACCUCGUGCGGGAUCUG

[1383] CCUCAGGGCUUCUCUGCUCUGGAACCCCUGGUGGAUCUGCCCAUCGGCAUCAACAUCAC

[1384] CCGGUUUCAGACACUGCUGGCCCUGCACAGAAGCUACCUGACACCUGGCGAUAGCAGCA

[1385] GCGGAUGGACAGCUGGUGCCGCCGCUUACUAUGUGGGCUACCUGCAGCCUAGAACCUU

[1386] CCUGCUGAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGAUUGUGCUCUGGAUC

[1387] CUCUGAGCGAGACAAAGUGCACCCUGAAGUCCUUCACCGUGGAAAAGGGCAUCUACCAG

[1388] ACCAGCAACUUCCGGGUGCAGCCCACCGAAUCCAUCGUGCGGUUCCCCAAUAUCACCAA

[1389] UCUGUGCCCCUUCGGCGAGGUGUUCAAUGCCACCAGAUUCGCCUCUGUGUACGCCUGG

[1390] AACCGGAAGCGGAUCAGCAAUUGCGUGGCCGACUACUCCGUGCUGUACAACUCCGCCAG

[1391] CUUCAGCACCUUCAAGUGCUACGGCGUGUCCCCUACCAAGCUGAACGACCUGUGCUUCA

[1392] CAAACGUGUACGCCGACAGCUUCGUGAUCCGGGGAGAUGAAGUGCGGCAGAUUGCCCCU

[1393] GGACAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUG

[1394] UGUGAUUGCCUGGAACAGCAACAACCUGGACUCCAAAGUCGGCGGCAACUACAAUUACC

[1395] UGUACCGGCUGUUCCGGAAGUCCAAUCUGAAGCCCUUCGAGCGGGACAUCUCCACCGAG

[1396] AUCUAUCAGGCCGGCAGCACCCCUUGUAACGGCGUGGAAGGCUUCAACUGCUACUUCCC

[1397] ACUGCAGUCCUACGGCUUUCAGCCCACAAAUGGCGUGGGCUAUCAGCCCUACAGAGUGG UGGUGCUGAGCUUCGAACUGCUGCAUGCCCCUGCCACAGUGUGCGGCCCUAAGAAAAGC

[1398] ACCAAUCUCGUGAAGAACAAAUGCGUGAACUUCAACUUCAACGGCCUGACCGGCACCGG

[1399] CGUGCUGACAGAGAGCAACAAGAAGUUCCUGCCAUUCCAGCAGUUUGGCCGGGAUAUCG

[1400] CCGAUACCACAGACGCCGUUAGAGAUCCCCAGACACUGGAAAUCCUGGACAUCACCCCU

[1401] UGCAGCUUCGGCGGAGUGUCUGUGAUCACCCCUGGCACCAACACCAGCAAUCAGGUAAG

[1402] UAUCAAGGUUACAAGACAGGUUUAAGGAGACCAAUAGAAACUGGGCUUGUCGAGACAGA

[1403] GACGACUCUUGCGUUUCUGAUAGGCACCUAUUGGUCUUACUGACAUCCACUUUGCCUUU

[1404] CUCUCCACAGGUGGCAGUGCUGUACCAGGACGUGAACUGUACCGAAGUGCCCGUGGCCA

[1405] UUCACGCCGAUCAGCUGACACCUACAUGGCGGGUGUACUCCACCGGCAGCAAUGUGUUU

[1406] CAGACCAGAGCCGGCUGUCUGAUCGGAGCCGAGCACGUGAACAAUAGCUACGAGUGCGA

[1407] CAUCCCCAUCGGCGCUGGAAUCUGCGCCAGCUACCAGACACAGACAAACAGCCCUCGGA

[1408] GAGCCAGAAGCGUGGCCAGCCAGAGCAUCAUUGCCUACACAAUGUCUCUGGGCGCCGAG

[1409] AACAGCGUGGCCUACUCCAACAACUCUAUCGCUAUCCCCACCAACUUCACCAUCAGCGUG

[1410] ACCACAGAGAUCCUGCCUGUGUCCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAU

[1411] CUGCGGCGAUUCCACCGAGUGCUCCAACCUGCUGCUGCAGUACGGCAGCUUCUGCACCC

[1412] AGCUGAAUAGAGCCCUGACAGGGAUCGCCGUGGAACAGGACAAGAACACCCAAGAGGUG

[1413] UUCGCCCAAGUGAAGCAGAUCUACAAGACCCCUCCUAUCAAGGACUUCGGCGGCUUCAA

[1414] UUUCAGCCAGAUUCUGCCCGAUCCUAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACC

[1415] UGCUGUUCAACAAAGUGACACUGGCCGACGCCGGCUUCAUCAAGCAGUAUGGCGAUUGU

[1416] CUGGGCGACAUUGCCGCCAGGGAUCUGAUUUGCGCCCAGAAGUUUAACGGACUGACAGU

[1417] GCUGCCUCCUCUGCUGACCGAUGAGAUGAUCGCCCAGUACACAUCUGCCCUGCUGGCCG

[1418] GCACAAUCACAAGCGGCUGGACAUUUGGAGCAGGCGCCGCUCUGCAGAUCCCCUUUGCU

[1419] AUGCAGAUGGCCUACCGGUUCAACGGCAUCGGAGUGACCCAGAAUGUGCUGUACGAGAA

[1420] CCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGA

[1421] GCAGCACAGCAAGCGCCCUGGGAAAGCUGCAGGACGUGGUCAACCAGAAUGCCCAGGCA

[1422] CUGAACACCCUGGUCAAGCAGCUGUCCUCCAACUUCGGCGCCAUCAGCUCUGUGCUGAA

[1423] CGAUAUCCUGAGCAGACUGGACCCUCCUGAGGCCGAGGUGCAGAUCGACAGACUGAUCA

[1424] CAGGCAGACUGCAGAGCCUCCAGACAUACGUGACCCAGCAGCUGAUCAGAGCCGCCGAG

[1425] AUUAGAGCCUCUGCCAAUCUGGCCGCCACCAAGAUGUCUGAGUGUGUGCUGGGCCAGAG

[1426] CAAGAGAGUGGACUUUUGCGGCAAGGGCUACCACCUGAUGAGCUUCCCUCAGUCUGCCC

[1427] CUCACGGCGUGGUGUUUCUGCACGUGACAUAUGUGCCCGCUCAAGAGAAGAAUUUCACC

[1428] ACCGCUCCAGCCAUCUGCCACGACGGCAAAGCCCACUUUCCUAGAGAAGGCGUGUUCGU

[1429] GUCCAACGGCACCCAUUGGUUCGUGACACAGCGGAACUUCUACGAGCCCCAGAUCAUCA

[1430] CCACCGACAACACCUUCGUGUCUGGCAACUGCGACGUCGUGAUCGGCAUUGUGAACAAU

[1431] ACCGUGUACGACCCUCUGCAGCCCGAGCUGGACAGCUUCAAAGAGGAACUGGACAAGUA

[1432] CUUUAAGAACCACACAAGCCCCGACGUGGACCUGGGCGAUAUCAGCGGAAUCAAUGCCA

[1433] GCGUCGUGAACAUCCAGAAAGAGAUCGACCGGCUGAACGAGGUGGCCAAGAAUCUGAAC

[1434] GAGAGCCUGAUCGACCUGCAAGAACUGGGGAAGUACGAGCAGUACAUCAAGUGGCCCUG

[1435] GUACAUCUGGCUGGGCUUUAUCGCCGGACUGAUUGCCAUCGUGAUGGUCACAAUCAUGC

[1436] UGUGUUGCAUGACCAGCUGCUGUAGCUGCCUGAAGGGCUGUUGUAGCUGUGGCAGCUG

[1437] CUGCAAGUUCGACGAGGACGAUUCUGAGCCCGUGCUGAAGGGCGUGAAACUGCACUACA

[1438] CAUGAUGAGUGAAAUUUGUGAUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUAUUUG

[1439] CACUCUG U UCCU G U UAAUCAACCUCUGGAUUACAAAAUUUGUGAAAGAUUGACUGGUAUU

[1440] CUUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUGUAUCA

[1441] UGCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUUGCUGU

[1442] CUCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACUGUGUU

[1443] UGCUGACGCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUCCGGGA

[1444] CUUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUUGCCCGC

[1445] UGCUGGACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGGGGAAGC

[1446] UGACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGGGACGUC

[1447] CUUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCCUGCUG

[1448] CCGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAUCUCCC

[1449] UUUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGGUCUUC ACCUGUGCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAUGCAAA UCGUCAACUUGGCAUGCCAAGUAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUU AACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCGGUAAUUAGGUGGUGUAAACUUGUUU AUUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCAU

[1450] UUUUUUCACUGC

[1451] 3.3 Protein sequence of db13

[1452] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTW

[1453] FHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKV CEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREF VFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWT AGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTE

[1454] SIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLND LCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLY RLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFEL LHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQT

[1455] LEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTR AGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSI AIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNT QEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDI

[1456] AARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGI GVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAIS SVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRV DFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWF

[1457] VTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDI SGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCC MTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT**

[1458] 4. db14

[1459] Name: NIAID product_4_db_optimised RNA

[1460] 4.1 DNA sequence of db14

[1461] >

[1462] CCAGATATACGCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACT

[1463] GGGCGGAGTTAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAAT TGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGG TTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTT TCCACACCCTAACTGACACACATTCCACAGCACTAGTTAGTTATTAATAGTAATCAATTACG

[1464] GGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCC GCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATA GTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCA CTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTA

[1465] AATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTAC ATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCG TGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGT TTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGAC

[1466] GCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAA CCGTCAGATCAATAAACTAGTATTCTTCTGGTCCCCACAGACTCAGAGAGAACCCGCCACCA TGTTCGTATTCCTGGTGCTACTGCCTCTGGTATCCAGCCAATGTGTGAACCTGACCACCAGA ACACAGCTGCCTCCAGCCTACACCAATAGCTTTACCAGAGGCGTGTACTACCCCGACAAGG

[1467] TGTTCAGATCCAGCGTGCTGCACTCTACCCAGGACCTGTTCCTGCCTTTCTTCAGCAACGTG ACCTGGTTCCACGCCATCCACGTGTCCGGCACCAATGGCACCAAGAGATTCGACAACCCCG TGCTGCCCTTCAACGACGGGGTGTACTTTGCCAGCACCGAGAAGTCCAACATCATCAGAGG

[1468] CTGGATCTTCGGCACCACACTGGACAGCAAGACCCAGAGCCTGCTTATCGTGAACAACGCC

[1469] ACCAACGTGGTCATCAAAGTGTGCGAGTTCCAGTTCTGCAACGACCCCTTCCTGGGCGTCT

[1470] ACTACCACAAGAACAACAAGAGTTGGATGGAAAGCGAGTTCCGGGTGTACAGCAGCGCCAA

[1471] CAACTGCACCTTCGAATACGTGTCCCAGCCTTTCCTGATGGACCTGGAAGGCAAGCAGGGC

[1472] AACTTCAAGAACCTGCGCGAGTTCGTGTTTAAGAACATCGACGGCTACTTCAAGATCTACAG

[1473] CAAGCACACCCCTATCAACCTCGTGCGGGATCTGCCTCAGGGCTTCTCTGCTCTGGAACCC

[1474] CTGGTGGATCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGCCCTGCACA

[1475] GAAGCTACCTGACACCTGGCGATAGCAGCAGCGGATGGACAGCTGGTGCCGCCGCTTACT

[1476] ATGTGGGCTACCTGCAGCCTAGAACCTTCCTGCTTAAGTACAACGAGAACGGCACCATCAC

[1477] CGACGCCGTGGATTGTGCTCTGGATCCTCTGAGCGAGACAAAGTGCACCCTGAAGTCCTTC

[1478] ACCGTGGAAAAGGGCATCTACCAGACCAGCAACTTCCGGGTGCAGCCCACCGAATCCATC

[1479] GTGCGGTTCCCCAATATCACCAATCTGTGCCCCTTCGGCGAGGTGTTCAATGCCACCAGAT

[1480] TCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCAGCAATTGCGTGGCCGACTACTCCG

[1481] TGCTGTACAACTCCGCCAGCTTCAGCACCTTCAAGTGCTACGGCGTGTCCCCTACCAAGCT

[1482] GAACGACCTGTGCTTCACAAACGTGTACGCCGACAGCTTCGTGATCCGGGGAGATGAAGTG

[1483] CGGCAGATTGCCCCTGGACAGACAGGCAAGATCGCCGACTACAACTACAAGCTGCCCGAC

[1484] GACTTCACCGGCTGTGTGATTGCCTGGAACAGCAACAACCTGGACTCCAAAGTCGGCGGCA

[1485] ACTACAATTACCTGTACCGGCTGTTCCGGAAGTCCAATCTGAAGCCCTTCGAGCGGGACAT

[1486] CTCCACCGAGATCTATCAGGCCGGCAGCACCCCTTGTAACGGCGTGGAAGGCTTCAACTG

[1487] CTACTTCCCACTGCAGTCCTACGGCTTTCAGCCCACAAATGGCGTGGGCTATCAGCCCTAC

[1488] AGAGTGGTGGTGCTGAGCTTCGAACTGCTGCATGCCCCTGCCACAGTGTGCGGCCCTAAG

[1489] AAAAGCACCAATCTCGTGAAGAACAAATGCGTGAACTTCAACTTCAACGGCCTGACCGGCA

[1490] CCGGCGTGCTGACAGAGAGCAACAAGAAGTTCCTGCCATTCCAGCAGTTTGGCCGGGATAT

[1491] CGCCGATACCACAGACGCCGTTAGAGATCCCCAGACACTGGAAATCCTGGACATCACCCCT

[1492] TGCTCCTTCGGCGGAGTGTCTGTGATCACCCCAGGAACGAACACGAGCAATCAGGT’AAGT'A

[1493] TCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAGACG

[1494] ACTCTTGCGTTTCTGATAGGCACCTATTGGTCTTACTGACATCCACTTTGCCTTTCTCTCCAC

[1495] AGGTGGCAGTGCTGTACCAGGACGTGAACTGTACCGAAGTGCCCGTGGCCATTCACGCCG

[1496] ATCAGCTGACACCTACATGGCGGGTGTACTCCACCGGCAGCAATGTGTTTCAGACCAGAGC

[1497] CGGCTGTCTGATCGGAGCCGAGCACGTGAACAATAGCTACGAGTGCGACATCCCCATCGG

[1498] CGCTGGAATCTGCGCCAGCTACCAGACACAGACAAACAGCCCTCGGAGAGCGAGAAGCGT

[1499] GGCCAGTCAGAGCATCATTGCCTACACAATGTCTCTGGGCGCCGAGAACAGCGTGGCCTA

[1500] CTCCAACAACTCTATCGCTATCCCCACCAACTTCACCATCAGCGTGACCACAGAGATCCTGC

[1501] CTGTGTCCATGACCAAGACCAGCGTGGACTGCACCATGTACATCTGCGGCGATTCCACCGA

[1502] GTGCTCCAACCTTCTGCTGCAATACGGCAGCTTCTGCACCCAGCTGAATAGAGCCCTGACA

[1503] GGGATCGCCGTGGAACAGGACAAGAACACCCAAGAGGTGTTCGCCCAAGTGAAGCAGATC

[1504] TACAAGACCCCTCCTATCAAGGACTTCGGCGGCTTCAATTTCAGTCAGATTCTGCCCGATCC

[1505] TAGCAAGCCCAGCAAGCGGAGCTTCATCGAGGACCTGCTGTTCAACAAAGTGACACTGGCC

[1506] GACGCCGGCTTCATCAAGCAGTATGGCGATTGTCTGGGCGACATTGCCGCCAGGGATCTG

[1507] ATTTGCGCCCAGAAGTTTAACGGACTGACAGTGCTGCCTCCTCTGCTTACCGATGAGATGAT

[1508] CGCCCAGTACACATCTGCCCTTCTGGCCGGCACAATCACAAGCGGCTGGACATTTGGAGCA

[1509] GGCGCCGCTCTGCAGATCCCCTTTGCTATGCAAATGGCCTACCGGTTCAACGGCATCGGAG

[1510] TGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACAGCGCCAT

[1511] CGGCAAGATCCAGGACAGCCTGAGCAGCACAGCAAGCGCCCTGGGAAAGCTGCAGGACGT

[1512] GGTCAACCAGAATGCCCAGGCACTGAACACCCTGGTCAAGCAGCTGTCCTCCAACTTCGGC

[1513] GCCATCAGCTCTGTGCTTAACGATATCCTGAGCAGACTGGACCCTCCTGAGGCCGAGGTGC

[1514] AGATCGACAGACTGATCACAGGCAGACTGCAGAGCCTCCAGACATACGTGACCCAGCAGCT

[1515] GATCAGAGCCGCCGAGATTAGAGCCTCTGCCAATCTGGCCGCCACCAAGATGTCTGAGTGT

[1516] GTGCTGGGCCAGAGCAAGAGAGTGGACTTTTGCGGCAAGGGCTACCACCTGATGAGCTTC

[1517] CCTCAGTCTGCCCCTCACGGCGTGGTGTTTCTGCACGTGACATATGTGCCCGCTCAAGAGA

[1518] AGAATTTCACCACCGCTCCAGCCATCTGCCACGACGGCAAAGCCCACTTTCCTAGAGAAGG

[1519] CGTGTTCGTGTCCAACGGCACCCATTGGTTCGTGACACAGCGGAACTTCTACGAGCCCCAG ATCATCACCACCGACAACACCTTCGTGTCTGGCAACTGCGACGTCGTGATCGGCATTGTGA

[1520] ACAATACCGTGTACGACCCTCTGCAGCCCGAGCTTGACAGCTTCAAAGAGGAACTGGACAA

[1521] GTACTTTAAGAATCACACAAGCCCCGACGTGGACCTGGGCGATATCAGCGGAATCAATGCC

[1522] AGCGTCGTGAACATCCAGAAAGAGATCGACCGGCTGAACGAGGTGGCCAAGAATCTGAAC

[1523] GAGAGCCTGATCGACCTGCAAGAACTGGGGAAGTACGAGCAGTACATCAAGTGGCCCTGG

[1524] TACATCTGGCTGGGCTTTATCGCCGGACTGATTGCCATCGTGATGGTCACAATCATGCTGT

[1525] GTTGCATGACCAGCTGCTGTAGCTGCCTGAAGGGCTGTTGTAGCTGTGGCAGCTGCTGCAA

[1526] GTTCGACGAGGACGATTCTGAGCCCGTCCTCAAGGGCGTGAAACTGCACTACACATGATGA

[1527] GTGAAATTTGTGATGCTATTGCAACATGTTAAGAAAATTTCCCGTTATTTGCACTCTGTTCCT

[1528] GTTAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCT

[1529] CCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATG

[1530] GCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCC

[1531] GTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGG

[1532] GGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCAC

[1533] GGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCA

[1534] CTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGT

[1535] TGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCG

[1536] GACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGC

[1537] CCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCTGTTTCGCCTCGGCGTCCG

[1538] GTCCGTGTTGCTTGGTCTTCACCTGTGCAGACTTGCGAACCATGGATTCCACCGTGAACTTT

[1539] GTCTCCTGGCATGCAAATCGTCAACTTGGCATGCCAAGTAAGGACCTTTGGACTCCTTATAT

[1540] AAAAGATCAATTATTAACTAAATGGGAGGAGGGTTACTTAAGCCCTGCGGTAATTAGGTGGT

[1541] GTAAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACA

[1542] AATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTGAA

[1543] 4.2 RNA sequence of db14

[1544] UCAGAUCAAUAAACUAGUAUUCUUCUGGUCCCCACAGACUCAGAGAGAACCCGCCACCAU

[1545] GUUCGUAUUCCUGGUGCUACUGCCUCUGGUAUCCAGCCAAUGUGUGAACCUGACCACCA

[1546] GAACACAGCUGCCUCCAGCCUACACCAAUAGCUUUACCAGAGGCGUGUACUACCCCGAC

[1547] AAGGUGUUCAGAUCCAGCGUGCUGCACUCUACCCAGGACCUGUUCCUGCCUUUCUUCAG

[1548] CAACGUGACCUGGUUCCACGCCAUCCACGUGUCCGGCACCAAUGGCACCAAGAGAUUCG

[1549] ACAACCCCGUGCUGCCCUUCAACGACGGGGUGUACUUUGCCAGCACCGAGAAGUCCAAC

[1550] AUCAUCAGAGGCUGGAUCUUCGGCACCACACUGGACAGCAAGACCCAGAGCCUGCUUAU

[1551] CGUGAACAACGCCACCAACGUGGUCAUCAAAGUGUGCGAGUUCCAGUUCUGCAACGACC

[1552] CCUUCCUGGGCGUCUACUACCACAAGAACAACAAGAGUUGGAUGGAAAGCGAGUUCCGG

[1553] GUGUACAGCAGCGCCAACAACUGCACCUUCGAAUACGUGUCCCAGCCUUUCCUGAUGGA

[1554] CCUGGAAGGCAAGCAGGGCAACUUCAAGAACCUGCGCGAGUUCGUGUUUAAGAACAUCG

[1555] ACGGCUACUUCAAGAUCUACAGCAAGCACACCCCUAUCAACCUCGUGCGGGAUCUGCCU

[1556] CAGGGCUUCUCUGCUCUGGAACCCCUGGUGGAUCUGCCCAUCGGCAUCAACAUCACCCG

[1557] GUUUCAGACACUGCUGGCCCUGCACAGAAGCUACCUGACACCUGGCGAUAGCAGCAGCG

[1558] GAUGGACAGCUGGUGCCGCCGCUUACUAUGUGGGCUACCUGCAGCCUAGAACCUUCCU

[1559] GCUUAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGAUUGUGCUCUGGAUCCUC

[1560] UGAGCGAGACAAAGUGCACCCUGAAGUCCUUCACCGUGGAAAAGGGCAUCUACCAGACC

[1561] AGCAACUUCCGGGUGCAGCCCACCGAAUCCAUCGUGCGGUUCCCCAAUAUCACCAAUCU

[1562] GUGCCCCUUCGGCGAGGUGUUCAAUGCCACCAGAUUCGCCUCUGUGUACGCCUGGAAC

[1563] CGGAAGCGGAUCAGCAAUUGCGUGGCCGACUACUCCGUGCUGUACAACUCCGCCAGCUU

[1564] CAGCACCUUCAAGUGCUACGGCGUGUCCCCUACCAAGCUGAACGACCUGUGCUUCACAA

[1565] ACGUGUACGCCGACAGCUUCGUGAUCCGGGGAGAUGAAGUGCGGCAGAUUGCCCCUGG

[1566] ACAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGACGACUUCACCGGCUGUG

[1567] UGAUUGCCUGGAACAGCAACAACCUGGACUCCAAAGUCGGCGGCAACUACAAUUACCUG

[1568] UACCGGCUGUUCCGGAAGUCCAAUCUGAAGCCCUUCGAGCGGGACAUCUCCACCGAGAU CUAUCAGGCCGGCAGCACCCCUUGUAACGGCGUGGAAGGCUUCAACUGCUACUUCCCAC

[1569] UGCAGUCCUACGGCUUUCAGCCCACAAAUGGCGUGGGCUAUCAGCCCUACAGAGUGGUG

[1570] GUGCUGAGCUUCGAACUGCUGCAUGCCCCUGCCACAGUGUGCGGCCCUAAGAAAAGCAC

[1571] CAAUCUCGUGAAGAACAAAUGCGUGAACUUCAACUUCAACGGCCUGACCGGCACCGGCG

[1572] UGCUGACAGAGAGCAACAAGAAGUUCCUGCCAUUCCAGCAGUUUGGCCGGGAUAUCGCC

[1573] GAUACCACAGACGCCGUUAGAGAUCCCCAGACACUGGAAAUCCUGGACAUCACCCCUUG

[1574] CUCCUUCGGCGGAGUGUCUGUGAUCACCCCAGGAACGAACACGAGCAAUCAGGUAAGUA

[1575] UCAAGGUUACAAGACAGGUUUAAGGAGACCAAUAGAAACUGGGCUUGUCGAGACAGAGA

[1576] CGACUCUUGCGUUUCUGAUAGGCACCUAUUGGUCUUACUGACAUCCACUUUGCCUUUCU

[1577] CUCCACAGGUGGCAGUGCUGUACCAGGACGUGAACUGUACCGAAGUGCCCGUGGCCAUU

[1578] CACGCCGAUCAGCUGACACCUACAUGGCGGGUGUACUCCACCGGCAGCAAUGUGUUUCA

[1579] GACCAGAGCCGGCUGUCUGAUCGGAGCCGAGCACGUGAACAAUAGCUACGAGUGCGACA

[1580] UCCCCAUCGGCGCUGGAAUCUGCGCCAGCUACCAGACACAGACAAACAGCCCUCGGAGA

[1581] GCGAGAAGCGUGGCCAGUCAGAGCAUCAUUGCCUACACAAUGUCUCUGGGCGCCGAGAA

[1582] CAGCGUGGCCUACUCCAACAACUCUAUCGCUAUCCCCACCAACUUCACCAUCAGCGUGAC

[1583] CACAGAGAUCCUGCCUGUGUCCAUGACCAAGACCAGCGUGGACUGCACCAUGUACAUCU

[1584] GCGGCGAUUCCACCGAGUGCUCCAACCUUCUGCUGCAAUACGGCAGCUUCUGCACCCAG

[1585] CUGAAUAGAGCCCUGACAGGGAUCGCCGUGGAACAGGACAAGAACACCCAAGAGGUGUU

[1586] CGCCCAAGUGAAGCAGAUCUACAAGACCCCUCCUAUCAAGGACUUCGGCGGCUUCAAUU

[1587] UCAGUCAGAUUCUGCCCGAUCCUAGCAAGCCCAGCAAGCGGAGCUUCAUCGAGGACCUG

[1588] CUGUUCAACAAAGUGACACUGGCCGACGCCGGCUUCAUCAAGCAGUAUGGCGAUUGUCU

[1589] GGGCGACAUUGCCGCCAGGGAUCUGAUUUGCGCCCAGAAGUUUAACGGACUGACAGUGC

[1590] UGCCUCCUCUGCUUACCGAUGAGAUGAUCGCCCAGUACACAUCUGCCCUUCUGGCCGGC

[1591] ACAAUCACAAGCGGCUGGACAUUUGGAGCAGGCGCCGCUCUGCAGAUCCCCUUUGCUAU

[1592] GCAAAUGGCCUACCGGUUCAACGGCAUCGGAGUGACCCAGAAUGUGCUGUACGAGAACC

[1593] AGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAGAUCCAGGACAGCCUGAGC

[1594] AGCACAGCAAGCGCCCUGGGAAAGCUGCAGGACGUGGUCAACCAGAAUGCCCAGGCACU

[1595] GAACACCCUGGUCAAGCAGCUGUCCUCCAACUUCGGCGCCAUCAGCUCUGUGCUUAACG

[1596] AUAUCCUGAGCAGACUGGACCCUCCUGAGGCCGAGGUGCAGAUCGACAGACUGAUCACA

[1597] GGCAGACUGCAGAGCCUCCAGACAUACGUGACCCAGCAGCUGAUCAGAGCCGCCGAGAU

[1598] UAGAGCCUCUGCCAAUCUGGCCGCCACCAAGAUGUCUGAGUGUGUGCUGGGCCAGAGCA

[1599] AGAGAGUGGACUUUUGCGGCAAGGGCUACCACCUGAUGAGCUUCCCUCAGUCUGCCCCU

[1600] CACGGCGUGGUGUUUCUGCACGUGACAUAUGUGCCCGCUCAAGAGAAGAAUUUCACCAC

[1601] CGCUCCAGCCAUCUGCCACGACGGCAAAGCCCACUUUCCUAGAGAAGGCGUGUUCGUGU

[1602] CCAACGGCACCCAUUGGUUCGUGACACAGCGGAACUUCUACGAGCCCCAGAUCAUCACC

[1603] ACCGACAACACCUUCGUGUCUGGCAACUGCGACGUCGUGAUCGGCAUUGUGAACAAUAC

[1604] CGUGUACGACCCUCUGCAGCCCGAGCUUGACAGCUUCAAAGAGGAACUGGACAAGUACU

[1605] UUAAGAAUCACACAAGCCCCGACGUGGACCUGGGCGAUAUCAGCGGAAUCAAUGCCAGC

[1606] GUCGUGAACAUCCAGAAAGAGAUCGACCGGCUGAACGAGGUGGCCAAGAAUCUGAACGA

[1607] GAGCCUGAUCGACCUGCAAGAACUGGGGAAGUACGAGCAGUACAUCAAGUGGCCCUGGU

[1608] ACAUCUGGCUGGGCUUUAUCGCCGGACUGAUUGCCAUCGUGAUGGUCACAAUCAUGCUG

[1609] UGUUGCAUGACCAGCUGCUGUAGCUGCCUGAAGGGCUGUUGUAGCUGUGGCAGCUGCU

[1610] GCAAGUUCGACGAGGACGAUUCUGAGCCCGUCCUCAAGGGCGUGAAACUGCACUACACA

[1611] UGAUGAGUGAAAUUUGUGAUGCUAUUGCAACAUGUUAAGAAAAUUUCCCGUUAUUUGCA

[1612] CUCUGUUCCUGUUAAUCAACCUCUGGAUUACAAAAUULIGUGAAAGAUUGACUGGUAUUC

[1613] UUAACUAUGUUGCUCCUUUUACGCUAUGUGGAUACGCUGCUUUAAUGCCUUUGUAUCAU

[1614] GCUAUUGCUUCCCGUAUGGCUUUCAUUUUCUCCUCCUUGUAUAAAUCCUGGUUGCUGUC

[1615] UCUUUAUGAGGAGUUGUGGCCCGUUGUCAGGCAACGUGGCGUGGUGUGCACUGUGUUU

[1616] GCUGACGCAACCCCCACUGGUUGGGGCAUUGCCACCACCUGUCAGCUCCUUUCCGGGAC

[1617] UUUCGCUUUCCCCCUCCCUAUUGCCACGGCGGAACUCAUCGCCGCCUGCCUUGCCCGCU

[1618] GCUGGACAGGGGCUCGGCUGUUGGGCACUGACAAUUCCGUGGUGUUGUCGGGGAAGCU

[1619] GACGUCCUUUCCAUGGCUGCUCGCCUGUGUUGCCACCUGGAUUCUGCGCGGGACGUCC

[1620] UUCUGCUACGUCCCUUCGGCCCUCAAUCCAGCGGACCUUCCUUCCCGCGGCCUGCUGC CGGCUCUGCGGCCUCUUCCGCGUCUUCGCCUUCGCCCUCAGACGAGUCGGAUCUCCCU UUGGGCCGCCUCCCCGCCUGUUUCGCCUCGGCGUCCGGUCCGUGUUGCUUGGUCUUCA CCUGUGCAGACUUGCGAACCAUGGAUUCCACCGUGAACUUUGUCUCCUGGCAUGCAAAU

[1621] CGUCAACUUGGCAUGCCAAGUAAGGACCUUUGGACUCCUUAUAUAAAAGAUCAAUUAUUA ACUAAAUGGGAGGAGGGUUACUUAAGCCCUGCGGUAAUUAGGUGGUGUAAACUUGUUUA UUGCAGCUUAUAAUGGUUACAAAUAAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCAUU

[1622] UUUUUCACUGC

[1623] 4.3 Protein sequence of db14

[1624] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTW

[1625] FHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKV

[1626] CEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREF

[1627] VFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWT

[1628] AGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTE

[1629] SIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLND

[1630] LCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLY

[1631] RLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFEL

[1632] LHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQT

[1633] LEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTR

[1634] AGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSI

[1635] AIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNT

[1636] QEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDI

[1637] AARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGI

[1638] GVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAIS

[1639] SVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRV

[1640] DFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWF

[1641] VTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDI SGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCC MTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT**

[1642] 5. db15

[1643] Name: NIAID product 5_db_trans-splicing RNA

[1644] 5.1 DNA sequence of db15

[1645] >

[1646] CCAGATATACGCGTTGACATTGATTATTGACTAGTCGATGGAGCGGAGAATGGGCGGAACT

[1647] GGGCGGAGTTAGGGGCGGGATGGGCGGAGTTAGGGGCGGGACTATGGTTGCTGACTAAT TGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTTTCCACACCTGG TTGCTGACTAATTGAGATGCATGCTTTGCATACTTCTGCCTGCTGGGGAGCCTGGGGACTT

[1648] TCCACACCCTAACTGACACACATTCCACAGCACTAGTTAGTTATTAATAGTAATCAATTACG

[1649] GGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCC

[1650] GCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATA

[1651] GTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCA

[1652] CTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTA

[1653] AATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTAC

[1654] ATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCG

[1655] TGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGT

[1656] TTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGAC

[1657] GCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAA

[1658] CCGTCAGATCGCGCGGGAGGAGTAATTACTATGAATATAACTAAATTAAATAGAAATTCAA

[1659] AAGAATCTCTACAGTTTTCCCAAGGGCCAACAAGCATCCATGTCCTCCTCCCGCGCAAGG AGGCGGCCCTCTCAACAGAAAACCAGTACATAATTCAAGTTCCCCATTCTAATTTAAACAA TATCCATTCCATTTCTCATGATCAGGGGCCGCCTCCAAGGATCGGGCGGACAAAGATATC

[1660] ACTTTTTTTCCTCCTCTCCGGCTTCTTCCAAAAGTGACAGCCCTCGCTCACTCAAATACAC

[1661] ATCCGCCCGATCCAACCTGTCCACCGGCCTAAAAAGACGTCCACTTGTCACTTTCCCCAAA

[1662] CACTAGGCAGTACCCTATCAGACCTCGGCOGGTGGACAGGCCTCAGCGG7~7TCA7~7T7~7~G7~

[1663] CTTTTTTTAACCTGGGCCTGGGCCTGGGTACTAACACGATCGTTTTTTTCCCTTTTTTTCCAG

[1664] GAAGCGGAGCAACAAACTTCAGCCTACTAAAGCAGGCTGGAGACGTGGAGGAGAACCCTG

[1665] GGCCTTTCGTGTTCCTGGTGCTGCTGCCTCTGGTGTCCAGCCAGTGTGTGAACCTGACCAC

[1666] CAGAACACAGCTGCCTCCAGCCTACACCAATAGCTTTACCAGAGGCGTGTACTACCCCGAC

[1667] AAGGTGTTCAGATCCAGCGTGCTGCACTCTACCCAGGACCTGTTCCTGCCTTTCTTCAGCAA

[1668] CGTGACCTGGTTCCACGCCATCCACGTGTCCGGCACCAATGGCACCAAGAGATTCGACAAC

[1669] CCCGTGCTGCCCTTCAACGACGGGGTGTACTTTGCCAGCACCGAGAAGTCCAACATCATCA

[1670] GAGGCTGGATCTTCGGCACCACACTGGACAGCAAGACCCAGAGCCTGCTTATCGTGAACAA

[1671] CGCCACCAACGTGGTCATCAAAGTGTGCGAGTTCCAGTTCTGCAACGACCCCTTCCTGGGC

[1672] GTCTACTACCACAAGAACAACAAGAGTTGGATGGAAAGCGAGTTCCGGGTGTACAGCAGCG

[1673] CCAACAACTGCACCTTCGAATACGTGTCCCAGCCTTTCCTGATGGACCTGGAAGGCAAGCA

[1674] GGGCAACTTCAAGAACCTGCGCGAGTTCGTGTTTAAGAACATCGACGGCTACTTCAAGATC

[1675] TACAGCAAGCACACCCCTATCAACCTCGTGCGGGATCTGCCTCAGGGCTTCTCTGCTCTGG

[1676] AACCCCTGGTGGATCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGCCCT

[1677] GCACAGAAGCTACCTGACACCTGGCGATAGCAGCAGCGGATGGACAGCTGGTGCCGCCGC

[1678] TTACTATGTGGGCTACCTGCAGCCTAGAACCTTCCTGCTTAAGTACAACGAGAACGGCACC

[1679] ATCACCGACGCCGTGGATTGTGCTCTGGATCCTCTGAGCGAGACAAAGTGCACCCTGAAGT

[1680] CCTTCACCGTGGAAAAGGGCATCTACCAGACCAGCAACTTCCGGGTGCAGCCCACCGAATC

[1681] CATCGTGCGGTTCCCCAATATCACCAATCTGTGCCCCTTCGGCGAGGTGTTCAATGCCACC

[1682] AGATTCGCCTCTGTGTACGCCTGGAACCGGAAGCGGATCAGCAATTGCGTGGCCGACTACT

[1683] CCGTGCTGTACAACTCCGCCAGCTTCAGCACCTTCAAGTGCTACGGCGTGTCCCCTACCAA

[1684] GCTGAACGACCTGTGCTTCACAAACGTGTACGCCGACAGCTTCGTGATCCGGGGAGATGAA

[1685] GTGCGGCAGATTGCCCCTGGACAGACAGGCAAGATCGCCGACTACAACTACAAGCTGCCC

[1686] GACGACTTCACCGGCTGTGTGATTGCCTGGAACAGCAACAACCTGGACTCCAAAGTCGGCG

[1687] GCAACTACAATTACCTGTACCGGCTGTTCCGGAAGTCCAATCTGAAGCCCTTCGAGCGGGA

[1688] CATCTCCACCGAGATCTATCAGGCCGGCAGCACCCCTTGTAACGGCGTGGAAGGCTTCAAC

[1689] TGCTACTTCCCACTGCAGTCCTACGGCTTTCAGCCCACAAATGGCGTGGGCTATCAGCCCT

[1690] ACAGAGTGGTGGTGCTGAGCTTCGAACTGCTGCATGCCCCTGCCACAGTGTGCGGCCCTA

[1691] AGAAAAGCACCAATCTCGTGAAGAACAAATGCGTGAACTTCAACTTCAACGGCCTGACCGG

[1692] CACCGGCGTGCTGACAGAGAGCAACAAGAAGTTCCTGCCATTCCAGCAGTTTGGCCGGGA

[1693] TATCGCCGATACCACAGACGCCGTTAGAGATCCCCAGACACTGGAAATCCTGGACATCACC

[1694] CCTTGCAGCTTCGGCGGAGTGTCTGTGATCACCCCAGGAACGAACACGAGCAATCAGG7A4 GTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGGCTTGTCGAGACAGAG ACGACTCTTGCGTTTCTGA TAGGCACCTA TTGGTCTTACTGACA TCCACTTTGCCTTTCTCTC

[1695] CACAGGTGGCAGTGCTGTACCAGGACGTGAACTGTACCGAAGTGCCCGTGGCCATTCACG

[1696] CCGATCAGCTGACACCTACATGGCGGGTGTACTCCACCGGCAGCAATGTGTTTCAGACCAG

[1697] AGCCGGCTGTCTGATCGGAGCCGAGCACGTGAACAATAGCTACGAGTGCGACATCCCCAT

[1698] CGGCGCTGGAATCTGCGCCAGCTACCAGACACAGACAAACAGCCCTCGGAGAGCGAGAAG

[1699] CGTGGCCAGTCAGAGCATCATTGCCTACACAATGTCTCTGGGCGCCGAGAACAGCGTGGC

[1700] CTACTCCAACAACTCTATCGCTATCCCCACCAACTTCACCATCAGCGTGACCACAGAGATCC

[1701] TGCCTGTGTCCATGACCAAGACCAGCGTGGACTGCACCATGTACATCTGCGGCGATTCCAC

[1702] CGAGTGCTCCAACCTTCTGCTGCAATACGGCAGCTTCTGCACCCAGCTGAATAGAGCCCTG

[1703] ACAGGGATCGCCGTGGAACAGGACAAGAACACCCAAGAGGTGTTCGCCCAAGTGAAGCAG

[1704] ATCTACAAGACCCCTCCTATCAAGGACTTCGGCGGCTTCAATTTCAGTCAGATTCTGCCCGA

[1705] TCCTAGCAAGCCCAGCAAGCGGAGCTTCATCGAGGACCTGCTGTTCAACAAAGTGACACTG

[1706] GCCGACGCCGGCTTCATCAAGCAGTATGGCGATTGTCTGGGCGACATTGCCGCCAGGGAT

[1707] CTGATTTGCGCCCAGAAGTTTAACGGACTGACAGTGCTGCCTCCTCTGCTTACCGATGAGA TGATCGCCCAGTACACATCTGCCCTTCTGGCCGGCACAATCACAAGCGGCTGGACATTTGG AGCAGGCGCCGCTCTGCAGATCCCCTTTGCTATGCAAATGGCCTACCGGTTCAACGGCATC GGAGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACAGCG

[1708] CCATCGGCAAGATCCAGGACAGCCTGAGCAGCACAGCAAGCGCCCTGGGAAAGCTGCAGG

[1709] ACGTGGTCAACCAGAATGCCCAGGCACTGAACACCCTGGTCAAGCAGCTGTCCTCCAACTT

[1710] CGGCGCCATCAGCTCTGTGCTTAACGATATCCTGAGCAGACTGGACCCTCCTGAGGCCGA

[1711] GGTGCAGATCGACAGACTGATCACAGGCAGACTGCAGAGCCTCCAGACATACGTGACCCA

[1712] GCAGCTGATCAGAGCCGCCGAGATTAGAGCCTCTGCCAATCTGGCCGCCACCAAGATGTCT

[1713] GAGTGTGTGCTGGGCCAGAGCAAGAGAGTGGACTTTTGCGGCAAGGGCTACCACCTGATG

[1714] AGCTTCCCTCAGTCTGCCCCTCACGGCGTGGTGTTTCTGCACGTGACATATGTGCCCGCTC

[1715] AAGAGAAGAATTTCACCACCGCTCCAGCCATCTGCCACGACGGCAAAGCCCACTTTCCTAG

[1716] AGAAGGCGTGTTCGTGTCCAACGGCACCCATTGGTTCGTGACACAGCGGAACTTCTACGAG

[1717] CCCCAGATCATCACCACCGACAACACCTTCGTGTCTGGCAACTGCGACGTCGTGATCGGCA

[1718] TTGTGAACAATACCGTGTACGACCCTCTGCAGCCCGAGCTTGACAGCTTCAAAGAGGAACT

[1719] GGACAAGTACTTTAAGAATCACACAAGCCCCGACGTGGACCTGGGCGATATCAGCGGAATC

[1720] AATGCCAGCGTCGTGAACATCCAGAAAGAGATCGACCGGCTGAACGAGGTGGCCAAGAAT

[1721] CTGAACGAGAGCCTGATCGACCTGCAAGAACTGGGGAAGTACGAGCAGTACATCAAGTGG

[1722] CCCTGGTACATCTGGCTGGGCTTTATCGCCGGACTGATTGCCATCGTGATGGTCACAATCA

[1723] TGCTGTGTTGCATGACCAGCTGCTGTAGCTGCCTGAAGGGCTGTTGTAGCTGTGGCAGCTG

[1724] CTGCAAGTTCGACGAGGACGATTCTGAGCCCGTCCTCAAGGGCGTGAAACTGCACTACACA

[1725] TGATGAAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTC

[1726] ACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTG

[1727] 5.2 RNA sequence of db15

[1728] UCAGAUCGCGCGGGAGGAGUAAUUACUAUGAAUAUAACUAAAUUAAAUAGAAAUUCAA

[1729] AAGAAUCUCUACAGUUUUCCCAAGGGCCAACAAGCAUCCAUGUCCUCCUCCCGCGCAA

[1730] GGAGGCGGCCCUCUCAACAGAAAACCAGUACAUAAUUCAAGUUCCCCAUUCUAAUUUA

[1731] AACAAUAUCCAUUCCAUUUCUCAUGAUCAGGGGCCGCCUCCAAGGAUCGGGCGGACAA

[1732] AGAUAUCACUUUUUUUCCUCCUCUCCGGCUUCUUCCAAAAGUGACAGCCCUCGCUCAC

[1733] UCAAAUACACAUCCGCCCGAUCCAACCUGUCCACCGGCCUAAAAAGACGUCCACUUGUC

[1734] ACUUUCCCCAAACACUAGGCAGUACCCUAUCAGACCUCGACAGCCCUCGCUCACUCAAA

[1735] UACACAUCCGCCCGAUCCAACCUGUCCACCGGCCUAAAAAGACGUCCACUUGUCACUUUC

[1736] CCCAAACACUAGGCAGUACCCUAUCAGACCUCGGCCGGUGGACAGGCCUCAGCGCLWC

[1737] AUUUUUGUCUUUUUUUAACCUGGGCCUGGGCCUGGGUACUAACACGAUCGUUUUUUUCC

[1738] CGGL / GGGGCCAGGAAGCGGAGCAACAAACUUCAGCCUACUAAAGCAGGCUGGAGACGUG

[1739] GAGGAGAACCCUGGGCCUUUCGUGUUCCUGGUGCUGCUGCCUCUGGUGUCCAGCCAGU

[1740] GUGUGAACCUGACCACCAGAACACAGCUGCCUCCAGCCUACACCAAUAGCUUUACCAGAG

[1741] GCGUGUACUACCCCGACAAGGUGUUCAGAUCCAGCGUGCUGCACUCUACCCAGGACCUG

[1742] UUCCUGCCUUUCUUCAGCAACGUGACCUGGUUCCACGCCAUCCACGUGUCCGGCACCAA

[1743] UGGCACCAAGAGAUUCGACAACCCCGUGCUGCCCUUCAACGACGGGGUGUACUUUGCCA

[1744] GCACCGAGAAGUCCAACAUCAUCAGAGGCUGGAUCUUCGGCACCACACUGGACAGCAAG

[1745] ACCCAGAGCCUGCUUAUCGUGAACAACGCCACCAACGUGGUCAUCAAAGUGUGCGAGUU

[1746] CCAGUUCUGCAACGACCCCUUCCUGGGCGUCUACUACCACAAGAACAACAAGAGUUGGA

[1747] UGGAAAGCGAGUUCCGGGUGUACAGCAGCGCCAACAACUGCACCUUCGAAUACGUGUCC

[1748] CAGCCUUUCCUGAUGGACCUGGAAGGCAAGCAGGGCAACUUCAAGAACCUGCGCGAGUU

[1749] CGUGUUUAAGAACAUCGACGGCUACUUCAAGAUCUACAGCAAGCACACCCCUAUCAACCU

[1750] CGUGCGGGAUCUGCCUCAGGGCUUCUCUGCUCUGGAACCCCUGGUGGAUCUGCCCAUC

[1751] GGCAUCAACAUCACCCGGUUUCAGACACUGCUGGCCCUGCACAGAAGCUACCUGACACC

[1752] UGGCGAUAGCAGCAGCGGAUGGACAGCUGGUGCCGCCGCUUACUAUGUGGGCUACCUG

[1753] CAGCCUAGAACCUUCCUGCUUAAGUACAACGAGAACGGCACCAUCACCGACGCCGUGGA

[1754] UUGUGCUCUGGAUCCUCUGAGCGAGACAAAGUGCACCCUGAAGUCCUUCACCGUGGAAA AGGGCAUCUACCAGACCAGCAACUUCCGGGUGCAGCCCACCGAAUCCAUCGUGCGGUUC

[1755] CCCAAUAUCACCAAUCUGUGCCCCUUCGGCGAGGUGUUCAAUGCCACCAGAUUCGCCUC

[1756] UGUGUACGCCUGGAACCGGAAGCGGAUCAGCAAUUGCGUGGCCGACUACUCCGUGCUG

[1757] UACAACUCCGCCAGCUUCAGCACCUUCAAGUGCUACGGCGUGUCCCCUACCAAGCUGAA

[1758] CGACCUGUGCUUCACAAACGUGUACGCCGACAGCUUCGUGAUCCGGGGAGAUGAAGUGC

[1759] GGCAGAUUGCCCCUGGACAGACAGGCAAGAUCGCCGACUACAACUACAAGCUGCCCGAC

[1760] GACUUCACCGGCUGUGUGAUUGCCUGGAACAGCAACAACCUGGACUCCAAAGUCGGCGG

[1761] CAACUACAAUUACCUGUACCGGCUGUUCCGGAAGUCCAAUCUGAAGCCCUUCGAGCGGG

[1762] ACAUCUCCACCGAGAUCUAUCAGGCCGGCAGCACCCCUUGUAACGGCGUGGAAGGCUUC

[1763] AACUGCUACUUCCCACUGCAGUCCUACGGCUUUCAGCCCACAAAUGGCGUGGGCUAUCA

[1764] GCCCUACAGAGUGGUGGUGCUGAGCUUCGAACUGCUGCAUGCCCCUGCCACAGUGUGC

[1765] GGCCCUAAGAAAAGCACCAAUCUCGUGAAGAACAAAUGCGUGAACUUCAACUUCAACGGC

[1766] CUGACCGGCACCGGCGUGCUGACAGAGAGCAACAAGAAGUUCCUGCCAUUCCAGCAGUU

[1767] UGGCCGGGAUAUCGCCGAUACCACAGACGCCGUUAGAGAUCCCCAGACACUGGAAAUCC

[1768] UGGACAUCACCCCUUGCAGCUUCGGCGGAGUGUCUGUGAUCACCCCAGGAACGAACACG

[1769] AGCAAUCAGGUAAGUAUCAAGGUUACAAGACAGGUUUAAGGAGACCAAUAGAAACUGGGC

[1770] UUGUCGAGACAGAGACGACUCUUGCGUUUCUGAUAGGCACCUAUUGGUCUUACUGACAU

[1771] CCACUUUGCCUUUCUCUCCACAGGUGGCAGUGCUGUACCAGGACGUGAACUGUACCGAA

[1772] GUGCCCGUGGCCAUUCACGCCGAUCAGCUGACACCUACAUGGCGGGUGUACUCCACCG

[1773] GCAGCAAUGUGUUUCAGACCAGAGCCGGCUGUCUGAUCGGAGCCGAGCACGUGAACAAU

[1774] AGCUACGAGUGCGACAUCCCCAUCGGCGCUGGAAUCUGCGCCAGCUACCAGACACAGAC

[1775] AAACAGCCCUCGGAGAGCGAGAAGCGUGGCCAGUCAGAGCAUCAUUGCCUACACAAUGU

[1776] CUCUGGGCGCCGAGAACAGCGUGGCCUACUCCAACAACUCUAUCGCUAUCCCCACCAAC

[1777] UUCACCAUCAGCGUGACCACAGAGAUCCUGCCUGUGUCCAUGACCAAGACCAGCGUGGA

[1778] CUGCACCAUGUACAUCUGCGGCGAUUCCACCGAGUGCUCCAACCUUCUGCUGCAAUACG

[1779] GCAGCUUCUGCACCCAGCUGAAUAGAGCCCUGACAGGGAUCGCCGUGGAACAGGACAAG

[1780] AACACCCAAGAGGUGUUCGCCCAAGUGAAGCAGAUCUACAAGACCCCUCCUAUCAAGGAC

[1781] UUCGGCGGCUUCAAUUUCAGUCAGAUUCUGCCCGAUCCUAGCAAGCCCAGCAAGCGGAG

[1782] CUUCAUCGAGGACCUGCUGUUCAACAAAGUGACACUGGCCGACGCCGGCUUCAUCAAGC

[1783] AGUAUGGCGAUUGUCUGGGCGACAUUGCCGCCAGGGAUCUGAUUUGCGCCCAGAAGUU

[1784] UAACGGACUGACAGUGCUGCCUCCUCUGCUUACCGAUGAGAUGAUCGCCCAGUACACAU

[1785] CUGCCCUUCUGGCCGGCACAAUCACAAGCGGCUGGACAUUUGGAGCAGGCGCCGCUCU

[1786] GCAGAUCCCCUUUGCUAUGCAAAUGGCCUACCGGUUCAACGGCAUCGGAGUGACCCAGA

[1787] AUGUGCUGUACGAGAACCAGAAGCUGAUCGCCAACCAGUUCAACAGCGCCAUCGGCAAG

[1788] AUCCAGGACAGCCUGAGCAGCACAGCAAGCGCCCUGGGAAAGCUGCAGGACGUGGUCAA

[1789] CCAGAAUGCCCAGGCACUGAACACCCUGGUCAAGCAGCUGUCCUCCAACUUCGGCGCCA

[1790] UCAGCUCUGUGCUUAACGAUAUCCUGAGCAGACUGGACCCUCCUGAGGCCGAGGUGCAG

[1791] AUCGACAGACUGAUCACAGGCAGACUGCAGAGCCUCCAGACAUACGUGACCCAGCAGCU

[1792] GAUCAGAGCCGCCGAGAUUAGAGCCUCUGCCAAUCUGGCCGCCACCAAGAUGUCUGAGU

[1793] GUGUGCUGGGCCAGAGCAAGAGAGUGGACUUUUGCGGCAAGGGCUACCACCUGAUGAG

[1794] CUUCCCUCAGUCUGCCCCUCACGGCGUGGUGUUUCUGCACGUGACAUAUGUGCCCGCU

[1795] CAAGAGAAGAAUUUCACCACCGCUCCAGCCAUCUGCCACGACGGCAAAGCCCACUUUCCU

[1796] AGAGAAGGCGUGUUCGUGUCCAACGGCACCCAUUGGUUCGUGACACAGCGGAACUUCUA

[1797] CGAGCCCCAGAUCAUCACCACCGACAACACCUUCGUGUCUGGCAACUGCGACGUCGUGA

[1798] UCGGCAUUGUGAACAAUACCGUGUACGACCCUCUGCAGCCCGAGCUUGACAGCUUCAAA

[1799] GAGGAACUGGACAAGUACUUUAAGAAUCACACAAGCCCCGACGUGGACCUGGGCGAUAU

[1800] CAGCGGAAUCAAUGCCAGCGUCGUGAACAUCCAGAAAGAGAUCGACCGGCUGAACGAGG

[1801] UGGCCAAGAAUCUGAACGAGAGCCUGAUCGACCUGCAAGAACUGGGGAAGUACGAGCAG

[1802] UACAUCAAGUGGCCCUGGUACAUCUGGCUGGGCUUUAUCGCCGGACUGAUUGCCAUCGU

[1803] GAUGGUCACAAUCAUGCUGUGUUGCAUGACCAGCUGCUGUAGCUGCCUGAAGGGCUGU

[1804] UGUAGCUGUGGCAGCUGCUGCAAGUUCGACGAGGACGAUUCUGAGCCCGUCCUCAAGG

[1805] GCGUGAAACUGCACUACACAUGAUGAAACUUGUUUAUUGCAGCUUAUAAUGGUUACAAAU

[1806] AAAGCAAUAGCAUCACAAAUUUCACAAAUAAAGCAUUUUUUUCACUGC 5.3 Protein sequence of db15

[1807] FVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWF

[1808] HAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVC

[1809] EFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV

[1810] FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTA

[1811] GAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESI

[1812] VRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDL

[1813] CFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYR

[1814] LFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELL

[1815] HAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTL

[1816] EILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRA

[1817] GCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIA

[1818] IPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQ

[1819] EVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAA

[1820] RDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVT

[1821] QNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVL

[1822] NDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFC

[1823] GKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQ

[1824] RNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGI

[1825] NASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTS

[1826] CCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT**

[1827] Examples

[1828] The present invention will now be described by way of example with particular reference to the figures.

[1829] Materials And Methods

[1830] 1. Manufacturing of SPRING: benchtop lateral scale

[1831] 1.1 Amplification of plasmid containing desired GOI: The desired gene of interest (GOI) was cloned in a plasmid backbone containing the binding site for stem-loop primers. The plasmid was then amplified in E.coli by shaking overnight at 37°C and purified using EndoFree Plasmid kit from Qiagen by following manufacturer’s instructions.

[1832] 1.2 Amplification by using gap-primer PCR: The isolated plasmid was linearized using desired restriction enzyme(s)and purified. The PCR reaction was set up by combining all components seen in table a.

[1833] Table a: Components for gap-primer PCR

[1834] 1.3 Ligation: Thaw and assemble the reagents for ligation on ice as per the table b. Add the reagents into the falcon containing the pooled PCR mixture, mix thoroughly, spin down and incubate the reaction mixture over night at 22 "C.

[1835] Table b: Components of Ligation

[1836] After ligation is completed, the mixture is purified in the desired volume.

[1837] 1.4 Exonuclease treatment: Set up the exonuclease treatment as per table c and incubate for 1 hour at 37"C, followed by deactivation of enzymes at 75°C for 10 mins.

[1838] Table c: Components of exonuclease treatment

[1839] 1.5 Final purification & Formulation: An aliquot of sample from each step is run on a 1% Agarose analytical gel for QC followed by purification in the desired volume. Store SPRING DNA in -20°C for long-term storage or at 4°C or RT for short-term storage.

[1840] 1.6 List of gap-PCR primers used for SPRING DNA manufacture

[1841] Legend to primer table

[1842] • Loop

[1843] • Stem

[1844] • Abasic site - denoted as idSp

[1845] • 5 ' phosphate - denoted as 5' P

[1846] 2. Formulation of Lipid Nanoparticles (LNPs) and commercial delivery reagents for in vivo applications

[1847] LNP formulations: The SPRING DNA solution was prepared in TE buffer at desired concentrations and mixed with pre-determined lipid solution mix in a specific ratio. The predetermined lipid solution mix contained validated molar ratios of various lipid components. The mix was then added in a microfluidic mixer to ensure rapid mixing and homogenous nanoparticle formation. The flow rates and ratio of lipid: SPRING DNA was pre-optimised in a different assay (not mentioned here) for effective encapsulation. After mixing, the LNPs were purified by performing dialysis, ultra centrifugation and / or size exclusion chromatography. The LNP-DNA complexes were then characterised for size, charge, polydispersity index, encapsulation efficiency and encapsulation yield. Method used were dynamic light scattering (DLS), zeta potential measurement and gel electrophoresis.

[1848] Three different kinds of LNPs were formulated with SPRING for validation in vivo.

[1849] Commercial delivery reagent: Commercial Liver delivery reagent was mixed with SPRING DNA in various ratios (1 :1 and 2:1 , etc) and formulated as per manufacturer’s instructions. Commercial siRNA delivery reagent was mixed with AVEC siRNAs by following manufacture’s protocol.

[1850] 3. Detection of immune responses

[1851] Custom panels of cytokines and chemokines relevant for gene therapy and genetic vaccination were designed to detect immune response (if any) generated by SPRING vectors in vivo in mice.

[1852] To select the cytokines and chemokines relevant for the applications, an initial screening was conducted using ProcartaPlex Convenience Panel 1 A 36plex from Thermo Fischer by following manufacturer’s protocol.

[1853] The list of cytokines and chemokines are documented below.

[1854] Chemokines: ENA-78 (CXCL5), Eotaxin (CCL1 1 ), GRO alpha (CXCL1 ), IP-10 (CXCL10), MCP-1 (CCL2), MIP-1 alpha (CCL3), MIP-1 beta (CCL4), MIP-2 alpha (CXCL2), RANTES (CCL5)

[1855] Cytokines: G-CSF (CSF-3), GM-CSF, IFN alpha, IFN gamma, IL-1 alpha, IL-1 beta, IL-2, IL- 3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15 / IL-15R, IL-17A (CTLA-8), IL-18, IL-22, IL- 23, IL-27, IL-28, IL-31 , LIF, MCP-3 (CCL7), M-CSF, TNF alpha

[1856] In brief, the sera from control and treated mice were collected at 4-8 hours and 24 hours after injection. After adding the capture beads in each well, equal volumes of universal assay buffer is mixed with sera. The plate is sealed and incubated at RT for 2 h with mild shaking. After the incubation, the plate was washed and 25 pL of detection antibody mix was added, followed by incubation and washed. After wash steps, 50 pL of Streptavidin PE beads are added, incubated and washed, followed by adding 120 pL of reading buffer.

[1857] The volume of sera used and the incubation time for steps were adjusted based on experimental variations. Data analyses was conducted to short-list a custom ordering of cytokines and chemokines. Panel GT contained 10 cytokine and chemokines relevant to detect DNA-mediated immune response for the OTC and PKL) gene therapy pipelines. Panel GV contained 10 cytokine and chemokines relevant to detect spike mediated immune response in a vaccine study.

[1858] 4. Detection of ALT and AST in plasma to determine liver health in mice

[1859] Plasma from animals were collected at pre-determined time points, and Alanine Aminotransferase and Aspartate Aminotransferase activities were measured via ALT / GPT and AST / GOT colorimetric activity kit assay respectively by following manufacturer’s protocol.

[1860] 5. Detection of OTC protein in liver of mice using LC-MS

[1861] The treated and control mice were sacrificed at specific timepoints and total protein from liver was extracted. In brief Buffer T-per containing protease inhibitors was added in 1 :10 (w / v) and homogenized using Qiagen Tissue Lyser following manufacturer’s protocol. The lysate was centrifuged at high speed for 10 min and the supernatant was collected.

[1862] The supernatant containing total liver proteins were quantified by BCA Assay. The total protein was digested with trypsin and desalted to generate peptides. The peptide samples were then loaded onto a liquid chromatography (LC) system coupled with an Orbitrap 240 mass spectrometer (MS). Data-dependent acquisition (DDA) analysis was conducted to detect and identify mouse and human-specific peptides within the samples. The data was analysed using bioinformatics software PD2.3 to distinguish and quantify the mouse and human peptides based on their unique mass-to-charge ratios and fragmentation patterns.

[1863] 6. Detection of OTC protein in mouse plasma using LC-MS

[1864] Synthetic protein coding for full length human OTC (hOTC)a.a 34-354 was synthesised and used to generate a titration curve. In brief, the linear sample preparation was done by spiking the synthetic hOTC protein in a digested matric system (matrix system consisted of blank mouse plasma, i.e., untreated mouse containing only mOTC (murine version of OTC). 1 uL of the peptide was injected in a Eclipse 240 Parallel Reaction Monitoring (PRM) system prior fitted with a LC system. A PRM method was designed by selecting target peptides that are unique to hOTC and mOTC and common to both hOTC and mOTC and only those peptides that should linearity in the titration curve was short-listed.

[1865] Proteins from 1.7 uL of plasma of treated mice were digested and 1 pL of each peptide was injected into the Eclipse 240-LC system for PRM analyses. The linear regression formula was applied to detect presence of hOTC peptides in the treated mice.

[1866] 7. Quantification of OTC activity in the mitochondria of mice liver To test the activity of hOTC protein in treated samples, a standard curve was generated by titrating different concentrations of L-Citrulline. A linear regression of standard curve was generated by plotting the A Intensity Standard versus micromoles of L-Citrulline for each standard.

[1867] To generate a positive control of hOTC, synthetic hOTC protein was added to reaction mixture of L-ornithine, carbamyl phosphate and Tris-acetate and incubated at 37°C for 30min. The reaction was stopped by adding phosphoric / sulfuric acid solution and 2,3-butanedione monoxime, and incubated at 95°C 15 min in the dark. Citrulline production was determined by measuring the absorbance at 490nm with SpectraMax M4 and optimized substrate and enzyme concentrations was determined as Michaelis constant (Km).

[1868] Liver from sacrificed mice at respective time points were lysed and homogenized in a mitochondrial lysis buffer. The lysate was centrifuged at max speed for 5 minutes and the supernatant was used to measure protein concentration by measuring the absorbance at 490nm with SpectraMax M4 and interpolating in the previously generated standard curve. The hOTC activity was calculated as the concentration of L-Citrulline (pM) divided by the sample quantity (mg) and incubation duration (minutes): pM L-Citrulline / mg Sample / min Incubation.

[1869] 8. Quantification of OTC activity in mouse plasma using LC-MS

[1870] To quantify OTC activity in plasma of treated and control mice, enzymatic incubation in a 96-well plate was performed, where 25 pl of plasma was mixed with 7.5pl of 0.1 U / pl shrimp alkaline phosphatase in PBS and 17.5 pl of 20 pg / ml purified Cit-D7 in PBS. After brief centrifugation and vortex mixing, the plate was incubated at 370 overnight. Next day, the enzymatic reaction was stopped by adding 350 pl of 0.2% formic acid in 80:20 (v / v) acetonitrile-methanol solution with 25 ng / ml of the internal standard [13C5]-L- Ornithine Hydrochloride. After constant vortexing at 1000 rpm for 5 min, the plate was centrifuged at 2800 x g for 10 min. Subsequently, 200 pl of supernatant was transferred to a new plate for LC-MS analysis. Calibration standards and quality control (QC) samples of Orn-D7 were prepared in plasma and extracted in the same way as the plasma samples.

[1871] 9. Detection of orotic acid in urine of mice by LC-MS

[1872] Urine samples at pre-defined time-points were collected in treated and untreated mice. To measure unknown amounts of orotic acid in urine sample, a calibration standard was generated in a LC-MS system by diluting synthetic orotic acid at various concentrations. A QC was set up by spiking and titrating low, medium and high amounts of orotic acid in water and blank urine. Creatinine was used as an internal control and was measured as mol / L via a colorimetric assay at 500nm.

[1873] An aliquot of 10 pL unknown sample, calibration standard, quality control, dilute quality control, single blank and double blank samples were added to the 96-well plate; calibration standard, quality control, single blank and double blank samples were preparation with 1 x PBS. Dilute quality control were preparation with urine. Each sample for orotic acid (except the double blank) was quenched with 50 pL IS respectively (double blank sample was quenched with 50 pL ACN), and then the mixture was vortexed for 5 min at 800 rpm and centrifuged for 15 min, 4000rpm at 4°C. 25 pL supernatant was diluted with 25 pL of H2O, and vortexed for 5 min, the diluted solution were directly injected for LC-MS / MS analysis.

[1874] The data was generated as Orotic acid / Creatinine mmol / mol.

[1875] 10. Detection of ammonia in mouse plasma

[1876] Ammonia in the plasma of treated and untreated mice were determined by using a quantitative enzymatic assay by following manufacturer’s protocol. In brief, ammonia assay reagent was mixed with water, sample and pre-made standard solutions to generate blank, test and standards respectively. The mixtures were incubated at RT for 5 minutes and absorbance was measured at 340nm. To determine the reduction of ammonia, L-Glutamate Dehydrogenase solution was added to the reaction mix, incubated at RT for 5 minutes and absorbance was again measured at 340nm. A titration of time was performed to ensure the competitive reaction involving the oxidation of NADPH has been completed.

[1877] 11. Determination of L-Tyr and L-Phe in plasma of mice using LC-MS

[1878] An LC / MS-MS method was established to evaluate the concentrations of Tyrosine and Phenylalanine in the blood of treated and untreated mice. Internal standards for L-Tyr and L- Phe was set up in a Triple Quad 6500 + Low Mass MS machine and the mobile phases for the LC was determined for both metabolites independently.

[1879] For Tyr: An aliquot of 10 pL unknown sample, calibration standard, quality control, single blank and double blank samples were added to the 96-well plate; except for the real sample, the remaining samples are prepared using artificial serum.^pjEach sample (except the double blank) was quenched with 100 pL IS respectively (double blank sample was quenched with 100 pL ACN, and then the mixture was vortex-mixed for 5 min at 800 rpm and centrifuged for 15 min at 4000rpm, 4°C. 30 pL supernatant were directly injected for LC-MS / MS analysis.

[1880] For Phe: An aliquot of 10 pL unknown sample, calibration standard, quality control, single blank and double blank samples were added to the 96-well plate; calibration standard, quality control, single blank and double blank samples were preparation with water. Dilute quality controls were prepared with purified plasma and diluted with water.s^Each sample for L-Phe (except the double blank) was quenched with 100 pL IS respectively (double blank sample was quenched with 100 pL MeOH), and then the mixture was vortex-mixed for 5 min at 800 rpm and centrifuged for 15 min at 4000rpm, 4°C.40 pL supernatant was diluted with 40 pL of H2O, and vortexed for 5 min, the diluted solution were directly injected for LC-MS / MS analysis.

[1881] 12. Formulation of adjuvants

[1882] SPRING DNA was dissolved in 1 ml of 0.9% saline, 20mM Sodium Phosphate the pH was adjusted to 7.2. The Adjuvant was formulated by following manufacturer’s instructions. In brief, the adjuvant was dissolved at a pre-determined amount in chloroform, and a dry organic film was created by evaporating the organic solvent. The dry film was then formulated with 0.9% of saline. The SPRING DNA and Adjuvant were mixed at a 1 :1 (v / v) ratio. Depending on the injection dose of animal groups, the SPRING DNA and Adjuvant were mixed at specific molar ratios (pre-determined by iterations), and the injection volume was topped up with saline before vaccination of animals.

[1883] 13. Detection of humoral immune response by ELISA in immune cells

[1884] Innate immune response (also called as IgG response) was quantified by a antibody binding ELISA assay.

[1885] To determine the innate immune response generated in the mice injected with various SPRING vectors, the mice were bled at 5 weeks and 7 weeks post prime. Blood samples were incubated at 37°C for 30 minutes and centrifuged at 3000g for 15 minutes at 4°C for serum collection. The extracted sera were used to detect SARS-C0V2 specific binding of spike by IgG binding ELISA assay.

[1886] The antigen SARS-CoV-2 (2019-nCoV) Spike S1 +S2 ECD (R683A, R685A, F817P, A892P, A899P, A942P, K986P, V987P)-His Recombinant Protein (HPLC-verified) was used to generate a standard curve and the unknown samples were interpolated. Manufacturer’s protocol was followed to perform the binding assay. SARS-C0V2 IgG binding was demonstrated as end point titres.

[1887] 14. Determination of adaptive immune response by EliSPOT in immune cells

[1888] To determine if SPRING DNA could generate an adaptive immune response in the vaccinated mice, T-cell response was measured by mouse IFN-gamma ELISpot assay following manufacturer's protocol. In brief, the splenocytes from mice were collected at week 5 and 7 post-prime and seeded. 5 x 10e5 cells / well were seeded and stimulated overnight in the presence of peptide pool (2 ug / ml) spanning complete spike sequence of SARS-CoV2 to accumulate the cytokines. The next day the cells were washed and incubated with biotinylated anti-mouse IFN-gamma antibody for pre-determined time. The plates were washed and substrate streptavidin-HRP was added and incubated for 1 hour at RT. After the spots have developed, the plates were washed, and the reading was quantified by counting the IFN- gamma producing cells (spots) using an ELISpot reader. As positive control, ConA was used and untreated plasma was used as negative control. The data was represented as spots forming unit (SFU) per 1 x 10e6 cells.

[1889] 15. Determination of adaptive immune response by intracellular staining of immune cells

[1890] To determine if SPRING DNA could generate an adaptive immune response in the vaccinated mice, IFN-gamma intracellular cytokine staining assay was performed in CD4+ and CD8+ T- cells.

[1891] Animals were sacrificed at 5 weeks and 7 weeks post primer, and the splenocytes were extracted. The cells were stimulated overnight in the presence of peptide pool (2 ug / ml) spanning complete spike sequence of SARS-CoV2 to accumulate the cytokines. Next day, the cells were washed with cold PBS before incubating in staining buffer for 20-30 minutes at 4°C in the dark. The staining buffer contained fluorochrome-conjugated antibodies against surface markers (e.g., anti-CD4 and anti-CD8). The cells were then fixed and permeabilized for approx. 10-15 minutes at room temperature. The cells were then incubated with fluorochrome-conjugated anti-IFN-gamma antibodies for 30-45 minutes at room temperature in the dark. The cells were washed and analysed using a flow cytometer. Specific gating was performed to identify CD4+ and CD8+ T cell populations and the fluorescence intensity of IFN- gamma was measured within the specific T-cell populations.

[1892] 16. Computational secondary structure prediction

[1893] Minimum free energy secondary structures of DNA and RNA were folded using the algorithms mfold and / or RNAfold (1 , 2).

[1894] 17. Statistical analysis

[1895] Diagrams represent mean values ± SEM of three independent experiments. The statistical analysis was performed using repeated one-way ANOVA with Tukey’s post hoc multiple comparison's test or using Student’s f-test. The GraphPad Prism version 7 software (Graph Pad, La Jolla, GA) was used for the statistical analysis. 18. General design of advanced dumbbell-shaped DNA vectors (SPRING DNA) of this invention

[1896] First, the mRNA sequence and structure to be expressed by the dumbbell-shaped DNA vectors was designed and sequences were ordered by gene synthesis. All mRNAs expressed by the SPRING DNA vectors of this invention were designed as follows. The mRNA design process includes (I) the thermodynamic stabilization of the ends of the mRNA, i.e. of the 3’ end, by adding a thermodynamically stable RNA secondary structure. Here, the posttranscriptional regulatory element of the Woodchuck hepatitis B virus (WPRE), was added to the 3’ end of those mRNAs which were not designed as trans-splicing RNAs to fulfil the 3’ stabilizing function and to facilitate pre-mRNA processing and nuclear mRNA export. The WPRE was added in a way that it’s active structure, the structure found in the context of Woodchuck hepatitis B viral transcripts, was not changed upon embedding this sequence into the new sequence context. The design process (ii) includes the thermodynamic destabilization of the RNA secondary structure around the ribosome binding site and translational start codon, (iii) the use of alternative codons to improve the overall flexibility of the mRNA, (iv) the implementation of multimerization domains, (v), the implementation of a spliceable intron, and (vi) a codon optimization procedure which includes usage of alternative codons with high abundance of available tRNAs and for the purpose of removal of cryptic splice sites and miRNA binding sites.

[1897] Selected mRNAs for vaccination purposes expressed by the SPRING DNA vectors of this invention were designed as trans-splicing RNAs to selectively target all professional antigen presenting cells (APCs) or distinct subpopulations thereof including macrophages, dendritic cells, B cells and Langerhans cells, to manipulate the resulting immune response.

[1898] All SPRING DNA vectors of this invention were featured with an active DNA nuclear import signal, i.e. the SV40 enhancer sequence.

[1899] Loop sequences of the SPRING DNA vectors of this invention were optimized for more efficient amplification during PCR and improved dumbbell ligation.

[1900] SPRING DNA vectors for targeting OTO deficiency and PKU were equipped either with the constitutive CMV promoter or alternatively with the liver-specific hAAT promoter. All vectors designed for vaccination purposes were featured with the CMV promoter.

[1901] Transcription of RNA from the SPRING DNA vectors was terminated using the SV40 or the BGH polyadenylation signal. Manufacture of advanced dumbbell-shaped DNA vectors (SPRING DNA) of this invention

[1902] Advanced dumbbell-shaped DNA (SPRING DNA) is manufactured enzymatically using a PCR-based process termed gap-primer PCR (Figure 1) (3, 4). For SPRING DNA manufacture, the sequences or genes of interest are PCR-amplified using chemically modified primers. In addition to the 3’ primer binding site, these primers harbour a gap, an abasic position which is a tetrahydrofuran-based mimic of one purine or pyridinic abasic site and which forces the DNA polymerase to stop primer extension during PCR. The 5’ ends are phosphorylated with the 5’ terminal positions to be self-complementary capable refolding and pre-shaping the dumbbells’ loops. PCR with these primers produces products with refolding 5’ overhangs whereby the 5' phosphates are positioned next to the 3’ OH groups ready for ligation. Subsequently, ligation yields covalently closed SPRING DNA with the characteristic mismatches close to the ends. SPRING DNA is purified by exonuclease treatment and / or chromatography.

[1903] Advanced dumbbell-shaped DNA vectors (SPRING DNA) of this invention exhibit significant advantages over alternative DNA based vectors

[1904] SPRING DNA vectors were extensively tested in vitro and ex vivo exhibiting significant advantages over mRNA, alternative DNA-based vectors and viral vectors. Dumbbell-shaped DNA vectors are more thermostable stable compared with plasmid or minicircle DNA with SPRING DNA being the most stable dumbbell-shaped DNA vector (Figure 2). Different vectors including a plasmid, a minicircle DNA, two commercial dumbbell-shaped vectors and the dumbbell-shaped vectors (SPRING DNA) were stored in TE buffer in the fridge (untreated - UT), at 37°C, or at 50°C for 1 month and analysed using 1 % agarose gel electrophoresis. All vectors except SPRING DNA exhibit disintegration as indicated by alternative isoforms popping up or increasing in abundance at the higher temperatures. After incubation, all samples but the minicircle DNA, were also treated with an exonuclease, analysed using 1 % agarose gel electrophoresis, and band intensities of the intact uncompromised vector DNA were quantified Imaged (bar diagram). Dumbbell vectors exhibit a higher integrity compared with the plasmid and SPRING DNA appears to be the most stable dumbbell-shaped DNA. Integrity of vectors after incubation at 50°C for 3 months was investigated. Different vectors including a plasmid, a minicircle DNA, two commercial dumbbell-shaped vectors and the dumbbell-shaped vectors (SPRING DNA) were stored in TE buffer at 50°C for 1 day, 1 week, 1 month, and some for 3 months and analysed using 1% agarose gel electrophoresis, and band intensities of the intact uncompromised vector DNA were quantified using Imaged (bar diagram). All vectors except SPRING DNA exhibit disintegration after 1 week. After 3 months, plasmid DNAwas completely disintegrated and minicircle DNA to 50%. SPRING DNA virtually did not show any disintegration after 3 months. Finally, SPRING and plasmid DNA were stored in TE buffer at room temperature for 1 year. After 1 year, analytical agarose gel electrophoreses did not show any disintegration of SPRING DNA but plasmid DNA was disintegrated to 50%.

[1905] Advanced dumbbell-shaped DNA (SPRING DNA) triggers long-lasting gene expression in murine liver after i.v. injection using liver-specific LNPs (Figure 3). BALB / c mice of 8-12 months age were injected i.v. with luciferase expressing SPRING or plasmid DNA formulated with the liver-specific transfection reagent from Thermo Fischer. Monitoring luciferase expression in the alive mice indicated long-lasting (up to -1 year, ongoing) luciferase expression in the murine livers. While SPRING DNA expression was found to be very specific for the murine livers, plasmid expression was more prominent in the spleen and also detected in the lungs.

[1906] Advanced dumbbell-shaped DNA (SPRING DNA) triggers long-lasting gene expression in murine hindlimb muscles when injected i.m. as naked (unformulated) DNA (Figure 4). BALB / c mice of 8-12 months age were injected i.m. with luciferase expressing naked SPRING or naked plasmid DNA. Monitoring luciferase expression in the alive mice indicated SPRING DNA but plasmid DNA triggers long-lasting (up to 200 days) luciferase expression in the injected hindlimb muscles. SPRING DNA expression was found to be specific for the injected hindlimb muscles with no vector copies detected in other organs after 1 week or in the liver after 1 or 3 months. Luciferase activity was exclusively detected in the injected muscles.

[1907] Naked (non-conjugated) or LNP-formulated advanced dumbbell-shaped DNA (SPRING DNA) is virtually not immunogenic following intravenous (i.v.) tail vein injection in mice (Figure 5). BALB / c mice of 8-12 months age were injected i.v. with luciferase expressing naked or LNP- formulated SPRING DNA or plasmid DNA and Cytokine responses were monitored 4 and 24 hours after injection. SPRING DNA shows only little or not sensed by the murine innate immune system.

[1908] Gene therapy with OTC expressing advanced dumbbell-shaped DNA (SPRING DNA) rescues OTC knockdown and knockout phenotypes in mice

[1909] OTC expressing advanced dumbbell-shaped DNA (SPRING DNA) can be efficiently delivered into the liver of mice (Figure 6). A single-dose i.v. injection of human OTC (hOTC) expressing advanced dumbbell-shaped DNA (SPRING DNA) lipid nanoparticle formulation triggers hOTC expression in 15-20% of hepatocytes. Advanced dumbbell-shaped DNA vectors completely rescued OTC RNAi knockdown phenotype in wildtype mice (Figure 7). Single-dose i.v. injection of human OTC (hOTC) expressing advanced dumbbell-shaped DNA (SPRING DNA) lipid nanoparticle formulation rescues siRNA triggered murine OTC (mOTC) knockdown phenotype in the liver of wildtype mice to 54% and elevates OTC plasma activity ~250-fold over the untreated control.

[1910] Advanced dumbbell-shaped DNA vectors also completely rescued the OTC phenotype in OTC knockout mice (Figure 8). Single-dose i.v. injection of human OTC (hOTC) expressing advanced dumbbell-shaped DNA (SPRING DNA) lipid nanoparticle formulation (Figure 8A) completely rescues OTC knockout phenotype in the liver of OTC KO-mice establishing an OTC plasma activity which is 20-fold above the activity in wildtype mice one day after injection as measured using mass spectrometry (Figure 8B) , and a significant rescue of OTC activity in the liver as measured on days 10 and 20 post injection by quantification of citrulline levels (Figure 8C).

[1911] Advanced dumbbell-shaped DNA (SPRING DNA) completely rescues PAH expression in RNAi knockdown mice

[1912] A single-dose i.v. injection of human PAH (hPAH) expressing advanced dumbbell DNA (SPRING DNA) lipid nanoparticle formulation elevated PAH mRNA levels in the liver of wildtype mice about 45-fold. A single-dose i.v. injection of a PAH targeting siRNA knocked down the mPAH mRNA levels in the liver virtually by 100%. A single-dose i.v. injection of the hPAH expressing SPRING DNA lipid nanoparticle formulation completely rescued siRNA triggered mPAH knockdown in wildtype mice establishing PAH mRNA levels that are 35-fold higher than those found in the livers of untreated control mice (Figure 9).

[1913] Advanced dumbbell-shaped DNA (SPRING DNA) based genetic vaccine triggers significant antibody & T cell responses against SARS-CoV-2

[1914] SARS-CoV-2 spike protein expressing advanced dumbbell-shaped DNA (SPRING DNA) triggers significant antibody & T cell responses against SARS-CoV-2 (Figure 10). Intramuscular injection (naked or LNP-formulated) of SARS-CoV-2 spike expressing SPRING DNA in BALB / c mice triggered significant levels of spike protein-specific antibodies comparable with those triggered by the only approved DNA (plasmid) based vaccine ZyCoV- D which requires needle-free jet injection but at lower doses. Intracellular cytokine staining at week 7 (4 weeks post-boost) demonstrated induction of IFN-gamma in both CD4+ CD8+ T- cells. The T-cell response triggered by the SPRING vaccine was long-lasting and at similar / higher levels compared with that triggered by alternative DNA vaccine platforms.

[1915] REFERENCES Zuker, M. (2003). Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31, 3406-3415. Hofacker, I.L. (2003). Vienna RNA secondary structure server. Nucleic Acids Res. 13, 3429-3431. Yu, H., Jiang, X., Hang, L., Tan, K.T. and Patzel, V. (2015). Efficient Production of Superior Dumbbell-Shaped DNA Minimal Vectors for Small Hairpin RNA Expression. Nucleic Acids Research. 43(18), e120. Loh PS & Patzel V. Efficient generation of superior dumbbell-shaped non-viral DNA delivery vectors using 1 -2-3 gap-primer PCR. Methods Mol Biol. 3, Gene Therapy of Cancer, Methods and Protocols, 2022; 2521 :329-338. doi: 10.1007 / 978-1 -0716-2441 - 8_18.

Claims

Claims1 . Dumbbell-shaped DNA vector, comprising- a transcriptional promoter,- a sequence for expressing an RNA, and- a transcriptional terminator.

2. Dumbbell-shaped DNA vector according to claim 1 , wherein the sequence for expressing an RNA is selected from the group consisting of- an ornithine transcarbamylase, in particular a human ornithine transcarbamylase,- a phenylalanine hydroxylase (PAH), in particular a human phenylalanine hydroxylase, and- a viral antigen, in particular a SARS-CoV-2 spike protein.

3. Dumbbell-shaped DNA vector according to claim 1 or 2, wherein said transcriptional promoter is selected from the group consisting of a CMV promoter and a hAAT promoter.

4. Dumbbell-shaped DNA vector according to any of the claims 1 to 3, wherein the transcriptional terminator is selected from the group consisting of a SV40 polyadenylation signal and a BGH polyadenylation signal.

5. Dumbbell-shaped DNA vector according to any of the claims 1 to 4, comprising a DNA nuclear import signal, in particular an SV40 enhancer sequence, which can be positioned upstream or downstream of the sequence for expressing an RNA.

6. Dumbbell-shaped DNA vector according to any of claims 1 to 5, wherein the RNA that is expressed from the sequence comprises an RNA nuclear export signal at a 5’ untranslated region.

7. Dumbbell-shaped DNA vector according to claim 6, wherein the RNA nuclear export signal is selected from the group consisting of a Woodchuck hepatitis virus post- transcriptional regulatory element (WPRE), a human hepatitis B virus post- transcriptional regulatory element (PRE), or a type D retroviral constitutive transport element (GTE).

8. Dumbbell-shaped DNA vector according to any of claims 1 to 7, wherein the sequence for expressing an RNA comprises an intron, in particular a beta-globin mini-intron.

9. Dumbbell-shaped DNA vector according to any of claims 1 to 8, wherein the sequence for expressing an RNA is a trans-splicing RNA.

10. Dumbbell-shaped DNA vector according to claim 9, wherein the trans-splicing RNA comprises at least once splice site and at least one binding domain specific for at least a part of the gene, in particular wherein the gene is specifically expressed in liver cells or is specifically expressed in a population of professional antigen presenting cells.11 . Cell containing a dumbbell-shaped DNA vector according to any of claims 1 to 10.

12. Vector containing a dumbbell-shaped DNA vector according to any of claims 1 to 10.

13. Method of transfecting a cell, comprising the use of a dumbbell-shaped vector of any of claims 1 to 10, in particular comprising topical application, intranasal application, alveolar application, systemic application, oral application, intravenous injection, intramuscular injection, subcutaneous application, cutaneous application, intraperitoneal application, or portal vein injection.

14. Method according to claim 13, wherein the cell is selected from the group consisting of a liver cell, and an antigen presenting cell.

15. Method of treating ornithine transcarbamylase deficiency, comprising targeting, transfecting, lipofection, transducing, electroporating, nucleofecting or transforming a liver cell with a dumbbell-shaped DNA vector according any of claims 1 to 10 ex vivo or in vivo, wherein the sequence for expressing an RNA is an ornithine transcarbamylase, in particular a human ornithine transcarbamylase.

16. Method of treating phenylketonuria comprising targeting, transfecting, lipofection, electroporating or nucleofecting a liver cell with a dumbbell-shaped DNA vector according any one of claims 1 to 10 ex vivo or in vivo, wherein the sequence for expressing an RNA is a phenylalanine hydroxylase, in particular a human phenylalanine hydroxylase.

17. Method of vaccinating against a viral disease comprising targeting, transfecting, lipofection, electroporating or nucleofecting antigen presenting cells with a dumbbellshaped DNA vector according any one of claims 1 to 10 ex vivo or in vivo wherein thesequence for expressing an RNA is a viral antigen, in particular a SARS-CoV-2 spike protein.

18. Method of claim 17, wherein the viral disease is SARS-CoV-2 and the sequence for expressing an RNA is a SARS-CoV-2 spike protein.

19. Pharmaceutical composition, in particular for use in the treatment of an ornithine transcarbamylase deficiency, phenylketonuria or a viral disease, comprising said dumbbell-shaped DNA vector according to any one of claims 1 to 10.

Images