Nuclear translocation enabling sequences for increased gene therapy potency

Abstract

Non-viral gene therapy treatments have a number of advantages over viral vectors including typical non-antigenicity, low manufacturing cost, simplicity, and efficiency of delivering genetic cargo into the cytoplasm. The potency of non-viral gene therapy systems can be enhanced by providing them with means to more efficiently transport the delivered DNA from the cytoplasm to the nucleus. Provided herein, at least in part, are means of enhancing potency of non-viral gene therapies by including novel nuclear translocation enhancing sequences and compositions that can result in optimized nuclear translocation as well as related compositions and methods.

Description

[0001]NUCLEAR TRANSLOCATION ENABLING SEQUENCES FOR INCREASED GENE THERAPY POTENCY RELATED APPLICATION This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 686,791, entitled “NUCLEAR TRANSLOCATION ENABLING SEQUENCES FOR INCREASED GENE THERAPY POTENCY”, filed on August 25, 2024, the entire contents of which is incorporated herein by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (R087270009WO00-SEQ-JAV.xml; Size: 176,260 bytes; and Date of Creation: August 25, 2025) is herein incorporated by reference in its entirety. BACKGROUND Gene therapies have revolutionized medicine, enabling the delivery of missing, replacement of malfunctioning, or augmentation of insufficiently expressing genes. Most successful gene therapies to date have been delivered using viral vectors, however, non-viral vectors such as lipid nanoparticles or polymeric nanoparticles have a number of advantages including cost, manufacturability, the ability to deliver large cargo, and oftentimes lack of antigenicity. These features greatly expand the potential therapeutic applications of gene therapy and increase accessibility. The delivery of DNA to the cytoplasm is typically efficient with non-viral gene therapies. As an example, nucleic acids are delivered to the cytoplasm with high efficiency using lipid nanoparticles. However, the delivery of DNA from the cytoplasm to the nucleus varies by cell type and its efficiency can be improved. The present invention provides, at least in part,s means of improving said efficiency for non-viral gene therapies enabling an increase in potency, productivity, efficacy, and broadening the therapeutic index. SUMMARY In one aspect is a non-viral gene therapy or non-virally delivered gene therapy comprising one or more DNA sequences delivered in cis with or as a part of an encoding DNA cassette and derived from protein binding sites of a protein or proteins expressed at quantifiable or moderate to high levels in the cell type being predominantly targeted by said non-viral gene therapy or are confirmed as expressed by immunohistochemistry, transcriptomic analysis, RNA-seq, qPCR, or other gene expression, protein expression or bioinformatic technique. In one embodiment of any one of the compositions or methods provided herein, the non-viral gene therapy is delivered by a delivery vehicle. In one embodiments of any one of the compositions or methods provided herein, the delivery vehicle is a physical method of gene delivery. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises lipid nanoparticles. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises virus-like particles. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises peptide or polymer carriers. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises lipid nanoparticles with covalently attached targeting moieties. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises lipid nanoparticles with one or more targeting moieties on the surface. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises polymeric nanoparticles. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises nanoparticles comprised of lipid and non-lipid components. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle comprises polymeric nanoparticles comprised of polymer and non- polymer components. In one embodiment of any one of the compositions or methods provided herein, the delivery vehicle is least in part comprised of metallic nanoparticles. In one embodiment, the one or more DNA sequences are any one or more DNA sequences as provided herein. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence recognized by the protein Myc. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence recognized by the protein Fosl1. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence recognized by the protein Has1. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence recognized by the protein Pparg. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence recognized by the protein Snai1. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence recognized by the protein Stat5a. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence that is at least 80% identical to any one of the sequences provided herein. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences comprise a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99 or 100% identical to any one of the sequences provided herein. In one embodiment of any one of the compositions or methods provided herein, at least one of the one or more DNA sequences is added before the promoter driving expression of the therapeutic gene and another is added after the PolyA signal of the therapeutic gene. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are any two or more DNA sequences as provided herein. In one embodiment, the at least two or more DNA sequences are separated by at least 6 nucleotides. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are linear double stranded DNA. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are linear single stranded DNA. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are circular double stranded DNA. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are circular single stranded DNA. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are partially double stranded DNA. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are a DNA-RNA hybrid. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are a DNA-peptide hybrid. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are a synthetically modified DNA or DNA hybrid. In one embodiment of any one of the compositions or methods provided herein, the one or more DNA sequences are comprised of chemically modified and unmodified DNA. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a mammalian transcription factor. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a nuclear protein. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a chromatin protein. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a DNA- binding protein. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a DNA- packaging protein. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a transcription regulation factor. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is related to epigenetic regulatory machinery. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a chromatin associated protein. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is a transcription factor, transcription factor complex, or transcriptional regulation related proteins. In one embodiment of any one of the compositions or methods provided herein, the expression level of the protein from which any one or more of the DNA sequences are derived is identified as moderate or high by RNA-seq analysis relative to other proteins, that is in the top 66% of expressed proteins. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is expressed in the target cell type, such as with positive confirmation by immunohistochemistry in an embodiment. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is expressed at moderate to high levels, such as confirmed by Affymetrix in an embodiment. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is expressed at moderate to high levels, such as confirmed by immunohistochemistry in an embodiment. In one embodiment of any one of the compositions or methods provided herein, the protein from which any one or more of the DNA sequences are derived is expressed at the protein level during the stage of the cell’s lifecycle at the time of treatment. In one embodiment of any one of the compositions or methods provided herein, at least 50% of the therapeutic DNA is delivered to the target cell type. In one embodiment of any one of the compositions or methods provided herein, target cell type is the predominant cell type by number or by volume in the treated area. In one embodiment of any one of the compositions or methods provided herein, more than 50% of the delivered non-viral gene therapy is delivered to the target cell type by copy number or vector number. In one embodiment of any one of the compositions or methods provided herein, the target cell type targeted is the most frequently targeted cell type from all of the cell types receiving the treatment directly or indirectly. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for human pathologies. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for animal pathologies. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for mammalian pathologies. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for augmentation of gene expression, which in an embodiment is reduced as a function of aging. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the replacing of missing or non-functioning genes. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies caused by metabolic diseases. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies caused by musculoskeletal diseases. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies caused by cardiovascular diseases. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies caused by diseases of the central and / or peripheral nervous systems. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies in autoimmune diseases. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies caused by infectious diseases. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for the alleviation of pathologies caused by environmental conditions. In one embodiment of any one of the compositions or methods provided herein, the composition or method is for genome modification, silencing, or otherwise altering the genome or level of expression. In one aspect, any one or more of the constructs provided herein, such as in the Examples, are provided. In one aspect, any one or more of the DNA nuclear targeting sequences, such as in the Examples section, are provided. In one aspect, a composition comprising any one or more of the constructs provided herein, such as in the Examples, is provided. In one aspect, a composition comprising any one or more of the DNA nuclear targeting sequences provided herein, such as in the Examples, is provided. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a glucagon (GCG)-coding therapeutic construct containing 3 repeats each of 2 separate DNA-binding motifs for HAS1; corresponds to Example 1. FIG. 2 shows a construct encoding full-length fibroblast growth factor 21 (FGF21), flanked on either side by the shortest DNA-binding motif from each identified protein; corresponds to Example 2. FIG. 3 shows a construct encoding full-length beta-glucocerebrosidase, flanked on either side by the longest DNA-binding motif from each identified protein; corresponds to Example 3. FIG. 4 shows a construct encoding full-length apelin, flanked on either side consensus sequences for SNAI1 and STAT5A; corresponds to Example 4. FIG. 5 shows a construct encoding interleukin 1 receptor antagonist (IL1RA) with a chained motif inserted upstream and downstream of the IL1RA sequence; corresponds to Example 5. FIG. 6 shows a construct encoding full-length insulin with MYC, FOSL1, HAS1, PPARG, SNAI1 and STAT5A sequences inserted upstream and downstream of the insulin sequence; corresponds to Example 6. FIG. 7 shows a construct encoding Exenatide with MYC, FOSL1, HAS1, PPARG, SNAI1 and STAT5A consensus sequences inserted upstream and downstream of the Exenatide sequence; corresponds to Example 7. FIG. 8 shows a construct encoding full-length ficolin-3 with five PPARG consensus sequences inserted upstream and downstream of the ficolin-3 sequence; corresponds to Example 8. FIG. 9 shows a construct encoding full-length orexin coupled with a secretion signal and consensus sequences for six identified proteins; corresponds to Example 9. FIG. 10 shows a construct encoding parathyroid hormone and six MYC consensus sequences; corresponds to Example 10. FIG. 11 shows a construct encoding a Pegvisomant peptide core; corresponds to Example 11. FIG. 12 shows results of optimization of a Pegvisomant peptide core through introduction of listed DNA-binding motifs; corresponds to Example 11. FIGs. 13A-13B show test sequences outperformed control vectors as assessed by reporter gene expression (nano-luciferase bioluminescent reporter) using Background Normalized Flux (unitless) (FIG. 13A) or Total Flux (photons per second or p / s) (FIG. 13B) in vivo; corresponds to Example 12. DETAILED DESCRIPTION Provided herein, in an embodiment, are means of increasing the potency of non-viral gene therapies. Alongside potency provided herein, in an embodiment, are means of increasing productivity of delivered DNA or modified DNA, efficacy, therapeutic index, as well as the safety of non-viral gene delivery. More specifically, provided herein, in an embodiment, are means of combining the therapeutic transgene or therapeutic non-coding DNA with a set of DNA nuclear-targeting sequences, which are derived from DNA binding sites of nuclear proteins expressed at moderate to high levels in the target cell type. Once the nuclear protein is translated in the cytoplasm, it can undergo a site-specific binding event with the inserted DNA sequences, and induce translocation of the DNA to the nucleus of the cell. Yet more specifically, provided herein, in an embodiment, are means of enabling DNA translocation to the nucleus in adipocytes, which can be targeted by a subcutaneously delivered gene therapy. Proteins that are expressed in adipocytes with positive immunohistochemical confirmation or at moderate to high levels as confirmed by RNA-seq or other transcriptomic analysis and are destined for the nucleus (nuclear localized proteins) have been selected and their binding sites have been determined. Addition of their binding sites to therapeutic genetic cassettes, which are delivered by non-viral gene therapies can increase the potency or transgene productivity per genome copy delivered. In an adipocyte-targeted gene therapy, where the majority of cells by volume, by nuclear count, or by type of all cells targeted are adipocytes, insertion of DNA sequences of protein binding sites of proteins that are expressed in adipocytes and destined for the nucleus promotes nuclear translocation of the delivered construct, can allow for increased transgene productivity per dosed construct, and potentially reduces side effects from intracellular DNA sensors that are present in the cellular cytoplasm due to decreased DNA residence time in the cytoplasm, decreased exposed (unbound) DNA in the cytoplasm, and / or decreased DNA quantity in the cytoplasm of the predominantly targeted cell type. In another embodiment, proteins expressed in the liver in for example hepatocytes, can be used to identify their DNA binding sites and insert them into DNA cassettes delivered by non-viral gene therapy, which are targeting hepatocytes to increase productivity, potency, efficacy, or the therapeutic index of said non-viral gene therapy by enabling transport of said genetic cassettes to the nucleus of hepatocytes in this particular situation. In other embodiments a cell type or cell types that is or that are targeted by a gene therapy can be identified, the nuclear-targeted proteins that are expressed in that cell type or those cell types be identified and their DNA binding sites inserted in part or in whole into the therapeutic constructs intended for delivery of therapeutic genes or therapeutic non-coding DNA to those cell types. The addition of said DNA sequence or sequences to the therapeutic cassettes can increase their potency, efficacy, efficiency, productivity, and / or therapeutic index. In general, DNA sequences that are protein binding sequences, bound by proteins that are destined for nuclear transport or nuclear proteins, or resident nuclear proteins, or proteins with a nuclear localization signal, or proteins that are predominantly localized in the nucleus and that are expressed at some level, ideally moderate to high level in the target cell type or cell types, which are targeted by a gene therapy treatment, are hereby referred to as “DNA nuclear targeting sequences” or “nuclear translocation enabling sequences” or “DNTS” or “DTS” or “DNA targeting sequences” or “DNA-binding motifs”. In general, when a DNA sequence is written in capital and lower-case letters, the capital letters signify high-frequency bases or high-consensus bases within that sequence, while the lower-case letters signify lower- frequency consensus sequence bases within that specific stretch of DNA. Alternatively, when a DNA sequence is written in all lower or all upper cases, the bases in the sequence are to be considered equal in importance to its intended purpose. Provided herein, in an embodiment, is a method for identifying DNA nuclear targeting sequences that are optimal for use in non-viral gene therapies or viral vector gene therapies where the transport of the DNA from the cytoplasm to the nucleus is not efficient, not effective, or sub-optimally effective, or viral vector gene therapies that have modified components that reduce the effectiveness of nuclear DNA transport, and in addition compositions of non-viral gene therapy treatments, and specifically DNA or modified-DNA cassettes that contain said DNTS sequences and have increased potency, efficiency, efficacy, therapeutic index, safety, or productivity over their non-DNTS containing counterparts. More specifically, provided herein, in an embodiment, are non-viral gene therapy treatments containing one or more DNA sequences delivered in cis with the therapeutic encoding DNA sequence and derived from protein binding sites of protein or proteins expressed in the cell type being predominantly targeted by said non-viral gene therapy or are confirmed as expressed by immunohistochemistry. In other embodiments, provided herein are means of enhancing viral vector gene therapies, which deliver DNA and which are in some way modified or not optimally efficient at delivering DNA from the cytoplasm to the nucleus of the cell and compositions that introduce DNA targeting sequences into the genomic DNA for delivery in cis with the therapeutic cassette and thereby have increased potency, efficiency, efficacy, therapeutic index, safety, or productivity over their non-DNTS containing counterparts. In an embodiment, a non-virally delivered gene therapy or nucleic acid or specifically DNA with or without chemical modifications to the DNA backbone or bases, is modified via the addition of DNA sequences that are delivered in cis with or as a part of the therapeutic encoding DNA cassette and derived from protein binding sites of a protein or proteins expressed at quantifiable or moderate to high levels in the cell type being predominantly targeted by said non-viral gene therapy or are confirmed as expressed by immunohistochemistry. These sequences may be used in conjunction with other DNA sequences, such as NFkB sites or 3NF sites, promoters, genes of interest, post transcriptional regulatory elements, polyA sites, IRES sites, enhancers, regulatory protein binding sites, chromatin binding sites, or other known mammalian, eukaryotic, bacterial, or viral DNA sequences. In other embodiments the gene therapy may be at least partially non-virally delivered or delivered by a modified viral vector, the efficacy, efficiency, potency, or the therapeutic index of which can be augmented via the addition of DNA sequences that bind proteins that are expressed in the target cell type of the gene therapy or at least some of the target cell types of the gene therapy and where said proteins are nuclear proteins or predominantly nuclear proteins or proteins that contain a nuclear localization sequence (NLS) or multiple NLSs or that are transported from the cytoplasm to the nucleus. The target cell type of a gene therapy can be generally defined as a cell or cells or a tissue containing cells or a set of cells or a set of cell types or lineages that is the target of the vector or DNA cassette or expression system such that the delivered therapeutic transgene is intended to be administered to that cell type, at least in addition to other cell types, but ideally as the predominant cell type receiving the treatment by nuclear count, by volume, by number of genome copies, or by its predominance or abundance in a target tissue. Some example cell types that are targeted by gene therapies can include adipocytes, hepatocytes, neurons, glial cells, astrocytes, cardiomyocytes or generally cells of the liver, cells of the subcutis, or cells of the central nervous system, or general tissue, organ, or collection of organs. The introduced DNA sequences, which can allow for or enhance binding of proteins and transport of the therapeutic cassette or therapeutic DNA sequence or strand that contains the gene of interest or the therapeutic gene or the therapeutic non-coding region, bind proteins or be bound by proteins that are expressed in the aforementioned target cell types, as confirmed in an embodiment by immunohistochemistry or by RNA-seq or other transcriptomic or proteomic technique as being expressed and in an embodiment expressed at a moderate or high level in the target cell type. Said proteins may be nuclear proteins or proteins that localize to the nucleus and in an embodiment proteins that predominantly localize to the nucleus in the target cell type. In an embodiment said proteins are known as DNA-binding proteins and the amino acid sequence of said proteins or at least a portion of their amino acid sequence has sequence specific affinity for binding DNA or at least >60% or at least >75% sequence homology to an amino acid sequence that binds DNA in a sequence specific manner. In some embodiments the non-viral gene delivery vehicles are lipid nanoparticles, virus-like particles, peptide or polymer carriers, lipid nanoparticles with covalently attached targeting moieties, lipid nanoparticles with one or more targeting moieties on the surface, polymeric nanoparticles, nanoparticles comprised of lipid and non-lipid components, polymeric nanoparticles comprised of polymer and non-polymer components, or are comprised at least in part from metallic components or metallic nanoparticles. In other embodiments the non-viral gene delivery method is a physical or chemical delivery method or is assisted by a physical or chemical method of gene delivery. In some embodiments the gene therapy is delivered by a non-viral vector, is targeting adipocytes or a subcutaneous space and / or is augmented with sequences recognized by the protein Myc, Fosl1, Pparg, Has 1, Snai1, Stat5a, or another protein that is expressed at high level in adipocytes or subcutaneous tissues and is a nuclear protein or predominantly localizes to the nucleus. In some embodiments one or more of the following sequences is introduced into the DNA cassette or delivered in cis with the DNA cassette that contains the therapeutic transgene or therapeutic non-coding DNA: In some embodiments one or more of the following sequences is introduced into the DNA cassette or delivered in cis with the DNA cassette that contains the therapeutic transgene or therapeutic non-coding DNA: HRACCACGTGGTYD (SEQ ID NO: 59), TASCACRTGTCW (SEQ ID NO: 60), GCCAYGYGSS (SEQ ID NO: 61), MRMGTRHCACGTGDYACKYK (SEQ ID NO: 62), CACGTGS, CCACSTGWCY (SEQ ID NO: 63), RACCACGTGSTC (SEQ ID NO: 64), KACCACGTGSYY (SEQ ID NO: 65), CASGTGGC, RGCCACGTGCC (SEQ ID NO: 66), GASCACGTGGY (SEQ ID NO: 67), RASCACGTGGT (SEQ ID NO: 68), SSCCACGTGCYS (SEQ ID NO: 69), CCACGTGC, CCACGTGAA, CGTGG, CACGTGC, CGTGC, GCACGTGCT, YMCCACGTGYMV (SEQ ID NO: 70), SSSCACGYGS (SEQ ID NO: 71), CCACGTGS, SGCCACGTGGCS (SEQ ID NO: 72), CCACGTGG, GGCACGTGKY (SEQ ID NO: 73), SCACGTGS, RRMCACGTGR (SEQ ID NO: 74), CCACGTG, SVRTGASTCAKCM (SEQ ID NO: 75), GACTCAWKSKB (SEQ ID NO: 76), TGACTCAD, TGAGTCAK, TGACTCAB, GRTGACGTCAYC (SEQ ID NO: 77), GRTGAWTCAYC (SEQ ID NO: 78), ATGAYRCG, ATGAYRCG, KATGASTCAYM (SEQ ID NO: 79), DRTGACTCATY (SEQ ID NO: 80), RRTGASTCAKS (SEQ ID NO: 81), KKRTGACTCATMM (SEQ ID NO: 82), DRATGACTCATHY (SEQ ID NO: 83), ATGACTCAT, RTGACTCAT, YKRTGACTMATMC (SEQ ID NO: 84), RRTGACTMAT (SEQ ID NO: 85), RTGACGYMAY (SEQ ID NO: 86), TGASTCAYCH (SEQ ID NO: 87), RTGACTCAYYC (SEQ ID NO: 88), KRRTGASTCAB (SEQ ID NO: 89), GRTGACGTMAT (SEQ ID NO: 90), RRTGASTCAB (SEQ ID NO: 91), RTGAGTCAY, RTGACGTMAT (SEQ ID NO: 92), RTGASTCA, KRTGASTCAY (SEQ ID NO: 93), KRTGACGTCAYM (SEQ ID NO: 94), KKRTKACGTCAYCGC (SEQ ID NO: 95), KKRTGAGTCAYM (SEQ ID NO: 96), KRTGASTCAYMV (SEQ ID NO: 97), KKRTGAGTCAYMV (SEQ ID NO: 98), RTGAGTCAYM (SEQ ID NO: 99), DRTGACGTCATMMKTY (SEQ ID NO: 100), TGAMTCA, TGACTCAK, KKWATGASKCATMY (SEQ ID NO: 101), RTGAGTCAYCS (SEQ ID NO: 102), DVTGASTCATB (SEQ ID NO: 103), BGATGACGTCATCR (SEQ ID NO: 104), TGASTCAT, ATGACGTCATCR (SEQ ID NO: 105), ATGACGTCAYC (SEQ ID NO: 106), GATGAYGTCATC (SEQ ID NO: 107), AGTCA, TGACTCA, RSTGACTCMGW (SEQ ID NO: 108), ACSMGGAAGTR (SEQ ID NO: 109), RASRMGGAAGTR (SEQ ID NO: 110), GAMCCGGAAGTR (SEQ ID NO: 111), AACRAGGAAGTR (SEQ ID NO: 112), ASRAGGAAGTR (SEQ ID NO: 113), AYWTCCKK, YYWRRGGTCAAAGGTCAHVBD (SEQ ID NO: 114), AASTRGGTCACSGTGACCYACWT (SEQ ID NO: 115), WASYRGGKCAAAGKTCA (SEQ ID NO: 116), WGAMCTTTGACCY (SEQ ID NO: 117), AGGTCAG, AWSTRGGKCAAAGGKCA (SEQ ID NO: 118), YYWRRGGTCAAAGGTCAYMK (SEQ ID NO: 119), STRGGTCACSGTGACCYACW (SEQ ID NO: 120), TRGGTCACSGTGACCYACW (SEQ ID NO: 121), AWSTRGGTYAST (SEQ ID NO: 122), MRRGGKYAAWRGGTCAC (SEQ ID NO: 123), AANNNAGGTCANNGGNCA (SEQ ID NO: 124), AANNAGGTNANNGGTCA (SEQ ID NO: 125), AAANNAGGTCA, TGNCNNNTGACCTNNNTT (SEQ ID NO: 126), TGACCTNNNTT, ARRGGTCAAAGGTCAH (SEQ ID NO: 127), RRGGTCAAAGGTCA (SEQ ID NO: 128), CWRAWCYAGGYCAWAGKTCA (SEQ ID NO: 129), YMRGGTCATWGGGGTSARG (SEQ ID NO: 130), TGACCTY, RGGTCARAGGTCA (SEQ ID NO: 131), AWGTRGGTCAAAGGTCAT (SEQ ID NO: 132), AWGTRGGTCAAAGGTCA (SEQ ID NO: 133), ARRGGTCRTGACCYYT (SEQ ID NO: 134), DGRGGTCAAAGGTCRY (SEQ ID NO: 135), ARRGGTCGYGACCYYK (SEQ ID NO: 136), MSTGWCCTB, RGGTCAR, AAAAGGTCAM (SEQ ID NO: 137), RAGGTCAAAAGGTCAM (SEQ ID NO: 138), RAGGTCRTGACCTY (SEQ ID NO: 139), AAAAGGTCAH (SEQ ID NO: 140), RAGGTCAAAAGGTCAH (SEQ ID NO: 141), RAGGTCRTGACCT (SEQ ID NO: 142), CCAGGTGG, GCCACCTGSCTGYD (SEQ ID NO: 143), CCACCTGCMN, DRCAGGTGYR (SEQ ID NO: 144), RCAGGTG, ARCAGGTGCA (SEQ ID NO: 145), RRCAGGTGYR (SEQ ID NO: 146), RRCAGGTGCR (SEQ ID NO: 147), YCAGGTG, KCACCTGM, SSSRSCKCACCTGS (SEQ ID NO: 148), CACCTGSRK, RRCAGGTGY, AYGCACCTGTMRY (SEQ ID NO: 149), GCACCTGT, WWWMRAKRCACCTGYTAKWHAW (SEQ ID NO: 150), TTCCCRKAA, DAWTTCYWGGAAWYH (SEQ ID NO: 151), TTCCCRGAAWTBSKWTWCCKRGRR (SEQ ID NO: 152), YAWTTCYW, SWYTTCYW, KRYWYTTCYKRGA (SEQ ID NO: 153), RSWTTTCTARGAA (SEQ ID NO: 154), TTCYYRGAAAY (SEQ ID NO: 155), TTTCYKRGAAW (SEQ ID NO: 156), KAWTTCYTGGAAWTY (SEQ ID NO: 157), RAWTTCCARGAAWTM (SEQ ID NO: 158), TTTCYKRGAAA (SEQ ID NO: 159), TTCYYAGGAAWYT (SEQ ID NO: 160), TTCCNGGAA, TTCCTGGAA, CCNNGGAANNNNNA, TTCC, GGAANNNNNA, TTCNNGG. In another specific embodiment of the present invention the DNA targeting sequence introduced to enhance efficacy or potency is derived from one or more of the following sequences: hrACCACGTGGTyd (SEQ ID NO: 59), TAsCACRTGtcw (SEQ ID NO: 60), gcCAyGyGss (SEQ ID NO: 61), mrmgtrhCACGTGdyackyk (SEQ ID NO: 62), CACGTGs, cCACsTGwcy (SEQ ID NO: 63), rACCACGTGsTC (SEQ ID NO: 64), kACCACGTGsyy (SEQ ID NO: 65), CAsGTGGc, gcCACGTGcc (SEQ ID NO: 161), GasCACGTGGy (SEQ ID NO: 67), rAsCACGTGGt (SEQ ID NO: 68), ssCCACGTGcys (SEQ ID NO: 69), CCACGTGc, CCACGTGAA, CgTGG, CCACGTGAA, CACGTGc, cGTGc, gCACGTGCT, ymcCACGTGymv (SEQ ID NO: 70), cCACsTGwcy (SEQ ID NO: 63), sssCACGyGs (SEQ ID NO: 71), ymcCACGTGymv (SEQ ID NO: 70), cCACGTGs, sgCCACGTGGcs (SEQ ID NO: 72), CCACGTGG, ggCACGTGky (SEQ ID NO: 73), sCACGTGs, rrmCACGTGr (SEQ ID NO: 74), CCaCGtG, cGtGG, svrTGAsTCAkcm (SEQ ID NO: 75), TGACtcAwkskb (SEQ ID NO: 162), rTGACtcAd, TgaGTCAk, TGAGTCAk, TGACTCAb, grTGACGTCAYc (SEQ ID NO: 77), grTGAwTCAyc (SEQ ID NO: 78), aATGAyrCg, rATGAyRCG, grTGACGTcAyc (SEQ ID NO: 77), kATGAsTCAym (SEQ ID NO: 79), drTGACTCAty (SEQ ID NO: 80), rrTGAsTCAks (SEQ ID NO: 81), kkrTGACTCAtmm (SEQ ID NO: 82), rTgACGTcAy (SEQ ID NO: 163), draTGACTCAthy (SEQ ID NO: 83), aTGACTCAt, rTGACTCAt, ykrTGAcTMAtmc (SEQ ID NO: 84), rrTGActmAt (SEQ ID NO: 85), rTGACgymay (SEQ ID NO: 86), kkrTGACTCAtmm (SEQ ID NO: 82), rTgACGTcAy (SEQ ID NO: 163), TGACtcAwkskb (SEQ ID NO: 162), rTGACtcAd, TgaGTCAk, TGAsTCAych (SEQ ID NO: 87), rTGACTCAyyc (SEQ ID NO: 88), krrTGAsTCAb (SEQ ID NO: 89), kkrTGAGTCAym (SEQ ID NO: 96), grTGACGTmAt (SEQ ID NO: 90), rrTGAsTCAb (SEQ ID NO: 91), RTGAGTCAy, rTGACGTmAt (SEQ ID NO: 92), rTGAsTcA, rTGACGTCAy (SEQ ID NO: 163), krTGAsTCAy (SEQ ID NO: 93), krTGACGTCAym (SEQ ID NO: 94), krTGAsTCAy (SEQ ID NO: 93), kkrTkACGTCAycgc (SEQ ID NO: 95), kkrTGAGTCAym (SEQ ID NO: 96), grTGACGTmAt (SEQ ID NO: 90), krTGAsTCAymv (SEQ ID NO: 97), kkrTGAGTCAymv (SEQ ID NO: 98), rTGAGTCAym (SEQ ID NO: 99), drTgACGTCAtmmkty (SEQ ID NO: 100), rsTGACtcmgw (SEQ ID NO: 108), svrTGAsTCAkcm (SEQ ID NO: 75), TGACtcAwkskb (SEQ ID NO: 162), rTGACtcAd, TgaGTCAk, TGAmTCA, TGACtcak, kkwATGAsKCATmy (SEQ ID NO: 101), rTGAGTCAycs (SEQ ID NO: 102), dvTGAsTCATb (SEQ ID NO: 103), bgATGACGTCATCr (SEQ ID NO: 104), TGAsTCAT, gATGACGTCATCr (SEQ ID NO: 164), bgATGACGTCATCr (SEQ ID NO: 104), gATGACGTCAyc (SEQ ID NO: 165), gATGAyGTCATc (SEQ ID NO: 107), AGTCA, TgACTca, rsTGACtcmgw (SEQ ID NO: 108), svrTGAsTCAkcm (SEQ ID NO: 75), TGACtcAwkskb (SEQ ID NO: 162), rTGACtcAd, TgaGTCAk, TGAmTCA, TGACtcak, kkwATGAsKCATmy (SEQ ID NO: 101), rTGAGTCAycs (SEQ ID NO: 102), dvTGAsTCATb (SEQ ID NO: 103), bgATGACGTCATCr (SEQ ID NO: 104), TGAsTCAT, gATGACGTCATCr (SEQ ID NO: 164), krTGAsTCAymv (SEQ ID NO: 97), kkrTGAGTCAymv (SEQ ID NO: 98), rTGAGTCAym (SEQ ID NO: 99), drTgACGTCAtmmkty (SEQ ID NO: 100), AcsmGGAAGTr (SEQ ID NO: 109), rasrmGGAAGtr (SEQ ID NO: 110), gAmcCGGAAGtr (SEQ ID NO: 111), aAcrAGGAAGTr (SEQ ID NO: 112), aAsrAGGAAGTr (SEQ ID NO: 166), waywTCCkk, acsmGGAAGtr (SEQ ID NO: 109), yywrrGGTCAAAGGTCAhvbd (SEQ ID NO: 114), AAsTRGGTCAcsgTGACCyAcWT (SEQ ID NO: 115), wasyrGGkcAAAGKTCA (SEQ ID NO: 116), wGAMCTtTGaCCy (SEQ ID NO: 117), AGGTcAg, awstrGGkcAAAGGkcA (SEQ ID NO: 118), yywrrGGTCAAAGGTCAymk (SEQ ID NO: 119), sTrGGTCAcsgTGACCyAcW (SEQ ID NO: 120), TrGGTCAcsgTGACCyAcW (SEQ ID NO: 121), awsTrGGtyAst (SEQ ID NO: 122), mrrGGkyAawrGGtCAc (SEQ ID NO: 123), aAnnnAGGTCAnnGGnCA (SEQ ID NO: 124), AannaGGTnannGGTCA (SEQ ID NO: 125), AAAnnAGGTcA, TGnCnnnTGACCTnnnTT (SEQ ID NO: 126), TGACCtnnnTT, WGAMCTtTGaCCy (SEQ ID NO: 117), arrGGTCAAAGGTCAh (SEQ ID NO: 127), rrGGTCAAAGGTCA (SEQ ID NO: 128), CwrAwCYAGGyCAWAGKTCA (SEQ ID NO: 129), ymrGGTCATwgGGGTsarg (SEQ ID NO: 130), wGAMCTtTGaCCy (SEQ ID NO: 117), TGACCTy, rGGtCArAGGTCA (SEQ ID NO: 131), AwgtrGGtcAaAGGTcAt (SEQ ID NO: 132), AwgtrGGtcAaAGGTcA (SEQ ID NO: 133), AwgtrGGtcAaAGGTcAt (SEQ ID NO: 132), ArrGGTCAAAGGTCAh (SEQ ID NO: 127), ArrGGTCrTGACCyyt (SEQ ID NO: 134), DgrGGTCAAAGGTCry (SEQ ID NO: 135), ArrGGTCGyGACCyyk (SEQ ID NO: 136), MstGwCCTb, RGGTCAr, aaAAGGTCAm (SEQ ID NO: 137), raGGTCAaaAGGTCAm (SEQ ID NO: 138), RAGGTCrTGACCTy (SEQ ID NO: 139), AaAAGGTCAh (SEQ ID NO: 140), RaGGTCAaaAGGTCAh (SEQ ID NO: 141), RaGGTCrTGACCTy (SEQ ID NO: 139), RAGGTCrTGACCT (SEQ ID NO: 142), CCAGGTGg, GcCACCTGsctgyd (SEQ ID NO: 143), CCACCTGcmn, DrCAGGTGyr (SEQ ID NO: 144), RCAGGTG, DrCAGGTGyr (SEQ ID NO: 144), ArCAGGTGcA (SEQ ID NO: 145), RrCAGGTGyr (SEQ ID NO: 146), RrCAGGTGCr (SEQ ID NO: 147), YCAGGTG, KCACCTGm, SssrsckCACCTGs (SEQ ID NO: 148), CACCTGsrk, RrCAGGTGy, AygCACCTGTmry (SEQ ID NO: 149), GCACCTGT, RrCAGGTGy, WwwmrakrCACCTGyTakwhaw (SEQ ID NO: 150), YCAGGTG, KCACCTGm, SssrsckCACCTGs (SEQ ID NO: 148), CACCTGsrk, RrCAGGTGy, AygCACCTGTmry (SEQ ID NO: 149), GCACCTGT, RrCAGGTGy, WwwmrakrCACCTGyTakwhaw (SEQ ID NO: 150), RrCAGGTGy, WwwmrakrCACCTGyTakwhaw (SEQ ID NO: 150), TTCCcrkAA, DawTTCywGGAAwyh (SEQ ID NO: 151), TTCccrGAAwtbskwTwCckrGrr (SEQ ID NO: 152), YawTTCyw, swyTTCyw, KrywyTTCykRGA (SEQ ID NO: 153), RswTTTCTarGAA (SEQ ID NO: 154), TTCyyrGAAay (SEQ ID NO: 155), DawTTCywGGAAwyh (SEQ ID NO: 151), TTTCykrGAAw (SEQ ID NO: 156), TTCCcrkAA, kawTTCytGGAAwty (SEQ ID NO: 157), KrywyTTCykRGA (SEQ ID NO: 153), RawTTCCarGAAwtm (SEQ ID NO: 158), TTTCykrGAAa (SEQ ID NO: 159), TTCyyaGGAAwyt (SEQ ID NO: 160), TTCCnGGAA, TtcCtGgaa, TTCCnGGAA, CCnnGGAAnnnnnA, TtcCtGgaa, TtcC, GgAannnnnA, TTCnngg, or at least the consensus sequences (capitalized bases) thereof, or at least the consensus sequences and non-degenerate bases thereof, or at least the non-degenerate base sequence thereof. When a sequence is obtained from the list of aforementioned sequences by for example obtaining only the consensus bases, the position of the consensus bases is maintained with respect to each other, as an example using only the consensus sequences from GgAannnnnA results in a sequence GnAnnnnnnA and using only non-degenerate bases from said sequence results in a sequence of GGAAnnnnnA. In yet other embodiments the aforementioned sequences can be introduced as fragments, but no smaller than a fragment that is 80% of the length of the original sequence. Sequences can be introduced in pairs, or two at a time, spaced by the gene of interest, or positioned next to each other or at a distance of 1 to 60 nucleotides apart. More than one sequence can be introduced at a time to increase the effect, and sequences can be introduced on either end of the construct on various regions of the construct that encodes for the therapeutic gene of interest or therapeutic non-coding DNA or therapeutic genes of interest or therapeutic non-coding DNA. Sequences can alternatively be covalently or non- covalently attached to the genetic cassette that encodes the therapeutic DNA or therapeutic non-coding DNA, but are delivered together, in cis, in tandem, or to the target cells in an embodiment. In an embodiment, the sequences are introduced into the same DNA cassette that encodes for the therapeutic transgene or therapeutic non-coding DNA. The sequences to enhance DNA transport to the nucleus can be positioned in front of the promoter, in the promoter region, in the intron region following the promoter, in the coding region, and / or following the coding region of a therapeutic gene, but in an embodiment they are positioned in a way that does not interfere with optimal transcription, gene expression, and coding. In an embodiment, an optimal position of said nuclear targeting sequences is in front of the promoter and following the polyA signal of the therapeutic gene or therapeutic non-coding DNA. In an embodiment at least one nuclear targeting sequence is introduced, but in another embodiment, at least two or more targeting sequences are introduced from different nuclear proteins that are expressed at a moderate to high level in the target cell type. The therapeutic gene therapy can be delivered by a vector, physical, or chemical means or a combination thereof, but a maximum effect of said sequences, in an embodiment, can be obtained when the method of delivery is efficient with respect to delivering DNA to the cytoplasm, such as for example lipid or polymeric nanoparticles, electroporation, metal particle bombardment, chemical transfection, or fluid or physical pressure. The delivered therapeutic construct may be a linear double stranded DNA, linear single stranded DNA, circular double stranded DNA, circular single stranded DNA, partially double stranded DNA, DNA-RNA hybrid, DNA-peptide hybrid, modified DNA or DNA hybrid, comprised of chemically modified and unmodified DNA, or a combination of one or more types or a plethora of constructs of one or more of the aforementioned classes. The nuclear targeting DNA sequences can be introduced into the therapeutic cassette or attached to the therapeutic cassette by physical or chemical means, but in an embodiment is delivered together or in cis to the target cell types, or at least predominantly together to the target cell type or types when delivering the gene therapy treatment. The DNA sequences can be selected such that their protein binding partners are derived from a set of mammalian transcription factors, or from nuclear proteins, or from chromatin proteins, or from DNA-binding proteins, or from DNA-packaging proteins, or from transcription regulation factors, or from proteins related to epigenetic regulatory machinery, or from chromatin associated proteins, or from transcription factor, transcription factor complex, or transcriptional regulation related proteins. In general, the protein binding partners can be expressed in the target cell type or target cell types and in an embodiment at a moderate or high level, and be nuclear proteins or nuclear destined proteins, or proteins with an NLS sequences, or proteins that are transported to the nucleus from the cytoplasm. Such proteins are expressed in the target cell type or cell types and said expression levels are in an embodiment detectable by proteomic or transcriptomic techniques such as immunohistochemistry (IHC) or RNA-seq respectively and are in a embodiment of moderate or high levels of expression. Moderate or high levels of expression can be defined as detectable by a conventional IHC technique, or expressed in the top 90% of proteins in the cell, or more in an embodiment expressed in the top 66% of proteins in the cell. Expression is in an embodiment present in the cell during the first month of DNA delivery, as such expression preferably in an embodiment is confirmed in the target cell type or cell types that are targeted by the gene therapy treatment or are the predominant cell type in the tissue targeted by the gene therapy treatment or are the predominant cell type in the route of administration of the therapeutic gene therapy. Other means of confirming expression of the protein binding partner of the DNA nuclear targeting sequence include microarray, Affymetrix, RNA-seq, qPCR, mass spectrometry, targeted MS proteomics, shotgun MS proteomic analysis or other means of detecting RNA or protein levels or measuring the level of gene expression or associated factors in a given cell, cells, or tissues. In an embodiment, the level of detection of the protein partner is confirmed by immunohistochemistry and preferably in an embodiment the level is confirmed by IHC to be moderate or high via for example quantitative analysis, semi-quantitative analysis, or semi-quantitative grading, such as for example a scale from 0 to 4, where 0 is not detected, 1 is low, 2-3 is moderate, and 4 is high. Preferably in an embodiment for the optimal functionality of the DNA nuclear targeting sequences the protein partner is expressed at detectable levels during the stage of the cell’s lifecycle at the time of treatment and preferably in an embodiment during the phase of the cell’s development at the time of treatment. The delivered DNA cassette can be in a form of a plasmid, miniaturized, minimal backbone, or nano-sized plasmid (NP), synthetic DNA, single stranded DNA, double stranded DNA, DNA / RNA hybrid, chemically modified DNA, DNA-peptide hybrid, single stranded linear DNA, double stranded linear DNA, partially double stranded linear DNA, single stranded circular DNA, double stranded circular DNA, or partially double stranded circular DNA. The construct may be a DNA-like molecule or contain DNA as part of a covalently linked or hybridized structure. The DNA may be delivered by any non-viral means or means derived from a virus without inherent or optimal or sufficiently optimal nuclear translocation capabilities. A target cell type can be an intended target cell type, predominantly targeted cell type such as one where at least 50% of the therapeutic DNA is delivered to the cell type, or one where the cell type is the predominant cell type by number or by volume in the treated area, or one where more than 50% of the delivered non-viral gene therapy is delivered to the cell type by copy number or vector number, or one where the cell type targeted is the most frequently targeted cell type from all of the cell types receiving the treatment directly or indirectly. In other embodiments the targeted cell type may be an important cell type within a given tissue for therapeutic purposes or the intended therapeutic target of the delivered DNA, or alternatively a cell that is intended to produce and secrete a therapeutic protein for mediating pathologies associated with the same or other cell types. Pathologies are generally defined as pathologies of animals, such as mammals or humans, or companion animals or farm animals, and treatment is defined as replacement of a defective or malfunctioning gene, augmentation of gene expression, enhancement of gene expression, replacement of gene expression or augmentation of its expression which is reduced as a function of aging or disease, or general augmentation, replacement, or enablement of gene expression, regulation of gene expression, or other therapeutic purpose. Treatments can be intended for replacement of missing or non-functioning genes, alleviation of pathologies caused by metabolic diseases, alleviation of pathologies caused by musculoskeletal diseases, alleviation of pathologies caused by cardiovascular diseases, alleviation of pathologies caused by diseases of the central and / or peripheral nervous systems, alleviation of pathologies in autoimmune diseases, alleviation of pathologies caused by infectious diseases, alleviation of pathologies caused by environmental conditions or other diseases of humans, mammals, or animals. Similarly, therapies may be intended for the modification of genome or epigenome or general regulation, permanent or transient, of gene expression via modification of DNA methylation, histone methylation, acetylation, or enablement of other histone or DNA modifications. Expression level of partner proteins can be measured and quantified to select the most optimal nuclear targeting DNA sequence to use in the genetic cassette, such expression levels can be compared across cell types such that the protein is not only expressed in the target cell type, but is expressed at a higher level in the target cell type or target cell types than other tissues, which are not the intended target of the gene therapy. Some example methods for quantifying gene expression are measurement of the construct per se by qPCR or other probe; measurement of transcribed mRNA from the construct by methods such as RT-qPCR, RNA-seq, in situ hybridization, or Affymetrix GeneChip (microarray); measurement of protein production by immunohistochemistry, ELISA, or mesoscale discovery; or measurement of activity using a reporter cell assay or a general cell- based assay. These techniques can be used to first confirm expression of the protein that will bind and carry the DNA cassette (or be carried and carry with it the DNA cassette) and then segment expression levels into none, low, medium or moderate, and high, and based on these segmentations prioritize the DNA sequence(s) to be added to the cassette. In some embodiments IHC, Affymetrix, and RNA-seq are used to identify high expressing proteins in adipocytes, for an adipocyte targeted or a subcutaneously delivered non- viral gene therapy treatment. The following segmentation was performed and proteins in each of the acceptable categories below were identified, followed by DNA-binding site identification and sequence selection for incorporation into the therapeutic construct: In some embodiments, the method of expression in adipocytes or evidence of expression in a target cell type can be derived from any conventional or hybrid technique such as single cell RNA-seq, RNA-seq, proteomics, transcriptomics, metabolomics, data mining, databases, artificial intelligence or other means providing evidence of expression or protein presence in adipocytes. So long as the protein has binding affinity to a stretch of at least two bases, and preferably more than 4 bases and most ideally between 5 and 32 bases either as one continuous stretch or as several stretches of DNA, the stretch or stretches of DNA can be valuable for incorporation into therapeutic constructs delivered by non-viral means to the cytoplasm for enhancing nuclear transport. Since adipose tissues present an easily targetable tissue, which is non-life- and non- function-sustaining when considered locally, and the predominant cell type by volume is the adipocyte, RNA-seq analysis of proteins expressed in adipocytes with DNA binding affinity can be used to generate DNA sequences that can be integrated to increase the potency of an adipocyte-targeted non-viral vector delivered gene therapy. Such sequences can be used for the augmentation of potency of a non-viral gene therapy treatment administered subcutaneously, or optionally systemically with, for example, adipocyte targeting, to enhance gene expression or potency of the therapeutic gene therapy. As such, the introduction of one or more of the sequences presented in the table below can serve as means of increasing potency and therefore therapeutic transgene expression or treatment efficiency, efficacy, or generally the therapeutic index. Inclusion of multiple sequences from the same protein or one or more proteins listed in the table below can provide additional benefit in some embodiments. It should be noted that the above table contains degenerate base sequences that are interpreted in accordance with their commonly accepted interpretation, as an example and irrespective of whether the base is lower or upper case: R = A / G, Y = C / T, M = A / C, K = G / T, S = C / G, W = A / T, B = C / G / T, D = A / G / T, H = A / C / T, V = A / C / G, and N = A / C / G / T. The sequences from the above table may be added in part or in whole, in an embodiment preferentially taking only the high frequency bases (capital letters) or 70%, 80%, 90%, or more than 90% of the total sequence length, and may be included by themselves, as one or more sequences, as a plethora of sequence in series, as a plethora of sequences in series separated by a non-coding or nonsense spacer, or at various locations around the therapeutic cassette, but generally in an embodiment in cis with at least one therapeutic gene or non-coding DNA. Consensus sequences can be generated from the above sequences to reduce the length of the sequence required for binding or enhance binding affinity. Such consensus sequences can be included on their own, together with the sequences in the above table or as partial sequences with or without partial or full sequences from the above table. The aforementioned sequences can be introduced in either the forward or reverse strand or in both the forward and reverse strands, with in an embodiment at least one sequence per DNA molecule that contains the therapeutic gene or non-coding region or at most such that up to 6500 bases of such sequences are introduced per strand, but preferably in an embodiment between 50 and 4500 bases and more preferably in an embodiment between 200 and 2500 bases. Sequences can be introduced without spacers, or with 1-60 base spacers that are preferably in an embodiment comprised of sequences that do not have affinity for proteins. Sequences can be introduced on only one side of the therapeutic transgene or therapeutic non-coding DNA sequence or on either side of said therapeutic transgene or therapeutic non-coding DNA sequence. The aforementioned consensus sequences can be incorporated on their own, partially or completely, in association with other sequences or other consensus sequence(s), in tandem or in multiple, on one side of the therapeutic transgene or non-coding DNA or on multiple sides of the transgene or non-coding DNA and with or without non-consensus sequences. It should be understood that within the scope of this invention the formulation, materials, genetic constructs, sequences, biological and chemical compositions, or methods of use may be varied by one skilled in the art, to the extent that the structures described herewithin perform the desired function and remain within the scope of the present invention. Various parts, components or characteristics may be used in combination, with or without modification by someone skilled in the art to achieve the desired functionality of the aforedescribed formulation. Moreover, all individual features and methods of use described herein, and each and every combination of two or more of such features and methods of use, are included within the scope of the present invention provided that these features and methods of use in such a combination are not mutually inconsistent. It is understood that certain portions or combinations of such portions can be varied by someone trained in the art while still achieving the main goal of the invention. Finally, it is understood that the specific ranges provided in the current invention are not restrictive and are for example purposes only, values outside of the specified ranges may be used to achieve the goal of the invention without modification to the proposed mechanistic principals. EXAMPLES Example 1 In the first example, a glucagon (GCG)-coding therapeutic construct containing 3 repeats each of 2 separate DNA-binding motifs for HAS1 is delivered by a lipid nanoparticle formulation, which predominantly transfects cells in the subcutaneous area of injection, and most predominantly adipocytes. The construct is presented in FIG. 1. Full FASTA Sequence (Without Miniaturized Plasmid Backbone): GGTACACCGGAAGTAACCGGAAGTAACCGGAAGTACGTTACATAACTTACGGTAAATGGCCCGCCTGG CTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATAGGGACTTTCCATTGACGTC AATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACG CCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCCAGTACATGACCTTATGGGA CTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGT TTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGG GCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTT TTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCG CGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGC GTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCTGAGCAAGAGGT AAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGGAGCACCTGCCTGAAATC ACTTTTTTTCAGGTTGGATGAAAAGCATTTACTTTGTGGCTGGATTATTTGTAATGCTGGTACAAGGC AGCTGGCAACGTTCCCTTCAAGACACAGAGGAGAAATCCAGATCATTCTCAGCTTCCCAGGCAGACCC ACTCAGTGATCCTGATCAGATGAACGAGGACAAGCGCCATTCACAGGGCACATTCACCAGTGACTACA GCAAGTATCTGGACTCCAGGCGTGCCCAAGATTTTGTGCAGTGGTTGATGAATACCAAGAGGAACAGG AATAACATTGCCAAACGTCACGATGAATTTGAGAGACATGCTGAAGGGACCTTTACCAGTGATGTAAG TTCTTATTTGGAAGGCCAAGCTGCCAAGGAATTCATTGCTTGGCTGGTGAAAGGCCGAGGAAGGCGAG ATTTCCCAGAAGAGGTCGCCATTGTTGAAGAACTTGGCCGCAGACATGCTGATGGTTCTTTCTCTGAT GAGATGAACACCATTCTTGATAATCTTGCCGCCAGGGACTTTATAAACTGGTTGATTCAGACCAAAAT CACTGACAGGAAATAACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTC CTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTC TGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAG AATAGCAGGCAGGCTGGGGATACTTCCTTTACTTCCTTTACTTCCTTCTAGC(SEQ ID NO: 1) HAS1 Binding Motif Area 1: ACCGGAAGTAACCGGAAGTAACCGGAAGTA(SEQ ID NO: 2) HAS1 Binding Motif Area 2: TACTTCCTTTACTTCCTTTACTTCCTT(SEQ ID NO: 3) CBh Promoter: CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAA TAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTG GCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGC CTGGCATTGTGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCA TCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCA CCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGG GCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAG CCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAA AAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTT CTCCTCCGGGCTGTAATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTA ATGTTTAATTACCTGGAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGG(SEQ ID NO: 4) Glucagon: ATGAAAAGCATTTACTTTGTGGCTGGATTATTTGTAATGCTGGTACAAGGCAGCTGGCAACGTTCCCT TCAAGACACAGAGGAGAAATCCAGATCATTCTCAGCTTCCCAGGCAGACCCACTCAGTGATCCTGATC AGATGAACGAGGACAAGCGCCATTCACAGGGCACATTCACCAGTGACTACAGCAAGTATCTGGACTCC AGGCGTGCCCAAGATTTTGTGCAGTGGTTGATGAATACCAAGAGGAACAGGAATAACATTGCCAAACG TCACGATGAATTTGAGAGACATGCTGAAGGGACCTTTACCAGTGATGTAAGTTCTTATTTGGAAGGCC AAGCTGCCAAGGAATTCATTGCTTGGCTGGTGAAAGGCCGAGGAAGGCGAGATTTCCCAGAAGAGGTC GCCATTGTTGAAGAACTTGGCCGCAGACATGCTGATGGTTCTTTCTCTGATGAGATGAACACCATTCT TGATAATCTTGCCGCCAGGGACTTTATAAACTGGTTGATTCAGACCAAAATCACTGACAGGAAATAA( SEQ ID NO: 5) Glucagon Protein Sequence: MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDYSKYLDS RRAQDFVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEV AIVEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK(SEQ ID NO: 6) Bovine Growth Hormone Polyadenlyation Sequence: CTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGT GCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTC TATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAATAGCAGGCAGGCTG GGGA(SEQ ID NO: 7) Example 2 In the second example, a therapeutic transgene encoding double stranded DNA delivered in miniaturized backbone plasmid form is modified with the shortest DNA-binding motif from each identified protein was added on to a base construct on either side of a sequence encoding full-length fibroblast growth factor 21 (FGF21) The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The construct is delivered via electroporation to the subcutaneous tissues in the abdomen for continuous production of FGF21 and the treatment of NASH. The construct is presented in FIG. 2. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACCGTGCTACTTCCTTTGACTCATAGGTCAACCAGGTGCATTTCCTCGTTACATAACTTACGGTA AATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATAGGGAC TTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATC ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCCAGTAC ATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGA GGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTAT TTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCG GGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCT CCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGG CGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGG CTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTA GCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGGAGC ACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGGACAGCGACGAGACCGGCTTCGAGCACAGCGGCC TGTGGGTGAGCGTGCTGGCCGGCCTGCTGCTGGGCGCCTGCCAGGCCCACCCCATCCCCGACAGCAGC CCCCTGCTGCAGTTCGGCGGCCAGGTGAGGCAGAGGTACCTGTACACCGACGACGCCCAGCAGACCGA GGCCCACCTGGAGATCAGGGAGGACGGCACCGTGGGCGGCGCCGCCGACCAGAGCCCCGAGAGCCTGC TGCAGCTGAAGGCCCTGAAGCCCGGCGTGATCCAGATCCTGGGCGTGAAGACCAGCAGGTTCCTGTGC CAGAGGCCCGACGGCGCCCTGTACGGCAGCCTGCACTTCGACCCCGAGGCCTGCAGCTTCAGGGAGCT GCTGCTGGAGGACGGCTACAACGTGTACCAGAGCGAGGCCCACGGCCTGCCCCTGCACCTGCCCGGCA ACAAGAGCCCCCACAGGGACCCCGCCCCCAGGGGCCCCGCCAGGTTCCTGCCCCTGCCCGGCCTGCCC CCCGCCCTGCCCGAGCCCCCCGGCATCCTGGCCCCCCAGCCCCCCGACGTGGGCAGCAGCGACCCCCT GAGCATGGTGGGCCCCAGCCAGGGCAGGAGCCCCAGCTACGCCAGCTAACTGTGCCTTCTAGTTGCCA GCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTT CCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTG GGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAATAGCAGGCAGGCTGGGGACGTGCTACTTCCTTT GACTCATAGGTCAACCAGGTGCATTTCCTCTAGC(SEQ ID NO: 8) Short Sequences CGTGCTACTTCCTTTGACTCATAGGTCAACCAGGTGCATTTCCT(SEQ ID NO: 9) FGF21 ATGGACAGCGACGAGACCGGCTTCGAGCACAGCGGCCTGTGGGTGAGCGTGCTGGCCGGCCTGCTGCT GGGCGCCTGCCAGGCCCACCCCATCCCCGACAGCAGCCCCCTGCTGCAGTTCGGCGGCCAGGTGAGGC AGAGGTACCTGTACACCGACGACGCCCAGCAGACCGAGGCCCACCTGGAGATCAGGGAGGACGGCACC GTGGGCGGCGCCGCCGACCAGAGCCCCGAGAGCCTGCTGCAGCTGAAGGCCCTGAAGCCCGGCGTGAT CCAGATCCTGGGCGTGAAGACCAGCAGGTTCCTGTGCCAGAGGCCCGACGGCGCCCTGTACGGCAGCC TGCACTTCGACCCCGAGGCCTGCAGCTTCAGGGAGCTGCTGCTGGAGGACGGCTACAACGTGTACCAG AGCGAGGCCCACGGCCTGCCCCTGCACCTGCCCGGCAACAAGAGCCCCCACAGGGACCCCGCCCCCAG GGGCCCCGCCAGGTTCCTGCCCCTGCCCGGCCTGCCCCCCGCCCTGCCCGAGCCCCCCGGCATCCTGG CCCCCCAGCCCCCCGACGTGGGCAGCAGCGACCCCCTGAGCATGGTGGGCCCCAGCCAGGGCAGGAGC CCCAGCTACGCCAGC(SEQ ID NO: 10) FGF21 Protein Sequence MDSDETGFEHSGLWVSVLAGLLLGACQAHPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGT VGGAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQ SEAHGLPLHLPGNKSPHRDPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLSMVGPSQGRS PSYAS(SEQ ID NO: 11) Example 3 In the third example, the longest DNA-binding motif from each identified protein was added on to a base construct on either side of a sequence encoding full-length beta- glucocerebrosidase to treat Gaucher's disease associated with beta-glucocerebrosidase enzyme deficiency. The coding region is preceded by a CBh promoter and adiponectin secretion signal, and followed by a bovine growth hormone polyadenylation sequence. The construct is administered via a subcutaneous injection in the thigh or abdomen and delivered via a polymeric nanoparticle to the cytoplasm of cells, predominantly targeting white subcutaneous adipocytes. The construct is presented in FIG. 3. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACACCGGAAGTAAGGTCAAGGTCAAGCGTATCACGTGGTACGCTGAATGACTCATCAGCCACCTG GCTGTATTCCCAGAAATTCTATTCCTGGAGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGAC CGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGG GTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCC TATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCCAGTACATGACCTTATGGGACTTTC CTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGC TTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTG TGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGG GCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATG GCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTG CCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTAC TCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCTGAGCAAGAGGTAAGGG TTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGGAGCACCTGCCTGAAATCACTTT TTTTCAGGTTGGATGCTGCTGCTGGGCGCCGTGCTGCTGCTGCTGGCCCTGCCCGGCCACGACCAGGC CAGGCCCTGCATCCCCAAGAGCTTCGGCTACAGCAGCGTGGTGTGCGTGTGCAACGCCACCTACTGCG ACAGCTTCGACCCCCCCACCTTCCCCGCCCTGGGCACCTTCAGCAGGTACGAGAGCACCAGGAGCGGC AGGAGGATGGAGCTGAGCATGGGCCCCATCCAGGCCAACCACACCGGCACCGGCCTGCTGCTGACCCT GCAGCCCGAGCAGAAGTTCCAGAAGGTGAAGGGCTTCGGCGGCGCCATGACCGACGCCGCCGCCCTGA ACATCCTGGCCCTGAGCCCCCCCGCCCAGAACCTGCTGCTGAAGAGCTACTTCAGCGAGGAGGGCATC GGCTACAACATCATCAGGGTGCCCATGGCCAGCTGCGACTTCAGCATCAGGACCTACACCTACGCCGA CACCCCCGACGACTTCCAGCTGCACAACTTCAGCCTGCCCGAGGAGGACACCAAGCTGAAGATCCCCC TGATCCACAGGGCCCTGCAGCTGGCCCAGAGGCCCGTGAGCCTGCTGGCCAGCCCCTGGACCAGCCCC ACCTGGCTGAAGACCAACGGCGCCGTGAACGGCAAGGGCAGCCTGAAGGGCCAGCCCGGCGACATCTA CCACCAGACCTGGGCCAGGTACTTCGTGAAGTTCCTGGACGCCTACGCCGAGCACAAGCTGCAGTTCT GGGCCGTGACCGCCGAGAACGAGCCCAGCGCCGGCCTGCTGAGCGGCTACCCCTTCCAGTGCCTGGGC TTCACCCCCGAGCACCAGAGGGACTTCATCGCCAGGGACCTGGGCCCCACCCTGGCCAACAGCACCCA CCACAACGTGAGGCTGCTGATGCTGGACGACCAGAGGCTGCTGCTGCCCCACTGGGCCAAGGTGGTGC TGACCGACCCCGAGGCCGCCAAGTACGTGCACGGCATCGCCGTGCACTGGTACCTGGACTTCCTGGCC CCCGCCAAGGCCACCCTGGGCGAGACCCACAGGCTGTTCCCCAACACCATGCTGTTCGCCAGCGAGGC CTGCGTGGGCAGCAAGTTCTGGGAGCAGAGCGTGAGGCTGGGCAGCTGGGACAGGGGCATGCAGTACA GCCACAGCATCATCACCAACCTGCTGTACCACGTGGTGGGCTGGACCGACTGGAACCTGGCCCTGAAC CCCGAGGGCGGCCCCAACTGGGTGAGGAACTTCGTGGACAGCCCCATCATCGTGGACATCACCAAGGA CACCTTCTACAAGCAGCCCATGTTCTACCACCTGGGCCACTTCAGCAAGTTCATCCCCGAGGGCAGCC AGAGGGTGGGCCTGGTGGCCAGCCAGAAGAACGACCTGGACGCCGTGGCCCTGATGCACCCCGACGGC AGCGCCGTGGTGGTGGTGCTGAACAGGAGCAGCAAGGACGTGCCCCTGACCATCAAGGACCCCGCCGT GGGCTTCCTGGAGACCATCAGCCCCGGCTACAGCATCCACACCTACCTGTGGAGGAGGCAGTAACTGT GCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCA CTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATT CTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAATAGCAGGCAGGCTGGGGA ACCGGAAGTAAGGTCAAGGTCAAGCGTATCACGTGGTACGCTGAATGACTCATCAGCCACCTGGCTGT ATTCCCAGAAATTCTATTCCTGGAGCTAGC(SEQ ID NO: 12) Long Sequences ACCGGAAGTAAGGTCAAGGTCAAGCGTATCACGTGGTACGCTGAATGACTCATCAGCCACCTGGCTGT ATTCCCAGAAATTCTATTCCTGGAG(SEQ ID NO: 13) Beta-Glucocerebrosidase with Adiponectin Secretion Signal ATGCTGCTGCTGGGCGCCGTGCTGCTGCTGCTGGCCCTGCCCGGCCACGACCAGGCCAGGCCCTGCAT CCCCAAGAGCTTCGGCTACAGCAGCGTGGTGTGCGTGTGCAACGCCACCTACTGCGACAGCTTCGACC CCCCCACCTTCCCCGCCCTGGGCACCTTCAGCAGGTACGAGAGCACCAGGAGCGGCAGGAGGATGGAG CTGAGCATGGGCCCCATCCAGGCCAACCACACCGGCACCGGCCTGCTGCTGACCCTGCAGCCCGAGCA GAAGTTCCAGAAGGTGAAGGGCTTCGGCGGCGCCATGACCGACGCCGCCGCCCTGAACATCCTGGCCC TGAGCCCCCCCGCCCAGAACCTGCTGCTGAAGAGCTACTTCAGCGAGGAGGGCATCGGCTACAACATC ATCAGGGTGCCCATGGCCAGCTGCGACTTCAGCATCAGGACCTACACCTACGCCGACACCCCCGACGA CTTCCAGCTGCACAACTTCAGCCTGCCCGAGGAGGACACCAAGCTGAAGATCCCCCTGATCCACAGGG CCCTGCAGCTGGCCCAGAGGCCCGTGAGCCTGCTGGCCAGCCCCTGGACCAGCCCCACCTGGCTGAAG ACCAACGGCGCCGTGAACGGCAAGGGCAGCCTGAAGGGCCAGCCCGGCGACATCTACCACCAGACCTG GGCCAGGTACTTCGTGAAGTTCCTGGACGCCTACGCCGAGCACAAGCTGCAGTTCTGGGCCGTGACCG CCGAGAACGAGCCCAGCGCCGGCCTGCTGAGCGGCTACCCCTTCCAGTGCCTGGGCTTCACCCCCGAG CACCAGAGGGACTTCATCGCCAGGGACCTGGGCCCCACCCTGGCCAACAGCACCCACCACAACGTGAG GCTGCTGATGCTGGACGACCAGAGGCTGCTGCTGCCCCACTGGGCCAAGGTGGTGCTGACCGACCCCG AGGCCGCCAAGTACGTGCACGGCATCGCCGTGCACTGGTACCTGGACTTCCTGGCCCCCGCCAAGGCC ACCCTGGGCGAGACCCACAGGCTGTTCCCCAACACCATGCTGTTCGCCAGCGAGGCCTGCGTGGGCAG CAAGTTCTGGGAGCAGAGCGTGAGGCTGGGCAGCTGGGACAGGGGCATGCAGTACAGCCACAGCATCA TCACCAACCTGCTGTACCACGTGGTGGGCTGGACCGACTGGAACCTGGCCCTGAACCCCGAGGGCGGC CCCAACTGGGTGAGGAACTTCGTGGACAGCCCCATCATCGTGGACATCACCAAGGACACCTTCTACAA GCAGCCCATGTTCTACCACCTGGGCCACTTCAGCAAGTTCATCCCCGAGGGCAGCCAGAGGGTGGGCC TGGTGGCCAGCCAGAAGAACGACCTGGACGCCGTGGCCCTGATGCACCCCGACGGCAGCGCCGTGGTG GTGGTGCTGAACAGGAGCAGCAAGGACGTGCCCCTGACCATCAAGGACCCCGCCGTGGGCTTCCTGGA GACCATCAGCCCCGGCTACAGCATCCACACCTACCTGTGGAGGAGGCAGTAA(SEQ ID NO: 14) Beta-Glucocerebrosidase with Adiponectin Secretion Signal Protein Sequence MLLLGAVLLLLALPGHDQARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRME LSMGPIQANHTGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNI IRVPMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWTSPTWLK TNGAVNGKGSLKGQPGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGLLSGYPFQCLGFTPE HQRDFIARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPEAAKYVHGIAVHWYLDFLAPAKA TLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRGMQYSHSIITNLLYHVVGWTDWNLALNPEGG PNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAVV VVLNRSSKDVPLTIKDPAVGFLETISPGYSIHTYLWRRQ(SEQ ID NO: 15) Example 4 In the present example, consensus sequences for SNAI1 and STAT5A were generated from a list of available DNA-binding motifs for each protein. A sequence matching the consensus sequence for each protein was inserted upstream and downstream of a sequence encoding full-length apelin. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The construct is delivered via an exosome following a subcutaneous injection. The construct is presented in FIG. 4. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACCCCACCTCACCTGCATGTAGACATTTCCTGGAAATTGTATWCCTAGAACGTTACATAACTTAC GGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATAG GGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTG TATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCCA GTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGG TCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTAT TTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGG GGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCG CGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGG CGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCC CCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTA ATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTG GAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGAATCTGCGGCTCTGCGTGCAGGCGCTCCTG CTGCTCTGGCTCTCCTTGACCGCGGTGTGTGGAGGGTCCCTGATGCCGCTTCCCGATGGGAATGGGCT GGAAGACGGCAATGTCCGCCACCTGGTGCAGCCCAGAGGGTCAAGGAATGGGCCAGGGCCCTGGCAGG GAGGTCGGAGGAAATTCCGCCGCCAGCGGCCCCGCCTCTCCCATAAGGGACCCATGCCTTTCTGACTG TGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCC ACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTAT TCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAATAGCAGGCAGGCTGGGG ACCCACCTCACCTGCATGTAGACATTTCCTGGAAATTGTATWCCTAGAACTAGC(SEQ ID NO: 16) SNAI1 Consensus CCCACCTCACCTGCATGTA(SEQ ID NO: 17) STAT5A Consensus GACATTTCCTGGAAATTGTATWCCTAGAA(SEQ ID NO: 18) Apelin ATGAATCTGCGGCTCTGCGTGCAGGCGCTCCTGCTGCTCTGGCTCTCCTTGACCGCGGTGTGTGGAGG GTCCCTGATGCCGCTTCCCGATGGGAATGGGCTGGAAGACGGCAATGTCCGCCACCTGGTGCAGCCCA GAGGGTCAAGGAATGGGCCAGGGCCCTGGCAGGGAGGTCGGAGGAAATTCCGCCGCCAGCGGCCCCGC CTCTCCCATAAGGGACCCATGCCTTTCTGA(SEQ ID NO: 19) Apelin Protein Sequence MNLRLCVQALLLLWLSLTAVCGGSLMPLPDGNGLEDGNVRHLVQPRGSRNGPGPWQGGRRKFRRQRPR LSHKGPMPF(SEQ ID NO: 20) Example 5 In the present example, a DNA-binding motif from each of the identified proteins was selected such the last 2 bp of one motif were identical to the first 2 bp of the next motif. The selected motifs were chained together with a 2 bp overlap, and the chained motif was inserted upstream and downstream of a sequence encoding interleukin 1 receptor antagonist (IL1RA). The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation signal. The therapeutic genetic cassette, which is a synthetic DNA construct is delivered via a virus-like particle to the subcutaneous adipocytes in the vicinity of the abdominal injection. The construct is presented in FIG. 5. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACTACTTCCTTCCCAGAATTGCTATTCCGAGGACCACGTGGTCAGGTGAGTCAGGTCAAAGGTCA CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAA TAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTG GCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGC CTGGCATTGTGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCA TCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCA CCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGG GCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAG CCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAA AAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGC CTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTT CTCCTCCGGGCTGTAATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTA ATGTTTAATTACCTGGAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGGAAATTTGTAGAGGC CTGAGATCTCATCTGATCACCCTGCTGCTGTTTCTGTTCCACAGCGAGACAATCTGCAGACCTAGCGG AAGAAAGAGCAGCAAGATGCAGGCCTTTAGAATCTGGGACGTGAATCAGAAAACCTTCTACCTGCGCA ACAACCAGCTCGTGGCCGGCTACCTGCAGGGCCCCAACGTGAACCTGGAAGAGAAGATCGACGTGGTC CCCATCGAGCCTCACGCCCTGTTCCTGGGCATCCACGGCGGCAAGATGTGCCTGTCCTGCGTGAAGTC TGGAGATGAGACAAGACTGCAACTGGAAGCTGTGAATATCACCGACCTGAGCGAGAACCGGAAACAGG ATAAGCGGTTCGCCTTCATCCGGAGCGACAGCGGCCCTACCACCAGCTTCGAGAGCGCCGCTTGTCCT GGCTGGTTCCTGTGCACAGCCATGGAAGCCGACCAGCCAGTGTCCCTGACCAACATGCCTGATGAAGG CGTTATGGTGACCAAGTTCTACTTCCAGGAGGACGAGTAACTGTGCCTTCTAGTTGCCAGCCATCTGT TGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAA ATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGAC AGCAAGGGGGAGGATTGGGAAGAGAATAGCAGGCAGGCTGGGGATACTTCCTTCCCAGAATTGCTATT CCGAGGACCACGTGGTCAGGTGAGTCAGGTCAAAGGTCACTAGC(SEQ ID NO: 21) Chained Motif TACTTCCTTCCCAGAATTGCTATTCCGAGGACCACGTGGTCAGGTGAGTCAGGTCAAAGGTCA(SEQ ID NO: 22) IL1RA ATGGAAATTTGTAGAGGCCTGAGATCTCATCTGATCACCCTGCTGCTGTTTCTGTTCCACAGCGAGAC AATCTGCAGACCTAGCGGAAGAAAGAGCAGCAAGATGCAGGCCTTTAGAATCTGGGACGTGAATCAGA AAACCTTCTACCTGCGCAACAACCAGCTCGTGGCCGGCTACCTGCAGGGCCCCAACGTGAACCTGGAA GAGAAGATCGACGTGGTCCCCATCGAGCCTCACGCCCTGTTCCTGGGCATCCACGGCGGCAAGATGTG CCTGTCCTGCGTGAAGTCTGGAGATGAGACAAGACTGCAACTGGAAGCTGTGAATATCACCGACCTGA GCGAGAACCGGAAACAGGATAAGCGGTTCGCCTTCATCCGGAGCGACAGCGGCCCTACCACCAGCTTC GAGAGCGCCGCTTGTCCTGGCTGGTTCCTGTGCACAGCCATGGAAGCCGACCAGCCAGTGTCCCTGAC CAACATGCCTGATGAAGGCGTTATGGTGACCAAGTTCTACTTCCAGGAGGACGAGTAA(SEQ ID NO: 23) IL1RA Protein Sequence MEICRGLRSHLITLLLFLFHSETICRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLE EKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSF ESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(SEQ ID NO: 24) Example 6 In the present example, all of the identified DNA-binding sequences were included on either side of a sequence encoding full-length insulin. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The construct is aimed at delivering a basal level of insulin expression for the treatment of insulin dependent diabetes or type 2 diabetes that requires basal insulin supplementation. The construct is presented in FIG. 6. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACCAACCACGTGGTCATACCACATGTCTGCCATGTGCCAGCGTATCACGTGGTACGCTCACGTGC CCACCTGACTGACCACGTGGTCTACCACGTGGTCCAGGTGGCAGCCACGTGCCCGTGCCCACCTGACT CCACGTGGACTGACTCAGTGAATGACTCATCATGACTCATGGTCGTGACTCAATGAGTCAGTGACTCA TTGACTCATTGTGGATGACGTCATCACCGGAAGTATACTTCCTTAGGTCAAGGTCACCTGACCTGAGG TCAACCAGGTGGGCCACCTGGCTGTACCACCTGCATCCAGGTGTCACCTGACCCAGCTCACCTGGCAC CTGGATTCAGGTGTCACCTGATTCCCGTAAGAATTCCAGGAAATTTTCCCAGAAATTCTATTCCTGGA GCATTTCCTGATTTCTAGACTCTTCTGAGAACTTTTCTAGGAATTCTCGGAAATCGTTACATAACTTA CGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATA GGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGT GTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCC AGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG GTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTA TTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCG GGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGC GCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCG GCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGC CCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGT AATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCT GGAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGGCCCTGTGGATGAGGCTGCTGCCCCTGCT GGCCCTGCTGGCCCTGTGGGGCCCCGACCCCGCCGCCGCCTTCGTGAACCAGCACCTGTGCGGCAGCC ACCTGGTGGAGGCCCTGTACCTGGTGTGCGGCGAGAGGGGCTTCTTCTACACCCCCAAGACCAGGAGG GAGGCCGAGGACCTGCAGGTGGGCCAGGTGGAGCTGGGCGGCGGCCCCGGCGCCGGCAGCCTGCAGCC CCTGGCCCTGGAGGGCAGCCTGCAGAAGAGGGGCATCGTGGAGCAGTGCTGCACCAGCATCTGCAGCC TGTACCAGCTGGAGAACTACTGCAACTAACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCT CCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATT GCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGA GGATTGGGAAGAGAATAGCAGGCAGGCTGGGGACAACCACGTGGTCATACCACATGTCTGCCATGTGC CAGCGTATCACGTGGTACGCTCACGTGCCCACCTGACTGACCACGTGGTCTACCACGTGGTCCAGGTG GCAGCCACGTGCCCGTGCCCACCTGACTCCACGTGGACTGACTCAGTGAATGACTCATCATGACTCAT GGTCGTGACTCAATGAGTCAGTGACTCATTGACTCATTGTGGATGACGTCATCACCGGAAGTATACTT CCTTAGGTCAAGGTCACCTGACCTGAGGTCAACCAGGTGGGCCACCTGGCTGTACCACCTGCATCCAG GTGTCACCTGACCCAGCTCACCTGGCACCTGGATTCAGGTGTCACCTGATTCCCGTAAGAATTCCAGG AAATTTTCCCAGAAATTCTATTCCTGGAGCATTTCCTGATTTCTAGACTCTTCTGAGAACTTTTCTAG GAATTCTCGGAAATCTAGC(SEQ ID NO: 25) MYC Sequences CAACCACGTGGTCATACCACATGTCTGCCATGTGCCAGCGTATCACGTGGTACGCTCACGTGCCCACC TGACTGACCACGTGGTCTACCACGTGGTCCAGGTGGCAGCCACGTGCCCGTGCCCACCTGACTCCACG TGG(SEQ ID NO: 26) FOSL1 Sequences ACTGACTCAGTGAATGACTCATCATGACTCATGGTCGTGACTCAATGAGTCAGTGACTCATTGACTCA TTGTGGATGACGTCATC(SEQ ID NO: 27) HAS1 Sequences ACCGGAAGTATACTTCCTT(SEQ ID NO: 28) PPARG Sequences AGGTCAAGGTCACCTGACCTGAGGTCAA(SEQ ID NO: 29) SNAI1 Sequences CCAGGTGGGCCACCTGGCTGTACCACCTGCATCCAGGTGTCACCTGACCCAGCTCACCTGGCACCTGG ATTCAGGTGTCACCTGA(SEQ ID NO: 30) STAT5A Sequences TTCCCGTAAGAATTCCAGGAAATTTTCCCAGAAATTCTATTCCTGGAGCATTTCCTGATTTCTAGACT CTTCTGAGAACTTTTCTAGGAATTCTCGGAAAT(SEQ ID NO: 31) Insulin ATGGCCCTGTGGATGAGGCTGCTGCCCCTGCTGGCCCTGCTGGCCCTGTGGGGCCCCGACCCCGCCGC CGCCTTCGTGAACCAGCACCTGTGCGGCAGCCACCTGGTGGAGGCCCTGTACCTGGTGTGCGGCGAGA GGGGCTTCTTCTACACCCCCAAGACCAGGAGGGAGGCCGAGGACCTGCAGGTGGGCCAGGTGGAGCTG GGCGGCGGCCCCGGCGCCGGCAGCCTGCAGCCCCTGGCCCTGGAGGGCAGCCTGCAGAAGAGGGGCAT CGTGGAGCAGTGCTGCACCAGCATCTGCAGCCTGTACCAGCTGGAGAACTACTGCAACTAA(SEQ ID NO: 32) Insulin Protein Sequence MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVEL GGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN(SEQ ID NO: 33) Example 7 In this example, a consensus sequence was generated for each identified protein. A sequence matching the consensus sequence for each protein was inserted upstream and downstream of a sequence encoding Exenatide. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The double stranded DNA construct with a chemically-modified backbone is delivered via gold-particle bombardment to the subcutaneous tissues for the continuous production of Exenatide for the treatment of type 2 diabetes. The construct is presented in FIG. 7. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACCACCGACCACGTGGCTAGTGGGATGACTCATTCTGACCGGAAGTAAGGTCAAGGTCACCCACC TCACCTGCATGTAGACATTTCCTGGAAATTGTATWCCTAGAACGTTACATAACTTACGGTAAATGGCC CGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATAGGGACTTTCCAT TGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCC AAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCCAGTACATGACCT TATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGC TTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGG GCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAG TTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGGAGT CGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGAC TGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCTGAGC AAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGGAGCACCTGCC TGAAATCACTTTTTTTCAGGTTGGATGGCCACAGACAGCAGAACAAGCTGGCTGCTCACCGTGTCCCT GCTGTGCCTGCTGTGGCCCCAGGAGGCCAGCGCCTTCCCCGCTATGCCTCTGAGCAGCCTGTTCAGCA ACGCCGTGCTGAGAGCCAGAGGCAAGCGGCACGGCGAGGGCACCTTCACCTCTGATCTGTCCAAGCAG ATGGAAGAGGAAGCTGTGCGGCTGTTTATCGAGTGGCTGAAAAACGGCGGACCTTCTAGCGGCGCCCC TCCACCTAGCTAACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTT GACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGA GTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAAT AGCAGGCAGGCTGGGGACACCGACCACGTGGCTAGTGGGATGACTCATTCTGACCGGAAGTAAGGTCA AGGTCACCCACCTCACCTGCATGTAGACATTTCCTGGAAATTGTATWCCTAGAACTAGC(SEQ ID NO: 34) MYC Consensus CACCGACCACGTGGCTAGTG(SEQ ID NO: 35) FOSL1 Consensus GGATGACTCATTCTG(SEQ ID NO: 36) HAS1 Consensus ACCGGAAGTA(SEQ ID NO: 37) PPARG Consensus AGGTCAAGGTCA(SEQ ID NO: 38) SNAI1 Consensus CCCACCTCACCTGCATGTA(SEQ ID NO: 17) STAT5A Consensus GACATTTCCTGGAAATTGTATWCCTAGAA(SEQ ID NO: 18) Exenatide ATGGCCACAGACAGCAGAACAAGCTGGCTGCTCACCGTGTCCCTGCTGTGCCTGCTGTGGCCCCAGGA GGCCAGCGCCTTCCCCGCTATGCCTCTGAGCAGCCTGTTCAGCAACGCCGTGCTGAGAGCCAGAGGCA AGCGGCACGGCGAGGGCACCTTCACCTCTGATCTGTCCAAGCAGATGGAAGAGGAAGCTGTGCGGCTG TTTATCGAGTGGCTGAAAAACGGCGGACCTTCTAGCGGCGCCCCTCCACCTAGCTAA(SEQ ID NO: 39) Exenatide Protein Sequence MATDSRTSWLLTVSLLCLLWPQEASAFPAMPLSSLFSNAVLRARGKRHGEGTFTSDLSKQMEEEAVRL FIEWLKNGGPSSGAPPPS(SEQ ID NO: 40) Example 8 In the present example, a consensus sequence was generated for PPARG and a sequence matching the consensus sequence was inserted several times on either side of a sequence encoding full-length ficolin-3 for treatment of ficolin-3 deficiency. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The construct is delivered by a lipid nanoparticle with a conjugated targeting moiety promoting uptake by adipocytes and preferential adipocyte targeting. The vector is administered via a subcutaneous injection and is delivered via an injection to the subcutis using a prefilled syringe or autoinjector. The construct is presented in FIG. 8. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCACGT TACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAG TAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCA GTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTG GCATTGTGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCG CTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCC CCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCG CGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCA ATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAG CGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTC GCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTC CTCCGGGCTGTAATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATG TTTAATTACCTGGAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGGACCTGCTGTGGATCCTG CCCAGCCTGTGGCTGCTGCTGCTGGGCGGCCCCGCCTGCCTGAAGACCCAGGAGCACCCCAGCTGCCC CGGCCCCAGAGAGCTGGAGGCCAGCAAGGTGGTGCTGCTGCCCAGCTGCCCCGGCGCCCCCGGCAGCC CCGGCGAGAAGGGCGCCCCCGGCCCCCAGGGCCCCCCCGGCCCCCCCGGCAAGATGGGCCCCAAGGGC GAGCCCGGCGACCCCGTGAACCTGCTGAGATGCCAGGAGGGCCCCAGAAACTGCAGAGAGCTGCTGAG CCAGGGCGCCACCCTGAGCGGCTGGTACCACCTGTGCCTGCCCGAGGGCAGAGCCCTGCCCGTGTTCT GCGACATGGACACCGAGGGCGGCGGCTGGCTGGTGTTCCAGAGAAGACAGGACGGCAGCGTGGACTTC TTCAGAAGCTGGAGCAGCTACAGAGCCGGCTTCGGCAACCAGGAGAGCGAGTTCTGGCTGGGCAACGA GAACCTGCACCAGCTGACCCTGCAGGGCAACTGGGAGCTGAGAGTGGAGCTGGAGGACTTCAACGGCA ACAGAACCTTCGCCCACTACGCCACCTTCAGACTGCTGGGCGAGGTGGACCACTACCAGCTGGCCCTG GGCAAGTTCAGCGAGGGCACCGCCGGCGACAGCCTGAGCCTGCACAGCGGCAGACCCTTCACCACCTA CGACGCCGACCACGACAGCAGCAACAGCAACTGCGCCGTGATCGTGCACGGCGCCTGGTGGTACGCCA GCTGCTACAGAAGCAACCTGAACGGCAGATACGCCGTGAGCGAGGCCGCCGCCCACAAGTACGGCATC GACTGGGCCAGCGGCAGAGGCGTGGGCCACCCCTACAGAAGAGTGAGAATGATGCTGAGATAACTGTG CCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCAC TCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTC TGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAATAGCAGGCAGGCTGGGGAA GGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCAAGGTCACTAGC(SEQ ID NO: 41) PPARG Consensus AGGTCAAGGTCA(SEQ ID NO: 38) Ficolin-3 ATGGACCTGCTGTGGATCCTGCCCAGCCTGTGGCTGCTGCTGCTGGGCGGCCCCGCCTGCCTGAAGAC CCAGGAGCACCCCAGCTGCCCCGGCCCCAGAGAGCTGGAGGCCAGCAAGGTGGTGCTGCTGCCCAGCT GCCCCGGCGCCCCCGGCAGCCCCGGCGAGAAGGGCGCCCCCGGCCCCCAGGGCCCCCCCGGCCCCCCC GGCAAGATGGGCCCCAAGGGCGAGCCCGGCGACCCCGTGAACCTGCTGAGATGCCAGGAGGGCCCCAG AAACTGCAGAGAGCTGCTGAGCCAGGGCGCCACCCTGAGCGGCTGGTACCACCTGTGCCTGCCCGAGG GCAGAGCCCTGCCCGTGTTCTGCGACATGGACACCGAGGGCGGCGGCTGGCTGGTGTTCCAGAGAAGA CAGGACGGCAGCGTGGACTTCTTCAGAAGCTGGAGCAGCTACAGAGCCGGCTTCGGCAACCAGGAGAG CGAGTTCTGGCTGGGCAACGAGAACCTGCACCAGCTGACCCTGCAGGGCAACTGGGAGCTGAGAGTGG AGCTGGAGGACTTCAACGGCAACAGAACCTTCGCCCACTACGCCACCTTCAGACTGCTGGGCGAGGTG GACCACTACCAGCTGGCCCTGGGCAAGTTCAGCGAGGGCACCGCCGGCGACAGCCTGAGCCTGCACAG CGGCAGACCCTTCACCACCTACGACGCCGACCACGACAGCAGCAACAGCAACTGCGCCGTGATCGTGC ACGGCGCCTGGTGGTACGCCAGCTGCTACAGAAGCAACCTGAACGGCAGATACGCCGTGAGCGAGGCC GCCGCCCACAAGTACGGCATCGACTGGGCCAGCGGCAGAGGCGTGGGCCACCCCTACAGAAGAGTGAG AATGATGCTGAGATAA(SEQ ID NO: 42) Ficolin-3 Protein Sequence MDLLWILPSLWLLLLGGPACLKTQEHPSCPGPRELEASKVVLLPSCPGAPGSPGEKGAPGPQGPPGPP GKMGPKGEPGDPVNLLRCQEGPRNCRELLSQGATLSGWYHLCLPEGRALPVFCDMDTEGGGWLVFQRR QDGSVDFFRSWSSYRAGFGNQESEFWLGNENLHQLTLQGNWELRVELEDFNGNRTFAHYATFRLLGEV DHYQLALGKFSEGTAGDSLSLHSGRPFTTYDADHDSSNSNCAVIVHGAWWYASCYRSNLNGRYAVSEA AAHKYGIDWASGRGVGHPYRRVRMMLR(SEQ ID NO: 43) Example 9 In the present example, sequences matching the consensus sequences of 6 identified proteins were inserted into a construct containing a sequence encoding full-length orexin coupled with a secretion signal. The consensus sequences were spaced out using DNA spacers or the other genetic elements of the construct. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The therapeutic construct is intended for the supplementation of orexin levels to facilitate treatment of narcolepsy type 1. The construct is presented in FIG. 9. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACACCGGAAGTACGTTCCCTCTCCAAGTCTCAGGTTCTCCTACACGTTAGAGTCAAAAGCAGGGC TATGGGAAGATTAAGTAAAATAAATTTTGAAAATGCCTTATGAAAATTACACTCCAAAGAACTCGCGA GGTCAAGGTCACGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCC ATTGACGTCAATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAA CTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGT AAATGGCCCGCCTGGCATTGTGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTA CGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCC CCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGG GGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGG TGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGC GGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGC TCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCG GGACGGCCCTTCTCCTCCGGGCTGTAATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTG GTGGGGTATTAATGTTTAATTACCTGGAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGAACC TGCCCAGCACCAAGGTGAGCTGGGCCGCCGTGACCCTGCTGCTGCTGCTGCTGCTGCTGCCCCCCGCC CTGCTGAGCAGCGGCGCCGCCGCCCAGCCCCTGCCCGACTGCTGCAGGCAGAAGACCTGCAGCTGCAG GCTGTACGAGCTGCTGCACGGCGCCGGCAACCACGCCGCCGGCATCCTGACCCTGGGCAAGAGGAGGA GCGGCCCCCCCGGCCTGCAGGGCAGGCTGCAGAGGCTGCTGCAGGCCAGCGGCAACCACGCCGCCGGC ATCCTGACCATGGGCAGGAGGGCCGGCGCCGAGCCCGCCCCCAGGCCCTGCCTGGGCAGGAGGTGCAG CGCCCCCGCCGCCGCCAGCGTGGCCCCCGGCGGCCAGAGCGGCATCTAACCCACCTCACCTGCATGTA CGTTCCCTCTCCAAGTCTCAGGTTCTCCTACACGTTAGAGTCAAAAGCAGGGCTATGGGAAGATTAAG TAAAATAAATTTTGAAAATGCCTTATGAAAATTACACTCCAAAGAACTCGCGGACATTTCCTGGAAAT TGTATWCCTAGAACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTT GACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGA GTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAAT AGCAGGCAGGCTGGGGACACCGACCACGTGGCTAGTGCGTTCCCTCTCCAAGTCTCAGGTTCTCCTAC ACGTTAGAGTCAAAAGCAGGGCTATGGGAAGATTAAGTAAAATAAATTTTGAAAATGCCTTATGAAAA TTACACTCCAAAGAACTCGCGGGATGACTCATTCTGCTAGC(SEQ ID NO: 44) MYC Consensus CACCGACCACGTGGCTAGTG(SEQ ID NO: 35) FOSL1 Consensus GGATGACTCATTCTG(SEQ ID NO: 36) HAS1 Consensus ACCGGAAGTA(SEQ ID NO: 37) PPARG Consensus AGGTCAAGGTCA(SEQ ID NO: 38) SNAI1 Consensus CCCACCTCACCTGCATGTA(SEQ ID NO: 17) STAT5A Consensus GACATTTCCTGGAAATTGTATWCCTAGAA(SEQ ID NO: 18) Spacer CGTTCCCTCTCCAAGTCTCAGGTTCTCCTACACGTTAGAGTCAAAAGCAGGGCTATGGGAAGATTAAG TAAAATAAATTTTGAAAATGCCTTATGAAAATTACACTCCAAAGAACTCGCG(SEQ ID NO: 45) Orexin ATGAACCTGCCCAGCACCAAGGTGAGCTGGGCCGCCGTGACCCTGCTGCTGCTGCTGCTGCTGCTGCC CCCCGCCCTGCTGAGCAGCGGCGCCGCCGCCCAGCCCCTGCCCGACTGCTGCAGGCAGAAGACCTGCA GCTGCAGGCTGTACGAGCTGCTGCACGGCGCCGGCAACCACGCCGCCGGCATCCTGACCCTGGGCAAG AGGAGGAGCGGCCCCCCCGGCCTGCAGGGCAGGCTGCAGAGGCTGCTGCAGGCCAGCGGCAACCACGC CGCCGGCATCCTGACCATGGGCAGGAGGGCCGGCGCCGAGCCCGCCCCCAGGCCCTGCCTGGGCAGGA GGTGCAGCGCCCCCGCCGCCGCCAGCGTGGCCCCCGGCGGCCAGAGCGGCATCTAA(SEQ ID NO: 46) Orexin Protein Sequence MNLPSTKVSWAAVTLLLLLLLLPPALLSSGAAAQPLPDCCRQKTCSCRLYELLHGAGNHAAGILTLGK RRSGPPGLQGRLQRLLQASGNHAAGILTMGRRAGAEPAPRPCLGRRCSAPAAASVAPGGQSGI(SEQ ID NO: 47) Example 10 In the present example, a consensus sequence was generated for MYC based on 14 identified DNA-binding motifs shared between mouse and human. A sequence matching this consensus sequence was inserted into a construct containing a sequence encoding parathyroid hormone. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. The therapeutic transgene is delivered on a linear or circular double stranded DNA cassette using a cationic transfection reagent mediated delivery to subcutaneous white adipocytes, the formulation is injected using a patch injector for large volume subcutaneous delivery. The construct is presented in FIG. 10. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACCACCGACCACGTGGCTAGTGCACCGACCACGTGGCTAGTGCGTTACATAACTTACGGTAAATG GCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAGTAACGCCAATAGGGACTTTC CATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATAT GCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTGTGCCCAGTACATGA CCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTG AGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTAT TTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGC GGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGA AAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGGG AGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCT GACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGCTG AGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGGTATTAATGTTTAATTACCTGGAGCACCT GCCTGAAATCACTTTTTTTCAGGTTGGATGATCCCCGCCAAGGACATGGCCAAGGTGATGATCGTGAT GCTGGCCATCTGCTTCCTGACCAAGAGCGACGGCAAGAGCGTGAAGAAGAGAAGCGTGAGCGAGATCC AGCTGATGCACAACCTGGGCAAGCACCTGAACAGCATGGAGAGAGTGGAGTGGCTGAGAAAGAAGCTG CAGGACGTGCACAACTTCGTGGCCCTGGGCGCCCCCCTGGCCCCCAGAGACGCCGGCAGCCAGAGACC CAGAAAGAAGGAGGACAACGTGCTGGTGGAGAGCCACGAGAAGAGCCTGGGCGAGGCCGACAAGGCCG ACGTGAACGTGCTGACCAAGGCCAAGAGCCAGTAACACCGACCACGTGGCTAGTGCACCGACCACGTG GCTAGTGCTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCT GGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGT GTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAGAATAGCAGG CAGGCTGGGGACACCGACCACGTGGCTAGTGCACCGACCACGTGGCTAGTGCTAGC(SEQ ID NO: 48) MYC Consensus CACCGACCACGTGGCTAGTG(SEQ ID NO: 35) Parathyroid Hormone ATGATCCCCGCCAAGGACATGGCCAAGGTGATGATCGTGATGCTGGCCATCTGCTTCCTGACCAAGAG CGACGGCAAGAGCGTGAAGAAGAGAAGCGTGAGCGAGATCCAGCTGATGCACAACCTGGGCAAGCACC TGAACAGCATGGAGAGAGTGGAGTGGCTGAGAAAGAAGCTGCAGGACGTGCACAACTTCGTGGCCCTG GGCGCCCCCCTGGCCCCCAGAGACGCCGGCAGCCAGAGACCCAGAAAGAAGGAGGACAACGTGCTGGT GGAGAGCCACGAGAAGAGCCTGGGCGAGGCCGACAAGGCCGACGTGAACGTGCTGACCAAGGCCAAGA GCCAGTAA(SEQ ID NO: 49) Parathyroid Hormone Protein Sequence MIPAKDMAKVMIVMLAICFLTKSDGKSVKKRSVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL GAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ(SEQ ID NO: 50) Example 11 In the present example, base pairs in the coding region of the peptide core of Pegvisomant were altered to introduce DNA-binding motifs from the table above. The final protein sequence remains the same following optimization. The coding region is preceded by a CBh promoter and followed by a bovine growth hormone polyadenylation sequence. Following optimization, the number of DNA-binding motifs in the coding region increased from 9 to 21. The construct is delivered via a lipid nanoparticle for the treatment of acromegaly. The injection is administered in the abdomen via a jet powered injector for predominantly subcutaneous administration with predominant targeting of subcutaneous white adipocytes for expression of the therapeutic transgene. The construct is presented in FIG. 11. Optimization results are shown in FIG. 12. Full FASTA Sequence (Without Miniaturized Plasmid Backbone) GGTACCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGAC GTCAATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCC ACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGG CCCGCCTGGCATTGTGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATT AGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCT CCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGG GGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGC GGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCT ATAAAAAGCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCC GCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGG CCCTTCTCCTCCGGGCTGTAATTAGCTGAGCAAGAGGTAAGGGTTTAAGGGATGGTTGGTTGGTGGGG TATTAATGTTTAATTACCTGGAGCACCTGCCTGAAATCACTTTTTTTCAGGTTGGATGGCCACCGGAA GCAGGACCAGCCTGCTGCTGGCCTTCGGCCTGCTGTGCCTTCCGTGGCTGCAGGAGGGCAGCGCCTTC CCCACCATTCCCCTGAGCAGGCTGTTCGACAACGCCATGCTGAGGGCCGACAGGCTGAATCAGCTGGC CTTCGACACCTACCAGGAGTTCGAGGAGGCCTACATTCCCAAGGAGCAGAAGTACAGCTTCCTGCAGA ACCCCCAGACCAGCCTGTGCTTCAGCGAGAGCATTCCCACCCCCAGCAACAGGGAGGAGACCCAGCAG AAGAGCAACCTGGAGCTGCTGAGGATCAGCCTGCTGCTGATCCAGAGCTGGCTGGAGCCCGTGCAATT CCTGAGGAGCGTGTTCGCCAACAGCCTGGTGTACGGCGCCAGCGACAGCAACGTGTACGACCTGCTGA AGGACCTGGAGGAGAAGATCCAGACCCTGATGGGCAGGCTGGAGGACGGAAGCCCCAGGACCGGCCAG ATCTTCAAGCAGACCTACAGCAAGTTCGACACCAACAGTCACAACGACGACGCCCTGCTGAAGAACTA CGGCCTGCTGTACTGCTTCAACGCCGACATGAGCAGGGTCAGCACCTTCCTGAGGACCGTGCAGTGCA GGAGCGTGGAGGGCAGCTGCGGCTTCTAACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCT CCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATT GCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGA GGATTGGGAAGAGAATAGCAGGCAGGCTGGGGACTAGC(SEQ ID NO: 51) Pegvisomant Peptide Core Before Optimization ATGGCCACCGGCAGCAGGACCAGCCTGCTGCTGGCCTTCGGCCTGCTGTGCCTGCCCTGGCTGCAGGA GGGCAGCGCCTTCCCCACCATCCCCCTGAGCAGGCTGTTCGACAACGCCATGCTGAGGGCCGACAGGC TGAACCAGCTGGCCTTCGACACCTACCAGGAGTTCGAGGAGGCCTACATCCCCAAGGAGCAGAAGTAC AGCTTCCTGCAGAACCCCCAGACCAGCCTGTGCTTCAGCGAGAGCATCCCCACCCCCAGCAACAGGGA GGAGACCCAGCAGAAGAGCAACCTGGAGCTGCTGAGGATCAGCCTGCTGCTGATCCAGAGCTGGCTGG AGCCCGTGCAGTTCCTGAGGAGCGTGTTCGCCAACAGCCTGGTGTACGGCGCCAGCGACAGCAACGTG TACGACCTGCTGAAGGACCTGGAGGAGAAGATCCAGACCCTGATGGGCAGGCTGGAGGACGGCAGCCC CAGGACCGGCCAGATCTTCAAGCAGACCTACAGCAAGTTCGACACCAACAGCCACAACGACGACGCCC TGCTGAAGAACTACGGCCTGCTGTACTGCTTCAACGCCGACATGAGCAGGGTGAGCACCTTCCTGAGG ACCGTGCAGTGCAGGAGCGTGGAGGGCAGCTGCGGCTTC(SEQ ID NO: 52) Pegvisomant Peptide Core After Optimization ATGGCCACCGGAAGCAGGACCAGCCTGCTGCTGGCCTTCGGCCTGCTGTGCCTTCCGTGGCTGCAGGA GGGCAGCGCCTTCCCCACCATTCCCCTGAGCAGGCTGTTCGACAACGCCATGCTGAGGGCCGACAGGC TGAATCAGCTGGCCTTCGACACCTACCAGGAGTTCGAGGAGGCCTACATTCCCAAGGAGCAGAAGTAC AGCTTCCTGCAGAACCCCCAGACCAGCCTGTGCTTCAGCGAGAGCATTCCCACCCCCAGCAACAGGGA GGAGACCCAGCAGAAGAGCAACCTGGAGCTGCTGAGGATCAGCCTGCTGCTGATCCAGAGCTGGCTGG AGCCCGTGCAATTCCTGAGGAGCGTGTTCGCCAACAGCCTGGTGTACGGCGCCAGCGACAGCAACGTG TACGACCTGCTGAAGGACCTGGAGGAGAAGATCCAGACCCTGATGGGCAGGCTGGAGGACGGAAGCCC CAGGACCGGCCAGATCTTCAAGCAGACCTACAGCAAGTTCGACACCAACAGTCACAACGACGACGCCC TGCTGAAGAACTACGGCCTGCTGTACTGCTTCAACGCCGACATGAGCAGGGTCAGCACCTTCCTGAGG ACCGTGCAGTGCAGGAGCGTGGAGGGCAGCTGCGGCTTCTAA(SEQ ID NO: 53) Pegvisomant Peptide Core Protein Sequence MATGSRTSLLLAFGLLCLPWLQEGSAFPTIPLSRLFDNAMLRADRLNQLAFDTYQEFEEAYIPKEQKY SFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNV YDLLKDLEEKIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFNADMSRVSTFLR TVQCRSVEGSCGF(SEQ ID NO: 54) Example 12 In the present example, a set of DNA binding sequences were introduced into the backbone of a non-viral vector double stranded DNA cassette to enhance potency of said vector. The sequences were derived from protein binding sites of nuclearly localized proteins expressed at moderate to high levels in adipocytes and compared to a vector containing a control set of 2x 3NF2 DNA Targeting Sequences (DTSs) – a widely utilized nuclear import assisting sequence, which was determined without regard for target cell specificity. The vector was administered via a subcutaneous injection in mice and comprised a non-viral vector designed to deliver DNA to preferentially adipocytes and said double stranded DNA cassette. The test sequences outperformed the control vectors as assessed by reporter gene expression (nano-luciferase bioluminescent reporter) using Total Flux (photons per second or p / s) (FIG. 13B) or Background Normalized Flux (unitless) (FIG. 13A) in vivo. Increase in gene expression varied between up to 1.5x to up to 4x and favored DTS sequences derived from nuclear, moderate to high expressing proteins found in adipocytes. Said sequences can therefore be utilized for increasing potency of therapeutic transgenes by inserting said sequences into double stranded DNA cassettes, which can be used to deliver therapeutic transgenes such as GLP-1, GIP, GLUC, Amylin, or generally incretins or other therapeutic peptides or proteins.

Claims

CLAIMS We claim:

1. Non-viral gene therapy treatments or non-virally delivered gene therapy treatments containing one or more DNA sequences delivered in cis with or as a part of the therapeutic encoding DNA cassette and derived from protein binding sites of a protein or proteins expressed at quantifiable or moderate to high levels in the cell type being predominantly targeted by said non-viral gene therapy or are confirmed as expressed by immunohistochemistry, transcriptomic analysis, RNA-seq, qPCR, or other gene expression, protein expression or bioinformatic technique.

2. Non-viral gene delivery vehicles in Claim 1, which are lipid nanoparticles.

3. Non-viral gene delivery vehicles in Claim 1, which are virus-like particles.

4. Non-viral gene delivery vehicles in Claim 1, which are peptide or polymer carriers.

5. Non-viral gene delivery vehicles in Claim 1, which are lipid nanoparticles with covalently attached targeting moieties.

6. Non-viral gene delivery vehicles in Claim 1, which are lipid nanoparticles with one or more targeting moieties on the surface.

7. Non-viral gene delivery vehicles in Claim 1, which are polymeric nanoparticles.

8. Non-viral gene delivery vehicles in Claim 1, which are nanoparticles comprised of lipid and non-lipid components.

9. Non-viral gene delivery vehicles in Claim 1, which are polymeric nanoparticles comprised of polymer and non-polymer components.

10. Non-viral gene delivery vehicles in Claim 1, which are comprised at least in part of metallic nanoparticles.

11. Non-viral gene delivery vehicles in Claim 1, which are physical methods of gene delivery.

12. DNA sequences in Claim 1, which contains sequences recognized by the protein Myc.

13. DNA sequences in Claim 1, which contain HRACCACGTGGTYD (SEQ ID NO: 59).

14. DNA sequences in Claim 1, which contain TASCACRTGTCW (SEQ ID NO: 60).

15. DNA sequences in Claim 1, which contain GCCAYGYGSS (SEQ ID NO: 61).

16. DNA sequences in Claim 1, which contain MRMGTRHCACGTGDYACKYK (SEQ ID NO: 62).

17. DNA sequences in Claim 1, which contain CACGTGS.

18. DNA sequences in Claim 1, which contain CCACSTGWCY (SEQ ID NO: 63).

19. DNA sequences in Claim 1, which contain RACCACGTGSTC (SEQ ID NO: 64).

20. DNA sequences in Claim 1, which contain KACCACGTGSYY (SEQ ID NO: 65).

21. DNA sequences in Claim 1, which contain CASGTGGC.

22. DNA sequences in Claim 1, which contain RGCCACGTGCC (SEQ ID NO: 66).

23. DNA sequences in Claim 1, which contain GASCACGTGGY (SEQ ID NO: 67).

24. DNA sequences in Claim 1, which contain RASCACGTGGT (SEQ ID NO: 68).

25. DNA sequences in Claim 1, which contain SSCCACGTGCYS (SEQ ID NO: 69).

26. DNA sequences in Claim 1, which contain CCACGTGC.

27. DNA sequences in Claim 1, which contain CCACGTGAA.

28. DNA sequences in Claim 1, which contain CGTGG.

29. DNA sequences in Claim 1, which contain CACGTGC.

30. DNA sequences in Claim 1, which contain CGTGC.

31. DNA sequences in Claim 1, which contain GCACGTGCT.

32. DNA sequences in Claim 1, which contain YMCCACGTGYMV (SEQ ID NO: 70).

33. DNA sequences in Claim 1, which contain SSSCACGYGS (SEQ ID NO: 71).

34. DNA sequences in Claim 1, which contain CCACGTGS.

35. DNA sequences in Claim 1, which contain SGCCACGTGGCS (SEQ ID NO: 72).

36. DNA sequences in Claim 1, which contain CCACGTGG.

37. DNA sequences in Claim 1, which contain GGCACGTGKY (SEQ ID NO: 73).

38. DNA sequences in Claim 1, which contain SCACGTGS.

39. DNA sequences in Claim 1, which contain RRMCACGTGR (SEQ ID NO: 74).

40. DNA sequences in Claim 1, which contain CCACGTG.

41. DNA sequences in Claim 1, which contains sequences recognized by the protein Fosl1.

42. DNA sequences in Claim 1, which contain SVRTGASTCAKCM (SEQ ID NO: 75).

43. DNA sequences in Claim 1, which contain TGACTCAWKSKB (SEQ ID NO: 162).

44. DNA sequences in Claim 1, which contain RTGACTCAD.

45. DNA sequences in Claim 1, which contain TGAGTCAK.

46. DNA sequences in Claim 1, which contain TGACTCAB.

47. DNA sequences in Claim 1, which contain GRTGACGTCAYC (SEQ ID NO: 77).

48. DNA sequences in Claim 1, which contain GRTGAWTCAYC (SEQ ID NO: 78).

49. DNA sequences in Claim 1, which contain AATGAYRCG.

50. DNA sequences in Claim 1, which contain RATGAYRCG.

51. DNA sequences in Claim 1, which contain KATGASTCAYM (SEQ ID NO: 79).

52. DNA sequences in Claim 1, which contain DRTGACTCATY (SEQ ID NO: 80).

53. DNA sequences in Claim 1, which contain RRTGASTCAKS (SEQ ID NO: 81).

54. DNA sequences in Claim 1, which contain KKRTGACTCATMM (SEQ ID NO: 82).

55. DNA sequences in Claim 1, which contain DRATGACTCATHY (SEQ ID NO: 83).

56. DNA sequences in Claim 1, which contain ATGACTCAT.

57. DNA sequences in Claim 1, which contain RTGACTCAT.

58. DNA sequences in Claim 1, which contain YKRTGACTMATMC (SEQ ID NO: 84).

59. DNA sequences in Claim 1, which contain RRTGACTMAT (SEQ ID NO: 85).

60. DNA sequences in Claim 1, which contain RTGACGYMAY (SEQ ID NO: 86).

61. DNA sequences in Claim 1, which contain TGASTCAYCH (SEQ ID NO: 87).

62. DNA sequences in Claim 1, which contain RTGACTCAYYC (SEQ ID NO: 88).

63. DNA sequences in Claim 1, which contain KRRTGASTCAB (SEQ ID NO: 89).

64. DNA sequences in Claim 1, which contain GRTGACGTMAT (SEQ ID NO: 90).

65. DNA sequences in Claim 1, which contain RRTGASTCAB (SEQ ID NO: 91).

66. DNA sequences in Claim 1, which contain RTGAGTCAY.

67. DNA sequences in Claim 1, which contain RTGACGTMAT (SEQ ID NO: 92).

68. DNA sequences in Claim 1, which contain RTGASTCA.

69. DNA sequences in Claim 1, which contain KRTGASTCAY (SEQ ID NO: 93).

70. DNA sequences in Claim 1, which contain KRTGACGTCAYM (SEQ ID NO: 94).

71. DNA sequences in Claim 1, which contain KKRTKACGTCAYCGC (SEQ ID NO: 95).

72. DNA sequences in Claim 1, which contain KKRTGAGTCAYM (SEQ ID NO: 96).

73. DNA sequences in Claim 1, which contain KRTGASTCAYMV (SEQ ID NO: 97).

74. DNA sequences in Claim 1, which contain KKRTGAGTCAYMV (SEQ ID NO: 98).

75. DNA sequences in Claim 1, which contain RTGAGTCAYM (SEQ ID NO: 99).

76. DNA sequences in Claim 1, which contain DRTGACGTCATMMKTY (SEQ ID NO: 100).

77. DNA sequences in Claim 1, which contain TGAMTCA.

78. DNA sequences in Claim 1, which contain TGACTCAK.

79. DNA sequences in Claim 1, which contain KKWATGASKCATMY (SEQ ID NO: 101).

80. DNA sequences in Claim 1, which contain RTGAGTCAYCS (SEQ ID NO: 102).

81. DNA sequences in Claim 1, which contain DVTGASTCATB (SEQ ID NO: 103).

82. DNA sequences in Claim 1, which contain BGATGACGTCATCR (SEQ ID NO: 104).

83. DNA sequences in Claim 1, which contain TGASTCAT.

84. DNA sequences in Claim 1, which contain GATGACGTCATCR (SEQ ID NO: 164).

85. DNA sequences in Claim 1, which contain GATGACGTCAYC (SEQ ID NO: 165).

86. DNA sequences in Claim 1, which contain GATGAYGTCATC (SEQ ID NO: 107).

87. DNA sequences in Claim 1, which contain AGTCA.

88. DNA sequences in Claim 1, which contain TGACTCA.

89. DNA sequences in Claim 1, which contain RSTGACTCMGW (SEQ ID NO: 108).

90. DNA sequences in Claim 1, which contains sequences recognized by the protein Has1.

91. DNA sequences in Claim 1, which contain ACSMGGAAGTR (SEQ ID NO: 109).

92. DNA sequences in Claim 1, which contain RASRMGGAAGTR (SEQ ID NO: 110).

93. DNA sequences in Claim 1, which contain GAMCCGGAAGTR (SEQ ID NO: 111).

94. DNA sequences in Claim 1, which contain AACRAGGAAGTR (SEQ ID NO: 112).

95. DNA sequences in Claim 1, which contain AASRAGGAAGTR (SEQ ID NO: 166).

96. DNA sequences in Claim 1, which contain WAYWTCCKK.

97. DNA sequences in Claim 1, which contains sequences recognized by the protein Pparg.

98. DNA sequences in Claim 1, which contain YYWRRGGTCAAAGGTCAHVBD (SEQ ID NO: 114).

99. DNA sequences in Claim 1, which contain AASTRGGTCACSGTGACCYACWT (SEQ ID NO: 115).

100. DNA sequences in Claim 1, which contain WASYRGGKCAAAGKTCA (SEQ ID NO: 116).

101. DNA sequences in Claim 1, which contain WGAMCTTTGACCY (SEQ ID NO: 117).

102. DNA sequences in Claim 1, which contain AGGTCAG.

103. DNA sequences in Claim 1, which contain AWSTRGGKCAAAGGKCA (SEQ ID NO: 118).

104. DNA sequences in Claim 1, which contain YYWRRGGTCAAAGGTCAYMK (SEQ ID NO: 119).

105. DNA sequences in Claim 1, which contain STRGGTCACSGTGACCYACW (SEQ ID NO: 120).

106. DNA sequences in Claim 1, which contain TRGGTCACSGTGACCYACW (SEQ ID NO: 121).

107. DNA sequences in Claim 1, which contain AWSTRGGTYAST (SEQ ID NO: 122).

108. DNA sequences in Claim 1, which contain MRRGGKYAAWRGGTCAC (SEQ ID NO: 123).

109. DNA sequences in Claim 1, which contain AANNNAGGTCANNGGNCA (SEQ ID NO: 124).

110. DNA sequences in Claim 1, which contain AANNAGGTNANNGGTCA (SEQ ID NO: 125).

111. DNA sequences in Claim 1, which contain AAANNAGGTCA.

112. DNA sequences in Claim 1, which contain TGNCNNNTGACCTNNNTT (SEQ ID NO: 126).

113. DNA sequences in Claim 1, which contain TGACCTNNNTT.

114. DNA sequences in Claim 1, which contain ARRGGTCAAAGGTCAH (SEQ ID NO: 127).

115. DNA sequences in Claim 1, which contain RRGGTCAAAGGTCA (SEQ ID NO: 128).

116. DNA sequences in Claim 1, which contain CWRAWCYAGGYCAWAGKTCA (SEQ ID NO: 129).

117. DNA sequences in Claim 1, which contain YMRGGTCATWGGGGTSARG (SEQ ID NO: 130).

118. DNA sequences in Claim 1, which contain TGACCTY.

119. DNA sequences in Claim 1, which contain RGGTCARAGGTCA (SEQ ID NO: 131).

120. DNA sequences in Claim 1, which contain AWGTRGGTCAAAGGTCAT (SEQ ID NO: 132).

121. DNA sequences in Claim 1, which contain AWGTRGGTCAAAGGTCA (SEQ ID NO: 133).

122. DNA sequences in Claim 1, which contain ARRGGTCRTGACCYYT (SEQ ID NO: 134).

123. DNA sequences in Claim 1, which contain DGRGGTCAAAGGTCRY (SEQ ID NO: 135).

124. DNA sequences in Claim 1, which contain ARRGGTCGYGACCYYK (SEQ ID NO: 136).

125. DNA sequences in Claim 1, which contain MSTGWCCTB.

126. DNA sequences in Claim 1, which contain RGGTCAR.

127. DNA sequences in Claim 1, which contain AAAAGGTCAM (SEQ ID NO: 137).

128. DNA sequences in Claim 1, which contain RAGGTCAAAAGGTCAM (SEQ ID NO: 138).

129. DNA sequences in Claim 1, which contain RAGGTCRTGACCTY (SEQ ID NO: 139).

130. DNA sequences in Claim 1, which contain AAAAGGTCAH (SEQ ID NO: 140).

131. DNA sequences in Claim 1, which contain RAGGTCAAAAGGTCAH (SEQ ID NO: 141).

132. DNA sequences in Claim 1, which contain RAGGTCRTGACCT (SEQ ID NO: 142).

133. DNA sequences in Claim 1, which contains sequences recognized by the protein Snai1.

134. DNA sequences in Claim 1, which contain CCAGGTGG.

135. DNA sequences in Claim 1, which contain GCCACCTGSCTGYD (SEQ ID NO: 143).

136. DNA sequences in Claim 1, which contain CCACCTGCMN.

137. DNA sequences in Claim 1, which contain DRCAGGTGYR (SEQ ID NO: 144).

138. DNA sequences in Claim 1, which contain RCAGGTG.

139. DNA sequences in Claim 1, which contain ARCAGGTGCA (SEQ ID NO: 145).

140. DNA sequences in Claim 1, which contain RRCAGGTGYR (SEQ ID NO: 146).

141. DNA sequences in Claim 1, which contain RRCAGGTGCR (SEQ ID NO: 147).

142. DNA sequences in Claim 1, which contain YCAGGTG.

143. DNA sequences in Claim 1, which contain KCACCTGM.

144. DNA sequences in Claim 1, which contain SSSRSCKCACCTGS (SEQ ID NO: 148).

145. DNA sequences in Claim 1, which contain CACCTGSRK.

146. DNA sequences in Claim 1, which contain RRCAGGTGY.

147. DNA sequences in Claim 1, which contain AYGCACCTGTMRY (SEQ ID NO: 149).

148. DNA sequences in Claim 1, which contain GCACCTGT.

149. DNA sequences in Claim 1, which contain WWWMRAKRCACCTGYTAKWHAW (SEQ ID NO: 150).

150. DNA sequences in Claim 1, which contains sequences recognized by the protein Stat5a.

151. DNA sequences in Claim 1, which contain TTCCCRKAA.

152. DNA sequences in Claim 1, which contain DAWTTCYWGGAAWYH (SEQ ID NO: 151).

153. DNA sequences in Claim 1, which contain TTCCCRGAAWTBSKWTWCCKRGRR (SEQ ID NO: 152).

154. DNA sequences in Claim 1, which contain YAWTTCYW.

155. DNA sequences in Claim 1, which contain SWYTTCYW.

156. DNA sequences in Claim 1, which contain KRYWYTTCYKRGA (SEQ ID NO: 153).

157. DNA sequences in Claim 1, which contain RSWTTTCTARGAA (SEQ ID NO: 154).

158. DNA sequences in Claim 1, which contain TTCYYRGAAAY (SEQ ID NO: 155).

159. DNA sequences in Claim 1, which contain TTTCYKRGAAW (SEQ ID NO: 156).

160. DNA sequences in Claim 1, which contain KAWTTCYTGGAAWTY (SEQ ID NO: 157).

161. DNA sequences in Claim 1, which contain RAWTTCCARGAAWTM (SEQ ID NO: 158).

162. DNA sequences in Claim 1, which contain TTTCYKRGAAA (SEQ ID NO: 159).

163. DNA sequences in Claim 1, which contain TTCYYAGGAAWYT (SEQ ID NO: 160).

164. DNA sequences in Claim 1, which contain TTCCNGGAA.

165. DNA sequences in Claim 1, which contain TTCCTGGAA.

166. DNA sequences in Claim 1, which contain CCNNGGAANNNNNA.

167. DNA sequences in Claim 1, which contain TTCC.

168. DNA sequences in Claim 1, which contain GGAANNNNNA.

169. DNA sequences in Claim 1, which contain TTCNNGG.

170. DNA sequences in Claim 1, which contain at least two of the following sequences HRACCACGTGGTYD (SEQ ID NO: 59), TASCACRTGTCW (SEQ ID NO: 60), GCCAYGYGSS (SEQ ID NO: 61), MRMGTRHCACGTGDYACKYK (SEQ ID NO: 62), CACGTGS, CCACSTGWCY (SEQ ID NO: 63), RACCACGTGSTC (SEQ ID NO: 64), KACCACGTGSYY (SEQ ID NO: 65), CASGTGGC, RGCCACGTGCC (SEQ ID NO: 66), GASCACGTGGY (SEQ ID NO: 67), RASCACGTGGT (SEQ ID NO: 68), SSCCACGTGCYS (SEQ ID NO: 69), CCACGTGC, CCACGTGAA, CGTGG, CACGTGC, CGTGC, GCACGTGCT, YMCCACGTGYMV (SEQ ID NO: 70), SSSCACGYGS (SEQ ID NO: 71), CCACGTGS, SGCCACGTGGCS (SEQ ID NO: 72), CCACGTGG, GGCACGTGKY (SEQ ID NO: 73), SCACGTGS, RRMCACGTGR (SEQ ID NO: 74),CCACGTG, SVRTGASTCAKCM (SEQ ID NO: 75), GACTCAWKSKB (SEQ ID NO: 76), TGACTCAD, TGAGTCAK, TGACTCAB, GRTGACGTCAYC (SEQ ID NO: 77), GRTGAWTCAYC (SEQ ID NO: 78), ATGAYRCG, ATGAYRCG, KATGASTCAYM (SEQ ID NO: 79), DRTGACTCATY (SEQ ID NO: 80), RRTGASTCAKS (SEQ ID NO: 81), KKRTGACTCATMM (SEQ ID NO: 82), DRATGACTCATHY (SEQ ID NO: 83), ATGACTCAT, RTGACTCAT, YKRTGACTMATMC (SEQ ID NO: 84), RRTGACTMAT (SEQ ID NO: 85), RTGACGYMAY (SEQ ID NO: 86), TGASTCAYCH (SEQ ID NO: 87), RTGACTCAYYC (SEQ ID NO: 88), KRRTGASTCAB (SEQ ID NO: 89), GRTGACGTMAT (SEQ ID NO: 90), RRTGASTCAB (SEQ ID NO: 91), RTGAGTCAY, RTGACGTMAT (SEQ ID NO: 92), RTGASTCA, KRTGASTCAY (SEQ ID NO: 93), KRTGACGTCAYM (SEQ ID NO: 94), KKRTKACGTCAYCGC (SEQ ID NO: 95), KKRTGAGTCAYM (SEQ ID NO: 96), KRTGASTCAYMV (SEQ ID NO: 97), KKRTGAGTCAYMV (SEQ ID NO: 98), RTGAGTCAYM (SEQ ID NO: 99), DRTGACGTCATMMKTY (SEQ ID NO: 100), TGAMTCA, TGACTCAK, KKWATGASKCATMY (SEQ ID NO: 101), RTGAGTCAYCS (SEQ ID NO: 102), DVTGASTCATB (SEQ ID NO: 103), BGATGACGTCATCR (SEQ ID NO: 104), TGASTCAT, ATGACGTCATCR (SEQ ID NO: 105), ATGACGTCAYC (SEQ ID NO: 106), GATGAYGTCATC (SEQ ID NO: 107), AGTCA, TGACTCA, RSTGACTCMGW (SEQ ID NO: 108), ACSMGGAAGTR (SEQ ID NO: 109), RASRMGGAAGTR (SEQ ID NO: 110), GAMCCGGAAGTR (SEQ ID NO: 111), AACRAGGAAGTR (SEQ ID NO: 112), ASRAGGAAGTR (SEQ ID NO: 113), AYWTCCKK, YYWRRGGTCAAAGGTCAHVBD (SEQ ID NO: 114), AASTRGGTCACSGTGACCYACWT (SEQ ID NO: 115), WASYRGGKCAAAGKTCA (SEQ ID NO: 116), WGAMCTTTGACCY (SEQ ID NO: 117), AGGTCAG, AWSTRGGKCAAAGGKCA (SEQ ID NO: 118), YYWRRGGTCAAAGGTCAYMK (SEQ ID NO: 119), STRGGTCACSGTGACCYACW (SEQ ID NO: 120), TRGGTCACSGTGACCYACW (SEQ ID NO: 121), AWSTRGGTYAST (SEQ ID NO: 122), MRRGGKYAAWRGGTCAC (SEQ ID NO: 123), AANNNAGGTCANNGGNCA (SEQ ID NO: 124), AANNAGGTNANNGGTCA (SEQ ID NO: 125), AAANNAGGTCA, TGNCNNNTGACCTNNNTT (SEQ ID NO: 126), TGACCTNNNTT, ARRGGTCAAAGGTCAH (SEQ ID NO: 127), RRGGTCAAAGGTCA (SEQ ID NO: 128), CWRAWCYAGGYCAWAGKTCA (SEQ ID NO: 129), YMRGGTCATWGGGGTSARG (SEQ ID NO: 130), TGACCTY, RGGTCARAGGTCA (SEQ ID NO: 131), AWGTRGGTCAAAGGTCAT (SEQ ID NO: 132), AWGTRGGTCAAAGGTCA (SEQ IDNO: 133), ARRGGTCRTGACCYYT (SEQ ID NO: 134), DGRGGTCAAAGGTCRY (SEQ ID NO: 135), ARRGGTCGYGACCYYK (SEQ ID NO: 136), MSTGWCCTB, RGGTCAR, AAAAGGTCAM (SEQ ID NO: 137), RAGGTCAAAAGGTCAM (SEQ ID NO: 138), RAGGTCRTGACCTY (SEQ ID NO: 139), AAAAGGTCAH (SEQ ID NO: 140), RAGGTCAAAAGGTCAH (SEQ ID NO: 141), RAGGTCRTGACCT (SEQ ID NO: 142), CCAGGTGG, GCCACCTGSCTGYD (SEQ ID NO: 143), CCACCTGCMN, DRCAGGTGYR (SEQ ID NO: 144), RCAGGTG, ARCAGGTGCA (SEQ ID NO: 145), RRCAGGTGYR (SEQ ID NO: 146), RRCAGGTGCR (SEQ ID NO: 147), YCAGGTG, KCACCTGM, SSSRSCKCACCTGS (SEQ ID NO: 148), CACCTGSRK, RRCAGGTGY, AYGCACCTGTMRY (SEQ ID NO: 149), GCACCTGT, WWWMRAKRCACCTGYTAKWHAW (SEQ ID NO: 150), TTCCCRKAA, DAWTTCYWGGAAWYH (SEQ ID NO: 151), TTCCCRGAAWTBSKWTWCCKRGRR (SEQ ID NO: 152), YAWTTCYW, SWYTTCYW, KRYWYTTCYKRGA (SEQ ID NO: 153), RSWTTTCTARGAA (SEQ ID NO: 154), TTCYYRGAAAY (SEQ ID NO: 155), TTTCYKRGAAW (SEQ ID NO: 156), KAWTTCYTGGAAWTY (SEQ ID NO: 157), RAWTTCCARGAAWTM (SEQ ID NO: 158), TTTCYKRGAAA (SEQ ID NO: 159), TTCYYAGGAAWYT (SEQ ID NO: 160), TTCCNGGAA, TTCCTGGAA, CCNNGGAANNNNNA, TTCC, GGAANNNNNA, TTCNNGG.

171. DNA sequences in Claim 1, which contain at least 80% of at least one of the following sequences HRACCACGTGGTYD (SEQ ID NO: 59), TASCACRTGTCW (SEQ ID NO: 60), GCCAYGYGSS (SEQ ID NO: 61), MRMGTRHCACGTGDYACKYK (SEQ ID NO: 62), CACGTGS, CCACSTGWCY (SEQ ID NO: 63), RACCACGTGSTC (SEQ ID NO: 64), KACCACGTGSYY (SEQ ID NO: 65), CASGTGGC, RGCCACGTGCC (SEQ ID NO: 66), GASCACGTGGY (SEQ ID NO: 67), RASCACGTGGT (SEQ ID NO: 68), SSCCACGTGCYS (SEQ ID NO: 69), CCACGTGC, CCACGTGAA, CGTGG, CACGTGC, CGTGC, GCACGTGCT, YMCCACGTGYMV (SEQ ID NO: 70), SSSCACGYGS (SEQ ID NO: 71), CCACGTGS, SGCCACGTGGCS (SEQ ID NO: 72), CCACGTGG, GGCACGTGKY (SEQ ID NO: 73), SCACGTGS, RRMCACGTGR (SEQ ID NO: 74), CCACGTG, SVRTGASTCAKCM (SEQ ID NO: 75), GACTCAWKSKB (SEQ ID NO: 76), TGACTCAD, TGAGTCAK, TGACTCAB, GRTGACGTCAYC (SEQ ID NO: 77), GRTGAWTCAYC (SEQ ID NO: 78), ATGAYRCG, ATGAYRCG, KATGASTCAYM (SEQ ID NO: 79), DRTGACTCATY (SEQ ID NO: 80), RRTGASTCAKS (SEQ ID NO: 81), KKRTGACTCATMM (SEQ ID NO: 82), DRATGACTCATHY (SEQ ID NO: 83), ATGACTCAT, RTGACTCAT, YKRTGACTMATMC (SEQ ID NO: 84), RRTGACTMAT(SEQ ID NO: 85), RTGACGYMAY (SEQ ID NO: 86), TGASTCAYCH (SEQ ID NO: 87), RTGACTCAYYC (SEQ ID NO: 88), KRRTGASTCAB (SEQ ID NO: 89), GRTGACGTMAT (SEQ ID NO: 90), RRTGASTCAB (SEQ ID NO: 91), RTGAGTCAY, RTGACGTMAT (SEQ ID NO: 92), RTGASTCA, KRTGASTCAY (SEQ ID NO: 93), KRTGACGTCAYM (SEQ ID NO: 94), KKRTKACGTCAYCGC (SEQ ID NO: 95), KKRTGAGTCAYM (SEQ ID NO: 96), KRTGASTCAYMV (SEQ ID NO: 97), KKRTGAGTCAYMV (SEQ ID NO: 98), RTGAGTCAYM (SEQ ID NO: 99), DRTGACGTCATMMKTY (SEQ ID NO: 100), TGAMTCA, TGACTCAK, KKWATGASKCATMY (SEQ ID NO: 101), RTGAGTCAYCS (SEQ ID NO: 102), DVTGASTCATB (SEQ ID NO: 103), BGATGACGTCATCR (SEQ ID NO: 104), TGASTCAT, ATGACGTCATCR (SEQ ID NO: 105), ATGACGTCAYC (SEQ ID NO: 106), GATGAYGTCATC (SEQ ID NO: 107), AGTCA, TGACTCA, RSTGACTCMGW (SEQ ID NO: 108), ACSMGGAAGTR (SEQ ID NO: 109), RASRMGGAAGTR (SEQ ID NO: 110), GAMCCGGAAGTR (SEQ ID NO: 111), AACRAGGAAGTR (SEQ ID NO: 112), ASRAGGAAGTR (SEQ ID NO: 113), AYWTCCKK, YYWRRGGTCAAAGGTCAHVBD (SEQ ID NO: 114), AASTRGGTCACSGTGACCYACWT (SEQ ID NO: 115), WASYRGGKCAAAGKTCA (SEQ ID NO: 116), WGAMCTTTGACCY (SEQ ID NO: 117), AGGTCAG, AWSTRGGKCAAAGGKCA (SEQ ID NO: 118), YYWRRGGTCAAAGGTCAYMK (SEQ ID NO: 119), STRGGTCACSGTGACCYACW (SEQ ID NO: 120), TRGGTCACSGTGACCYACW (SEQ ID NO: 121), AWSTRGGTYAST (SEQ ID NO: 122), MRRGGKYAAWRGGTCAC (SEQ ID NO: 123), AANNNAGGTCANNGGNCA (SEQ ID NO: 124), AANNAGGTNANNGGTCA (SEQ ID NO: 125), AAANNAGGTCA, TGNCNNNTGACCTNNNTT (SEQ ID NO: 126), TGACCTNNNTT, ARRGGTCAAAGGTCAH (SEQ ID NO: 127), RRGGTCAAAGGTCA (SEQ ID NO: 128), CWRAWCYAGGYCAWAGKTCA (SEQ ID NO: 129), YMRGGTCATWGGGGTSARG (SEQ ID NO: 130), TGACCTY, RGGTCARAGGTCA (SEQ ID NO: 131), AWGTRGGTCAAAGGTCAT (SEQ ID NO: 132), AWGTRGGTCAAAGGTCA (SEQ ID NO: 133), ARRGGTCRTGACCYYT (SEQ ID NO: 134), DGRGGTCAAAGGTCRY (SEQ ID NO: 135), ARRGGTCGYGACCYYK (SEQ ID NO: 136), MSTGWCCTB, RGGTCAR, AAAAGGTCAM (SEQ ID NO: 137), RAGGTCAAAAGGTCAM (SEQ ID NO: 138), RAGGTCRTGACCTY (SEQ ID NO: 139), AAAAGGTCAH (SEQ ID NO: 140), RAGGTCAAAAGGTCAH (SEQ ID NO: 141), RAGGTCRTGACCT (SEQ ID NO: 142), CCAGGTGG, GCCACCTGSCTGYD (SEQ ID NO: 143), CCACCTGCMN,DRCAGGTGYR (SEQ ID NO: 144), RCAGGTG, ARCAGGTGCA (SEQ ID NO: 145), RRCAGGTGYR (SEQ ID NO: 146), RRCAGGTGCR (SEQ ID NO: 147), YCAGGTG, KCACCTGM, SSSRSCKCACCTGS (SEQ ID NO: 148), CACCTGSRK, RRCAGGTGY, AYGCACCTGTMRY (SEQ ID NO: 149), GCACCTGT, WWWMRAKRCACCTGYTAKWHAW (SEQ ID NO: 150), TTCCCRKAA, DAWTTCYWGGAAWYH (SEQ ID NO: 151), TTCCCRGAAWTBSKWTWCCKRGRR (SEQ ID NO: 152), YAWTTCYW, SWYTTCYW, KRYWYTTCYKRGA (SEQ ID NO: 153), RSWTTTCTARGAA (SEQ ID NO: 154), TTCYYRGAAAY (SEQ ID NO: 155), TTTCYKRGAAW (SEQ ID NO: 156), KAWTTCYTGGAAWTY (SEQ ID NO: 157), RAWTTCCARGAAWTM (SEQ ID NO: 158), TTTCYKRGAAA (SEQ ID NO: 159), TTCYYAGGAAWYT (SEQ ID NO: 160), TTCCNGGAA, TTCCTGGAA, CCNNGGAANNNNNA, TTCC, GGAANNNNNA, TTCNNGG.

172. DNA sequences in Claim 1, which are comprised of at least two of the following sequences, HRACCACGTGGTYD (SEQ ID NO: 59), TASCACRTGTCW (SEQ ID NO: 60), GCCAYGYGSS (SEQ ID NO: 61), MRMGTRHCACGTGDYACKYK (SEQ ID NO: 62), CACGTGS, CCACSTGWCY (SEQ ID NO: 63), RACCACGTGSTC (SEQ ID NO: 64), KACCACGTGSYY (SEQ ID NO: 65), CASGTGGC, RGCCACGTGCC (SEQ ID NO: 66), GASCACGTGGY (SEQ ID NO: 67), RASCACGTGGT (SEQ ID NO: 68), SSCCACGTGCYS (SEQ ID NO: 69), CCACGTGC, CCACGTGAA, CGTGG, CACGTGC, CGTGC, GCACGTGCT, YMCCACGTGYMV (SEQ ID NO: 70), SSSCACGYGS (SEQ ID NO: 71), CCACGTGS, SGCCACGTGGCS (SEQ ID NO: 72), CCACGTGG, GGCACGTGKY (SEQ ID NO: 73), SCACGTGS, RRMCACGTGR (SEQ ID NO: 74), CCACGTG, SVRTGASTCAKCM (SEQ ID NO: 75), GACTCAWKSKB (SEQ ID NO: 76), TGACTCAD, TGAGTCAK, TGACTCAB, GRTGACGTCAYC (SEQ ID NO: 77), GRTGAWTCAYC (SEQ ID NO: 78), ATGAYRCG, ATGAYRCG, KATGASTCAYM (SEQ ID NO: 79), DRTGACTCATY (SEQ ID NO: 80), RRTGASTCAKS (SEQ ID NO: 81), KKRTGACTCATMM (SEQ ID NO: 82), DRATGACTCATHY (SEQ ID NO: 83), ATGACTCAT, RTGACTCAT, YKRTGACTMATMC (SEQ ID NO: 84), RRTGACTMAT (SEQ ID NO: 85), RTGACGYMAY (SEQ ID NO: 86), TGASTCAYCH (SEQ ID NO: 87), RTGACTCAYYC (SEQ ID NO: 88), KRRTGASTCAB (SEQ ID NO: 89), GRTGACGTMAT (SEQ ID NO: 90), RRTGASTCAB (SEQ ID NO: 91), RTGAGTCAY, RTGACGTMAT (SEQ ID NO: 92), RTGASTCA, KRTGASTCAY (SEQ ID NO: 93), KRTGACGTCAYM (SEQ ID NO: 94), KKRTKACGTCAYCGC (SEQ ID NO: 95), KKRTGAGTCAYM (SEQ ID NO: 96), KRTGASTCAYMV (SEQ ID NO: 97),KKRTGAGTCAYMV (SEQ ID NO: 98), RTGAGTCAYM (SEQ ID NO: 99), DRTGACGTCATMMKTY (SEQ ID NO: 100), TGAMTCA, TGACTCAK, KKWATGASKCATMY (SEQ ID NO: 101), RTGAGTCAYCS (SEQ ID NO: 102), DVTGASTCATB (SEQ ID NO: 103), BGATGACGTCATCR (SEQ ID NO: 104), TGASTCAT, ATGACGTCATCR (SEQ ID NO: 105), ATGACGTCAYC (SEQ ID NO: 106), GATGAYGTCATC (SEQ ID NO: 107), AGTCA, TGACTCA, RSTGACTCMGW (SEQ ID NO: 108), ACSMGGAAGTR (SEQ ID NO: 109), RASRMGGAAGTR (SEQ ID NO: 110), GAMCCGGAAGTR (SEQ ID NO: 111), AACRAGGAAGTR (SEQ ID NO: 112), ASRAGGAAGTR (SEQ ID NO: 113), AYWTCCKK, YYWRRGGTCAAAGGTCAHVBD (SEQ ID NO: 114), AASTRGGTCACSGTGACCYACWT (SEQ ID NO: 115), WASYRGGKCAAAGKTCA (SEQ ID NO: 116), WGAMCTTTGACCY (SEQ ID NO: 117), AGGTCAG, AWSTRGGKCAAAGGKCA (SEQ ID NO: 118), YYWRRGGTCAAAGGTCAYMK (SEQ ID NO: 119), STRGGTCACSGTGACCYACW (SEQ ID NO: 120), TRGGTCACSGTGACCYACW (SEQ ID NO: 121), AWSTRGGTYAST (SEQ ID NO: 122), MRRGGKYAAWRGGTCAC (SEQ ID NO: 123), AANNNAGGTCANNGGNCA (SEQ ID NO: 124), AANNAGGTNANNGGTCA (SEQ ID NO: 125), AAANNAGGTCA, TGNCNNNTGACCTNNNTT (SEQ ID NO: 126), TGACCTNNNTT, ARRGGTCAAAGGTCAH (SEQ ID NO: 127), RRGGTCAAAGGTCA (SEQ ID NO: 128), CWRAWCYAGGYCAWAGKTCA (SEQ ID NO: 129), YMRGGTCATWGGGGTSARG (SEQ ID NO: 130), TGACCTY, RGGTCARAGGTCA (SEQ ID NO: 131), AWGTRGGTCAAAGGTCAT (SEQ ID NO: 132), AWGTRGGTCAAAGGTCA (SEQ ID NO: 133), ARRGGTCRTGACCYYT (SEQ ID NO: 134), DGRGGTCAAAGGTCRY (SEQ ID NO: 135), ARRGGTCGYGACCYYK (SEQ ID NO: 136), MSTGWCCTB, RGGTCAR, AAAAGGTCAM (SEQ ID NO: 137), RAGGTCAAAAGGTCAM (SEQ ID NO: 138), RAGGTCRTGACCTY (SEQ ID NO: 139), AAAAGGTCAH (SEQ ID NO: 140), RAGGTCAAAAGGTCAH (SEQ ID NO: 141), RAGGTCRTGACCT (SEQ ID NO: 142), CCAGGTGG, GCCACCTGSCTGYD (SEQ ID NO: 143), CCACCTGCMN, DRCAGGTGYR (SEQ ID NO: 144), RCAGGTG, ARCAGGTGCA (SEQ ID NO: 145), RRCAGGTGYR (SEQ ID NO: 146), RRCAGGTGCR (SEQ ID NO: 147), YCAGGTG, KCACCTGM, SSSRSCKCACCTGS (SEQ ID NO: 148), CACCTGSRK, RRCAGGTGY, AYGCACCTGTMRY (SEQ ID NO: 149), GCACCTGT, WWWMRAKRCACCTGYTAKWHAW (SEQ ID NO: 150), TTCCCRKAA, DAWTTCYWGGAAWYH (SEQ ID NO: 151), TTCCCRGAAWTBSKWTWCCKRGRR(SEQ ID NO: 152), YAWTTCYW, SWYTTCYW, KRYWYTTCYKRGA (SEQ ID NO: 153), RSWTTTCTARGAA (SEQ ID NO: 154), TTCYYRGAAAY (SEQ ID NO: 155), TTTCYKRGAAW (SEQ ID NO: 156), KAWTTCYTGGAAWTY (SEQ ID NO: 157), RAWTTCCARGAAWTM (SEQ ID NO: 158), TTTCYKRGAAA (SEQ ID NO: 159), TTCYYAGGAAWYT (SEQ ID NO: 160), TTCCNGGAA, TTCCTGGAA, CCNNGGAANNNNNA, TTCC, GGAANNNNNA, TTCNNGG, where one is added before the promoter driving expression of the therapeutic gene and another is added after the PolyA signal of the therapeutic gene.

173. DNA sequences in Claim 1, which are comprised of at least two of the following sequences, HRACCACGTGGTYD (SEQ ID NO: 59), TASCACRTGTCW (SEQ ID NO: 60), GCCAYGYGSS (SEQ ID NO: 61), MRMGTRHCACGTGDYACKYK (SEQ ID NO: 62), CACGTGS, CCACSTGWCY (SEQ ID NO: 63), RACCACGTGSTC (SEQ ID NO: 64), KACCACGTGSYY (SEQ ID NO: 65), CASGTGGC, RGCCACGTGCC (SEQ ID NO: 66), GASCACGTGGY (SEQ ID NO: 67), RASCACGTGGT (SEQ ID NO: 68), SSCCACGTGCYS (SEQ ID NO: 69), CCACGTGC, CCACGTGAA, CGTGG, CACGTGC, CGTGC, GCACGTGCT, YMCCACGTGYMV (SEQ ID NO: 70), SSSCACGYGS (SEQ ID NO: 71), CCACGTGS, SGCCACGTGGCS (SEQ ID NO: 72), CCACGTGG, GGCACGTGKY (SEQ ID NO: 73), SCACGTGS, RRMCACGTGR (SEQ ID NO: 74), CCACGTG, SVRTGASTCAKCM (SEQ ID NO: 75), GACTCAWKSKB (SEQ ID NO: 76), TGACTCAD, TGAGTCAK, TGACTCAB, GRTGACGTCAYC (SEQ ID NO: 77), GRTGAWTCAYC (SEQ ID NO: 78), ATGAYRCG, ATGAYRCG, KATGASTCAYM (SEQ ID NO: 79), DRTGACTCATY (SEQ ID NO: 80), RRTGASTCAKS (SEQ ID NO: 81), KKRTGACTCATMM (SEQ ID NO: 82), DRATGACTCATHY (SEQ ID NO: 83), ATGACTCAT, RTGACTCAT, YKRTGACTMATMC (SEQ ID NO: 84), RRTGACTMAT (SEQ ID NO: 85), RTGACGYMAY (SEQ ID NO: 86), TGASTCAYCH (SEQ ID NO: 87), RTGACTCAYYC (SEQ ID NO: 88), KRRTGASTCAB (SEQ ID NO: 89), GRTGACGTMAT (SEQ ID NO: 90), RRTGASTCAB (SEQ ID NO: 91), RTGAGTCAY, RTGACGTMAT (SEQ ID NO: 92), RTGASTCA, KRTGASTCAY (SEQ ID NO: 93), KRTGACGTCAYM (SEQ ID NO: 94), KKRTKACGTCAYCGC (SEQ ID NO: 95), KKRTGAGTCAYM (SEQ ID NO: 96), KRTGASTCAYMV (SEQ ID NO: 97), KKRTGAGTCAYMV (SEQ ID NO: 98), RTGAGTCAYM (SEQ ID NO: 99), DRTGACGTCATMMKTY (SEQ ID NO: 100), TGAMTCA, TGACTCAK, KKWATGASKCATMY (SEQ ID NO: 101), RTGAGTCAYCS (SEQ ID NO: 102), DVTGASTCATB (SEQ ID NO: 103), BGATGACGTCATCR (SEQ ID NO: 104),TGASTCAT, ATGACGTCATCR (SEQ ID NO: 105), ATGACGTCAYC (SEQ ID NO: 106), GATGAYGTCATC (SEQ ID NO: 107), AGTCA, TGACTCA, RSTGACTCMGW (SEQ ID NO: 108), ACSMGGAAGTR (SEQ ID NO: 109), RASRMGGAAGTR (SEQ ID NO: 110), GAMCCGGAAGTR (SEQ ID NO: 111), AACRAGGAAGTR (SEQ ID NO: 112), ASRAGGAAGTR (SEQ ID NO: 113), AYWTCCKK, YYWRRGGTCAAAGGTCAHVBD (SEQ ID NO: 114), AASTRGGTCACSGTGACCYACWT (SEQ ID NO: 115), WASYRGGKCAAAGKTCA (SEQ ID NO: 116), WGAMCTTTGACCY (SEQ ID NO: 117), AGGTCAG, AWSTRGGKCAAAGGKCA (SEQ ID NO: 118), YYWRRGGTCAAAGGTCAYMK (SEQ ID NO: 119), STRGGTCACSGTGACCYACW (SEQ ID NO: 120), TRGGTCACSGTGACCYACW (SEQ ID NO: 121), AWSTRGGTYAST (SEQ ID NO: 122), MRRGGKYAAWRGGTCAC (SEQ ID NO: 123), AANNNAGGTCANNGGNCA (SEQ ID NO: 124), AANNAGGTNANNGGTCA (SEQ ID NO: 125), AAANNAGGTCA, TGNCNNNTGACCTNNNTT (SEQ ID NO: 126), TGACCTNNNTT, ARRGGTCAAAGGTCAH (SEQ ID NO: 127), RRGGTCAAAGGTCA (SEQ ID NO: 128), CWRAWCYAGGYCAWAGKTCA (SEQ ID NO: 129), YMRGGTCATWGGGGTSARG (SEQ ID NO: 130), TGACCTY, RGGTCARAGGTCA (SEQ ID NO: 131), AWGTRGGTCAAAGGTCAT (SEQ ID NO: 132), AWGTRGGTCAAAGGTCA (SEQ ID NO: 133), ARRGGTCRTGACCYYT (SEQ ID NO: 134), DGRGGTCAAAGGTCRY (SEQ ID NO: 135), ARRGGTCGYGACCYYK (SEQ ID NO: 136), MSTGWCCTB, RGGTCAR, AAAAGGTCAM (SEQ ID NO: 137), RAGGTCAAAAGGTCAM (SEQ ID NO: 138), RAGGTCRTGACCTY (SEQ ID NO: 139), AAAAGGTCAH (SEQ ID NO: 140), RAGGTCAAAAGGTCAH (SEQ ID NO: 141), RAGGTCRTGACCT (SEQ ID NO: 142), CCAGGTGG, GCCACCTGSCTGYD (SEQ ID NO: 143), CCACCTGCMN, DRCAGGTGYR (SEQ ID NO: 144), RCAGGTG, ARCAGGTGCA (SEQ ID NO: 145), RRCAGGTGYR (SEQ ID NO: 146), RRCAGGTGCR (SEQ ID NO: 147), YCAGGTG, KCACCTGM, SSSRSCKCACCTGS (SEQ ID NO: 148), CACCTGSRK, RRCAGGTGY, AYGCACCTGTMRY (SEQ ID NO: 149), GCACCTGT, WWWMRAKRCACCTGYTAKWHAW (SEQ ID NO: 150), TTCCCRKAA, DAWTTCYWGGAAWYH (SEQ ID NO: 151), TTCCCRGAAWTBSKWTWCCKRGRR (SEQ ID NO: 152), YAWTTCYW, SWYTTCYW, KRYWYTTCYKRGA (SEQ ID NO: 153), RSWTTTCTARGAA (SEQ ID NO: 154), TTCYYRGAAAY (SEQ ID NO: 155), TTTCYKRGAAW (SEQ ID NO: 156), KAWTTCYTGGAAWTY (SEQ ID NO: 157), RAWTTCCARGAAWTM (SEQ ID NO: 158), TTTCYKRGAAA (SEQ ID NO: 159),TTCYYAGGAAWYT (SEQ ID NO: 160), TTCCNGGAA, TTCCTGGAA, CCNNGGAANNNNNA, TTCC, GGAANNNNNA, TTCNNGG, which are separated by at least 6 nucleotides.

174. DNA in Claim 1, which is linear double stranded DNA.

175. DNA in Claim 1, which is linear single stranded DNA.

176. DNA in Claim 1, which is circular double stranded DNA.

177. DNA in Claim 1, which is circular single stranded DNA.

178. DNA in Claim 1, which is partially double stranded DNA.

179. DNA in Claim 1, which is a DNA-RNA hybrid.

180. DNA in Claim 1, which is a DNA-peptide hybrid.

181. DNA in Claim 1, which is a synthetically modified DNA or DNA hybrid.

182. DNA in Claim 1, which is comprised of chemically modified and unmodified DNA.

183. A protein or proteins in Claim 1, which are derived from a set of mammalian transcription factors.

184. A protein or proteins in Claim 1, which are derived from nuclear proteins.

185. A protein or proteins in Claim 1, which are derived from chromatin proteins.

186. A protein or proteins in Claim 1, which are derived from DNA-binding proteins.

187. A protein or proteins in Claim 1, which are derived from DNA-packaging proteins.

188. A protein or proteins in Claim 1, which are derived from transcription regulation factors.

189. A protein or proteins in Claim 1, which are derived from proteins related to epigenetic regulatory machinery.

190. A protein or proteins in Claim 1, which are derived from chromatin associated proteins.

191. A protein or proteins in Claim 1, which are derived from transcription factor, transcription factor complex, or transcriptional regulation related proteins.

192. Expression levels in Claim 1, which are identified as moderate or high by RNA-seq analysis relative to other proteins, that is in the top 66% of expressed proteins.

193. Expression levels in Claim 1, which are expressed in the target cell type with positive confirmation by immunohistochemistry.

194. Expression levels in Claim 1, which are expressed at moderate to high levels as confirmed by Affymetrix.

195. Expression levels in Claim 1, which are expressed at moderate to high levels as confirmed by immunohistochemistry.

196. Expression levels in Claim 1, which are expressed at the protein level during the stage of the cell’s lifecycle at the time of treatment.

197. Predominantly targeted cell type in Claim 1, where at least 50% of the therapeutic DNA is delivered to the cell type.

198. Predominantly targeted cell type in Claim 1, where the cell type is the predominant cell type by number or by volume in the treated area.

199. Predominantly targeted cell type in Claim 1, where more than 50% of the delivered non-viral gene therapy is delivered to the cell type by copy number or vector number.

200. Predominantly targeted cell type in Claim 1, where the cell type targeted is the most frequently targeted cell type from all of the cell types receiving the treatment directly or indirectly.

201. Treatments in Claim 1 which are intended for human pathologies.

202. Treatments in Claim 1 which are intended for animal pathologies.

203. Treatments in Claim 1 which are intended for mammalian pathologies.

204. Treatments in Claim 1 which are intended for augmentation of gene expression, which is reduced as a function of aging.

205. Treatments in Claim 1 which are intended for the replacing of missing or non- functioning genes.

206. Treatments in Claim 1, which are intended for the alleviation of pathologies caused by metabolic diseases.

207. Treatments in Claim 1, which are intended for the alleviation of pathologies caused by musculoskeletal diseases.

208. Treatments in Claim 1, which are intended for the alleviation of pathologies caused by cardiovascular diseases.

209. Treatments in Claim 1, which are intended for the alleviation of pathologies caused by diseases of the central and / or peripheral nervous systems.

210. Treatments in Claim 1, which are intended for the alleviation of pathologies in autoimmune diseases.

211. Treatments in Claim 1, which are intended for the alleviation of pathologies caused by infectious diseases.

212. Treatments in Claim 1, which are intended for the alleviation of pathologies caused by environmental conditions.

213. Treatments in Claim 1 which are intended for genome modification, silencing, or otherwise altering the genome or level of expression.

214. Each and all of the constructs in the Examples section.

215. Each and all of the DNA nuclear targeting sequences in the Examples section.

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