Compositions and methods of using gene coding for treating ocular disease

Abstract

The present disclosure describes methods of using lipid nanoparticle (LNP) compositions for treating ocular- related disorders or diseases. In particular, methods are provided for using LNP compositions in gene therapy for targeting an ATP binding cassette subfamily A member 4 (ABCA4) or a functional fragment thereof, in a subject, thereby treating or mitigating Inherited Macular Degenerations including a Stargardt disease or other diseases that involve retinal degeneration.

Description

[0001]SAL-043PC / 126933-5043 COMPOSITIONS AND METHODS OF USING GENE CODING FOR TREATING OCULAR DISEASE FIELD The present disclosure relates to lipid nanoparticles and uses thereof, e.g. for treating Stargardt disease. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 561,564, filed on March 5, 2024, U.S. Provisional Patent Application No.63 / 642,295, filed on May 3, 2024, and U.S. Provisional Patent Application No.63 / 688,045 filed on August 28, 2024, the entire contents of which are hereby incorporated herein by reference in their entireties. SEQUENCE LISTING The instant application contains a Sequence Listing that has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. The Sequence Listing for this application is labeled “SAL-043PC_SequenceListing”, which was created on March 4, 2025, and is 54,698 bytes in size. BACKGROUND Macular Degeneration is a condition in which cells of the macula, found in the center of the retina - the tissue at the back of the eye that senses light - become damaged. Vision loss usually occurs gradually and typically affects both eyes at different rates. Inherited Macular Degeneration (IMD), also called Macular Dystrophy (MD) refers to a group of heritable disorders that cause ophthalmoscopically visible abnormalities in the retina. Stargardt disease (STGD1) is a common macular dystrophy characterized by bilateral progressive loss of visual acuity and central vision. The phenotype is caused by more than 2000 DNA variants in the 6.8 kb coding region of the ATP Binding Cassette Subfamily A Member 4 gene (ABCA4). The gene encodes for a retinal-specific transmembrane protein in the photoreceptor (PR) outer segment (OS) that transports retinoids for visual cycle processing. STGD1 is manifested by deposition of lipofuscin, a fluorescent mixture of partially digested proteins and lipids, in the lysosomal compartment of the retinal pigment epithelium (RPE), which precedes photoreceptor degeneration. An increasing amount of research on the clinical and molecular genetics of STGD1 / ABCA4 has been performed over the past 15 years. 1DB1 / 146899640.4 SAL-043PC / 126933-5043 However, gene therapy development for MD diseases has been challenging because commonly used adeno- associated viruses (AAVs) do not have the capacity for a gene with a coding sequence larger than 5 kb, which includes ABCA4 (6.8 kb), the gene responsible for STGD, among other retinal disorders. Lipid nanoparticles (LNPs) are a type of lipid vesicles that possess a lipid core. These vesicles are used in, e.g., nucleic acid delivery. Messenger RNA (mRNA) is inherently unstable and prone to degradation by nucleases and self-hydrolysis. Encapsulation of mRNA within LNPs protects the mRNA from extracellular ribonucleases and assists with intracellular mRNA delivery. A variety of lipids have been developed for use in LNPs, yet there remains a need for specific formulations for nucleic acid delivery, especially large size and complicated nucleic acid cargoes involving mRNA, that can effectively be used in specific tissues or organs (e.g., retina) for efficiently preventing and treating IMD such as Stargardt disease. SUMMARY In various aspects, the present invention provides compositions and methods for treating and / or mitigating Inherited Macular Degeneration (IMD) disorders, which are a major cause of blindness worldwide such as IMD includes Stargardt disease. Accordingly, the present disclosure describes, in part, methods of using various lipid nanoparticles, e.g., for delivering one or more nucleic acid-based agents to the retina and preventing and / or treating Stargardt disease. In one aspect, disclosed is a method useful for preventing or decreasing the rate of photoreceptor loss in a subject in need thereof. The disclosed method comprises administering to a subject in need thereof a composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid encoding a mobile element enzyme, and a donor DNA, a transgene, or a mobile element, and (b) one or more lipids, the one or more lipids comprising:(i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid. In another aspect, disclosed is a method for treating and / or mitigating an Inherited Macular Degeneration (IMD) in a subject in need thereof. The disclosed method comprises administering to the subject a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid encoding a mobile element enzyme, and a donor DNA, a transgene, or a mobile element,, and (b) one or more lipids, the one or more lipids comprising:(i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid. DB1 / 146899640.4 2 SAL-043PC / 126933-5043 In yet another aspect, disclosed is a method for treating and / or mitigating Stargardt (STGD) disease in a subject in need thereof (e.g., STGD Type 1 (STGD1) disease). The disclosed method comprises administering to the subject a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid encoding a mobile element enzyme, and a donor DNA, a transgene, or a mobile element,, and (b) one or more lipids, the one or more lipids comprising:(i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid. In embodiments, the delivery lipid is SS-OP. In embodiments, the helper lipid is selected from distearoylphosphatidylcholine (DSPC), 1,2-Dioleoyl-sn- glycero-3-phosphocholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), and any combination thereof. In embodiments, the PEGylated lipid is selected from PEG-2K-DMG, C8 PEG 2K, and C16 PEG 2K. In embodiments, the disclosed methods comprise (i) a delivery lipid comprising from about 15 mol % to about 75 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 40 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 0.5 mol % to about 7 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 25 mol % to about 75 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, optionally being one or more of: DOPC from about 5 mol % to about 35 mol % of the total lipid present, and DOPE from about 2.5 mol % to about 30 mol % of the total lipid present, and(iv) a PEGylated lipid comprising from about 0.5 mol % to about 5 mol % of the total lipid present, being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 30 mol % to about 40 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 40 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 15 mol % of the total lipid present, optionally being: DOPE from about 5 mol % to about 15 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 3 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 35 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 50 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being: DOPE comprising about 10 mol % of the total lipid DB1 / 146899640.4 3 SAL-043PC / 126933-5043 present, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG- 2K-DMG. In embodiments the one or more lipids associate into an aggregate. In embodiments the one or more lipids associate into a lipid nanoparticle (LNP). In embodiments the one or more lipids, e.g., LNP, encapsulate the one or more nucleic acid-based agents. In embodiments the LNP comprising the one or more nucleic acid- based agents is suitable for delivery of the one or more nucleic acid-based agents in a subject. In embodiments the LNP comprising the one or more nucleic acid-based agents is formulated with a pharmaceutically acceptable carrier or excipient. In embodiments, the nucleic acid-based agent comprises both a nucleic acid encoding a mobile element enzyme in the form of modified mRNA (mmRNA) and a donor DNA or transgene or mobile element in the form of plasmid DNA. In embodiments, the weight to weight ratio of plasmid DNA : mmRNA is about 5 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 5. In embodiments, the administering to the subject is through systemic delivery. In embodiments, the administering to the subject is through intravenous, subcutaneous, or intraperitoneal delivery. In embodiments, the administering to the subject is through local delivery. In embodiments, the administering to the subject is through ocular, subretinal, sub-retinal pigment epithelium (sub-RPE), intraretinal, subvitreal, intravitreal, juxtasceral, subconjunctival, intracameral, or retrobulbar delivery. In embodiments, the administering to the subject is a single administration. In embodiments, the disclosed methods improve distance visual acuity of the subject. In embodiments, the disclosed methods provide a lowering of one or more of retinaldehyde, N-retinylidene- N-retinylethanolamine (A2E) and iso-A2E relative to a level of one or more of retinaldehyde, A2E and iso- A2E without the administration, optionally greater than about a 40%, or greater than about a 50%, or greater than about a 60%, or greater than about a 70%, or greater than about a 80%, or greater than about a 90% lowering. In embodiments, the disclosed methods result in improvement of best corrected visual acuity (BCVA) to greater than about 20 / 200. In embodiments, the disclosed methods result in improvement of retinal or foveal morphology, as measured by fundus autofluorescence (FAF) or Spectral Domain-Optical Coherence Tomography (SD-OCT). In embodiments, the disclosed methods result in reduction or prevention of one or more of wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired color vision, and difficulty adapting to dim lighting (delayed dark adaptation) in the subject. DB1 / 146899640.4 4 SAL-043PC / 126933-5043 In embodiments, the disclosed methods reduce or prevent lipofuscin accumulation in the retina, optionally in the retinal pigment epithelium (RPE). In embodiments, the disclosed methods reduce or prevent the formation of retinal pigment epithelium (RPE) debris. In embodiments, the disclosed methods are performed in the absence of a steroid treatment. In embodiments, the disclosed methods are substantially non-immunogenic. In embodiments, the STGD disease is characterized by one or more mutations in ABCA4 gene and wherein the ABCA4 mutations optionally being autosomal recessive mutations. In embodiments, the one or more nucleic acid-based agents comprise a ABCA4 gene or a functional fragment thereof, optionally wherein ABC4A gene is codon optimized. In embodiments, ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon-optimized form thereof. In embodiments, there is provided a composition comprising, one or more nucleic-acid based agents comprising a nucleic acid which encodes a mobile element enzyme that has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, and a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, and one or more lipids, the one or more lipids comprising: a delivery lipid, cholesterol, a helper lipid, and optionally, a PEGylated lipid. BRIEF DESCRIPTION OF DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee. FIG. 1 is a histogram demonstrating the therapeutic window for SS-OP / ABCA4 DNA delivery and that tolerability is driven by the copy number of DNA delivered. GFP vs. Abca4 were used as cargo within SS-OP LNPs (36.3% SS-OP, 50.7% Cholesterol, 9.8% DOPE, 5% PEG) and the therapeutic index was evaluated. OCT measurements were taken at day 12 (D12) of the mice injected subretinally with the LNPs. The degeneration score indicated that tolerability is driven by the number of molecules of DNA delivery, regardless of the DNA size or sequence. The x axis provides the nucleic acid concentration in nM and corresponding abca4 and GFP amounts in ng. Based on the differences in cargo base pair size, the amount DB1 / 146899640.4 5 SAL-043PC / 126933-5043 of abca4 or GFP was modified to match the same nM of nucleic acid. Here, 7 nM was shown to be the therapeutic index for the DNA regardless of the cargo size with an OCT degeneration score <1 on average. The green highlights represent GFP DNA, and the grey highlights represent the abca4 DNA. FIGS.2A-2B are series of histograms depicting that SS-OP / ABCA4 delivery to photoreceptors (PRs) and retinal pigment epithelial (RPE) cells following subretinal (SR) injection was within current therapeutic index (TI). FIG.2A: Disclosed formulations deliver preferentially to the RPE, with lower efficiency in the neural retina. Quantifying DNA delivery and the transcript produced. For 7 nM of DNA (25 ng for GFP and 50 ng for Abca4) Copy number per cell are graphed.0.01 copies / cell for neural retina and 1 copy / cell for RPE are seen for both Abca4 and GFP. Overall, abca4 DNA delivery is lowered compared to GFP. FIG.2B: Transcription of the DNA into mRNA by using RT-qPCR fold change compared to PBS blank. Both Abca4 and GFP have the same level of fold change indicating increased levels of mRNA produced from the DNA, indicating that LNP delivery of Abca4 is productive and leads to transcription of mRNA as well. FIGS.3A-3B are series of images and a graph showing neural retina integration following subretinal (SR) delivery of AAV5 with LNP and the present mobile element enzyme (SEQ ID NO: 1). The study evaluated dual subretinal delivery into mice staggered by 21 days (AAV followed by LNP with Cre mRNA+Mobile element enzyme (SEQ ID NO: 1) mRNA (36.3% SS-OP, 50.7% Cholesterol, 9.8% DOPE, 5% PEG)). FIG. 3A: fundus images taken in the Green GFP channel indicating GFP expression of AAV5 and red-tdTomato channel indicating widespread expression by the Cre LNP. In the dual injected groups, the merge demonstrated a large population of cells received dual mRNA leading to dual protein expression. It is concluded that cells that received Cre mRNA and showed a positive expression, also received the present mobile element enzyme (SEQ ID NO: 1) mRNA given that they were coencapsulated in the same LNP. FIG. 3B: The copy number per cell via ddPCR of cells in the neural retina (~80% photoreceptors) that express both GFP from AAV and cre / mobile element enzyme (SEQ ID NO: 1) from LNP. All doses, with 0.05 ug / ml being the highest show an increase in DNA copy number compared to AAV alone, indicative of integration via Mobile element enzyme (SEQ ID NO: 1). Increased levels of mobile element enzyme (SEQ ID NO: 1) showed low tolerability, as demonstrated by a decrease in DNA copy number. FIGS.4A-4B are series of images and a graph showing that ABCA4 + mobile element enzyme (SEQ ID NO: 1) mRNA delivery into photoreceptors (PRs) occurred with good tolerability. The formulation evaluated was SS-OP LNP (36.3% SS-OP, 50.7% Cholesterol, 9.8% DOPE, 5% PEG)) with CAG-hAbca4 NP and mobile element enzyme (SEQ ID NO: 1) mRNA. FIG.4A: Minimal to a no degeneration was observed with SS- DB1 / 146899640.4 6 SAL-043PC / 126933-5043 OP / ABCA4+ mobile element enzyme (SEQ ID NO: 1) delivery to the retina. The OCT degeneration score of the ONL is within the tolerable range for LNPs for both doses. An average score of < 0.5 indicates high tolerability for this dual loaded LNP. FIG. 4B: ABCA4 expression corresponds to about 5-10% of photoreceptors (PRs) in the entire retina FACS showing data isolating photoreceptors (CD73+) from the whole retina and further isolating for Abca4+ cells. Compared to background (2.7%) both doses of LNP indicate increased Abca4 expression of > 5%. Abca4 protein is therefore expressed in 5-10% of the Photoreceptors in the neural retina whereas only 10-15% of Abca4+ cells are needed in the treated area. Note: treated area is 1 / 3 of whole retina. FIG.5 is a series of images demonstrating that SS-OP / ABCA4 and mobile element enzyme (SEQ ID NO: 1) are expressed in mouse photoreceptors (PRs). Immunohistochemistry (IHC) assays showed DAPI stained in blue, PNA lectin stains the inner and outer segments of the photoreceptors (red), RPE65 (purple) stains the RPE layer, and Abca4 is labelled green. As expected, the Abca4 was localized to the outer segments of the photoreceptors which themselves were naturally expressed as a transport protein. The localization showed that the LNP was able to deliver the Abca4 DNA and the DNA was able to be translated into protein that is expressed in the OS of the photoreceptors. FIG.6 shows a bar graph demonstrating samples treated with SS-OP / ABCA4 and mobile element enzyme showed 40% reduction in A2E signal when compared to vehicle control. FIGs.7A-7B show two graphs that demonstrate that SS-OP was delivered to target tissues within treated areas. FIG.7A shows a bar graph comparing copy numbers in neural retina and RPE / eye cup samples after treatment with 6 ug and 12 ug of SS-OP / ABCA4 and mobile element enzyme. FIG.7B shows a bar graph comparing hABCA4 transcript in neural retina and RPE / eye cup samples after treatment with 6 ug and 12 ug of SS-OP / ABCA4 and mobile element enzyme. FIG.8 is a series of images demonstrating that SS-OP / ABCA4 and mobile element enzyme (SEQ ID NO: 1) are expressed in nonhuman primates (NHP) photoreceptors using SSOP as ABCA4 co-localizes with arrestin-C, a marker for PR cones in the NHP. FIGs.9A – 9D show data related to outer nuclear layer (ONL) thinning and treatments with LNP / ABCA4 DNA + mobile element enzyme mRNA, LNP co-encapsulating mRNA, DNA, mRNA and DNA. FIG.9A shows a series of images of the thinning of the ONL. FIG.9B shows a graph of the OCT degeneration score of post- subretinal injection ONL thinning and treating the area with LNPs encapsulated with a mRNA, DNA, or mRNA / DNA cargo. FIG.9C shows an image of the ONL with indication of placement of subretinal injection. DB1 / 146899640.4 7 SAL-043PC / 126933-5043 FIG.9D is a graph comparing the OCT degeneration score of ONL thinning after treatment with LNP / ABCA4 DNA + mobile element enzyme mRNA. FIGs.10A – 10C are a series of images and graphs showing that LNP achieves high levels of mRNA expression in the retina at levels required for clinical efficacy in Stargardt disease. FIG. 10A shows fundoscopic images showing delivery of LNP with eGFP DNA and NLS-Cre recombinase mRNA into TdTom mice eyes. FIG.10B shows flat mount images revealing LNP eGFP coverage post-SR injection into TdTom mice, with ImageJ used to measure the treated area and determine LNP interaction with tissue. FIG.10C shows a graph of the entire retina of TdTom mice treated with vehicle alone and three LNP doses containing dual mRNA and DNA cargos. FIG.11A – 11B show graph demonstrating that ABCA4 constructs screened for in vivo targeting demonstrate robust in vitro transcript and protein expression. FIG.11A shows a graph of ARPE19 and HEK293T cells dosed with various full length ABCA4 donor DNA elements to access expression using RT-qPCR after 72 hours incubation. FIG.11B shows flow cytometric quantification of ABCA4 and ABCA4 / Flag dual expression in ARPE19 and HEK-293T cell lines, 72 hours after transfection, demonstrated robust in vitro construct protein expression. FIG.12 shows a bar graph demonstrating samples treated with SS-OP / ABCA4 and mobile element enzyme showed 40% reduction in A2E signal when compared to vehicle control. FIGs.13A – 13E show data demonstrating LNPs co-encapsulating ABCA4 DNA and mobile element enzyme mRNA show delivery, tolerability and expression in neural retina. FIG.13A shows a graph depicting OCT degeneration scores demonstrated that LNPs with mobile element enzyme mRNA and ABCA4 DNA were well tolerated at low and high doses. FIG.13B shows a graph demonstrating that ABCA4 transcript was detectable by RTqPCR at both doses in Abca4- / - mice retina. FIG.13C shows a graph demonstrating that ABCA4 DNA was successfully delivered to the Abca4- / - mice retina. FIG. 13D shows representative pseudocolor flow cytometry plots show the gating strategy. FIG.13E shows a graph demonstrating ABCA4 expression was analyzed as a function of viable Cd73+ PRs from Abca4- / - mice. FIG.14 shows images of retinal immunohistochemistry (IHC) using antibodies against ABCA4, PNA lectin [(cones and inner (IS) and outer segment (OS)], RPE65 (retinal pigment epithelium), and DAPI (nuclear stain). The boxed area is magnified in the composite image is shown in the last column of images. DB1 / 146899640.4 8 SAL-043PC / 126933-5043 FIG. 15 shows a graph demonstrating that LNP / ABCA4 DNA and mobile element enzyme mRNA are expressed in nonhuman primates (NHP) photoreceptors. FIGs. 16A – 16C demonstrate SSOP DOPE formulation showed higher GFP DNA / mCherry RNA expressions when increasing the DOPE helper lipid molar ratio. FIG.16A shows the formulations tested with increasingly higher DOPE helper lipid molar ratio. FIG. 16B shows a series of fluorescent images demonstrating LNP-mediated gene expressions in ARPE-19 cells treated with SSOP DOPE formulations at 1 µg / mL for 48 hours. The NanoFCM analysis showed LNP population (red color) fully loaded with DNA and mRNA with high DOPE formulation (FIG.16C). FIGs.17A – 17E demonstrate various SSOP DOPE PEG lipid formulations and their efficacy in vitro. FIG. 17A shows SSOP DOPE PEG lipid formulation designs. FIG.17B shows a bar graph comparing the size (nm) of various SSOP DOPE PEG lipid formulations. FIG. 17C shows a bar graph comparing the encapsulation efficiency of various SSOP DOPE PEG lipid formulations. FIG. 17D shows a series of fluorescent images demonstrating LNP-mediated GFP DNA / mCherry mRNA expressions. FIG.17E shows a series of fluorescent images demonstrating LNP-mediated GFP DNA / mCherry mRNA expressions. FIGs.18A – 18B demonstrate that SSOP DOPE formulations with high helper (38% DOPE) showed higher GFP DNA / mCherry mRNA expressions when increasing the SSOP molar ratio. FIG.18A shows SSOP DOPE formulations with high helper (38% DOPE) and different ratios of SSOP. FIG.18B shows a series of fluorescent images demonstrating LNP-mediated gene expressions in ARPE-19 cells treated with SSOP DOPE formulations with high helper (38% DOPE) formulations at 1 µg / mL for 48 hours. FIGs.19A – 19B demonstrate that SSOP DOPE formulations with balanced SSOP and high DOPE maintain stable GFP DNA / mCherry mRNA expressions with minimum effect on PEG molar ratio changes. FIG.19A shows various SSOP DOPE PEG formulations. FIG.19B shows a series of fluorescent images demonstrating LNP-mediated gene expression in ARPE-19 cells treated with SSOP DOPE PEG formulations at 1 µg / mL for 48 hours. FIG. 20 shows a series of fluorescent images demonstrating LNP-mediated gene expressions when comparing the SSOP high helper formulation with other comparative formulations. IRD-062 F1 represents CAG-GFP DNA + Mobile element enzyme (SEQ ID NO: 1) 34 mRNA. IRD-062 F1 represents CAG-GFP DNA + Mobile element enzyme (SEQ ID NO: 1) Opt26 mRNA, KM E148 F2 represents CAG-GFP DNA + mCherry mRNA. DB1 / 146899640.4 9 SAL-043PC / 126933-5043 FIGs.21A – 21C demonstrate SSOP DOPE high helper formulation showed the highest gene expression in malate buffer (high salt) compared to acetate buffer. FIG.21A shows various SSOP high helper formulations in different buffers. FIG.21B shows a series of fluorescent images demonstrating LNP-mediated GFP DNA expression of SSOP high helper formulations in sodium malate and sodium acetate. Lipofectamine was used as the positive control for GFP DNA transfection and expression. FIG.21C shows a bar graph comparing ABCA4 expression in ARPE-19 cells after dosing of various SSOP high helper formulations at 1 µg / mL for 48 h (12-well plate), total dosage of 1.6 µg nucleic acids (NAs). FIGs.22A – 22D SSOP DOPE high helper formulation demonstrated higher Abca4 DNA delivery and expression in vitro compared to the test formulation. FIG.22A shows SSOP DOPE high helper formulation and comparative formulation. FIG.22B shows a bar graph comparing ABCA4 expression in ARPE-19 cells after dosing of SSOP DOPE high helper formulation LNP and comparative formulation LNP. FIG.22C shows a graph comparing size of SSOP DOPE high helper formulation LNP and comparative formulation LNP. FIG. 22D shows a graph comparing zeta potential of SSOP DOPE high helper formulation LNP and comparative formulation LNP. FIGs.23A – 23C shows a series of graphs comparing SSOP DOPE high helper formulations prepared in sodium malate buffer at different pH levels (F1: pH 3; F2: pH 4; F3: pH 5) and sodium maleate buffer at different pH levels (F4: pH 3; F5: pH 4; F6: pH 5). FIG.23A shows a graph comparing cell viability of SSOP DOPE high helper formulations treated cells. FIG.23B shows a graph comparing percentage of GFP+ cells of viable cells of SSOP DOPE high helper formulations treated cells. FIG.23C shows a graph comparing GFP MFI of SSOP DOPE high helper formulations treated cells. DETAILED DESCRIPTION The present methods and compositions are useful for, inter alia, retina-directed gene therapy for Stargardt disease (STGD) caused by mutations in an ATP binding cassette subfamily A member 4 (ABCA4). ABCA4 is responsible for the clearance of all-trans-retinal (reactive vitamin A aldehyde) from photoreceptor cells, and loss of ABCA4 function leads to the accumulation of bis-retinoids (such as retinal pigment epithelium (RPE)) in the outer segment membranes of the photoreceptor cells, which in turn causes the formation of lipofuscin. This ultimately leads to accumulation of high levels of lipofuscin in the RPE, increased retinal autofluorescence and progressive RPE and photoreceptor cell loss. In aspects, the presently disclosed methods and compositions (also referred to as “formulations” herein) provide in part one or more lipids in association with one or more nucleic acid-based agents for preventing DB1 / 146899640.4 10 SAL-043PC / 126933-5043 or decreasing the rate of photoreceptor loss in a subject in need thereof; for ocular delivery of nucleic acid to a subject in need thereof; for treating an ocular disease or disorder in a subject in need thereof; and for treating and / or mitigating Inherited Macular Degeneration (IMD) in a subject in need thereof. In embodiments the one or more lipids useful for the disclosed methods associate into an aggregate. In embodiments the one or more lipids associate into a lipid nanoparticle (LNP). In embodiments, the one or more lipids, e.g., LNP, encapsulate the one or more nucleic acid-based agents. In embodiments, the composition or LNP comprising the one or more nucleic acid-based agents is suitable for delivery of the one or more nucleic acid-based agents in a subject. In embodiments, the disclosed composition or LNP comprising the one or more nucleic acid-based agents is formulated with a pharmaceutically acceptable carrier or excipient. In embodiments, there is provided a composition comprising, one or more nucleic-acid based agents comprising a nucleic acid which encodes a mobile element enzyme that has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, and a nucleic acid-based agent comprising ABCA4 gene or functional fragment thereof, and one or more lipids, the one or more lipids comprising: a delivery lipid, cholesterol, a helper lipid, and optionally, a PEGylated lipid. Methods In aspects, there is provided a method for introducing a nucleic acid into a cell, the method comprising contacting the cell with a composition described herein. In aspects, there is provided a method for the in vivo delivery of a nucleic acid, the method comprising administering to a subject in need thereof a composition described herein. In aspects, there is provided a method for ocular delivery of nucleic acid, the method comprising ocularly administering to a subject in need thereof a composition described herein. In aspects, there is provided a method for preventing or decreasing the rate of photoreceptor loss in a subject, comprising administering to a subject in need thereof a composition described herein. In aspects, there is provided a method for treating and / or mitigating an Inherited Macular Degeneration (IMD) in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition described herein. DB1 / 146899640.4 11 SAL-043PC / 126933-5043 In aspects, there is provided a method for treating and / or mitigating Stargardt (STGD) disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition described herein. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) a PEGylated lipid. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, or about 45 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) a cholesterol comprising about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol %, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, or about 60 mol % of the total lipid present, (iii) a helper lipid comprising about 5 mol %, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about DB1 / 146899640.4 12 SAL-043PC / 126933-5043 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 3 mol %, about 4 mol%, about 5 mol%, about 6 mol%, or about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 22 mol % to about 26 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 46 mol % to about 50 mol % of the total lipid present, (iii) a helper lipid comprising from about 22 mol % to about 26 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 4 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 34 mol % to about 38 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 48 mol % to about 52 mol % of the total lipid present, (iii) a helper lipid comprising from about 8 mol % to about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 4 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 36 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 51 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and DB1 / 146899640.4 13 SAL-043PC / 126933-5043 (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 36 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 51 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 35 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 50 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 35 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 50 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and DB1 / 146899640.4 14 SAL-043PC / 126933-5043 (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 24 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 48 mol % of the total lipid present, (iii) a helper lipid comprising about 24 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 24 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 48 mol % of the total lipid present, (iii) a helper lipid comprising about 24 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the one or more lipids comprise a dual nucleic acid-based agent as a cargo. In embodiments, the one or more lipids comprising a dual nucleic acid-based agent comprise SS-OP as a delivery lipid. DB1 / 146899640.4 15 SAL-043PC / 126933-5043 In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol% of the total lipid present, the delivery lipid being SS-EC, (ii) cholesterol comprising about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol %, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, or about 60 mol % of the total lipid present, (iii) a helper lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 3 mol %, about 4 mol%, about 5 mol%, about 6 mol%, or about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) a PEGylated lipid. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about DB1 / 146899640.4 16 SAL-043PC / 126933-5043 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, or about 45 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) a cholesterol comprising about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol %, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, or about 60 mol % of the total lipid present, (iii) a helper lipid comprising about 5 mol %, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 3 mol %, about 4 mol%, about 5 mol%, about 6 mol%, or about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 22 mol % to about 26 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 46 mol % to about 50 mol % of the total lipid present, (iii) a helper lipid comprising from about 22 mol % to about 26 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 4 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: DB1 / 146899640.4 17 SAL-043PC / 126933-5043 (i) a delivery lipid comprising from about 34 mol % to about 38 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 48 mol % to about 52 mol % of the total lipid present, (iii) a helper lipid comprising from about 8 mol % to about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 4 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 36 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 51 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 36 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 51 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. DB1 / 146899640.4 18 SAL-043PC / 126933-5043 In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 24 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 48 mol % of the total lipid present, (iii) a helper lipid comprising about 24 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 24 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 48 mol % of the total lipid present, (iii) a helper lipid comprising about 24 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the one or more lipids comprises: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, wherein the ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of DB1 / 146899640.4 19 SAL-043PC / 126933-5043 SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon- optimized form thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 35.7 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising about 49.8 mol % of the total lipid present, (iii) a helper lipid comprising about 9.6 mol % of the total lipid present, optionally being: DOPE comprising about 9.6 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 4.9 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the nucleotide sequence of SEQ ID NO: 27, or a nucleotide sequence having at least about 80%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, wherein the ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon- optimized form thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 35.7 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising about 49.8 mol % of the total lipid present, (iii) a helper lipid comprising about 9.6 mol % of the total lipid present, optionally being: DOPE comprising about 9.6 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 4.9 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprise a dual nucleic acid-based agent as a cargo. In embodiments, the one or more lipids comprising a dual nucleic acid-based agent comprise SS-OP as a delivery lipid. DB1 / 146899640.4 20 SAL-043PC / 126933-5043 In embodiments, the one or more lipids comprises: (v) a delivery lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol% of the total lipid present, the delivery lipid being SS-EC, (vi) cholesterol comprising about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol %, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, or about 60 mol % of the total lipid present, (vii) a helper lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (viii) a PEGylated lipid comprising from about 3 mol %, about 4 mol%, about 5 mol%, about 6 mol%, or about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the delivery lipid is SS-OP. In embodiments, the helper lipid is selected from distearoylphosphatidylcholine (DSPC), 1,2-Dioleoyl-sn- glycero-3-phosphocholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), and any combination thereof. In embodiments, PEGylated lipid is selected from PEG-2K-DMG, C8 PEG 2K, and C16 PEG 2K. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 25 mol % to about 75 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, optionally being one or more of: DOPC from about 5 mol % to about 35 mol % of the total lipid present, and DOPE from about 2.5 mol % to about 30 mol % of the total lipid present, and DB1 / 146899640.4 21 SAL-043PC / 126933-5043 (iv) a PEGylated lipid comprising from about 0.5 mol % to about 5 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 15 mol % to about 35 mol % of the total lipid present, the delivery lipid being SS-EC, (ii) cholesterol comprising from about 35 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 15 mol % to about 35 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 3 mol % to about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 30 mol % to about 40 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 40 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 15 mol % of the total lipid present, optionally being: DOPE from about 5 mol % to about 15 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 3 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 35 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 50 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being: DOPE comprising about 10 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: DB1 / 146899640.4 22 SAL-043PC / 126933-5043 (i) a delivery lipid comprising from about 5 mol % to about 50 mol % of the total lipid present, (ii) cholesterol comprising from about 15 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 50 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the delivery lipid is selected from SS-OP, MC3, SS_EC, and any combination thereof. In embodiments, the helper lipid is selected from dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylcholine (DSPC), and 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC). In embodiments, the PEGylated lipid is selected from PEG-2K-DMG, C8 PEG 2K, and C16 PEG 2K. In embodiments, the one or more lipids do not comprise a PEGylated lipid. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents of about 7:1, or about 8:1, or about 9:1, or about 10:1, or about 11:1, or about 12:1, or about 13:1, and / or a has a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 14:1, or about 15:1, or about 16:1, or about 17:1, or about 18:1, or about 19:1, or about 20:1, or about 21:1, or about 22:1, or about 23:1, or about 24:1, or about 25:1, or about 26:1. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents from about 7:1 to about 13:1 and / or a has a weight to weight ratio of total lipid to one or more nucleic acid-based agents from about 14:1 to about 26:1. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents of about 7:1 and / or a has a weight to weight ratio of total lipid to one or more nucleic acid- based agents of about 25:1. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 20 mol % to about 40 mol % of the total lipid present, (ii) cholesterol comprising from about 20 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 10 mol % to about 50 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. DB1 / 146899640.4 23 SAL-043PC / 126933-5043 In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 20 mol % to about 40 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 20 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 15 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, or about 40 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 20 mol %, about 21 mol %, about 22 mol %, about 23 mol %, about 24 mol %, about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, or about 55 mol% of the total lipid present, (iii) a helper lipid comprising about 15 mol %, about 16 mol %, about 17 mol %, about 18 mol %, about 19 mol %, about 20 mol %, about 21 mol %, about 22 mol %, about 23 mol %, about 24 mol %, about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, or about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, or about 3 mol % of the total lipid present. DB1 / 146899640.4 24 SAL-043PC / 126933-5043 In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, (ii) cholesterol comprising from about 15 mol % to about 35 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 15 mol % to about 35 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, or about 45 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol %, about 20 mol %, about 21 mol %, about 22 mol %, about 23 mol %, about 24 mol %, about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol % of the total lipid present, (iii) a helper lipid comprising about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about DB1 / 146899640.4 25 SAL-043PC / 126933-5043 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, or about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, about 3 mol %, about 3.5 mol %, about 4 mol %, about 4.5 mol %, or about 5 mol % of the total lipid present. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 5%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol %, about 30 mol %, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about DB1 / 146899640.4 26 SAL-043PC / 126933-5043 35 mol %, about 36 mol %, about 37 mol %, about 38 mol %, about 39 mol %, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol %, about 46 mol %, about 47 mol %, about 48 mol %, about 49 mol %, about 50 mol %, about 51 mol %, about 52 mol %, about 53 mol %, about 54 mol %, or about 55 mol % of the total lipid present, (iii) a helper lipid comprising about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, or about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, or about 3 mol %, of the total lipid present. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 20 mol % to about 30 mol % of the total lipid present, (ii) cholesterol comprising from about 30 mol % to about 40 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 20 mol % to about 30 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 30 mol % to about 40 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: DB1 / 146899640.4 27 SAL-043PC / 126933-5043 (i) a delivery lipid comprising about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, or about 30 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 30 mol %, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, or about 40 mol% of the total lipid present, (iii) a helper lipid comprising about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol %, about 36 mol %, about 37 mol %, about 38 mol %, about 39 mol %, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, about 3.0 mol %, about 3.5 mol%, about 4.0 mol %, about 4.5 mol%, or about 5.0 mol% of the total lipid present. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 25 mol % of the total lipid present; (ii) cholesterol comprising about 34.5 mol % of the total lipid present; (iii) a helper lipid comprising about 38 mol % of the total lipid present; and (iv) a PEGylated lipid comprising about 2.5 mol % of the total lipid present. In embodiments, the delivery lipid is SSOP. In embodiments, the helper lipid is DOPE. In embodiments, the delivery lipid is SSOP; and the helper lipid is DOPE. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: DB1 / 146899640.4 28 SAL-043PC / 126933-5043 (i) a delivery lipid comprising from about 25 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 34.5 mol % of the total lipid present, (iii) a helper lipid comprising from about 38 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 2.5 mol % of the total lipid present. In embodiments, the one or more lipids comprises a formulation in Table 1. TABLE 1: Exemplary formulations Delivery % Mol of Delivery % Mol of Helper % Mol of Helper % Mol of PEGylated Lipid Lipid (% mol IL) Cholesterol Lipid Lipid Lipid In embodiments, the one or more lipids comprises a formulation in Table 2. TABLE 2: Exemplary formulations Delivery Lipid % Mol of SSOP % Mol of % Mol of % Mol of PEG DB1 / 146899640.4 29 SAL-043PC / 126933-5043 SSOP DOPE F3 about 35.7 about 23.3 about 38 about 3 In embodiments, the one or more lipids comprises a formulation in Table 3. TABLE 3: Exemplary formulations Delivery Lipid % Mol of SSOP % Mol of Cholesterol % Mol of % Mol of PEG In embodiments, the one or more lipids comprises a formulation in Table 4. TABLE 4: Exemplary formulations DB1 / 146899640.4 30 SAL-043PC / 126933-5043 Delivery Lipid % Mol of SSOP % Mol of Cholesterol % Mol of % Mol of PEG DOPE In embodiments, the composition comprises one of the formulations of FIG.16A. In embodiments, the composition comprises one of the formulations of FIG.17A. In embodiments, the composition comprises one of the formulations of FIG.18A. In embodiments, the composition comprises one of the formulations of FIG.19A. In embodiments, the composition comprises one of the formulations of FIG.21A. In embodiments, the composition comprises one of the formulations of FIG.22A. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents of about 5:1 to about 15:1, or about 7:1 to about 13:1, or about 8:1 to about 12:1, or about 5:1, or about 6:1, or about 7:1, or about 8:1, or about 9:1, or about 10:1, or about 11:1, or about 12:1, or about 13:1, or about 14:1, or about 15:1. In embodiments, the composition has a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 10:1 to about 35:1, or about 15:1 to about 30:1, or about 20:1 to about 25:1, or about 15:1, or about 20:1, or about 25:1, or about 30:1. In embodiments, the composition forms a nucleic acid / lipid particle. In embodiments, the one or more lipids associate into a lipid nanoparticle (LNP). In embodiments, the LNP encapsulates the one or more nucleic acid-based agents. DB1 / 146899640.4 31 SAL-043PC / 126933-5043 In embodiments the LNP comprising the one or more nucleic acid-based agents is formulated with a pharmaceutically acceptable carrier or excipient. Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, N.Y.). For example, pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and the fluid should be easy to draw up by a syringe. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Therapeutic compounds can be prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and DB1 / 146899640.4 32 SAL-043PC / 126933-5043 microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as collagen, ethylene vinyl acetate, polyanhydrides (e.g., poly[1,3-bis(carboxyphenoxy)propane-co-sebacic-acid] (PCPP- SA) matrix, fatty acid dimer-sebacic acid (FAD-SA) copolymer, poly(lactide-co-glycolide)), polyglycolic acid, collagen, polyorthoesters, polyethyleneglycol-coated liposomes, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. Semisolid, gelling, soft-gel, or other formulations (including controlled release) can be used, e.g., when administration to a surgical site is desired. Methods of making such formulations are known in the art and can include the use of biodegradable, biocompatible polymers. See, e.g., Sawyer et al., Yale J Biol Med. 2006; 79(3-4): 141-152. In embodiments, the one or more nucleic acid-based agents comprise a nucleic acid which encodes a mobile element enzyme. In embodiments, the mobile element enzyme has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the mobile element enzyme comprises an amino acid other than serine at the position corresponding to position 2 of SEQ ID NO: 1. In embodiments, the amino acid is a non-polar aliphatic amino acid, optionally a non-polar aliphatic amino acid optionally selected from G, A, V, L, I, and P, optionally A. In embodiments, the mobile element enzyme does not have additional residues at the C terminus relative to SEQ ID NO: 1. In embodiments, the enzyme has one or more mutations which confer hyperactivity. In embodiments, the enzyme has one or more amino acid substitutions selected from S8X1, C13X2, N125X3, and D416X4, or positions corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has S8X1 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has C13X2 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has N125X3substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the mobile element enzyme has D416X4 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, X4is selected N, C, Q, S, and T. In embodiments, X1is selected from G, A, V, L, I, and P. In embodiments, X2is selected from K, R, and H. In embodiments, X3 is selected K, R, and H. In embodiments, X1 is P, X2 is R, and X4 is N. In embodiments, the enzyme is capable of inserting a donor DNA at a TA dinucleotide site. DB1 / 146899640.4 33 SAL-043PC / 126933-5043 In embodiments, the enzyme is capable of inserting a donor DNA at a TTAA tetranucleotide site. In embodiments, the enzyme is capable of inserting a donor DNA at a ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site In embodiments, the enzyme comprises: a targeting element and an enzyme that is capable of inserting the donor DNA (e.g., a mobile element) comprising a gene, optionally at a TA dinucleotide site or a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site in a genomic safe harbor site (GSHS). In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having the sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid other than serine at the position corresponding to position 2 of SEQ ID NO: 1. In embodiments, the amino acid is a non- polar aliphatic amino acid, optionally a non-polar aliphatic amino acid optionally selected from G, A, V, L, I, and P, optionally A. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid that does not have additional residues at the C terminus relative to SEQ ID NO: 1. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having a sequence comprising one or more mutations which confer hyperactivity. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having one or more amino acid substitutions selected from S8X1, C13X2, N125X3, and D416X4or positions corresponding thereto relative to SEQ ID NO: 1. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having S8X1 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having C13X2 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having N125X3substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the nucleic acid encoding the mobile element enzyme encodes an amino acid having D416X4 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. DB1 / 146899640.4 34 SAL-043PC / 126933-5043 In embodiments, the encoded mobile element enzyme is capable of inserting a donor DNA at a TA dinucleotide site. In embodiments, the encoded mobile element enzyme is capable of inserting a donor DNA at a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site. In embodiments, the the nucleic acid encoding the mobile element enzyme comprises a sequence encoding: a targeting element and an enzyme that is capable of inserting the donor DNA (e.g., a mobile element) comprising a gene, optionally at a TA dinucleotide site or a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site in a genomic safe harbor site (GSHS). In embodiments, the targeting element comprises one or more of a gRNA, optionally associated with a Cas enzyme, which is optionally catalytically inactive or a transcription activator-like effector (TALE). In embodiments, the targeting element comprises a transcription activator-like effector (TALE) DNA binding domain (DBD) and zinc fingers (ZF) DBD. In embodiments, the targeting element comprises a Cas9 enzyme guide RNA complex. In embodiments, the Cas9 enzyme guide RNA complex comprises a nuclease-deficient dCas9 guide RNA complex. In embodiments, the GSHS is in an open chromatin location in a chromosome. In embodiments, the GSHS is selected from adeno-associated virus site 1 (AAVS1), chemokine (C-C motif) receptor 5 (CCR5) gene, HIV-1 coreceptor, and human Rosa26 locus. In embodiments, the enzyme and the targeting element are connected. In embodiments, tthe enzyme and the targeting element are fused to one another or linked via a linker to one another. In embodiments, the linker is a flexible linker. In embodiments, the flexible linker is substantially comprised of glycine and serine residues, optionally wherein the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 12. In embodiments, the flexible linker is of about 20, or about 30, or about 40, or about 50, or about 60 amino acid residues. In embodiments, the one or more nucleic acid-based agents comprise a donor DNA or transgene or mobile element. In embodiments, the donor DNA or transgene or mobile element comprises a gene encoding a complete polypeptide. In embodiments, the donor DNA or transgene or mobile element comprises a gene which is defective or substantially absent in a disease state. In embodiments, the donor DNA or transgene or mobile element is flanked by one or more ends. In embodiments, the donor DNA or transgene or mobile element has a size of up to about 10 kb, or up to about 12 kb, or up to about 15 kb, or about 7.5 to about 15 kb, or about 10 to about 15 kb. DB1 / 146899640.4 35 SAL-043PC / 126933-5043 In embodiments, the one or more nucleic acid-based agents is in the form of RNA. In embodiments, the RNA is or comprises messenger RNA (mRNA). In embodiments, the mRNA is or comprises modified mRNA (mmRNA). In embodiments, the mmRNA comprises one or more of a 5’-m7G cap (cap0, cap1, or cap2), a pseudouridine or n-methyl-pseudouridine substitution, and a poly-A tail of about 30, or of about 50, or of about 100, or of about 150 nucleotides in length. In embodiments, the one or more nucleic acid-based agents is in the form of DNA. In embodiments, the DNA is or comprises plasmid DNA or miniplasmid DNA. In embodiments, the plasmid DNA has a size of up to about 10 kb, or up to about 12 kb, or up to about 15 kb, or about 7.5 to about 15 kb, or about 10 to about 15 kb. In embodiments, the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme and a donor DNA or transgene or mobile element. In embodiments, the nucleic acid-based agent comprises both RNA and DNA. In embodiments, the nucleic acid-based agent comprises both mRNA and DNA. In embodiments, the weight to weight ratio of DNA : mRNA is from about 10:1 to about 1:10, or about 10 : about 1, or about 9 : about 1, or about 8 : about 1, or about 7 : about 1, or about 6 : about 1, or about 5 : about 1, or about 4 : about 1, or about 3 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 3, or about 1 : about 4, or about 1 : about 5, or about 1 : about 6, or about 1 : about 7, or about 1 : about 8, or about 1 : about 9, or about 1 : about 10. In embodiments, the nucleic acid-based agent comprises both mmRNA and plasmid DNA. In embodiments, the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA. In embodiments, the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA and the weight to weight ratio of plasmid DNA : mmRNA is about 5 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 5. In embodiments, the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA and DB1 / 146899640.4 36 SAL-043PC / 126933-5043 the weight to weight ratio of plasmid DNA : mmRNA is about 2 : about 1. In embodiments, the composition useful for the disclosed methods provides high encapsulation of the nucleic acid-based agents. In embodiments, the composition provides an encapsulation efficiency of greater than about 90%, or greater than about 95%, or greater than about 98%. In embodiments, the composition provides low polydispersity. In embodiments, the composition is an LNP having a particle size of about 60 to about 200 nm, or about 100 to about 150 nm, or about 60 to about 120 nm. In embodiments, the method improves distance visual acuity of the subject. In embodiments, the method provides a lowering of one or more of retinaldehyde, N-retinylidene-N-retinylethanolamine (A2E) and iso-A2E relative to a level of one or more of retinaldehyde, A2E and iso-A2E without the administration, optionally greater than about a 40%, or greater than about a 50%, or greater than about a 60%, or greater than about a 70%, or greater than about a 80%, or greater than about a 90% lowering. In embodiments, the method results in improvement of best corrected visual acuity (BCVA) to greater than about 20 / 200. In embodiments, the method results in improvement of retinal or foveal morphology, as measured by fundus autofluorescence (FAF) or Spectral Domain-Optical Coherence Tomography (SD-OCT). FAF is a non- invasive retinal imaging modality used to provide a density map of lipofuscin in the retinal pigment epithelium. See Madeline et al., Int J Retin Vitr 2, 12 (2016); Sepah et al., Saudi J Ophthalmol.2014;28(2):111–116; Sparrow et al., Investigative Ophthalmology & Visual Science September 2010; vol.51:4351-4357. SD-OCT is an interferometric technique that provides depth-resolved tissue structure information encoded in the magnitude and delay of the back-scattered light by spectral analysis of the interference fringe pattern. Yaqoob et al., Biotechniques, vol.39, No.6S; published Online:30 May 2018. Other imaging technologies can be used as well, including, e.g., a scanning laser ophthalmoscopy (SLO), Fluorescence lifetime imaging ophthalmoscopy (FLIO), and two-photon microscopic imaging (TPM). Images (of one or both eyes) acquired using a suitable technology can be analyzed to assess parameters of a patient, including fluorescence intensity. For example, FAF that is characterized by a general increase of autofluorescence intensity is indicative of the Stargardt disease, at early stages of the disease. Burke et al., Invest Ophthalmol Vis Sci. 2014; 55: 2841 –2852. In embodiments, the method results in reduction or prevention of one or more of wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired color vision, and difficulty adapting to dim lighting (delayed dark adaptation) in the subject. DB1 / 146899640.4 37 SAL-043PC / 126933-5043 In embodiments, the method reduces or prevents lipofuscin accumulation in the retina, optionally in the retinal pigment epithelium (RPE). In embodiments, the method reduces or prevents the formation of retinal pigment epithelium (RPE) debris. As mentioned above, accumulation of lipofuscin in the RPE has been associated with the development of STGD, age-related macular degeneration, and other retinal diseases. The clumps of lipofuscin, a yellow substance that forms flecks, accumulate in and around the macula, impairing central vision. A main component of lipofuscin is the bis-retinoid N-retinylidene-N-retinylethanolamine (A2E), though lipofuscin includes other bis-retinoids. A2E is a fluorescent material that accumulates, with age or in some retinal disorders such as STGD, in the lysosomes of RPE of the eye. RPE lipofuscin includes A2E and an additional fluorophore – a double bond isomer of A2E, iso-A2E. Studies on the photochemistry of A2E and iso-A2E indicated that they exist in a photoequilibrium of 44 (A2E):1 (iso-A2E). See Parish et al., Proc Natl Acad Sci USA.1998;95(25):14609–13. A2E was shown to trigger the accumulation of lipofuscin-like debris in the RPE. Mihai & Washington. Cell Death & Disease 5, e1348(2014). A2E can be responsible for RPE debris found in the human eye, which encompass lipofuscin-like bodies, late-stage lysosomes, abnormal glycogen and lipid deposits, and inclusions that show heterogeneous electron density. Id. A2E thus drives retinal senescence and associated degeneration. A2E’s chemical precursor, vitamin A aldehyde (retinaldehyde), also plays a role in the degenerative process. Lowering levels of one or more of retinaldehyde, A2E, and iso-A2E can treat or mitigate lipofuscin accumulation in the retina, e.g., in the RPE and / or the underlying Bruch’s membrane. In some embodiments, the method reduces or prevents the formation of RPE debris. In some embodiments, the lowering levels of one or more of retinaldehyde, A2E, and iso-A2E can treat or mitigate accumulation of vitamin A dimers in the RPE and Bruch’s membrane (BM). Accordingly, in embodiments, the method provides a lowering of one or more of retinaldehyde, N-retinylidene- N-retinylethanolamine (A2E) and iso-A2E relative to a level of one or more of retinaldehyde, A2E, and iso- A2E without the administration of the present composition. In some embodiments, levels of one or more of retinaldehyde, A2E, and iso-A2E are lowered (relative to a level of one or more of retinaldehyde, A2E, and iso-A2E without the administration of the present composition) by greater than at least about a 40%. In some embodiments, the method provides greater than about a 40%, or greater than about a 50%, or greater than about a 60%, or greater than about a 70%, or greater than about a 80%, or greater than about a 90% lowering. DB1 / 146899640.4 38 SAL-043PC / 126933-5043 In embodiments, the disclosed method(s) is performed in the absence of a steroid treatment. Steroids, such as glucocorticoid steroids (e.g., prednisone) have been used to improve effectiveness of AAV-based gene therapy by reducing immune response. However, steroid treatment is not without side effects. The compositions and methods of the present disclosure can be substantially non-immunogenic, and can therefore eliminate the need for a steroid treatment. In embodiments, the methods are performed in combination with a steroid treatment. In embodiments, the disclosed method(s) can be used to administer the described composition in combination with one or more additional therapeutic agents. Non-limiting examples of the additional therapeutic agents comprise one or more of an anti-Vascular endothelial growth factor (VEGF) therapeutic agents including aflibercept (EYLEA), ranibizumab (LUCENTIS), bevacizumab (Avastin), Soraprazan, Isotretinoin, Dobesilate, 4-methylpyrazole, ALK-0019 (C20 deuterated vitamin A), Fenretinide (a synthetic form of vitamin A), LBS-500, A1120, Emixustat, Fenofibrate, and Avacincaptad pegol. The additional therapeutic agents can include deuterated vitamin A and / or other vitamins or nutritional supplements (e.g., beta carotene, lutein, and zeaxanthin). In embodiments, the method is performed in the absence of a steroid treatment. In embodiments, the method is substantially non-immunogenic. In embodiments, the method described herein can treat and slow progression of various Inherited Macular Degenerations (IMDs) which are a heterogeneous group of disorders characterized by bilateral symmetrical central visual loss. IMDs include Stargardt disease, Best disease, X-linked retinoschisis, pattern dystrophy, Sorsby fundus dystrophy, and autosomal dominant drusen. Best disease is an autosomal dominant condition associated with disease-causing variants in BEST1; X-linked retinoschisis (XLRS) is the most common form of juvenile-onset retinal degeneration in male adolescents; pattern dystrophy (PD) is a group of disorders characterized by variable distributions of pigment deposition at the level of the RPE; Sorsby fundus dystrophy (SFD) is a rare macular dystrophy often leading to bilateral central visual loss in the fifth decade of life; and autosomal dominant drusen (ADD) is an autosomal dominant condition characterized by drusen-like deposits at the macula, which may have a radiating or honeycomb-like appearance. See Rahman et al., Br J Ophthalmol.2020;104(4):451–460. In embodiments, the Inherited Macular Degeneration (IMD) is stargardt (STGD) disease. In embodiments, the STGD disease optionally is STGD Type 1 (STGD1). In embodiments, the STGD disease can be STGD Type 3 (STGD3) or STGD Type 4 (STGD4) disease. In embodiments, the IMD is characterized by one or DB1 / 146899640.4 39 SAL-043PC / 126933-5043 more mutations in ABCA4 gene and wherein the ABCA4 mutations optionally being autosomal recessive mutations. In embodiments, the one or more nucleic acid-based agents comprise a ABCA4 gene, optionally wherein ABC4A gene is codon optimized. In embodiments, the ABCA4 codon optimized nucleic acid sequence is set forth in SEQ ID NO: 10 or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In embodiments, the ABCA4 codon optimized nucleic acid sequence is set forth in SEQ ID NO: 20 or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In embodiments, the ABCA4 codon optimized nucleic acid sequence is set forth in any one of SEQ ID NO: 10, or SEQ ID NO: 20. In embodiments, ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon-optimized form thereof. Codon optimization of a gene of interest (e.g. a transgene) can be used to optimize therapeutic potential of the transgene and its expression in the host organism. Codon optimization is performed to match the codon usage in the transgene with the abundance of transfer RNA (tRNA) for each codon in a host organism or cell. Codon optimization methods are known in the art and described in, for example, WO 2007 / 142954, which is incorporated by reference herein in its entirety. Optimization strategies can include, for example, the modification of translation initiation regions, alteration of mRNA structural elements, and the use of different codon biases. The gene transfer construct includes several other regulatory elements that are selected to ensure stable expression of the construct. Thus, in embodiments, the non-viral vector is a DNA plasmid that can comprise one or more insulator sequences that prevent or mitigate activation or inactivation of nearby genes. In embodiments, the one or more insulator sequences comprise an HS4 insulator (1.2-kb 5′-HS4 chicken β- globin (cHS4) insulator element) and an D4Z4 insulator (tandem macrosatellite repeats linked to Facio- Scapulo-Humeral Dystrophy (FSHD). In embodiments, the sequences of the HS4 insulator and the D4Z4 insulator are as described in Rival-Gervier et al. Mol Ther.2013 Aug; 21(8):1536-50, which is incorporated herein by reference in its entirety. In embodiments, the gene of the gene transfer construct is capable of transposition in the presence of a transposase. In embodiments, the non-viral vector in accordance with embodiments of the present disclosure comprises a nucleic acid construct encoding a transposase. The transposase can be an RNA transposase plasmid. In embodiments, the non-viral vector further comprises a DB1 / 146899640.4 40 SAL-043PC / 126933-5043 nucleic acid construct encoding a DNA transposase plasmid. In some embodiments, the transposase is an in vitro-transcribed mRNA transposase. The transposase is capable of excising and / or transposing the gene from the gene transfer construct to site- or locus-specific genomic regions. Lipids In embodiments, the one or more lipids compact the one or more nucleic acid-based agents to be delivered. In embodiments, the one or more lipids protect the one or more nucleic acid-based agents to be delivered from nuclease degradation. In embodiments, the one or more lipids cause, promote or enhance receptor-mediated uptake of the one or more nucleic acid-based agents, e.g., by a cell. In embodiments, the one or more lipids, e.g., when contacted with a cell, cause, promote or enhance association with negatively charged cellular membranes. In embodiments, the one or more lipids, e.g., when contacted with a cell, cause, promote or enhance fusion with endosomal membranes, without wishing to be bound by theory, facilitating the release of complexes from endosomal compartments. In embodiments, the one or more lipids, e.g., when contacted with a cell, cause, promote or enhance transport of the one or more nucleic acid-based agents from the cytoplasm to the nucleus. In embodiments, the one or more lipids comprise cationic lipids; anionic lipids; neutral lipids; multi-valent charged lipids; and zwitterionic lipids. In embodiments, the one or more lipids include a delivery lipid. In embodiments, the delivery lipid is or comprises a cationic lipid. In embodiments, the cationic lipid is ionizable and / or hydrolysable. In embodiments, the delivery lipid encapsulates, in whole or in part, the one or more nucleic acid-based agents. In embodiments, the delivery lipid, e.g., when contacted with a cell, promotes or increases endosomal escape. In embodiments, the delivery lipid is or comprises SS-OP (ssPalmO-Phe), [(4- hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate). In embodiments, the one or more lipids include one type of delivery lipid. In embodiments, the one or more lipids include more than one type of delivery lipid. In embodiments, the one or more lipids include two types of delivery lipid. DB1 / 146899640.4 41 SAL-043PC / 126933-5043 In embodiments, the one or more lipids include cholesterol. In embodiments, the cholesterol provides increased or enhanced LNP stability. In embodiments, the one or more lipids include a helper lipid. In embodiments, the helper lipid encapsulates, in whole or in part, the one or more nucleic acid-based agents. In embodiments, the helper lipid, e.g., when contacted with a cell, promotes or increases endosomal escape. In embodiments, the helper lipid is a phospholipid. In embodiments the helper lipid is a neutral lipid. In embodiments, the neutral lipid is or comprises dioleoylphosphatidylethanolamine (DOPE) and / or 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC). In embodiments, the helper lipid is a cationic lipid. In embodiments, the cationic lipid is or comprises N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleoyloxy)-3-3- (trimethylammonia) propane (DOTAP), or 1,2-dioleoyl-3-dimethylammonium-propane (DODAP). In embodiments, the helper lipid is or comprises DOPE, DOPC, and / or Distearoylphosphatidylcholine (DSPC). In embodiments, the helper lipid is or comprises both DOPE and DSPC. In embodiments, the helper lipid is or comprises both DOPE and DOPC. In embodiments, the helper lipid is or comprises all of DOPE, DSPC, and DOPC. In embodiments, the one or more lipids include a PEGylated lipid. In embodiments, the PEGylated lipid shields the LNP and reduces or prevents degradation of the LNP, e.g., in the bloodstream. In embodiments, the PEGylated lipid has a PEG molecule covalently attached to it, where the PEG has an average molecular weight of from about 1 kDa to about 50 kDa, or about 1 kDa to about 30 kDa, or from about 1 kDa to about 10 kDa, or about 1 kDa, or about 2 kDa, or about 3 kDa, or about 4 kDa, or about 5 kDa, or about 10 kDa. In embodiments, the PEG is a linear, a branched PEG, a star PEG, or a comb PEG. In embodiments the PEG is selected from PEG200, PEG300, PEG400, PEG600, PEG800, PEG1000, PEG1500, PEG2000, PEG3000, and PEG4000. In embodiments, the PEG is PEG2000. In embodiments the PEGylated lipid is or comprises 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG). In embodiments, the DMG- PEG is or comprises 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (PEG-2k- DMG) and / or a PEG conjugated to a ceramide, e.g., C8 PEG 2k Ceramide, C16 PEG 2k Ceramide. In embodiments the PEGylated lipid is or comprises PEG-dimyristyloxypropyl (PEG-DMA), a PEG-distearyloxypropyl (PEG-DSA), PEG-diacylglycerol (PEG-DAG), or PEG-dialkyloxypropyl (PEG-DAA). In embodiments, the one or more lipids do not include a PEGylated lipid. In embodiments, the one or more lipids do not include a PEGylated lipid, e.g., when being formulated for local administration. In embodiments, the composition comprises a mixture of PEGylated lipids and free PEG chains. DB1 / 146899640.4 42 SAL-043PC / 126933-5043 Compositions / Formulations In embodiments, there is provided a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) a PEGylated lipid. In embodiments, the delivery lipid is SS-OP. In embodiments, the helper lipid is selected from distearoylphosphatidylcholine (DSPC), 1,2-Dioleoyl-sn- glycero-3-phosphocholine (DOPC), and dioleoylphosphatidylethanolamine (DOPE). In embodiments, the PEGylated lipid is selected from PEG-2K-DMG, C8 PEG 2K, and C16 PEG 2K. In embodiments, the one or more lipids do not comprise a PEGylated lipid. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents of about 7:1, or about 8:1, or about 9:1, or about 10:1, or about 11:1, or about 12:1, or about 13:1, and / or a has a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 14:1, or about 15:1, or about 16:1, or about 17:1, or about 18:1, or about 19:1, or about 20:1, or about 21:1, or about 22:1, or about 23:1, or about 24:1, or about 25:1, or about 26:1. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents from about 7:1 to about 13:1 and / or a has a weight to weight ratio of total lipid to one or more nucleic acid-based agents from about 14:1 to about 26:1. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents of about 7:1 and / or a has a weight to weight ratio of total lipid to one or more nucleic acid- based agents of about 25:1. In embodiments, the (i) a delivery lipid comprising from about 15 mol % to about 75 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, DB1 / 146899640.4 43 SAL-043PC / 126933-5043 (iii) a helper lipid comprising from about 5 mol % to about 40 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 0.5 mol % to about 7 mol % of the total lipid present. In embodiments, the (i) a delivery lipid comprising from about 25 mol % to about 75 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 40 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 0.5 mol % to about 3 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 25 mol % to about 75 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 30 mol % of the total lipid present, optionally being one or more of: DOPC from about 5 mol % to about 30 mol % of the total lipid present, and DOPE from about 2.5 mol % to about 30 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 0.5 mol % to about 3 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: Delivery % Mol of Delivery % Mol of Helper % Mol of PEGylated % Mol of d In embodiments, the one or more lipids comprises: DB1 / 146899640.4 44 SAL-043PC / 126933-5043 Delivery % Mol of Delivery % Mol of Helper % Mol of PEGylated % Mol of Lipid Lipid (% mol IL) Cholesterol Lipid Helper Lipid Lipid PEGylated Lipid In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, or about 45 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol %, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, or about 60 mol % of the total lipid present, (iii) a helper lipid comprising about 5 mol %, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol %, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 3 mol %, about 4 mol%, about 5 mol%, about 6 mol%, or about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 15 mol % to about 45 mol % of the total lipid present, the delivery lipid being SS-OP, DB1 / 146899640.4 45 SAL-043PC / 126933-5043 (ii) cholesterol comprising from about 35 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 3 mol % to about 7 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 22 mol % to about 39 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 46 mol % to about 53 mol % of the total lipid present, (iii) a helper lipid comprising from about 7 mol % to about 26 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 4.5 mol % to about 5.5 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 22 mol % to about 26 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 46 mol % to about 50 mol % of the total lipid present, (iii) a helper lipid comprising from about 22 mol % to about 26 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising from about 4 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 34 mol % to about 38 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 48 mol % to about 52 mol % of the total lipid present, (iii) a helper lipid comprising from about 8 mol % to about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and DB1 / 146899640.4 46 SAL-043PC / 126933-5043 (iv) a PEGylated lipid comprising from about 4 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 36 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 51 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 36 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 51 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 24 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 48 mol % of the total lipid present, (iii) a helper lipid comprising about 24 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and DB1 / 146899640.4 47 SAL-043PC / 126933-5043 (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 24 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 48 mol % of the total lipid present, (iii) a helper lipid comprising about 24 mol % of the total lipid present, optionally being one or more of DOPE or DSPC, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG, and a nucleic acid-based agent having a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1 and / or a having a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising from about 5 mol % to about 50 mol % of the total lipid present, (ii) cholesterol comprising from about 15 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 50 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 20 mol % to about 40 mol % of the total lipid present, (ii) cholesterol comprising from about 20 mol % to about 55 mol % of the total lipid present, DB1 / 146899640.4 48 SAL-043PC / 126933-5043 (iii) a helper lipid comprising from about 10 mol % to about 50 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 20 mol % to about 40 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 20 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 15 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, or about 40 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 20 mol %, about 21 mol %, about 22 mol %, about 23 mol %, about 24 mol %, about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol %, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, or about 55 mol% of the total lipid present, (iii) a helper lipid comprising about 15 mol %, about 16 mol %, about 17 mol %, about 18 mol %, about 19 mol %, about 20 mol %, about 21 mol %, about 22 mol %, about 23 mol %, about 24 mol %, about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, DB1 / 146899640.4 49 SAL-043PC / 126933-5043 about 43 mol %, about 44 mol %, or about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, or about 3 mol % of the total lipid present. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, (ii) cholesterol comprising from about 15 mol % to about 35 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 15 mol % to about 35 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, or about 45 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol %, about 20 mol %, about 21 mol %, about 22 mol %, about 23 mol %, about 24 mol %, about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol % of the total lipid present, DB1 / 146899640.4 50 SAL-043PC / 126933-5043 (iii) a helper lipid comprising about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, or about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, about 3 mol %, about 3.5 mol %, about 4 mol %, about 4.5 mol %, or about 5 mol % of the total lipid present. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising about 5%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, or about 35 mol% of the total lipid present, optionally the delivery lipid being SS-OP, DB1 / 146899640.4 51 SAL-043PC / 126933-5043 (ii) cholesterol comprising about 25 mol %, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol %, about 30 mol %, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol %, about 37 mol %, about 38 mol %, about 39 mol %, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol %, about 46 mol %, about 47 mol %, about 48 mol %, about 49 mol %, about 50 mol %, about 51 mol %, about 52 mol %, about 53 mol %, about 54 mol %, or about 55 mol % of the total lipid present, (iii) a helper lipid comprising about 30 mol%, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, or about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, or about 3 mol %, of the total lipid present. In embodiments, the one or more lipids comprises, (i) a delivery lipid comprising from about 20 mol % to about 30 mol % of the total lipid present, (ii) cholesterol comprising from about 30 mol % to about 40 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: (i) a delivery lipid comprising from about 20 mol % to about 30 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 30 mol % to about 40 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present. In embodiments, the one or more lipids comprises: DB1 / 146899640.4 52 SAL-043PC / 126933-5043 (i) a delivery lipid comprising about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, or about 30 mol% of the total lipid present, optionally the delivery lipid being SS-OP, (ii) cholesterol comprising about 30 mol %, about 31 mol %, about 32 mol %, about 33 mol %, about 34 mol %, about 35 mol %, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, or about 40 mol% of the total lipid present, (iii) a helper lipid comprising about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol %, about 36 mol %, about 37 mol %, about 38 mol %, about 39 mol %, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol % of the total lipid present, optionally of the helper lipid being DOPE, and (iv) a PEGylated lipid comprising from about 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, about 3.0 mol %, about 3.5 mol%, about 4.0 mol %, about 4.5 mol%, or about 5.0 mol% of the total lipid present. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 25 mol % of the total lipid present; (ii) cholesterol comprising about 34.5 mol % of the total lipid present; (iii) a helper lipid comprising about 38 mol % of the total lipid present; and (iv) a PEGylated lipid comprising about 2.5 mol % of the total lipid present. In embodiments, the delivery lipid is SSOP. In embodiments, the helper lipid is DOPE. In embodiments, the delivery lipid is SSOP; and the helper lipid is DOPE. In embodiments, the disclosed methods comprise administering to the subject’s a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents, and (b) one or more lipids, the one or more lipids comprising: DB1 / 146899640.4 53 SAL-043PC / 126933-5043 (i) a delivery lipid comprising from about 25 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 34.5 mol % of the total lipid present, (iii) a helper lipid comprising from about 38 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 2.5 mol % of the total lipid present. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid- based agents of about 5:1 to about 15:1, or about 7:1 to about 13:1, or about 8:1 to about 12:1, or about 5:1, or about 6:1, or about 7:1, or about 8:1, or about 9:1, or about 10:1, or about 11:1, or about 12:1, or about 13:1, or about 14:1, or about 15:1. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents from about 7:1 to about 13:1. In embodiments, the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 7:1, or of about 13:1. In embodiments, the composition has a weight to weight ratio of total lipid to one or more nucleic acid-based agents about 10:1 to about 35:1, about 15:1 to about 30:1, about 20:1 to about 25:1, or about 15:1, or about 20:1, or about 25:1, or about 30:1. In embodiments, the composition has a weight to weight ratio of total lipid to one or more nucleic acid-based agents from about 14:1 to about 26:1. In embodiments, the composition has a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 25:1. In embodiments, the composition forms a nucleic acid / lipid particle. In embodiments, the one or more lipids associate into a lipid nanoparticle (LNP). In embodiments, the LNP encapsulates the one or more nucleic acid-based agents. Nucleic Acid-Based Agents : Mobile Element Enzyme In embodiments, the one or more nucleic acid-based agents comprise a nucleic acid which encodes a mobile element enzyme. In embodiments, the mobile element enzyme has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least DB1 / 146899640.4 54 SAL-043PC / 126933-5043 about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. SEQ ID NO: 1: Myotis lucifugus mobile element enzyme protein (572 amino acids, positions 2, 8, 13, and 125, shown in bold and underline) MAQHSDYSDDEFCADKLSNYSCDSDLENASTSDEDSSDDEVMVRPRTLRRRRISSSSSDSESDIEGGREEW SHVDNPPVLEDFLGHQGLNTDAVINNIEDAVKLFIGDDFFEFLVEESNRYYNQNRNNFKLSKKSLKWKDIT PQEMKKFLGLIVLMGQVRKDRRDDYWTTEPWTETPYFGKTMTRDRFRQIWKAWHFNNNADIVNESDRLCKV RPVLDYFVPKFINIYKPHQQLSLDEGIVPWRGRLFFRVYNAGKIVKYGILVRLLCESDTGYICNMEIYCGE GKRLLETIQTVVSPYTDSWYHIYMDNYYNSVANCEALMKNKFRICGTIRKNRGIPKDFQTISLKKGETKFI RKNDILLQVWQSKKPVYLISSIHSAEMEESQNIDRTSKKKIVKPNALIDYNKHMKGVDRADQYLSYYSILR RTVKWTKRLAMYMINCALFNSYAVYKSVRQRKMGFKMFLKQTAIHWLTDDIPEDMDIVPDLQPVPSTSGMR AKPPTSDPPCRLSMDMRKHTLQAIVGSGKKKNILRRCRVCSVHKLRSETRYMCKFCNIPLHKGACFEKYHT LKNY In embodiments, the mobile element enzyme comprises an amino acid other than serine at the position corresponding to position 2 of SEQ ID NO: 1. In embodiments, the amino acid is a non-polar aliphatic amino acid, optionally a non-polar aliphatic amino acid optionally selected from G, A, V, L, I, and P, optionally A. In embodiments, the mobile element enzyme does not have additional residues at the C terminus relative to SEQ ID NO: 1. In embodiments, the enzyme has one or more mutations which confer hyperactivity. In embodiments, the enzyme has one or more amino acid substitutions selected from S8X1, C13X2, N125X3, and D416X4or positions corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has S8X1substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has C13X2 substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has N125X3substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, the enzyme has D416X4substitution, or at a position corresponding thereto relative to SEQ ID NO: 1. In embodiments, X1 is selected from G, A, V, L, I, and P. In embodiments, X2 is selected from K, R, and H. In embodiments, X3is selected K, R, and H. In embodiments, X4is selected N, C, Q, S, and T. In embodiments, X1is P, X2is R and X4is N. SEQ ID NO: 26: Hyperactive Myotis lucifugus mobile element enzyme protein (572 amino acids, positions 2, 8, 13, 125, and 416 described in the text, reshown in bold and underline) 1 MAQHSDYPDD EFRADKLSNY SCDSDLENAS TSDEDSSDDE VMVRPRTLRR RRISSSSSDS 61 ESDIEGGREE WSHVDNPPVL EDFLGHQGLN TDAVINNIED AVKLFIGDDF FEFLVEESNR 121 YYNQKRNNFK LSKKSLKWKD ITPQEMKKFL GLIVLMGQVR KDRRDDYWTT EPWTETPYFG 181 KTMTRDRFRQ IWKAWHFNNN ADIVNESDRL CKVRPVLDYF VPKFINIYKP HQQLSLDEGI 241 VPWRGRLFFR VYNAGKIVKY GILVRLLCES DTGYICNMEI YCGEGKRLLE TIQTVVSPYT 301 DSWYHIYMDN YYNSVANCEA LMKNKFRICG TIRKNRGIPK DFQTISLKKG ETKFIRKNDI 361 LLQVWQSKKP VYLISSIHSA EMEESQNIDR TSKKKIVKPN ALIDYNKHMK GVDRANQYLS DB1 / 146899640.4 55 SAL-043PC / 126933-5043 421 YYSILRRTVK WTKRLAMYMI NCALFNSYAV YKSVRQRKMG FKMFLKQTAI HWLTDDIPED 481 MDIVPDLQPV PSTSGMRAKP PTSDPPCRLS MDMRKHTLQA IVGSGKKKNI LRRCRVCSVH 541 KLRSETRYMC KFCNIPLHKG ACFEKYHTLK NY In embodiments, the mobile element enzyme has the amino acid sequence of SEQ ID NO: 26, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the mobile element enzyme comprises mRNA. In embodiments, the mobile element enzyme comprises a nucleotide sequence of SEQ ID NO: 27, or a nucleotide sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. SEQ ID NO: 27: mRNA sequence of Myotis lucifugus mobile element enzyme that is being delivered to the cell 5’ aggaagcuuucuucugguccccacagacucagagagaacccccgccaccauggcccagcacagcgacuacccagacg acgaguucagggccgacaagcugagcaacuacagcugcgacagcgaccuggaaaacgccagcaccagcgacgaggac agcagcgacgacgaagugauggugaggccaagaacccugagaagaaggagaaucagcagcagcagcagcgacagcga gagcgacauagagggcggacgggaagaauggagccacguggacaaccccccugugcuggaagacuuccugggacacc aaggccugaacacagacgcagugaucaacaacaucgaggacgccgugaagcuguuuaucggcgacgacuucuucgag uuccucgucgaggagagcaaccgguacuacaaccagaacagaaacaacuucaaacugagcaaaaagagccugaagug gaaggacaucaccccccaggaaaugaagaaguuccugggccugaucgugcugaugggccaggucagaaaggaccgca gagacgacuacuggacaacagaaccuuggaccgaaacacccuacuucggcaagaccaugacaagagaccgcuucaga cagauauggaaggccuggcacuuuaacaacaacgccgacaucgugaacgagagcgacagacugugcaaggugagacc cgugcuggacuacuucgucccaaaguucaucaacaucuacaaaccacaccagcagcugagccuggacgagggcaucg ugccauggcggggcagacuguucuucagaguguacaacgccgggaagaucgugaaguacggcauccuggugcgacug cugugcgagagcgacaccggcuacaucuguaacauggagaucuacugcggcgaaggcaagcggcugcuggagaccau ccagacggugguaagccccuacacagauagcugguaccauaucuacauggacaauuacuacaacagcguggccaacu gcgaggcccugaugaagaacaaguuccgcaucugcggaaccaucagaaaaaacagaggcaucccuaaagacuuccag accaucagccugaagaagggcgagacaaaguucauccggaaaaacgacauccugcugcagguguggcaaagcaagaa gcccguguaccucaucagcagcauccacagcgccgagauggaagagagccagaacauagacagaaccagcaagaaaa agaucgugaagccuaacgcccugaucgacuacaacaaacacaugaaaggcguggacagagccgaccaguaccugagc uacuacagcauccuccggcggaccgugaaguggaccaaacggcucgcaauguacaugaucaacugugcccuguucaa uagcuacgcuguguacaagagcgugagacaacggaagaugggcuucaagauguuccugaaacagaccgcgauccacu ggcugaccgacgacaucccugaggacauggacaucgugccggaccugcagccugugcccagcaccagcggcaugcgg gccaagcccccgaccuccgacccacccuguagacuguccauggacaugagaaagcacacacugcaggccaucguggg cagcggcaagaagaagaacauccugagacggugccgggugugcagcgugcacaagcuacggagcgagacccgguaca ugugcaaguucugcaacaucccgcugcacaagggagccugcuucgaaaaguaccacacccugaaaaacuacuaggcu ggagccucgguggccaugcuucuugccccuugggccuccccccagccccuccuccccuuccugcacccguacccccg uggucuuugaauaaagucugagugggcggcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa – 3” In embodiments, the enzyme is capable of inserting a donor DNA at a TA dinucleotide site. DB1 / 146899640.4 56 SAL-043PC / 126933-5043 In embodiments, the enzyme is capable of inserting a donor DNA at a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site. In embodiments, the enzyme comprises: (a) a targeting element, and (b) an enzyme that is capable of inserting the donor DNA (e.g., a mobile element) comprising a gene, optionally at a TA dinucleotide site or a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site in a genomic safe harbor site (GSHS). In embodiments, the nucleic acid-based agents comprise a left inverted terminal repeat (ITR) and a right ITR flanking the nucleic acid encoding the mobile element enzyme. In embodiments, the left ITR comprises a nucleic acid sequence as set forth in SEQ ID NO: 2. In embodiments, the right ITR comprises a nucleic acid sequence as set forth in SEQ ID NO: 14. In embodiments, the targeting element targets the enzyme to a locus of interest. In embodiments, the targeting element comprises one or more of a gRNA, optionally associated with a Cas enzyme, which is optionally catalytically inactive or a transcription activator-like effector (TALE). In embodiments, the targeting element comprises a transcription activator-like effector (TALE) DNA binding domain (DBD) and zinc fingers (ZF) DBD. In embodiments, the TALE DBD comprises one or more repeat sequences. In embodiments, the TALE DBD comprises about 14, or about 15, or about, 16, or about 17, or about 18, or about 18.5 repeat sequences. In embodiments, the TALE DBD repeat sequences comprise 33 or 34 amino acids. In embodiments, the TALE DBD repeat sequences comprise a repeat variable di-residue (RVD) at residue 12 or 13 of the 33 or 34 amino acids. In embodiments, the RVD recognizes one base pair in the nucleic acid molecule. In embodiments, the RVD recognizes a C residue in the nucleic acid molecule and is selected from HD, N(gap), HA, ND, and HI. In embodiments, the RVD recognizes a G residue in the nucleic acid molecule and is selected from NN, NH, NK, HN, and NA. In embodiments, the RVD recognizes an A residue in the nucleic acid molecule and is selected from NI and NS. In embodiments, the RVD recognizes a T residue in the nucleic acid molecule and is selected from NG, HG, H(gap), and IG. In embodiments, the targeting element comprises CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) associated protein 9 (Cas9), or a variant thereof. A CRISPR / Cas9 tool only requires Cas9 nuclease for DNA cleavage and a single-guide RNA (sgRNA) for target specificity. See Jinek et al. (2012) Science 337, 816–821; Chylinski et al. (2014) Nucleic Acids Res 42, 6091–6105. The inactivated form of Cas9, which is a nuclease-deficient (or inactive, or “catalytically dead” Cas9, is typically denoted as “dCas9,” has no substantial nuclease activity. Qi, L. S. et al. (2013). Cell 152, 1173–1183. CRISPR / dCas9 DB1 / 146899640.4 57 SAL-043PC / 126933-5043 binds precisely to specific genomic sequences through targeting of guide RNA (gRNA) sequences. See Dominguez et al., Nat Rev Mol Cell Biol.2016;17:5–15; Wang et al., Annu Rev Biochem.2016;85:227–64. dCas9 is utilized to edit gene expression when applied to the transcription binding site of a desired site and / or locus in a genome. When the dCas9 protein is coupled to guide RNA (gRNA) to create dCas9 guide RNA complex, dCas9 prevents the proliferation of repeating codons and DNA sequences that might be harmful to an organism's genome. Essentially, when multiple repeat codons are produced, it elicits a response, or recruits an abundance of dCas9 to combat the overproduction of those codons and results in the shut-down of transcription. Thus, dCas9 works synergistically with gRNA and directly affects the DNA polymerase II from continuing transcription. In embodiments, the targeting element comprises a nuclease-deficient Cas enzyme guide RNA complex. In embodiments, the targeting element comprises a nuclease-deficient (or inactive, or “catalytically dead” Cas, e.g., Cas9, typically denoted as “dCas” or “dCas9”) guide RNA complex. In embodiments, the targeting element comprises a Cas9 enzyme guide RNA complex. In embodiments, the Cas9 enzyme guide RNA complex comprises a nuclease-deficient dCas9 guide RNA complex. Embodiments of the present disclosure make use of the ability of TALE or Cas or dCas9 / gRNA DBDs to target specific sites in a host genome. The DNA targeting ability of a TALE or Cas DBD or dCas9 / gRNA DBD is provided by TALE repeat sequences (e.g., modular arrays) or gRNA which are linked together to recognize flanking DNA sequences. Each TALE or gRNA can recognize certain base pair(s) or residue(s). In embodiments, the GSHS is in an open chromatin location in a chromosome. In embodiments, the GSHS is selected from adeno-associated virus site 1 (AAVS1), chemokine (C-C motif) receptor 5 (CCR5) gene, HIV-1 coreceptor, and human Rosa26 locus. In embodiments, the enzyme and the targeting element are connected. In embodiments, the enzyme and the targeting element are fused to one another or linked via a linker to one another. In embodiments, the linker is a flexible linker. In embodiments, the flexible linker is substantially comprised of glycine and serine residues, optionally wherein the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 12. In embodiments, the flexible linker is of about 20, or about 30, or about 40, or about 50, or about 60 amino acid residues. Nucleic Acid-Based Agents: Donor DNA or Transgene or Mobile Element DB1 / 146899640.4 58 SAL-043PC / 126933-5043 In embodiments, the one or more nucleic acid-based agents comprise a donor DNA or transgene or mobile element. In embodiments, the donor DNA or transgene or mobile element comprises a gene encoding a complete polypeptide. In embodiments, the donor DNA or transgene or mobile element comprises a gene which is defective or substantially absent in a disease state. In embodiments, the donor DNA or transgene or mobile element is flanked by one or more ends. In embodiments, the mobile element enzyme recognizes the one or more ends. In embodiments, the donor DNA or transgene or mobile element has a size of up to about 10 kb, or up to about 12 kb, up to about 15 kb, or about 7.5 to about 15 kb, or about 10 to about 15 kb. In embodiments, the donor DNA comprises the nucleic acid sequence of ATP binding cassette subfamily A member 4 (ABCA4). In embodiments the nucleic acid sequence of ABCA4 is codon optimized. In embodiments, the ABCA4 codon optimized nucleic acid sequence is set forth in any one of SEQ ID NO: 10, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto; or SEQ ID NO: 20, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In embodiments, ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon-optimized form thereof. RNA / DNA and Ratios Thereof In embodiments, the one or more nucleic acid-based agents is in the form of RNA. In embodiments, the RNA is or comprises mRNA. In embodiments, the mRNA is or comprises mmRNA. In embodiments, the mmRNA comprises one or more of a 5'-m7G cap (cap0, cap1, or cap2), a pseudouridine or n-methyl-pseudouridine substitution, and a poly-A tail of about 30, or about 50, or about 100, of about 150 nucleotides in length. In embodiments, the mobile element enzyme comprises mRNA. In embodiments, the mobile element enzyme comprises a nucleotide sequence of SEQ ID NO: 27, or a nucleotide sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. SEQ ID NO: 27: mRNA sequence of Myotis lucifugus mobile element enzyme that is being delivered to the cell DB1 / 146899640.4 59 SAL-043PC / 126933-5043 5’ aggaagcuuucuucugguccccacagacucagagagaacccccgccaccauggcccagcacagcgacuacccagacg acgaguucagggccgacaagcugagcaacuacagcugcgacagcgaccuggaaaacgccagcaccagcgacgaggac agcagcgacgacgaagugauggugaggccaagaacccugagaagaaggagaaucagcagcagcagcagcgacagcga gagcgacauagagggcggacgggaagaauggagccacguggacaaccccccugugcuggaagacuuccugggacacc aaggccugaacacagacgcagugaucaacaacaucgaggacgccgugaagcuguuuaucggcgacgacuucuucgag uuccucgucgaggagagcaaccgguacuacaaccagaacagaaacaacuucaaacugagcaaaaagagccugaagug gaaggacaucaccccccaggaaaugaagaaguuccugggccugaucgugcugaugggccaggucagaaaggaccgca gagacgacuacuggacaacagaaccuuggaccgaaacacccuacuucggcaagaccaugacaagagaccgcuucaga cagauauggaaggccuggcacuuuaacaacaacgccgacaucgugaacgagagcgacagacugugcaaggugagacc cgugcuggacuacuucgucccaaaguucaucaacaucuacaaaccacaccagcagcugagccuggacgagggcaucg ugccauggcggggcagacuguucuucagaguguacaacgccgggaagaucgugaaguacggcauccuggugcgacug cugugcgagagcgacaccggcuacaucuguaacauggagaucuacugcggcgaaggcaagcggcugcuggagaccau ccagacggugguaagccccuacacagauagcugguaccauaucuacauggacaauuacuacaacagcguggccaacu gcgaggcccugaugaagaacaaguuccgcaucugcggaaccaucagaaaaaacagaggcaucccuaaagacuuccag accaucagccugaagaagggcgagacaaaguucauccggaaaaacgacauccugcugcagguguggcaaagcaagaa gcccguguaccucaucagcagcauccacagcgccgagauggaagagagccagaacauagacagaaccagcaagaaaa agaucgugaagccuaacgcccugaucgacuacaacaaacacaugaaaggcguggacagagccgaccaguaccugagc uacuacagcauccuccggcggaccgugaaguggaccaaacggcucgcaauguacaugaucaacugugcccuguucaa uagcuacgcuguguacaagagcgugagacaacggaagaugggcuucaagauguuccugaaacagaccgcgauccacu ggcugaccgacgacaucccugaggacauggacaucgugccggaccugcagccugugcccagcaccagcggcaugcgg gccaagcccccgaccuccgacccacccuguagacuguccauggacaugagaaagcacacacugcaggccaucguggg cagcggcaagaagaagaacauccugagacggugccgggugugcagcgugcacaagcuacggagcgagacccgguaca ugugcaaguucugcaacaucccgcugcacaagggagccugcuucgaaaaguaccacacccugaaaaacuacuaggcu ggagccucgguggccaugcuucuugccccuugggccuccccccagccccuccuccccuuccugcacccguacccccg uggucuuugaauaaagucugagugggcggcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa – 3” In embodiments, the one or more nucleic acid-based agents is in the form of DNA. In embodiments, the DNA is or comprises plasmid DNA or miniplasmid DNA. In embodiments, the plasmid DNA has a size of up to about 10 kb, or up to about 12 kb, up to about 15 kb, or about 7.5 to about 15 kb, or about 10 to about 15 kb. In embodiments, the nucleic acid-based agent comprises both a nucleic acid encoding a mobile element enzyme and a donor DNA or transgene or mobile element. In embodiments, the nucleic acid-based agent comprises both RNA and DNA. In embodiments, the nucleic acid-based agent comprises both mRNA and DNA. In embodiments, the weight to weight ratio of DNA : mRNA is from about 10:1 to about 1:10, or about 10 : about 1, or about 9 : about 1, or about 8 : about 1, or about 7 : about 1, or about 6 : about 1, or about 5 : about 1, or about 4 : about 1, or about 3 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 3, or about 1 : about 4, or about 1 : about 5, or about 1 : about 6, or about 1 : about 7, or about 1 : about 8, or about 1 : about 9, or about 1 : about 10. In embodiments, the nucleic acid-based agent comprises both mmRNA and plasmid DNA. DB1 / 146899640.4 60 SAL-043PC / 126933-5043 In embodiments, the nucleic acid-based agent comprises both a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA. In embodiments, the nucleic acid-based agent comprises both a nucleic acid encoding a mobile element enzyme of SEQ ID NO: 1 in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA. In embodiments, the nucleic acid-based agent comprises both a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA and the weight to weight ratio of plasmid DNA : mmRNA is about 5 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 5. In embodiments, the nucleic acid-based agent comprises both a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA and the weight to weight ratio of plasmid DNA : mmRNA about 2 : about 1. Features of the LNP In embodiments, the composition provides high encapsulation of the nucleic acid-based agent, e.g., compared a different collection of lipids, e.g., a different LNP. In embodiments, the composition provides an encapsulation efficiency of greater than about 90%, greater than about 95%, greater than about 98%. Encapsulation efficiency can be measured as is known in the art, e.g., using fluorescent dye that is used in the detection and quantification of nucleic acids, e.g., using the RiboGreen assay (THERMO), or a similar assay. In embodiments, the composition provides low polydispersity, e.g., compared a different collection of lipids, e.g., a different LNP. Assays / calculations used for the determination of polydispersity are known in the art, e.g., using parameters are defined in the ISO standard documents 13321:1996 E and ISO 22412:2008. In embodiments, the composition is an LNP having a particle size of about 60 to about 200 nm, or about 100 to about 150 nm, or about 60 to about 120 nm. Assays / calculations used for the determination of particle size are known in the art, e.g., using parameters are defined in the ISO standard documents 13321:1996 E and ISO 22412:2008. Administration DB1 / 146899640.4 61 SAL-043PC / 126933-5043 In embodiments, the composition is suitable for systemic delivery in a subject. In embodiments, the composition is suitable for intravenous, subcutaneous, or intraperitoneal delivery in a subject. In embodiments, the composition is suitable for local delivery in a subject. In embodiments, the composition is suitable for subretinal delivery in a subject. In embodiments, the methods comprise administering the disclosed composition to the subject through systemic delivery. In embodiments, the administering to the subject is through intravenous, subcutaneous, or intraperitoneal delivery. In embodiments, the administering to the subject is through local delivery. In embodiments, the administering to the subject is through subretinal delivery. In embodiments, the administering to the subject is through a single administration. Kits In embodiments, the compositions, or one or more lipids, optionally with the nucleic acid-based agents, is included in a container, kit, pack, or dispenser together with instructions for administration and / or association (e.g., to form an LNP). In embodiments, the kit includes instructions for administration and / or association (e.g., to form an LNP) in accordance with the method of the present disclosure. Definitions The following definitions are used in connection with the disclosure disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs. As used herein, “a,” “an,” or “the” can mean one or more than one. Further, the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language “about 50” covers the range of 45 to 55. An “effective amount,” when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest. DB1 / 146899640.4 62 SAL-043PC / 126933-5043 As used herein, the term “variant” encompasses but is not limited to nucleic acids or proteins which comprise a nucleic acid or amino acid sequence which differs from the nucleic acid or amino acid sequence of a reference by way of one or more substitutions, deletions and / or additions at certain positions. The variant may comprise one or more conservative substitutions. Conservative substitutions may involve, e.g., the substitution of similarly charged or uncharged amino acids. As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features. Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.” Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to about 50% of the population) and the ED50(the dose therapeutically effective in about 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50. In some embodiments, compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50as determined in cell culture, or in an appropriate animal model. Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. As used herein, “methods of treatment” are equally applicable to use of a composition for treating the diseases or disorders described herein and / or compositions for use and / or uses in the manufacture of a medicaments for treating the diseases or disorders described herein. SELECTED SEQUENCES DB1 / 146899640.4 63 SAL-043PC / 126933-5043 In embodiments, the present disclosure provides for any of the sequence provided herein, including the below, and a variant sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, or at least about 10 mutations, or at least about 9 mutations, or at least about 8 mutations, or at least about 7 mutations, or at least about 6 mutations, or at least about 5 mutations, or at least about 4 mutations, or at least about 3 mutations, or at least about 2 mutations, or at least about 1 mutation. SEQ ID NO: 1: Myotis lucifugus mobile element enzyme protein (572 amino acids, positions 2, 8, 13, 125, and 416 described in the text, reshown in bold and underline) 1 MSQHSDYSDD EFCADKLSNY SCDSDLENAS TSDEDSSDDE VMVRPRTLRR RRISSSSSDS 61 ESDIEGGREE WSHVDNPPVL EDFLGHQGLN TDAVINNIED AVKLFIGDDF FEFLVEESNR 121 YYNQNRNNFK LSKKSLKWKD ITPQEMKKFL GLIVLMGQVR KDRRDDYWTT EPWTETPYFG 181 KTMTRDRFRQ IWKAWHFNNN ADIVNESDRL CKVRPVLDYF VPKFINIYKP HQQLSLDEGI 241 VPWRGRLFFR VYNAGKIVKY GILVRLLCES DTGYICNMEI YCGEGKRLLE TIQTVVSPYT 301 DSWYHIYMDN YYNSVANCEA LMKNKFRICG TIRKNRGIPK DFQTISLKKG ETKFIRKNDI 361 LLQVWQSKKP VYLISSIHSA EMEESQNIDR TSKKKIVKPN ALIDYNKHMK GVDRADQYLS 421 YYSILRRTVK WTKRLAMYMI NCALFNSYAV YKSVRQRKMG FKMFLKQTAI HWLTDDIPED 481 MDIVPDLQPV PSTSGMRAKP PTSDPPCRLS MDMRKHTLQA IVGSGKKKNI LRRCRVCSVH 541 KLRSETRYMC KFCNIPLHKG ACFEKYHTLK NY SEQ ID NO: 26: Hyperactive Myotis lucifugus mobile element enzyme protein (572 amino acids, positions 2, 8, 13, 125, and 416 described in the text, reshown in bold and underline) 1 MAQHSDYPDD EFRADKLSNY SCDSDLENAS TSDEDSSDDE VMVRPRTLRR RRISSSSSDS 61 ESDIEGGREE WSHVDNPPVL EDFLGHQGLN TDAVINNIED AVKLFIGDDF FEFLVEESNR 121 YYNQNRNNFK LSKKSLKWKD ITPQEMKKFL GLIVLMGQVR KDRRDDYWTT EPWTETPYFG 181 KTMTRDRFRQ IWKAWHFNNN ADIVNESDRL CKVRPVLDYF VPKFINIYKP HQQLSLDEGI 241 VPWRGRLFFR VYNAGKIVKY GILVRLLCES DTGYICNMEI YCGEGKRLLE TIQTVVSPYT 301 DSWYHIYMDN YYNSVANCEA LMKNKFRICG TIRKNRGIPK DFQTISLKKG ETKFIRKNDI 361 LLQVWQSKKP VYLISSIHSA EMEESQNIDR TSKKKIVKPN ALIDYNKHMK GVDRANQYLS 421 YYSILRRTVK WTKRLAMYMI NCALFNSYAV YKSVRQRKMG FKMFLKQTAI HWLTDDIPED 481 MDIVPDLQPV PSTSGMRAKP PTSDPPCRLS MDMRKHTLQA IVGSGKKKNI LRRCRVCSVH 541 KLRSETRYMC KFCNIPLHKG ACFEKYHTLK NY SEQ ID NO: 27: mRNA sequence of Myotis lucifugus mobile element enzyme that is being delivered to the cell 5’ aggaagcuuucuucugguccccacagacucagagagaacccccgccaccauggcccagcacagcgacuacccagacg acgaguucagggccgacaagcugagcaacuacagcugcgacagcgaccuggaaaacgccagcaccagcgacgaggac agcagcgacgacgaagugauggugaggccaagaacccugagaagaaggagaaucagcagcagcagcagcgacagcga gagcgacauagagggcggacgggaagaauggagccacguggacaaccccccugugcuggaagacuuccugggacacc aaggccugaacacagacgcagugaucaacaacaucgaggacgccgugaagcuguuuaucggcgacgacuucuucgag uuccucgucgaggagagcaaccgguacuacaaccagaacagaaacaacuucaaacugagcaaaaagagccugaagug gaaggacaucaccccccaggaaaugaagaaguuccugggccugaucgugcugaugggccaggucagaaaggaccgca gagacgacuacuggacaacagaaccuuggaccgaaacacccuacuucggcaagaccaugacaagagaccgcuucaga cagauauggaaggccuggcacuuuaacaacaacgccgacaucgugaacgagagcgacagacugugcaaggugagacc DB1 / 146899640.4 64 SAL-043PC / 126933-5043 cgugcuggacuacuucgucccaaaguucaucaacaucuacaaaccacaccagcagcugagccuggacgagggcaucg ugccauggcggggcagacuguucuucagaguguacaacgccgggaagaucgugaaguacggcauccuggugcgacug cugugcgagagcgacaccggcuacaucuguaacauggagaucuacugcggcgaaggcaagcggcugcuggagaccau ccagacggugguaagccccuacacagauagcugguaccauaucuacauggacaauuacuacaacagcguggccaacu gcgaggcccugaugaagaacaaguuccgcaucugcggaaccaucagaaaaaacagaggcaucccuaaagacuuccag accaucagccugaagaagggcgagacaaaguucauccggaaaaacgacauccugcugcagguguggcaaagcaagaa gcccguguaccucaucagcagcauccacagcgccgagauggaagagagccagaacauagacagaaccagcaagaaaa agaucgugaagccuaacgcccugaucgacuacaacaaacacaugaaaggcguggacagagccgaccaguaccugagc uacuacagcauccuccggcggaccgugaaguggaccaaacggcucgcaauguacaugaucaacugugcccuguucaa uagcuacgcuguguacaagagcgugagacaacggaagaugggcuucaagauguuccugaaacagaccgcgauccacu ggcugaccgacgacaucccugaggacauggacaucgugccggaccugcagccugugcccagcaccagcggcaugcgg gccaagcccccgaccuccgacccacccuguagacuguccauggacaugagaaagcacacacugcaggccaucguggg cagcggcaagaagaagaacauccugagacggugccgggugugcagcgugcacaagcuacggagcgagacccgguaca ugugcaaguucugcaacaucccgcugcacaagggagccugcuucgaaaaguaccacacccugaaaaacuacuaggcu ggagccucgguggccaugcuucuugccccuugggccuccccccagccccuccuccccuuccugcacccguacccccg uggucuuugaauaaagucugagugggcggcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa – 3” Constructs for ABCA4 nucleic acids delivery ATP binding cassette subfamily A member 4 (ABCA4) protein is a retina-specific ABC transporter with N- retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essential molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile- onset macular degeneration. Mutations in this gene are also associated with other conditions such as retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. In embodiments, the ABCA4 nucleic acid is operably coupled to a promoter that can influence overall expression levels and cell-specificity of the transgenes (e.g. ABCA4 or a functional fragment thereof). In some embodiments, the promoter is a CAG promoter (cytomegalovirus (CMV) enhancer fused to the chicken β-actin promoter and rabbit beta-Globin splice acceptor) (1732 bp), which expresses in both RPE and photoreceptor levels in vivo and in vitro. In some embodiments, the CAG promoter comprises the following nucleotide sequence. Nucleic acid-based agent (1) SG-D2-0034 Cag-hABCA4 (Insulator.Cag.hABCA4-CO.rBG.Insulator) Left Mobile element enzyme ITR (SEQ ID NO: 2) TTAACACTTGGATTGCGGGAAACGAGTTAAGTCGGCTCGCGTGAATTGCGCGTACTCCGCGGGAGCC GTCTTAACTCGGTTCATATAGATTTGCGGTGGAGTGCGGGAAACGTGTAAACTCGGGCCGATTGTAAC TGCGTATTACCAAATATTTGTT DB1 / 146899640.4 65 SAL-043PC / 126933-5043 Spacer sequence 1 (SEQ ID NO: 3) AGATCCTCTAGCGATAAGCTTGATATCGAATTCGAGGTCGACT Dimer HS4 Insulator (SEQ ID NO: 4) GGCGCGCCTGTCATTCTAAATCTCTCTTTCAGCCTAAAGCTTTTTCCCCGTATCCCCCCAGGTGTCTGC AGGCTCAAAGAGCAGCGAGAAGCGTTCAGAGGAAAGCGATCCCGTGCCACCTTCCCCGTGCCCGGG CTGTCCCCGCACGCTGCCGGCTCGGGGATGCGGGGGGAGCGCCGGACCGGAGCGGAGCCCCGGG CGGCTCGCTGCTGCCCCCTAGCGGGGGAGGGACGTAATTACATCCCTGGGGGCTTTGGGAGGGGGC TGTCCCCGTGAGCTCCCAGGCGCGCCTGTCATTCTAAATCTCTCTTTCAGCCTAAAGCTTTTTCCCCGT ATCCCCCCAGGTGTCTGCAGGCTCAAAGAGCAGCGAGAAGCGTTCAGAGGAAAGCGATCCCGTGCCA CCTTCCCCGTGCCCGGGCTGTCCCCGCACGCTGCCGGCTCGGGGATGCGGGGGGAGCGCCGGACC GGAGCGGAGCCCCGGGCGGCTCGCTGCTGCCCCCTAGCGGGGGAGGGACGTAATTACATCCCTGG GGGCTTTGGGGGGGGGCTGTCCCCGT Spacer Sequence 2 (SEQ ID NO: 5) TCTAGAGAGCTCAATAAAAGAGCCCACAACCCCTCACTCGGC Cag Promoter (combination of the CMV Enhancer, Chicken B-Actin Promoter, and Chimeric Intron) CMV Enhancer (SEQ ID NO: 6) GTCGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATAT GGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTG GAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATT GACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTAC TTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG Chicken B-Actin Promoter (SEQ ID NO: 7) GTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTA TTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGC GGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAG AGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGA AGCGCGCGGCGGGCG DB1 / 146899640.4 66 SAL-043PC / 126933-5043 Chimeric Intron (SEQ ID NO: 8) GGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCG GCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAAT TAGCGCTTGGTTTAATGACGGCTTGTTTCTTTTCTGTGGCTGCGTGAAAGCCTTGAGGGGCTCCGGGA GGGCCCTTTGTGCGGGGGGAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCG CGTGCGGCTCCGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTC CGCAGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGCGGGGGGGGCTGCGAG GGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGGTGTGGGCGCGTCGGT CGGGCTGCAACCCCCCCTGCACCCCCCTCCCCGAGTTGCTGAGCACGGCCCGGCTTCGGGTGCGGG GCTCCGTACGGGGCGTGGCGCGGGGCTCGCCGTGCCGGGCGGGGGGTGGCGGCAGGTGGGGGTG CCGGGCGGGGCGGGGCCGCCTCGGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGG AGCGCCGGCGGCTGTCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGG GCGCAGGGACTTCCTTTGTCCCAAATCTGTGCGGAGCCGAAATCTGGGAGGCGCCGCCGCACCCCCT CTAGCGGGCGCGGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGGGCGGGGAGGGCCTTCG TGCGTCGCCGCGCCGCCGTCCCCTTCTCCCTCTCCAGCCTCGGGGCTGTCCGCGGGGGGACGGCTG CCTTCGGGGGGGACGGGGCAGGGCGGGGTTCGGCTTCTGGCGTGTGACCGGCGGCTCTAGAGCCT CTGCTAACCATGTTCATGCCTTCTTCTTTTTCCTACAGCTCCTGGGCAACGTGCTGGTTATTGTGCTGT CTCATCATTTTGGCAAAGAATTC attB1 / Partial Kozak Sequence (SEQ ID NO: 9) CAAGTTTGTACAAAAAAGCAGGCTGCCACC SEQ ID NO: 28: ABCA4 Amino Acid Sequence (Sequence from uniProt, P78363 · ABCA4_HUMAN) 10 20 30 40 50 60 MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA 70 80 90 100 110 120 MPSAGMLPWL QGIFCNVNNP CFQSPTPGES PGIVSNYNNS ILARVYRDFQ ELLMNAPESQ 130 140 150 160 170 180 HLGRIWTELH ILSQFMDTLR THPERIAGRG IRIRDILKDE ETLTLFLIKN IGLSDSVVYL 190 200 210 220 230 240 LINSQVRPEQ FAHGVPDLAL KDIACSEALL ERFIIFSQRR GAKTVRYALC SLSQGTLQWI 250 260 270 280 290 300 310 320 330 340 350 360 RPLMQNGGPE TFTKLMGILS DLLCGYPEGG GSRVLSFNWY EDNNYKAFLG IDSTRKDPIY 370 380 390 400 410 420 SYDRRTTSFC NALIQSLESN PLTKIAWRAA KPLLMGKILY TPDSPAARRI LKNANSTFEE 430 440 450 460 470 480 LEHVRKLVKA WEEVGPQIWY FFDNSTQMNM IRDTLGNPTV KDFLNRQLGE EGITAEAILN 490 500 510 520 530 540 FLYKGPRESQ ADDMANFDWR DIFNITDRTL RLVNQYLECL VLDKFESYND ETQLTQRALS 550 560 570 580 590 600 LLEENMFWAG VVFPDMYPWT SSLPPHVKYK IRMDIDVVEK TNKIKDRYWD SGPRADPVED 610 620 630 640 650 660 FRYIWGGFAY LQDMVEQGIT RSQVQAEAPV GIYLQQMPYP CFVDDSFMII LNRCFPIFMV 670 680 690 700 710 720 DB1 / 146899640.4 67 SAL-043PC / 126933-5043 LAWIYSVSMT VKSIVLEKEL RLKETLKNQG VSNAVIWCTW FLDSFSIMSM SIFLLTIFIM 730 740 750 760 770 780 HGRILHYSDP FILFLFLLAF STATIMLCFL LSTFFSKASL AAACSGVIYF TLYLPHILCF 790 800 810 820 830 840 AWQDRMTAEL KKAVSLLSPV AFGFGTEYLV RFEEQGLGLQ WSNIGNSPTE GDEFSFLLSM 850 860 870 880 890 900 910 920 930 940 950 960 TEETEDPEHP EGIHDSFFER EHPGWVPGVC VKNLVKIFEP CGRPAVDRLN ITFYENQITA 970 980 990 1000 1010 1020 FLGHNGAGKT TTLSILTGLL PPTSGTVLVG GRDIETSLDA VRQSLGMCPQ HNILFHHLTV 1030 1040 1050 1060 1070 1080 AEHMLFYAQL KGKSQEEAQL EMEAMLEDTG LHHKRNEEAQ DLSGGMQRKL SVAIAFVGDA 1090 1100 1110 1120 1130 1140 KVVILDEPTS GVDPYSRRSI WDLLLKYRSG RTIIMSTHHM DEADLLGDRI AIIAQGRLYC 1150 1160 1170 1180 1190 1200 SGTPLFLKNC FGTGLYLTLV RKMKNIQSQR KGSEGTCSCS SKGFSTTCPA HVDDLTPEQV 1210 1220 1230 1240 1250 1260 LDGDVNELMD VVLHHVPEAK LVECIGQELI FLLPNKNFKH RAYASLFREL EETLADLGLS 1270 1280 1290 1300 1310 1320 SFGISDTPLE EIFLKVTEDS DSGPLFAGGA QQKRENVNPR HPCLGPREKA GQTPQDSNVC 1330 1340 1350 1360 1370 1380 SPGAPAAHPE GQPPPEPECP GPQLNTGTQL VLQHVQALLV KRFQHTIRSH KDFLAQIVLP 1390 1400 1410 1420 1430 1440 ATFVFLALML SIVIPPFGEY PALTLHPWIY GQQYTFFSMD EPGSEQFTVL ADVLLNKPGF 1450 1460 1470 1480 1490 1500 GNRCLKEGWL PEYPCGNSTP WKTPSVSPNI TQLFQKQKWT QVNPSPSCRC STREKLTMLP 1520 1530 1540 1550 1560 ECPEGAGGLP PPQRTQRSTE ILQDLTDRNI SDFLVKTYPA LIRSSLKSKF WVNEQRYGGI 1570 1580 1590 1600 1610 1620 SIGGKLPVVP ITGEALVGFL SDLGRIMNVS GGPITREASK EIPDFLKHLE TEDNIKVWFN 1630 1640 1650 1660 1670 NKGWHALVSF LNVAHNAILR ASLPKDRSPE EYGITVISQP LNLTKEQLSE ITVLTTSVDA 1690 1700 1710 1720 1730 1740 VVAICVIFSM SFVPASFVLY LIQERVNKSK HLQFISGVSP TTYWVTNFLW DIMNYSVSAG LVVGIFIGFQ KKAYTSPENL PALVALLLLY GWAVIPMMYP ASFLFDVPST AYVALSCANL 1810 1820 1830 1840 1850 1860 FIGINSSAIT FILELFENNR TLLRFNAVLR KLLIVFPHFC LGRGLIDLAL SQAVTDVYAR 1870 1880 1890 1900 1910 1920 FGEEHSANPF HWDLIGKNLF AMVVEGVVYF LLTLLVQRHF FLSQWIAEPT KEPIVDEDDD 1930 1940 1950 1960 1970 1980 VAEERQRIIT GGNKTDILRL HELTKIYPGT SSPAVDRLCV GVRPGECFGL LGVNGAGKTT 1990 2000 2010 2020 2030 2040 TFKMLTGDTT VTSGDATVAG KSILTNISEV HQNMGYCPQF DAIDELLTGR EHLYLYARLR 2050 2060 2070 2080 2090 2100 GVPAEEIEKV ANWSIKSLGL TVYADCLAGT YSGGNKRKLS TAIALIGCPP LVLLDEPTTG 2110 2120 2130 2140 2150 2160 MDPQARRMLW NVIVSIIREG RAVVLTSHSM EECEALCTRL AIMVKGAFRC MGTIQHLKSK 2170 2180 2190 2200 2210 2220 FGDGYIVTMK IKSPKDDLLP DLNPVEQFFQ GNFPGSVQRE RHYNMLQFQV SSSSLARIFQ 2230 2240 2250 2260 DB1 / 146899640.4 68 SAL-043PC / 126933-5043 ABCA4 (Hs) Codon Optimized NM_000350.3 (SEQ ID NO: 10) ATGGGTTTCGTGCGCCAGATCCAGCTGCTGCTTTGGAAGAACTGGACCCTGAGAAAAAGGCAGAAGA TCAGGTTCGTGGTGGAGCTGGTGTGGCCTCTGAGTCTGTTTCTGGTGCTGATCTGGCTGAGGAACGC CAACCCACTTTACAGTCACCACGAATGCCATTTTCCCAATAAGGCCATGCCAAGCGCCGGCATGCTGC CATGGCTGCAGGGCATCTTCTGCAATGTGAACAACCCTTGCTTCCAGAGCCCAACCCCCGGCGAGAG CCCTGGCATCGTGTCTAATTATAACAACTCCATCCTGGCCAGGGTGTACCGTGATTTTCAGGAACTGC TGATGAATGCCCCCGAGAGCCAGCATCTGGGCAGGATCTGGACAGAGCTCCATATTCTGTCACAGTTT ATGGATACTTTGCGCACTCACCCTGAACGCATCGCCGGCAGAGGCATCAGGATCCGCGACATCTTGA AGGACGAAGAAACCCTGACCCTGTTTCTCATCAAAAATATCGGCCTGTCCGATTCCGTGGTGTATCTTC TGATTAATAGCCAGGTGAGGCCCGAACAGTTCGCCCACGGCGTGCCTGATCTGGCTCTGAAGGACAT TGCCTGTAGCGAGGCCCTGCTGGAGCGCTTTATCATTTTCTCCCAGCGGAGGGGCGCCAAAACTGTG CGCTACGCCCTGTGCTCTCTGAGCCAGGGCACCCTGCAGTGGATCGAGGATACTCTGTATGCCAACG TCGACTTCTTTAAGCTGTTCCGGGTGCTGCCAACCCTCCTGGACAGTCGGAGCCAGGGAATCAATCTG CGGTCCTGGGGCGGCATTCTGTCCGACATGTCACCTAGAATACAGGAGTTCATCCACAGGCCATCCAT GCAGGACCTGCTGTGGGTGACAAGGCCACTGATGCAGAACGGCGGCCCTGAGACATTCACAAAGCTG ATGGGAATCTTGTCTGACCTGCTGTGTGGGTATCCAGAGGGGGGGGGCTCCCGGGTGCTGAGCTTTA ACTGGTACGAGGACAATAATTACAAAGCCTTTCTCGGCATCGACTCTACCAGAAAGGACCCGATTTATT CTTACGACAGGAGGACCACCAGCTTCTGCAATGCCCTGATCCAGAGCCTGGAGTCCAACCCTCTGAC AAAAATTGCCTGGAGAGCAGCCAAGCCTCTGCTGATGGGAAAAATCCTGTACACCCCCGATTCACCTG CCGCCAGGCGCATCCTCAAGAACGCAAATAGTACCTTCGAGGAACTCGAGCACGTGAGGAAACTGGT GAAGGCCTGGGAGGAGGTGGGACCTCAGATCTGGTACTTTTTCGATAATTCTACACAGATGAATATGA TCAGAGATACACTGGGCAATCCTACCGTGAAGGACTTCCTGAATAGACAGCTGGGCGAGGAGGGCAT CACTGCCGAAGCCATTCTGAACTTCCTGTACAAGGGACCAAGGGAGAGCCAAGCAGATGACATGGCC AACTTCGATTGGAGAGATATTTTCAACATCACTGATCGGACCCTGAGGCTGGTGAATCAGTACCTGGA ATGCCTGGTGCTGGACAAGTTCGAGTCCTACAATGACGAGACCCAGCTGACACAGCGGGCACTGAGC CTGCTCGAGGAAAATATGTTTTGGGCAGGGGTGGTGTTCCCCGACATGTACCCATGGACTAGCTCTCT GCCCCCCCACGTGAAATATAAGATCAGAATGGACATCGACGTGGTGGAGAAGACCAACAAGATCAAA GACAGATACTGGGATAGTGGGCCACGCGCAGACCCCGTGGAGGATTTCCGCTACATCTGGGGCGGC TTCGCCTACCTGCAGGACATGGTGGAACAGGGCATCACTCGCAGCCAGGTGCAGGCCGAGGCACCC GTGGGCATCTACCTGCAGCAGATGCCCTACCCCTGCTTCGTGGACGATTCATTCATGATCATTCTGAA CCGCTGTTTTCCCATTTTTATGGTGTTGGCCTGGATCTACAGCGTGTCCATGACCGTGAAATCCATCGT GCTGGAGAAGGAGCTCAGGCTGAAGGAGACCCTGAAGAACCAGGGTGTGTCAAATGCCGTGATCTG GTGCACCTGGTTCCTGGATTCCTTTTCCATCATGAGCATGTCTATCTTCCTGCTGACCATCTTTATTATG CATGGGAGGATTCTCCATTACTCCGATCCCTTTATCCTGTTCCTGTTCCTGCTGGCCTTCTCTACCGCC ACCATCATGCTGTGCTTCCTGCTGAGCACCTTTTTTAGCAAGGCCTCCCTGGCCGCCGCCTGCAGCG GCGTGATTTACTTTACCCTGTACCTGCCCCATATTCTGTGTTTTGCATGGCAGGACAGAATGACCGCC GAGCTGAAGAAGGCCGTGAGTCTGCTGTCTCCTGTGGCCTTCGGGTTTGGGACCGAGTACCTGGTGC GGTTCGAGGAGCAGGGCCTCGGCCTCCAGTGGAGCAACATCGGCAACAGCCCCACAGAGGGAGACG AGTTCTCTTTCCTGCTGTCCATGCAGATGATGCTGCTGGACGCCGCTGTGTACGGCCTGCTCGCCTG GTATCTGGACCAGGTGTTCCCCGGGGATTATGGCACTCCTCTGCCCTGGTACTTCCTGCTGCAAGAAA GCTACTGGCTGGGCGGGGAGGGGTGTTCCACTCGCGAGGAGCGCGCCCTGGAAAAGACAGAACCCC TGACAGAGGAGACCGAAGATCCCGAGCATCCTGAGGGCATACACGACTCATTCTTCGAGCGCGAGCA CCCAGGCTGGGTGCCAGGCGTGTGTGTGAAAAATCTTGTCAAAATTTTCGAACCTTGCGGTAGACCTG CAGTGGACAGACTCAACATAACATTCTACGAGAACCAGATCACCGCCTTCCTGGGACACAACGGCGC CGGCAAAACCACCACCCTGAGCATCCTGACAGGCCTGCTCCCTCCAACCAGTGGAACCGTGCTGGTT GGAGGCAGAGACATCGAGACCAGCCTGGACGCCGTCCGGCAGAGCCTGGGCATGTGCCCTCAGCAC DB1 / 146899640.4 69 SAL-043PC / 126933-5043 AACATTCTCTTCCACCACCTGACCGTGGCCGAGCACATGCTCTTCTACGCCCAGCTGAAGGGCAAGA GCCAGGAAGAGGCCCAGCTCGAGATGGAGGCTATGCTGGAGGACACAGGCCTGCACCATAAGAGAA ACGAAGAGGCACAGGATCTGAGCGGCGGCATGCAGAGGAAACTGTCCGTGGCCATCGCCTTCGTGG GGGACGCTAAAGTTGTGATCCTGGACGAGCCCACATCAGGGGTGGACCCCTATAGCAGGCGGTCCAT CTGGGACCTTCTGCTGAAGTATCGCAGTGGACGCACAATCATCATGTCAACCCATCACATGGACGAGG CTGACCTGCTGGGCGACCGCATCGCTATCATCGCCCAGGGCAGGCTGTATTGCTCTGGGACTCCTCT GTTTCTGAAGAACTGCTTTGGCACCGGCCTGTACCTGACACTGGTGCGGAAAATGAAAAATATACAGA GCCAGAGAAAGGGCAGCGAGGGAACCTGCAGCTGTTCTTCCAAGGGCTTTTCCACCACCTGTCCTGC GCACGTGGACGACCTGACCCCCGAGCAGGTGCTGGACGGCGACGTGAACGAGCTGATGGACGTGGT GCTGCACCATGTGCCCGAGGCCAAGCTGGTGGAGTGTATCGGGCAGGAGCTGATCTTTCTGTTGCCA AATAAGAATTTCAAACATAGGGCCTACGCATCCCTGTTCCGGGAGCTCGAAGAGACCCTGGCTGATCT GGGACTGTCCTCTTTCGGGATCTCCGATACCCCCCTGGAGGAGATTTTTCTGAAAGTGACCGAGGATA GCGATTCTGGGCCACTGTTTGCCGGGGGCGCTCAGCAGAAGAGGGAGAATGTGAACCCCAGACACC CTTGCCTGGGCCCCAGGGAGAAGGCTGGCCAGACACCTCAGGACTCTAACGTGTGCTCCCCTGGCG CCCCCGCCGCCCATCCCGAGGGCCAACCCCCTCCCGAGCCCGAATGCCCTGGCCCCCAGCTGAATA CCGGAACTCAGCTGGTGCTTCAGCATGTGCAGGCACTGCTGGTCAAACGGTTCCAGCACACCATCAG GTCCCACAAAGACTTCCTGGCCCAGATCGTGCTGCCAGCCACATTTGTGTTCCTGGCCCTGATGCTGT CTATCGTGATACCTCCTTTTGGCGAGTACCCCGCTCTCACCCTGCACCCTTGGATTTACGGCCAGCAG TATACATTCTTCTCCATGGACGAGCCAGGAAGCGAGCAGTTCACCGTGCTGGCCGACGTGCTGCTGA ACAAGCCAGGGTTCGGCAACAGGTGCCTGAAAGAAGGATGGCTGCCTGAGTATCCCTGCGGAAACAG CACACCCTGGAAGACTCCAAGCGTGTCTCCCAACATCACACAGCTGTTCCAGAAGCAGAAGTGGACTC AGGTGAATCCCTCCCCCAGCTGTAGATGTTCCACCAGAGAGAAACTGACGATGCTGCCAGAGTGTCCT GAGGGAGCCGGCGGGCTGCCCCCTCCTCAGCGCACTCAGCGGAGCACCGAAATCCTGCAGGACCTG ACAGATCGGAACATCTCTGACTTTCTGGTTAAGACCTACCCCGCCCTGATCAGGTCTAGCCTGAAGAG CAAATTCTGGGTGAATGAGCAGCGCTATGGAGGCATCTCCATTGGAGGCAAGCTGCCAGTGGTGCCC ATTACAGGTGAGGCCCTCGTGGGCTTCCTGTCCGACCTGGGCAGAATTATGAACGTGTCAGGAGGAC CTATCACCCGCGAGGCCTCCAAGGAGATCCCTGATTTCCTCAAGCACCTGGAGACCGAAGACAACATT AAGGTGTGGTTCAATAACAAGGGCTGGCACGCCCTGGTGTCCTTCCTGAATGTGGCTCACAACGCCAT CCTGCGGGCCTCTCTGCCAAAGGACAGGTCTCCTGAGGAGTACGGAATAACAGTGATCTCTCAGCCA CTGAACCTCACCAAGGAGCAGCTGAGCGAAATTACTGTGCTGACCACCAGCGTGGACGCCGTGGTGG CCATCTGTGTAATCTTTTCCATGTCATTCGTGCCCGCTTCCTTCGTGCTCTACCTGATCCAGGAGAGGG TGAATAAGTCTAAGCATTTGCAGTTCATCTCTGGTGTCTCCCCCACTACCTACTGGGTGACGAATTTCC TGTGGGACATCATGAACTACTCCGTGAGTGCCGGCCTGGTGGTGGGCATTTTCATCGGATTCCAGAA GAAGGCCTATACCAGCCCTGAGAATCTGCCTGCCCTTGTGGCACTGCTGCTCCTGTACGGATGGGCC GTGATCCCTATGATGTACCCTGCCTCCTTCCTGTTCGATGTGCCCAGCACCGCCTACGTGGCCCTGTC ATGCGCCAACCTGTTCATTGGGATCAATAGCTCCGCCATCACCTTTATCCTGGAGCTGTTCGAGAACA ACCGCACCCTGCTGCGCTTCAACGCCGTGCTGAGGAAATTGCTGATCGTGTTTCCCCACTTTTGCCTG GGCCGGGGCCTGATTGACCTGGCCCTGTCACAGGCCGTGACCGACGTGTATGCCCGGTTCGGCGAG GAGCATTCTGCCAACCCCTTCCACTGGGACCTGATCGGCAAGAACTTGTTCGCCATGGTGGTGGAGG GCGTGGTGTATTTCCTGCTGACTTTGCTGGTCCAGAGGCATTTCTTCCTGAGCCAGTGGATCGCCGAG CCAACAAAGGAACCCATCGTGGACGAGGACGACGACGTCGCCGAAGAGCGGCAGAGGATCATCACC GGCGGCAACAAGACAGACATCCTGAGACTGCATGAGCTCACCAAGATCTATCCCGGAACATCCAGCC CTGCCGTGGATAGGTTGTGTGTGGGCGTGCGGCCAGGCGAGTGTTTCGGACTGCTGGGCGTGAATG GTGCCGGCAAAACAACAACCTTTAAGATGCTGACTGGCGACACCACCGTGACCAGTGGCGATGCGAC CGTGGCCGGCAAGTCCATCCTGACTAACATTTCAGAGGTGCACCAGAACATGGGGTATTGCCCCCAG TTTGACGCCATTGATGAGCTGCTGACTGGCAGGGAGCACCTCTACCTGTATGCGCGTCTGCGGGGCG TGCCTGCCGAGGAAATCGAAAAGGTGGCCAACTGGTCTATTAAATCACTGGGCCTGACCGTGTACGC DB1 / 146899640.4 70 SAL-043PC / 126933-5043 AGATTGCCTGGCCGGCACCTACTCAGGCGGTAACAAGAGGAAGCTGTCAACAGCAATCGCCCTGATC GGCTGCCCTCCTTTGGTGCTGCTGGATGAACCCACAACCGGAATGGACCCCCAGGCCCGGAGAATGC TGTGGAACGTGATCGTGTCCATCATCAGGGAAGGCCGGGCCGTGGTGCTGACCAGCCACAGCATGG AAGAGTGCGAAGCCCTGTGCACACGCCTGGCAATCATGGTGAAGGGCGCCTTCCGATGTATGGGCAC CATCCAGCACCTGAAGAGCAAGTTCGGTGACGGCTATATCGTGACTATGAAGATCAAGAGCCCCAAAG ATGATCTGCTGCCTGACCTGAACCCAGTGGAGCAGTTCTTCCAGGGCAATTTCCCAGGCAGCGTGCA GCGAGAGAGACACTACAACATGCTGCAGTTCCAGGTGTCCTCCTCATCCCTGGCACGGATCTTTCAGC TGCTGCTGTCCCACAAGGACAGCCTGCTGATCGAAGAGTACTCTGTGACACAGACTACACTGGACCA GGTGTTCGTGAATTTCGCTAAGCAGCAGACCGAAAGTCACGACCTGCCTCTGCATCCACGGGCCGCC GGGGCCAGTAGACAGGCTCAGGATTGA attB2 (SEQ ID NO: 11) ACCCAGCTTTCTTGTACAAAGTGG rBG PA (includes B-globin Poly(A) Signal) (SEQ ID NO: 12) TCCTCAGGTGCAGGCTGCCTATCAGAAGGTGGTGGCTGGTGTGGCCAATGCCCTGGCTCACAAATAC CACTGAGATCTTTTTCCCTCTGCCAAAAATTATGGGGACATCATGAAGCCCCTTGAGCATCTGACTTCT GGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGA CATATGGGAGGGCAAATCATTTAAAACATCAGAATGAGTATTTGGTTTAGAGTTTGGCAACATATGCCC ATATGCTGGCTGCCATGAACAAAGGTTGGCTATAAAGAGGTCATCAGTATATGAAACAGCCCCCTGCT GTCCATTCCTTATTCCATAGAAAAGCCTTGACTTGAGGTTAGATTTTTTTTATATTTTGTTTTGTGTTATT TTTTTCTTTAACATCCCTAAAATTTTCCTTACATGTTTTACTAGCCAGATTTTTCCTCCTCTCCTGACTAC TCCCAGTCATAGCTGTCCCTCTTCTCTTATGGAGATC D4Z4-c insulator (SEQ ID NO: 13) CCTCCTGGCTGCACCTGCCGCAGTGCACAGTCCGGCTGAGGTGCACGGGAGCCCGCCGGCCTCTCT CTGCCCGCGTCCGTCCGTGAAATTCCGGCCGGGGCTCACCGCGATGGCCCTCCCGACACCCTCGGA CAGCACCCTCCCCGCGGAAGCCCGGGGACGAGGACGGCCACGGAGACTCGTTTGGACCCCGAGCC AAAGCGAGGCCCTGCGAGCCTGCTTTGAGCGGAACCCGTACCCGGGCATCGCCACCAGAGAACGGC TGGCCCAGGCCATCGGCATTCCGGAGCCCAGGGTCCAGATTTGGTTTCAGAATGAGAGGTCACGCCA GCTGAGGCAGCACCGGCGGGAATCTCGGCCCTGGCCCGGGAGACGCGGCCCGCCAGAAGGCCGGC GAAAGCGGACCGCCGTCACCGGATCCCAGACCGCCCTGCTCCTCCGAGCCTTTGAGAAGGATCGCTT TCCAGGCATCGCCGCCCGGGAGGAGCTGGCCAGAGAGACGGGCCTCCCGGAGTCCAGGATTCAGAT CTGGTTTCAGAATCGAAGGGCCAGGCACCCGGGACAGGGTGGCAGGGCGCCCGCGCAGGCAGGCG GCCTGTGCAGCGCGGCCCCCGGCGGGGGTCACCCTGCTCCCTCGTGGGTCGCCTTCGCCCACACCG GCGCGTGGGGAACGGGGCTTCCCGCACCCCACGTGCCCTGCGCGCCTGGGGCTCTCCCACAGGGG GCTTTCGTGAGCCAGGCAGCGAGGGCCGCCCCCGCGCTGCAGCCCAGCCAGGCCGCGCCGGCAGA GGGGGTCTCCCAACCTGCCCCGGCGCGCGGGGATTTCGCCTACGCCGCCCCGGCTCCTCCGGAGC CGGGGCGCTCTCCCACCCTCAGGCTCCTCGGTGGCCTCCGCACCCGGGCAAAAGCCGGGAGGACC GGGACCCGCAGCGCGACGGCCTGCCGGGCCCCTGCGCGGTGGCACAGCCTGGGCCCGCTCAAGCG DB1 / 146899640.4 71 SAL-043PC / 126933-5043 GGGCCGCAGGCCAAGGGGTGCTTGCGCCACCCACGTCCCAGGGGAGTCCGTGGTGGGGCTGGGGC CGGGGTCCCCAGGTCGCCGGGGCGGCGTGGGAACCCCAAGCCGGGGCAGCTCCACCTCCCCAGCC CGCGCCCCCGGGACGCCTCCGCCTCCGCGCGGCAGGGGCAGATGCAAGGCATCCCGGCGCCCTCC CAGGCGCTCCAGGAGCCGGCGCCCTGGTCTGCACTCCCCTGCGGCCTGCTGCTGGATGAGCTCCTG GCGAGCCCGGAGTTTCTGCAGCAGGCGCAACCTCTCCTAGAAACGGAGGCCCCGGGGGAGCTGGAG G Right Mobile element enzyme ITR (SEQ ID NO: 14) AATTATTTATGTACTGAATAGATAAAAAAATGTCTGTGATTGAATAAATTTTCATTTTTTACACAAGAAAC CGAAAATTTCATTTCAATCGAACCCATACTTCAAAAGATATAGGCATTTTAAACTAACTCTGATTTTGCG CGGGAAACCTAAATAATTGCCCGCGCCATCTTATATTTTGGCGGGAAATTCACCCGACACCGTAGTGT TAA (2) VCD-0031-D2 mCMV-hABCA4 (NP-pSFK-mCMV_HBI-Optimized hABCA4) Left Mobile element enzyme ITR (SEQ ID NO: 2) TTAACACTTGGATTGCGGGAAACGAGTTAAGTCGGCTCGCGTGAATTGCGCGTACTCCGCGGGAGCC GTCTTAACTCGGTTCATATAGATTTGCGGTGGAGTGCGGGAAACGTGTAAACTCGGGCCGATTGTAAC TGCGTATTACCAAATATTTGTT Restriction Site B (used for modular cloning backbones) GTCGAC Modified hCMV IE promoter (SEQ ID NO: 15) GTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAAT AATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGACTATTTACG GTAAACTGCCTGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTC AATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTG ACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTC AGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCT CCGCGGCCGGGAACGGTGCATTGGAACG Spacer 1 GGATCCGA DB1 / 146899640.4 72 SAL-043PC / 126933-5043 Human Beta-globin Intron II (SEQ ID NO: 16) GTGAGTCTATGGGACGCTTGATGTTTTCTTTCCCCTTCTTTTCTATGGTTAAGTTCATGTCATAGGAAG GGGATAAGTAACAGGGTACAGTTTAGAATGGGAAACAGACGAATGATTGCATCAGTGTGGAAGTCTCA GGATCGTTTTAGTTTCTTTTATTTGCTGTTCATAACAATTGTTTTCTTTTGTTTAATTCTTGCTTTCTTTTT TTTTCTTCTCCGCAATTTTTACTATTATACTTAATGCCTTAACATTGTGTATAACAAAAGGAAATATCTCT GAGATACATTAAGTAACTTAAAAAAAAACTTTACACAGTCTGCCTAGTACATTACTATTTGGAATATATG TGTGCTTATTTGCATATTCATAATCTCCCTACTTTATTTTCTTTTATTTTTAATTGATACATAATCATTATA CATATTTATGGGTTAAAGTGTAATGTTTTAATATGTGTACACATATTGACCAAATCAGGGTAATTTTGCA TTTGTAATTTTAAAAAATGCTTTCTTCTTTTAATATACTTTTTTGTTTATCTTATTTCTAATACTTTCCCTAA TCTCTTTCTTTCAGGGCAATAATGATACAATGTATCATGCCTCTTTGCACCATTCTAAAGAATAACAGTG ATAATTTCTGGGTTAAGGCAATAGCAATATCTCTGCATATAAATATTTCTGCATATAAATTGTAACTGAT GTAAGAGGTTTCATATTGCTAATAGCAGCTACAATCCAGCTACCATTCTGCTTTTATTTTATGGTTGGGA TAAGGCTGGATTATTCTGAGTCCAAGCTAGGCCCTTTTGCTAATCATGTTCATACCTCTTATCTTCCTCC CACAG Spacer 2 (including partial Kozak Sequence) (SEQ ID NO: 17) ATCTGTTCCAACCACGGTCACGCTTCGGTGGCCACC hABCA4_optimized_FY_060523 (SEQ ID NO: 18) ATGGGCTTCGTGCGCCAGATCCAACTGCTGCTGTGGAAAAACTGGACCTTACGGAAGAGACAGAAGA TCAGATTCGTGGTTGAGCTGGTGTGGCCACTGTCTCTCTTCCTGGTGCTGATCTGGCTGAGAAACGCC AACCCCCTCTACAGCCATCACGAGTGCCACTTCCCTAACAAGGCTATGCCCAGCGCCGGCATGCTGC CCTGGCTGCAGGGAATcTTTTGCAACGTGAATAATCCTTGCTTCCAAAGCCCTACTCCTGGCGAgAGCC CAGGCATCGTGAGCAAcTACAACAACAGCATTCTGGCGAGAGTGTACAGAGACTTCCAGGAACTGCTG ATGAACGCCCCTGAGTCCCAGCACTTAGGCAGGATCTGGACCGAGCTGCACATCCTGTCCCAGTTTAT GGACACCCTGAGGACCCACCCTGAACGGATCGCAGGCAGGGGCATCAGAATCCGCGATATCCTGAAA GATGAGGAAACCCTGACCCTGTTCCTGATCAAGAATATCGGACTTAGCGATAGCGTGGTGTACTTACT AATCAACAGCCAAGTGCGGCCCGAGCAGTTCGCCCACGGCGTGCCCGATCTGGCTCTGAAGGACATC GCCTGTTCCGAGGCACTCTTGGAGCGCTTCATCATCTTCAGTCAGAGAAGAGGCGCCAAGACAGTGC GGTACGCCCTTTGTTCACTGTCCCAGGGCACCCTTCAGTGGATCGAGGATACCCTGTACGCCAACGT GGACTTCTTcAAGCTGTTCCGTGTGCTGCCTACACTGCTGGATTCAAGAAGCCAAGGCATCAACCTGA GAAGCTGGGGTGGTATCTTGTCCGATATGAGCCCTAGAATCCAGGAGTTCATCCACAGACCTAGCATG CAAGATCTCCTGTGGGTGACAAGGCCCCTGATGCAGAATGGCGGACCCGAGACATTCACGAAGCTGA TGGGAATCCTGTCGGACCTATTGTGCGGATACCCTGAAGGAGGGGGTTCCAGAGTGCTGAGCTTcAA CTGGTATGAGGACAACAACTACAAAGCCTTTTTGGGCATCGACAGCACTAGGAAGGATCCTATCTACA GCTACGACAGAAGAACCACCTCATTCTGCAACGCCCTGATCCAAAGCCTGGAAAGCAATCCTCTTACA AAGATCGCCTGGAGAGCTGCTAAGCCTCTGCTGATGGGCAAGATCCTCTACACCCCAGATTCCCCTG CCGCTAGAAGAATCCTGAAGAACGCCAACAGCACCTTCGAGGAGCTGGAGCACGTTCGAAAGTTGGT GAAAGCCTGGGAGGAAGTGGGCCCTCAGATCTGGTACTTCTTCGACAACAGCACGCAGATGAACATG ATCAGAGACACCCTGGGTAATCCTACCGTCAAGGATTTTCTCAACAGACAGCTGGGAGAAGAGGGCAT CACCGCCGAAGCCATCCTCAAcTTTCTGTACAAGGGACCCCGAGAAAGCCAGGCGGACGATATGGCC DB1 / 146899640.4 73 SAL-043PC / 126933-5043 AAcTTCGACTGGCGGGACATCTTCAACATCACAGATAGAACCCTGAGACTGGTGAACCAGTACCTGGA ATGTTTGGTGTTGGATAAGTTCGAAAGCTATAACGACGAGACACAGTTGACTCAGCGGGCCCTGTCTC TCCTGGAAGAgAACATGTTCTGGGCCGGGGTCGTATTCCCTGATATGTATCCCTGGACCAGTTCTCTG CCACCTCACGTGAAGTACAAGATCCGTATGGACATCGACGTGGTGGAgAAgACAAACAAGATCAAGGA TAGATACTGGGACAGCGGCCCACGGGCCGACCCTGTGGAAGACTTCAGATACATCTGGGGAGGATTT GCTTACCTGCAAGACATGGTCGAACAGGGCATCACCCGGTCTCAGGTCCAGGCCGAGGCCCCTGTG GGAATCTACCTGCAGCAGATGCCTTACCCGTGCTTCGTGGATGACTCCTTCATGATCATCCTGAATAG ATGCTTCCCTATCTTCATGGTGCTGGCCTGGATCTACAGCGTGAGCATGACCGTCAAGTCCATCGTCC TGGAAAAGGAACTGAGATTGAAAGAGACCCTGAAGAACCAGGGCGTGAGCAACGCCGTAATCTGGTG CACTTGGTTCCTGGATTCTTTCAGCATAATGAGCATGAGCATCTTCCTGCTGACCATCTTCATTATGCA CGGCAGAATCCTGCATTATTCCGACCCGTTCATCCTGTTCCTGTTCCTGCTGGCCTTCAGCACCGCTA CCATCATGCTGTGCTTCTTGCTGAGTACATTCTTCAGCAAGGCCAGCCTCGCCGCCGCCTGCAGCGG CGTGATCTACTTCACCCTGTACCTGCCCCACATTCTTTGCTTCGCCTGGCAAGACAGAATGACAGCTG AACTGAAGAAGGCCGTGTCCCTGCTGAGCCCCGTGGCCTTCGGCTTCGGCACCGAGTATCTTGTGAG ATTTGAGGAGCAGGGCCTGGGCCTGCAGTGGAGCAACATCGGAAAcTCACCCACAGAGGGCGACGA GTTCAGCTTTTTGCTGAGTATGCAGATGATGCTGCTGGACGCCGCTGTGTACGGCCTGCTCGCATGGT ACCTGGACCAGGTCTTTCCGGGCGACTACGGCACCCCCCTGCCTTGGTACTTTCTCCTGCAGGAGTC TTACTGGCTGGGTGGAGAAGGCTGCAGCACCCGGGAGGAGAGAGCACTCGAAAAAACAGAGCCTCT GACAGAGGAAACCGAAGATCCCGAGCACCCCGAAGGCATCCACGACTCTTTCTTcGAGAGAGAACAC CCCGGCTGGGTGCCAGGAGTGTGTGTGAAgAACCTGGTgAAGATCTTTGAGCCCTGCGGCAGACCAG CCGTGGACCGGCTgAACATCACCTTCTACGAGAACCAAATCACCGCCTTCCTGGGCCACAACGGCGC CGGCAAGACCACGACCCTGTCCATCCTGACCGGCCTGCTGCCTCCTACAAGCGGGACTGTGCTCGTC GGAGGCAGAGACATCGAGACATCTCTGGACGCCGTGAGACAGTCACTAGGCATGTGCCCTCAACAcA ATATCCTATTCCACCACCTGACAGTAGCAGAACACATGCTGTTCTACGCCCAGCTGAAGGGAAAGAGC CAGGAGGAAGCCCAGCTGGAGATGGAAGCTATGCTCGAGGATACCGGACTGCACCATAAGCGAAATG AGGAAGCCCAGGACCTGTCCGGCGGAATGCAGAGAAAGCTGTCTGTGGCCATAGCCTTCGTAGGGG ACGCCAAGGTGGTGATCCTGGACGAGCCCACCTCTGGCGTGGACCCTTACTCGCGGAGATCAATATG GGACCTGCTCCTGAAGTACAGGTCGGGCAGAACCATCATCATGTCCACACACCACATGGACGAGGCC GATCTGCTAGGCGACCGGATCGCCATTATCGCACAGGGACGACTGTACTGTAGTGGCACACCTCTGT TCCTGAAGAACTGCTTTGGCACAGGCCTGTACCTCACCCTGGTGAGAAAAATGAAgAATATCCAAAGC CAAAGGAAAGGCTCTGAGGGAACCTGTAGCTGTAGCAGCAAGGGCTTTAGCACCACCTGCCCTGCCC ATGTGGATGACCTAACACCTGAGCAGGTGCTGGACGGCGATGTGAACGAGCTGATGGATGTGGTGCT CCACCACGTGCCGGAAGCCAAACTAGTGGAATGCATCGGCCAGGAGCTGATCTTCCTGCTGCCAAAC AAGAAcTTCAAGCACCGGGCCTACGCCAGCCTGTTCAGAGAGCTGGAAGAGACATTGGCAGATCTGG GACTGAGCTCTTTCGGCATCAGCGATACCCCGCTGGAGGAAATcTTTCTCAAGGTGACGGAGGATAGC GATAGCGGCCCTCTGTTCGCCGGCGGCGCCCAACAGAAGCGTGAGAACGTGAACCCCAGACACCCA TGCCTGGGCCCCCGGGAgAAAGCGGGGCAGACCCCTCAAGACAGCAACGTCTGCTCTCCGGGcGCC CCTGCcGCTCAcCCTGAGGGGCAGCCTCCCCCCGAGCCAGAGTGTCCTGGACCACAGCTGAATACCG GCACACAACTGGTGCTCCAACACGTTCAGGCCCTGCTGGTGAAGCGGTTCCAGCACACCATCAGGAG CCACAAAGATTTCCTGGCCCAGATCGTGTTGCCCGCCACGTTCGTGTTCCTGGCACTGATGCTGTCCA TCGTGATCCCTCCTTTCGGCGAGTATCCTGCCCTGACCCTGCACCCTTGGATCTATGGCCAGCAGTAC ACCTTcTTCTCAATGGATGAACCTGGCAGCGAGCAGTTTACAGTGCTGGCTGACGTGCTGCTGAACAA GCCCGGCTTCGGAAACCGGTGCCTGAAGGAAGGCTGGCTGCCCGAGTACCCTTGCGGCAACAGCAC ACCTTGGAAGACCCCTAGCGTCAGTCCTAACATCACACAGCTGTTCCAGAAGCAGAAGTGGACACAAG TgAATCCCTCCCCTAGTTGCCGGTGTAGCACACGGGAGAAGCTGACCATGCTGCCCGAATGCCCTGA GGGCGCCGGTGGTCTGCCGCCTCCTCAGAGAACCCAACGTAGTACCGAGATCCTGCAGGACCTCAC CGACAGAAACATCAGCGACTTCCTTGTTAAGACCTACCCCGCCctgATTCGGAGCAGCCTGAAGAGCAA DB1 / 146899640.4 74 SAL-043PC / 126933-5043 GTTCTGGGTGAACGAACAGAGATATGGCGGCATCTCTATCGGCGGCAAgTTGCCTGTCGTGCCCATTA CCGGCGAGGCACTGGTGGGCTTCCTGAGCGACCTGGGCCGTATTATGAACGTGAGCGGTGGTCCTAT CACAAGAGAGGCCTCTAAAGAGATCCCTGACTTCCTGAAGCACCTGGAGACAGAGGATAACATCAAG GTGTGGTTcAACAACAAGGGCTGGCACGCCCTAGTCTCGTTCTTGAACGTGGCACACAACGCCATTCT GCGGGCCTCTCTGCCTAAGGATAGATCCCCTGAAGAGTACGGCATCACGGTGATCAGCCAACCTCTG AATCTGACCAAGGAGCAGCTGAGCGAGATCACTGTGTTGACCACAAGCGTGGACGCCGTCGTGGCTA TCTGCGTGATCTTCAGTATGAGCTTCGTGCCCGCCAGCTTCGTGCTGTACCTGATCCAGGAGAGAGTG AACAAGAGCAAACACCTGCAGTTCATCTCTGGGGTTAGCCCTACAACCTACTGGGTCACCAATTTCTTA TGGGATATCATGAACTACAGCGTATCCGCCGGACTGGTAGTGGGCATTTTCATTGGCTTCCAGAAAAA GGCCTACACGTCTCCTGAAAATCTGCCCGCTCTGGTAGCTCTACTCCTGCTGTACGGCTGGGCCGTG ATCCCTATGATGTACCCTGCCAGTTTTCTATTCGACGTGCCCAGCACCGCCTACGTGGCCTTATCCTG CGCCAACCTGTTTATCGGCATCAACAGCAGCGCCATCACTTTCATTCTCGAGCTGTTCGAGAACAACC GGACACTGCTGAGATTCAACGCAGTCCTTCGGAAGCTGCTGATCGTGTTTCCTCACTTTTGTCTGGGC CGTGGCCTGATCGACCTGGCTCTGTCTCAGGCAGTGACCGATGTGTACGCCAGATTCGGCGAAGAGC ACTCTGCCAACCCCTTCCACTGGGACCTGATCGGcAAAAATCTGTTCGCCATGGTGGTGGAGGGTGTG GTTTATTTCCTCCTGACACTGCTGGTGCAGAGACACTTCTTCTTGAGCCAGTGGATCGCCGAACCAAC AAAGGAACCTATCGTGGACGAAGATGATGATGTGGCTGAAGAGAGACAGAGAATCATCACTGGCGGT AAcAAAACTGATATCCTGAGACTGCATGAACTAACAAAGATCTATCCTGGTACCTCTTCACCTGCCGTG GACCGGCTTTGTGTGGGAGTTAGGCCTGGCGAGTGCTTCGGCTTGTTGGGCGTGAACGGCGCAGGC AAGACAACAACATTCAAGATGCTGACCGGCGACACAACCGTTACCAGCGGCGACGCCACAGTGGCTG GAAAGTCTATCCTGACAAACATCAGCGAGGTCCACCAGAACATGGGCTACTGCCCCCAGTTTGACGCC ATCGACGAGCTGCTGACCGGCAGAGAACACCTCTACCTCTACGCCCGACTGCGAGGCGTGCCTGCC GAAGAGATTGAGAAGGTGGCCAATTGGAGCATCAAGTCCCTGGGCCTCACTGTGTACGCCGATTGCC TGGCTGGTACTTACAGCGGCGGCAACAAGCGGAAGTTGAGCACCGCCATTGCCCTAATcGGCTGCCCt CCCCTGGTGCTGCTGGACGAGCCTACCACAGGAATGGATCCTCAGGCCAGAAGAATGCTATGGAACG TGATCGTATCCATcATTAGAGAGGGCCGGGCCGTGGTGTTGACTTCTCACAGCATGGAAGAATGCGAA GCCCTGTGCACCCGCCTGGCGATTATGGTGAAGGGAGCCTTCCGGTGCATGGGAACCATCCAGCACC TGAAGTCAAAGTTTGGAGACGGCTACATCGTGACCATGAAAATCAAGTCGCCTAAGGACGACCTGCTC CCAGACCTGAACCCTGTGGAGCAGTTCTTCCAGGGCAACTTTCCTGGTTCTGTGCAGAGAGAGCGCC ACTACAATATGCTTCAGTTCCAGGTGTCTAGCAGTAGCCTTGCTAGAATCTTCCAGCTCCTGCTGAGCC ACAAGGACAGCCTGCTGATTGAGGAATACTCCGTCACCCAGACTACCCTGGATCAGGTCTTCGTGAAC TTCGCTAAGCAGCAGACCGAGTCCCACGACCTGCCCCTGCACCCTCGGGCCGCTGGCGCTTCCAGA CAGGCCCAGGACTGA Spacer 3 (SEQ ID NO: 19) TAGTAAACGCGT bGH Poly A (SEQ ID NO: 20) GCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCC TTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTG DB1 / 146899640.4 75 SAL-043PC / 126933-5043 AGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGAC AATAGCAG Spacer 4 (including restriction site E for our modular cloning backbone) (SEQ ID NO: 21) GCATGCTCTAGAACTAGT Right Mobile element enzyme ITR (SEQ ID NO: 14) AATTATTTATGTACTGAATAGATAAAAAAATGTCTGTGATTGAATAAATTTTCATTTTTTACACAAGAAAC CGAAAATTTCATTTCAATCGAACCCATACTTCAAAAGATATAGGCATTTTAAACTAACTCTGATTTTGCG CGGGAAACCTAAATAATTGCCCGCGCCATCTTATATTTTGGCGGGAAATTCACCCGACACCGTAGTGT TAA Other constructs for nucleic acids delivery Exemplary plasmid DNA useful for the compositions and methods of the present disclosure is listed below herein: Moiety: - Opt-26 or mobile C C A DB1 / 146899640.4 76 SAL-043PC / 126933-5043 GTGATCAACAACATCGAGGACGCCGTGAAGCTGTTTATCGGCGACGACTTCTTCG AGTTCCTCGTCGAGGAGAGCAACCGGTACTACAACCAGAACAGAAACAACTTCAA ACTGAGCAAAAAGAGCCTGAAGTGGAAGGACATCACCCCCCAGGAAATGAAGAAG C T C A T T A A A C A T C C A T C C A A c ag a g a a g c a cc ca g a a a u a c uc DB1 / 146899640.4 SAL-043PC / 126933-5043 gcaauguacaugaucaacugugcccuguucaauagcuacgcuguguacaagagcgugagacaacggaagau gggcuucaagauguuccugaaacagaccgcgauccacuggcugaccgacgacaucccugaggacauggacau cgugccggaccugcagccugugcccagcaccagcggcaugcgggccaagcccccgaccuccgacccacccugu agacuguccauggacaugagaaagcacacacugcaggccaucgugggcagcggcaagaagaagaacauccu gagacggugccgggugugcagcgugcacaagcuacggagcgagacccgguacaugugcaaguucugcaaca ucccgcugcacaagggagccugcuucgaaaaguaccacacccugaaaaacuacuaggcuggagccucggugg ccaugcuucuugccccuugggccuccccccagccccuccuccccuuccugcacccguacccccguggucuuug aauaaagucugagugggcggcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa – 3’ (SEQ ID NO: 27) Open Reading 5’ATGGCCCAGCACAGCGACTACCCAGACGACGAGTTCAGGGCCGACAAGCTGAG Frame / CAACTACAGCTGCGACAGCGACCTGGAAAACGCCAGCACCAGCGACGAGGACAG G A A G G G G G C A C G G G C G T A G A A C A T G DB1 / 146899640.4 78 SAL-043PC / 126933-5043 mRNA Kozak 5’- CCGCCACC – 3’ Sequence D B1 / 146899640.4 SAL-043PC / 126933-5043 N1-Methylpseudouridine-5'-Triphosphate This invention is further illustrated by the following non-limiting examples. EXAMPLES Hereinafter, the present disclosure will be described in further detail with reference to examples. These examples are illustrative purposes only and are not to be construed to limit the scope of the present invention. In addition, various modifications and variations can be made without departing from the technical scope of the present invention. Constructs for ABCA4 nucleic acids delivery ATP binding cassette subfamily A member 4 (ABCA4) protein is a retina-specific ABC transporter with N- retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essential molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile- onset macular degeneration. Mutations in this gene are also associated with other conditions such as retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. To assess the therapeutic window for SS-OP / ABCA4 DNA delivery, GFP vs. Abca4 were used as cargo within SS-OP LNPs (36.3% SS-OP, 50.7% Cholesterol, 9.8% DOPE, 5% PEG) and the current therapeutic index was evaluated (FIG.1). OCT measurements were taken at day 12 (D12) of the mice injected sub- retinally with the LNPs. Based on the differences in cargo base pair size, the amount of abca4 or GFP was modified to match the same nM of nucleic acid.7 nM was shown to be the therapeutic index for the DNA regardless of the cargo size with an OCT degeneration score lower than 1 on average. The degeneration DB1 / 146899640.4 80 SAL-043PC / 126933-5043 score indicated that tolerability is driven by the number of molecules of DNA delivery, regardless of the DNA size or sequence. Plasmid 1 (SG-D2-0034 Cag-hABCA4 (Insulator.Cag.hABCA4-CO.rBG.Insulator)) was used in the SS-OP / ABCA4 DNA delivery. As shown in FIGS.2A-2B, the SS-OP / ABCA4 delivery to photoreceptors (PRs) and retinal pigment epithelial (RPE) cells following subretinal (SR) injection was within current therapeutic index (TI). For 7 nM of DNA (25 ng for GFP and 50 ng for Abca4), 0.01 copies / cell for neural retina and 1 copy / cell for RPE were detected for both Abca4 and GFP. Overall, abca4 DNA delivery was lowered compared to GFP. The disclosed formulations deliver preferentially to the RPE, with lower efficiency in the neural retina. Quantifying DNA delivery and the generated transcript (FIG.2A). As shown in FIG.2B, both Abca4 and GFP have the same level of fold change indicating increased levels of mRNA produced from the DNA. Thus, LNP delivery of Abca4 was productive and led to transcription of mRNA as well. As shown in FIGS.3A-3B, following subretinal (SR) delivery of AAV5 with LNP / mobile element enzyme (SEQ ID NO: 1), neural retina integration was detected. AAV was used as a tool for DNA delivery and to evaluate mobile element enzyme (SEQ ID NO: 1) integration. Dual subretinal delivery was evaluated into mice staggered by 21 days (AAV followed by LNP with Cre mRNA+mobile element enzyme (SEQ ID NO: 1) mRNA (36.3% SS-OP, 50.7% Cholesterol, 9.8% DOPE, 5% PEG)). A widespread expression by the Cre LNP was detected and in the dual injected groups, a large population of cells received dual mRNA leading to dual protein expression (FIG.3A). It was concluded that cells that received Cre mRNA and showed a positive expression, also received mobile element enzyme (SEQ ID NO: 1) mRNA given that they were coencapsulated in the same LNP. The copy number per cell via ddPCR of cells in the neural retina (~80% photoreceptors) that express both GFP from AAV and cre / mobile element enzyme (SEQ ID NO: 1) from LNP was assessed (FIG.3B). All doses, with 0.05 ug / ml being the highest show an increase in DNA copy number compared to AAV alone was indicative of integration via mobile element enzyme (SEQ ID NO: 1) (FIG.3B). Increased levels of mobile element enzyme (SEQ ID NO: 1) showed low tolerability, as demonstrated by a decrease in DNA copy number. Example 1: Successful in vivo ABCA4 gene replacement in a mouse model of Stargardt disease using a mammalian transposon system An engineered mammalian transposase was co-encapsulated in a nanoparticle to integrate ABCA4 in the genome (e.g. by using construct (1) and / or (2) as provided elsewhere above herein). DB1 / 146899640.4 81 SAL-043PC / 126933-5043 DNA and RNA dosing with 7nM (low dose, LD) nucleic acid and 13nM (high dose, HD) nucleic acid. Transcript production were analyzed in ARPE19, HEK293T cells, and Abca4- / - mice using ABCA4+ fluorescence-activated cell sorting (FACS), droplet digital polymerase chain reaction (ddPCR), and quantitative reverse transcription (RTqPCR). To assess dosing, tolerability, and delivery in vivo subretinal injections were performed in 24 mice (1uL per eye) in three groups of Abca4- / - mouse eyes: vehicle alone (n=8) and treated groups with LD (n=8) and HD (n=8). The mice were analyzed by serial fundoscopy, optical coherence tomography (OCT), ecto-5′- nucleotidase (CD73+) / ABCA4+ photoreceptor sorting of dissected neural retina by FACS, histology, immunohistochemistry (IHC), ddPCR, and RT-qPCR analyses. FACS analysis identified a single ABCA4+ and dual ABCA4+ / FLAG+ in ARPE19 and HEK293T cell populations. Following confirmation of genomic integration, both treated Abca4- / mouse groups showed ABCA4 expression by FACS (P<0.05) in 10% of all retinal photoreceptors with no difference (P>0.1) in OCT retinal layer measurements between the vehicle alone and treated groups. As shown in FIGS.4A-4B, the delivery of CAG-hABCA4 + Mobile element enzyme (SEQ ID NO: 1) mRNA into photoreceptors (PRs) exhibited a good tolerability with a SS-OP LNP (36.3% SS-OP, 50.7% Cholesterol, 9.8% DOPE, 5% PEG)). In particular, minimal to a no degeneration was observed with SS-OP / ABCA4+ Mobile element enzyme (SEQ ID NO: 1) delivery to the retina (FIG.4A). The OCT degeneration score of the ONL was within the tolerable range for LNPs for both doses. Compared to the background (2.7%) both doses of LNP indicated an increase in Abca4 expression of more than 5% (FIG.4B). Plasmid 1 (SG-D2-0034 Cag- hABCA4 (Insulator.Cag.hABCA4-CO.rBG.Insulator)) was used in the SS-OP / ABCA4 and mobile enzyme construct. As shown in FIG.5 SS-OP / ABCA4 and mobile element enzyme (SEQ ID NO: 1) are expressed in mouse photoreceptors (PRs). Immunohistochemistry (IHC) assays showed that the Abca4 was localized to the outer segments of the photoreceptors which themselves were naturally expressed as a transport protein. The localization showed that the LNP was able to deliver the Abca4 DNA and the DNA was able to be translated into protein that is expressed in the OS of the photoreceptors. Thus, Retinal IHC proved precise restoration of the ABCA4 protein in its natural photoreceptor OS location. ABCA4 ddPCR and RTqPCR confirmed these findings. DB1 / 146899640.4 82 SAL-043PC / 126933-5043 The results supported the feasibility and tolerability of subretinal administration of a non-viral, integrative gene therapy to deliver a large gene such as ABCA4 to photoreceptors in a mouse model of STGD1. In a ABCA4 and Rdh8 double knockout mouse model, it was seen that 50 days post injection, the A2 levels dropped to 40% of the vehicle (PBS) injected group (FIG.6). This mouse model was an example of an efficacy model which shows rapid disease progression building up the toxic byproducts shown in Stargardts disease. This reduction was consistent with 100% of transfected cells showing reduction by day 50. Copy number showed that SSOP was delivering successfully to the target tissues within the treated area and when size exclusion was performed showed indications of integration into the cells (FIG.7A). In post-size exclusion, remaining copy number is a result of potential integration events. Both SSOP doses showed dose-dependent expression for retina and RPE / eye cup. SSOP was also shown in a dose dependent nature when injected into the target area with stronger expression in the higher dose (FIG.7B). FIG.8 provides evidence of ABCA4 and mobile element enzyme delivery into NHP PRs using SSOP as ABCA4 co-localized with arrestin-C, a marker for PR cones in the NHP. FIG.8 shows both delivery and expression of the mobile element enzyme cargo into the target cells in an NHP. In vivo tolerability using mRNA-LNPs, DNA-LNPs, co-encapsulated mRNA / DNA-LNPs Utilizing a qualitative ocular coherence tomography (OCT) degeneration scoring system, the thinning of the outer nuclear layer (ONL) was assessed (FIG.9A). Three days post-subretinal (SR) injection ONL thinning did not extend beyond the treated area with LNPs encapsulated with a mRNA, DNA, or mRNA / DNA cargos. OCT degeneration scores showed that the LNP co-encapsulating DNA and RNA cargo was well tolerated (FIG.9B). FIG.9C further shows the ONL with indication of placement of subretinal injection. FIG.9D compares the OCT degeneration score of ONL thinning after treatment with LNP / ABCA4 DNA + mobile element enzyme mRNA at low and high dose. LNP achieves high levels of mRNA expression in the retina at levels required for clinical efficacy in Stargardt disease Fundoscopic images demonstrated successful delivery of LNP with eGFP DNA and NLS-Cre recombinase mRNA into TdTom mice eyes (FIG.10A). Flat mount images revealed LNP eGFP coverage post-SR injection into TdTom mice, with ImageJ used to measure the treated area and determine LNP interaction with tissue (FIG.10B). The entire retina of TdTom mice treated with vehicle alone and three LNP doses containing dual DB1 / 146899640.4 83 SAL-043PC / 126933-5043 mRNA and DNA cargos shows a dose-dependent increase in TdTomato signal (FIG.10C). Percentages were corrected for the treated area when measured by flow cytometry based off the flat mount. ABCA4 constructs screened for in vivo targeting demonstrate robust in vitro transcript and protein expression ARPE19 and HEK293T cells were dosed with various full length ABCA4 donor DNA elements to access expression using RT-qPCR after 72 hours incubation (FIG.11A). Flow cytometric quantification of ABCA4 and ABCA4 / Flag dual expression in ARPE19 and HEK-293T cell lines, 72 hours after transfection, demonstrated robust in vitro construct protein expression (FIG.11B). In a ABCA4 and Rdh8 double knockout mouse model, it was seen that A2 levels dropped to 40% of the vehicle (PBS) injected group after treatment of LNP / ABCA4 DNA and mobile element enzyme mRNA at both the low dose and high dose (FIG.12). LNPs co-encapsulating ABCA4 DNA and mobile element enzyme mRNA show excellent delivery, tolerability and expression in neural retina OCT degeneration scores demonstrated that LNPs with mobile element enzyme mRNA and ABCA4 DNA were well tolerated at low and high doses (FIG.13A). ABCA4 transcript was detectable by RTqPCR at both doses in Abca4- / - mice retina (FIG.13B). ABCA4 DNA was successfully delivered to the Abca4- / - mice retina (FIG.13C). Representative pseudocolor flow cytometry plots show the gating strategy (FIG.13D). ABCA4 expression was analyzed as a function of viable Cd73+ PRs from Abca4- / - mice (FIG.13E). These mice were injected SR with a dual cargo LNP (ABCA4 DNA and mobile element enzyme mRNA). The results showed a ~20-35% positive signal in Cd73+ PRs (adjusted for PRs in the treated area), in a dose-dependent manner. IHC shows full length human ABCA4 expression in the photoreceptors in Abca4- / - mice FIG.14 shows a retinal immunohistochemistry (IHC) using antibodies against ABCA4, PNA lectin [(cones and inner (IS) and outer segment (OS)], RPE65 (retinal pigment epithelium), and DAPI (nuclear stain). The boxed area is magnified in the composite image is shown in the last column of images. Furthermore, FIG. 15 demonstrated that LNP / ABCA4 DNA and mobile element enzyme mRNA were expressed in nonhuman primates (NHP) photoreceptors. Without being bound to a particular theory, flat mount and dissection / digestion of the neural retinal provide insight into the total surface area of a 1µL subretinal injection and the percentage of viable Cd73+ photoreceptors expressing the dual mRNA and DNA donor cargos. LNPs co-encapsulating both reporter cargos or a bioengineered transposase mRNA (Myotis lucifugus mobile element enzyme) and DNA donor DB1 / 146899640.4 84 SAL-043PC / 126933-5043 with full length (6.8 kb) human ABCA4 were well tolerated in Abca4- / - mice. After treatment with an LNP co- encapsulating mobile element enzyme mRNA and ABCA4 DNA donor, Abca4- / - mice showed ABCA4 protein expression by flow cytometry (p<0.05) in 10% of all retinal photoreceptors with no difference (p>0.1)* in OCT denegation scores (i.e., no difference in OCT retinal layer measurements between the vehicle alone and treated group). Retinal IHC showed precise restoration of the ABCA4 protein in its natural photoreceptor outer segment location. The example shows, inter alia, the feasibility and tolerability of subretinal administration of a non-viral, integrative gene therapy to deliver a large gene such as ABCA4 to photoreceptors in a mouse model of STGD1. Example 2: SSOP Formulation for Helper Lipid Study and PEG Study Helper lipid molar ratio is important for SSOP DOPE formulations to deliver nucleic acids. SSOP DOPE formulation showed higher GFP DNA / mCherry RNA expressions when increasing the DOPE helper lipid molar ratio from 22% up to 38% (FIG.16A – 16C). FIG.16A shows the formulations tested with increasingly higher DOPE helper lipid molar ratio. FIG. 16B shows a series of fluorescent images demonstrating LNP-mediated gene expressions in ARPE-19 cells treated with SSOP DOPE formulation at 1 µg / mL for 48 hours. The NanoFCM analysis showed LNP population (red color) fully loaded with DNA and mRNA with high DOPE formulation (FIG.16C). FIG.17A shows SSOP DOPE PEG lipid formulation designs. FIG.17B shows a bar graph comparing the size (nm) of various SSOP DOPE PEG lipid formulations. FIG.17C shows a bar graph comparing the encapsulation efficiency of various SSOP DOPE PEG lipid formulations. For DNA, CAG-GFP nanoplasmids were used, for mRNA, mCherry mRNA were used. PEG lipid ratio effected LNP delivery of nucleic acids in vitro. SSOP DOPE High Helper (38% or 33%) formulations showed decreasing DNA / RNA expressions when increasing the PEG lipid molar ratio from 2 to 4%. FIG.17D – 17E shows a series of fluorescent images demonstrating LNP-mediated gene expressions in ARPE-19 cells treated SSOP DOPE PEG lipid formulations. SSOP DOPE formulations with higher PEG% 4 or 4.9% did not show robust DNA / mRNA expression, though 4% PEGylated LNP showed slightly better expression than 4.9% PEGylated ones. Balancing the SSOP molar ratio for high helper is important for gene delivery. SSOP DOPE formulations with high helper (38% DOPE) showed higher GFP DNA / mCherry mRNA expressions when increasing the SSOP molar ratio from 20% to 30%. FIG.18A shows SSOP DOPE formulations with high helper (38% DOPE). FIG. DB1 / 146899640.4 85 SAL-043PC / 126933-5043 18B shows a series of fluorescent images demonstrating LNP-mediated gene expressions in ARPE-19 cells treated with SSOP DOPE formulations with high helper (38% DOPE) formulations at 1 µg / mL for 48 hours. Engineering the PEG molar ratio was important for LNP stability and delivery efficiency. SSOP DOPE formulations with balanced SSOP and high DOPE maintained stable GFP DNA / mCherry mRNA expressions with minimum effect on PEG molar ratio changes from 2 to 4%. FIG.19A shows SSOP DOPE PEG formulations. FIG.19B shows a series of fluorescent images demonstrating LNP-mediated gene expressions in ARPE-19 cells treated with SSOP DOPE PEG formulations at 1 µg / mL for 48 hours. SSOP High Helper formulation (KM E148 F2) showed much higher GFP DNA expressions in vitro compared to the other formulations (IRD-062 F1 and F2) (FIG.20). IRD-062 F1 represents CAG-GFP DNA + mobile element enzyme (SEQ ID NO: 1) 34 mRNA. IRD-062 F1 represents CAG-GFP DNA + mobile element enzyme (SEQ ID NO: 1) Opt26 mRNA, KM E148 F2 represents CAG-GFP DNA + mCherry mRNA. The SSOP high helper formulation was also used for Abca4 DNA and mobile element enzyme (SEQ ID NO: 1) mRNA dual cargo delivery. SSOP DOPE high helper formulation showed the highest gene expression in malate buffer (high salt) compared to acetate buffer. SSOP high helper formulation with 2.5% PEG and 2:1 FRR in Malate buffer in the presence of 30 mM NaCl showed the highest level of expressions for both GFP and Abca4 DNA in vitro (FIG.21A). FIG.21B shows a series of fluorescent images demonstrating LNP- mediated gene expressions of SSOP high helper formulations in sodium malate and sodium acetate. Lipofectamine was used as the positive control for GFP DNA transfection and expression. FIG.21C shows a bar graph comparing ABCA4 expression in ARPE-19 cells after dosing of various SSOP high helper formulation LNPs at 1 µg / mL for 48 h (12-well plate), total dosage of 1.6 ug NAs. SSOP DOPE high helper formulation demonstrated much higher Abca4 DNA delivery and expression in vitro compared to a reference formulation (FIG.22A – 22B). FIG.22A shows SSOP DOPE high helper formulation and comparative formulation. FIG.22B shows a bar graph comparing ABCA4 expression in ARPE-19 cells after dosing of SSOP DOPE high helper formulation LNP and a reference formulation LNP. FIG.22C shows a graph comparing size of SSOP DOPE high helper formulation LNP and a reference formulation LNP. FIG. 22D shows a graph comparing zeta potential of SSOP DOPE high helper formulation LNP and a reference formulation LNP. The engineered high helper formulation encapsulating gene of interest, GFP DNA, with transposase mRNA were prepared using different acidification buffers at different pH levels. The formulation treated APRE-19 cells were analyzed using Flow Cytometry. Without being bound to a particular theory, all the LNP DB1 / 146899640.4 86 SAL-043PC / 126933-5043 formulations treated cells have better viability and more GFP positive cells than the Lipofectamine transfected group (FIG.23A – 23C). Formulation F1 showed the highest GFP median fluorescence intensity (MFI). Formulations F1 – F6 are shown in Table 6 shown below (FIG.23A – 23C). TABLE 6: Exemplary SSOP DOPE Formulations Formulation SSOP % Cholesterol % DOPE % PEG % Materials and Methods The nucleic acids were prepared in 20 mM sodium malate buffer with 30 mM sodium chloride at pH range from 3 to 4. The lipid formulation has a molar ratio of 25:34.5:38:2.5 (SSOP:cholesterol:DOPE:PEG lipid). The SSOP to nucleic acids weight ratio is between 12:1 to 13:1. The volume ratio of nucleic acids to lipids when pumping to mix was 2:1. The formulations after mixing were dialyzed against phosphate buffer saline (PBS), pH 7.4 at volumes of 300 times of the formulation volume using a Floate-A-Lyzer dialysis device (Spectrum Labs) with a molecular weight cutoff (MWCO) of 300 kDa. The first dialysis was conducted at room temperature for 2 hours and then the formulations were dialyzed in fresh PBS overnight at 4°C. The formulations were collected after dialysis and centrifuged at 3000 g using a Amicon Ultra Centrifugal Filter (100 kDa MWCO) for concentration. Formulations were finally filtered through 0.22 µm membrane for sterilization. EQUIVALENTS While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or DB1 / 146899640.4 87 SAL-043PC / 126933-5043 adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features herein set forth and as follows in the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. INCORPORATION BY REFERENCE All patents and publications referenced herein are hereby incorporated by reference in their entireties. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. DB1 / 146899640.4 88

Claims

SAL-043PC / 126933-5043 CLAIMS 1. A method for preventing or decreasing the rate of photoreceptor loss in a subject in need thereof, comprising administering to a subject in need thereof a composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid encoding a mobile element enzyme, and a donor DNA, a transgene, or a mobile element, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid.

2. A method for treating and / or mitigating an Inherited Macular Degeneration (IMD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid encoding a mobile element enzyme, and a donor DNA, a transgene, or a mobile element, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid.

3. A method for treating and / or mitigating Stargardt (STGD) disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid encoding a mobile element enzyme, and a donor DNA, a transgene, or a mobile element, and (b) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid.

4. The method of any one of claims 1-3, wherein the delivery lipid is SS-OP. DB1 / 146899640.4 89SAL-043PC / 126933-5043 5. The method of any one of claims 1-4, wherein the helper lipid is selected from distearoylphosphatidylcholine (DSPC), 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), and any combination thereof.

6. The method of any one of claims 1-5, wherein the PEGylated lipid is selected from PEG-2K-DMG, C8 PEG 2K, and C16 PEG 2K.

7. The method of any one of claims 1-6, comprising: (i) a delivery lipid comprising from about 15 mol % to about 75 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 40 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 0.5 mol % to about 7 mol % of the total lipid present.

8. The method of any one of claims 1-7, wherein the one or more lipids comprises: (i) a delivery lipid comprising from about 25 mol % to about 75 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 65 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, optionally being one or more of: DOPC from about 5 mol % to about 35 mol % of the total lipid present, and DOPE from about 2.5 mol % to about 30 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 0.5 mol % to about 5 mol % of the total lipid present, optionally being PEG-2K-DMG.

9. The method of any one of claims 1-8, wherein the one or more lipids comprises: (i) a delivery lipid comprising from about 30 mol % to about 40 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 40 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 5 mol % to about 15 mol % of the total lipid present, optionally being: DOPE from about 5 mol % to about 15 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 3 mol % to about 6 mol % of the total lipid present, optionally being PEG-2K-DMG.

10. The method of any one of claims 1-9, wherein the one or more lipids comprises: DB1 / 146899640.4 90SAL-043PC / 126933-5043 (i) a delivery lipid comprising about 35 mol % of the total lipid present, the delivery lipid being SS- OP, (ii) cholesterol comprising about 50 mol % of the total lipid present, (iii) a helper lipid comprising about 10 mol % of the total lipid present, optionally being: DOPE comprising about 10 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 5 mol % of the total lipid present, optionally being PEG-2K- DMG.

11. The method of any one of claims 1-6, comprising: (i) a delivery lipid comprising from about 5 mol % to about 50 mol % of the total lipid present, (ii) cholesterol comprising from about 15 mol % to about 60 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 50 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present.

12. The method of claim 11, wherein the one or more lipids comprises: (i) a delivery lipid comprising from about 20 mol % to about 40 mol % of the total lipid present, (ii) cholesterol comprising from about 20 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 15 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present.

13. The method of claim 12, wherein the one or more lipids comprises: (i) a delivery lipid comprising from about 20 mol % to about 40 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 20 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 15 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present.

14. The method of any one of claims 1-6, comprising: (i) a delivery lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, (ii) cholesterol comprising from about 15 mol % to about 35 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present.

15. The composition of claim 14, wherein the one or more lipids comprises: DB1 / 146899640.4 91SAL-043PC / 126933-5043 (i) a delivery lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 15 mol % to about 35 mol % of the total lipid present, (iii) a helper lipid comprising from about 25 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present.

16. The composition of any one of claims 1-6, comprising: (i) a delivery lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, (ii) cholesterol comprising from about 25 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present.

17. The composition of claim 16, wherein the one or more lipids comprises: (i) a delivery lipid comprising from about 5 mol % to about 35 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 25 mol % to about 55 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 3.0 mol % of the total lipid present.

18. The composition of any one of claims 1-6, comprising: (i) a delivery lipid comprising from about 20 mol % to about 30 mol % of the total lipid present, (ii) cholesterol comprising from about 30 mol % to about 40 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present.

19. The composition of claim 18, wherein the one or more lipids comprises: DB1 / 146899640.4 92SAL-043PC / 126933-5043 (i) a delivery lipid comprising from about 20 mol % to about 30 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising from about 30 mol % to about 40 mol % of the total lipid present, (iii) a helper lipid comprising from about 30 mol % to about 45 mol % of the total lipid present, the helper lipid being DOPE and (iv) a PEGylated lipid comprising from about 1.0 mol % to about 5.0 mol % of the total lipid present.

20. The method of any one of claims 1-19, wherein the composition has a weight to weight ratio of delivery lipid to one or more nucleic acid-based agents of about 5:1 to about 15:1, or about 7:1 to about 13:1, or about 8:1 to about 12:1, or about 5:1, or about 6:1, or about 7:1, or about 8:1, or about 9:1, or about 10:1, or about 11:1, or about 12:1, or about 13:1, or about 14:1, or about 15:

1.

21. The method of any one of claims 1-20, wherein the composition has a weight to weight ratio of total lipid to one or more nucleic acid-based agents of about 10:1 to about 35:1, or about 15:1 to about 30:1, or about 20:1 to about 25:1, or about 15:1, or about 20:1, or about 25:1, or about 30:

1.

22. The method of any one of claims 1-21, wherein the composition forms a nucleic acid / lipid particle.

23. The method of any one of claims 1-22, wherein the one or more lipids associate into a lipid nanoparticle (LNP).

24. The method of claim 1-23, wherein the LNP encapsulates the one or more nucleic acid-based agents.

25. The method of claim 1-24, wherein the mobile element enzyme has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

26. The method of any one of claims 1-25, wherein the mobile element enzyme comprises an amino acid other than serine at the position corresponding to position 2 of SEQ ID NO:

1.

27. The method of claim 26, wherein the amino acid is a non-polar aliphatic amino acid, optionally a non- polar aliphatic amino acid optionally selected from G, A, V, L, I, and P, optionally A.

28. The method of any one of claims 1-27, wherein the mobile element enzyme does not have additional residues at the C terminus relative to SEQ ID NO:

1.

29. The method of any one of claims 1-28, wherein the mobile element enzyme has one or more mutations which confer hyperactivity. DB1 / 146899640.4 93SAL-043PC / 126933-5043 30. The method of any one of claims 1-29, wherein the mobile element enzyme has one or more amino acid substitutions selected from S8X1, C13X2, N125X3, and D416N4, or positions corresponding thereto relative to SEQ ID NO:

1.

31. The method of any one of claims 1-30, wherein the mobile element enzyme has S8X1 substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

32. The method of any one of claims 1-31, wherein the mobile element enzyme has C13X2substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

33. The method of any one of claims 1-32, wherein the mobile element enzyme has N125X3substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

34. The method of any one of claims 1-33, wherein the mobile element enzyme has D416X4 substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

35. The method of any one of claims 1-34, wherein X1is selected from G, A, V, L, I, and P.

36. The method of any one of claims 1-35, wherein X2 is selected from K, R, and H.

37. The method of any one of claims 1-36, wherein X3is selected from K, R, and H.

38. The method of any one of claims 1-37, wherein X4 is selected N, C, Q, S, and T.

39. The method of any one of claims 1-38, wherein: X1 is P, X2 is R, and X4 is N.

40. The method of any one of claims 1-39, wherein the mobile element enzyme is capable of inserting a donor DNA at a TA dinucleotide site.

41. The method of any one of claims 1-40, wherein the mobile element enzyme is capable of inserting a donor DNA at a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site.

42. The method of any one of claims 1-41, wherein the mobile element enzyme comprises: a targeting element and an enzyme that is capable of inserting the donor DNA (e.g., a mobile element) comprising a gene, optionally at a TA dinucleotide site or a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 26) octanucleotide site, or taTTAAta (SEQ ID NO: 27) octanucleotide site in a genomic safe harbor site (GSHS).

43. The method of claim 1-42, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid having the sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. DB1 / 146899640.4 94SAL-043PC / 126933-5043 44. The method of any one of claims 1-43, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid other than serine at the position corresponding to position 2 of SEQ ID NO:

1.

45. The method of claim 44, wherein the amino acid is a non-polar aliphatic amino acid, optionally a non- polar aliphatic amino acid optionally selected from G, A, V, L, I, and P, optionally A.

46. The method of any one of claims 1-45, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid that does not have additional residues at the C terminus relative to SEQ ID NO:

1.

47. The method of any one of claims 1-46, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid having a sequence comprising one or more mutations which confer hyperactivity.

48. The method of any one of claims 1-47, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid having one or more amino acid substitutions selected from S8X1, C13X2, N125X3, or D416X4positions corresponding thereto relative to SEQ ID NO:

1.

49. The method of any one of claims 1-48, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid having S8X1substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

50. The method of any one of claims 1-49, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid having C13X2substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

51. The method of any one of claims 1-50, wherein the nucleic acid encoding the mobile element enzyme encodes an amino acid having N125X3substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

52. The method of any one of claims 1-51, wherein the mobile element enzyme has D416X4 substitution, or at a position corresponding thereto relative to SEQ ID NO:

1.

53. The method of any one of claims 1-52, wherein X1 is selected from G, A, V, L, I, and P.

54. The method of any one of claims 1-53, wherein X2 is selected from K, R, and H.

55. The method of any one of claims 1-54, wherein X3is selected from K, R, and H.

56. The method of any one of claims 1-55, wherein X4 is selected N, C, Q, S, and T.

57. The method of any one of claims 1-56, wherein: X1is P, X2is R, and X4is N.

58. The method of any one of claims 1-57, the encoded mobile element enzyme is capable of inserting a donor DNA at a TA dinucleotide site. DB1 / 146899640.4 95SAL-043PC / 126933-5043 59. The method of any one of claims 1-58, the encoded mobile element enzyme is capable of inserting a donor DNA at a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site.

60. The method of any one of claims 1-59, wherein the nucleic acid encoding the mobile element enzyme comprises a sequence encoding: a targeting element and an enzyme that is capable of inserting the donor DNA (e.g., a mobile element) comprising a gene, optionally at a TA dinucleotide site or a TTAA tetranucleotide site, or ttTTAAaa (SEQ ID NO: 29) octanucleotide site, or taTTAAta (SEQ ID NO: 30) octanucleotide site in a genomic safe harbor site (GSHS).

61. The method of any one of claims 1-60, wherein the targeting element comprises one or more of a gRNA, optionally associated with a Cas enzyme, which is optionally catalytically inactive or a transcription activator-like effector (TALE).

62. The method of any one of claims 1-61, wherein the targeting element comprises a transcription activator- like effector (TALE) DNA binding domain (DBD) and zinc fingers (ZF) DBD.

63. The method of any one of claims 1-62, wherein the targeting element comprises a Cas9 enzyme guide RNA complex.

64. The method of claim 1-63, wherein the Cas9 enzyme guide RNA complex comprises a nuclease-deficient dCas9 guide RNA complex.

65. The method of any one of claims 1-64, wherein the GSHS is in an open chromatin location in a chromosome.

66. The method of any one of claims 1-65, wherein the GSHS is selected from adeno-associated virus site 1 (AAVS1), chemokine (C-C motif) receptor 5 (CCR5) gene, HIV-1 coreceptor, and human Rosa26 locus.

67. The method of any one of claims 1-66, wherein the enzyme and the targeting element are connected.

68. The method of any one of claims 1-67, wherein the enzyme and the targeting element are fused to one another or linked via a linker to one another.

69. The method of claim 1-68, wherein the linker is a flexible linker.

70. The method of claim 1-69, wherein the flexible linker is substantially comprised of glycine and serine residues, optionally wherein the flexible linker comprises (Gly4Ser)n, where n is from about 1 to about 12.

71. The method of claim 1-70, wherein the flexible linker is of about 20, or about 30, or about 40, or about 50, or about 60 amino acid residues. DB1 / 146899640.4 96SAL-043PC / 126933-5043 72. The method of any one of claims 1-71, wherein the one or more nucleic acid-based agents comprise a donor DNA or transgene or mobile element.

73. The method of any one of claims 1-72, wherein the donor DNA or transgene or mobile element comprises a gene encoding a complete polypeptide.

74. The method of any one of claims 1-73, wherein the donor DNA or transgene or mobile element comprises a gene which is defective or substantially absent in a disease state.

75. The method of any one of claims 1-74, wherein the donor DNA or transgene or mobile element is flanked by one or more ends.

76. The method of any one of claims 1-75, wherein the donor DNA or transgene or mobile element has a size of up to about 10 kb, or up to about 12 kb, or up to about 15 kb, or about 7.5 to about 15 kb, or about 10 to about 15 kb.

77. The method of any one of claims 1-76, wherein the one or more nucleic acid-based agents is in the form of RNA.

78. The method of claim 1-77, wherein the RNA is or comprises messenger RNA (mRNA).

79. The method of claim 1-78, wherein the mRNA is or comprises modified mRNA (mmRNA).

80. The method of claim 1-79, wherein the mmRNA comprises one or more of a 5’-m7G cap (cap0, cap1, or cap2), a pseudouridine or n-methyl-pseudouridine substitution, and a poly-A tail of about 30, or of about 50, or of about 100, or of about 150 nucleotides in length.

81. The method of any one of claims 1-80, wherein the one or more nucleic acid-based agents is in the form of DNA.

82. The method of claim 1-81, wherein the DNA is or comprises plasmid DNA or miniplasmid DNA.

83. The method of claim 1-82, wherein the plasmid DNA has a size of up to about 10 kb, or up to about 12 kb, or up to about 15 kb, or about 7.5 to about 15 kb, or about 10 to about 15 kb.

84. The method of any one of claims 1-83, wherein the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme and a donor DNA or transgene or mobile element.

85. The method of any one of claims 1-84, wherein the nucleic acid-based agent comprises both RNA and DNA.

86. The method of any one of claims 1-85, wherein the nucleic acid-based agent comprises both mRNA and DNA. DB1 / 146899640.4 97SAL-043PC / 126933-5043 87. The method of claim 1-86, wherein the weight to weight ratio of DNA : mRNA is from about 10:1 to about 1:10, or about 10 : about 1, or about 9 : about 1, or about 8 : about 1, or about 7 : about 1, or about 6 : about 1, or about 5 : about 1, or about 4 : about 1, or about 3 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 3, or about 1 : about 4, or about 1 : about 5, or about 1 : about 6, or about 1 : about 7, or about 1 : about 8, or about 1 : about 9, or about 1 : about 10.

88. The method of any one of claims 1-87, wherein the nucleic acid-based agent comprises both mmRNA and plasmid DNA.

89. The method of any one of claims 1-88, wherein the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA.

90. The method of any one of claims 1-89, wherein the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA and the weight to weight ratio of plasmid DNA: mmRNA is about 5 : about 1, or about 2 : about 1, or about 1 : about 1, or about 1 : about 2, or about 1 : about 5.

91. The method of any one of claims 1-90, wherein the nucleic acid-based agent comprises both: a nucleic acid encoding a mobile element enzyme in the form of mmRNA and a donor DNA or transgene or mobile element in the form of plasmid DNA and the weight to weight ratio of plasmid DNA: mmRNA is about 2 : about 1.

92. The method of any one of claims 1-91, wherein the composition provides high encapsulation of the nucleic acid-based agents.

93. The method of any one of claims 1-92, wherein the composition provides an encapsulation efficiency of greater than about 90%, or greater than about 95%, or greater than about 98%.

94. The method of any one of claims 1-93, wherein the composition provides low polydispersity.

95. The method of any one of claims 1-94, wherein the composition is an LNP having a particle size of about 60 to about 200 nm, or about 100 to about 150 nm, or about 60 to about 120 nm.

96. The method of any one of claims 1-95, wherein the administering to the subject is through systemic delivery.

97. The method of any one of claims 1-96, wherein the administering to the subject is through intravenous, subcutaneous, or intraperitoneal delivery.

98. The method of any one of claims 1-97, wherein the administering to the subject is through local delivery. DB1 / 146899640.4 98SAL-043PC / 126933-5043 99. The method of any one of claims 1-98, wherein the administering to the subject is through ocular, subretinal, sub-retinal pigment epithelium (sub-RPE), intraretinal, subvitreal, intravitreal, juxtasceral, subconjunctival, intracameral, or retrobulbar delivery.

100. The method of any one of claims 1-99, wherein the administering to the subject is a single administration.

101. The method of any one of claims 1-100, wherein the method improves distance visual acuity of the subject.

102. The method of any one of claims 1-101, wherein the method provides a lowering of one or more of retinaldehyde, N-retinylidene-N-retinylethanolamine (A2E) and iso-A2E relative to a level of one or more of retinaldehyde, A2E and iso-A2E without the administration, optionally greater than about a 40%, or greater than about a 50%, or greater than about a 60%, or greater than about a 70%, or greater than about a 80%, or greater than about a 90% lowering.

103. The method of any one of claims 1-102, wherein the method results in improvement of best corrected visual acuity (BCVA) to greater than about 20 / 200.

104. The method of any one of claims 1-103, wherein the method results in improvement of retinal or foveal morphology, as measured by fundus autofluorescence (FAF) or Spectral Domain-Optical Coherence Tomography (SD-OCT).

105. The method of any one of claims 1-104, wherein the method results in reduction or prevention of one or more of wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired color vision, and difficulty adapting to dim lighting (delayed dark adaptation) in the subject.

106. The method any one of claims 1-105, wherein the method reduces or prevents lipofuscin accumulation in the retina, optionally in the retinal pigment epithelium (RPE).

107. The method any one of claims 1-106, wherein the method reduces or prevents the formation of retinal pigment epithelium (RPE) debris.

108. The method any one of claims 1-107, wherein the method is performed in the absence of a steroid treatment.

109. The method of any one of claims 1-108, wherein the method is substantially non-immunogenic.

110. The method of any one of claims 3-109, wherein the STGD disease optionally is STGD Type 1 (STGD1). DB1 / 146899640.4 99SAL-043PC / 126933-5043 111. The method of any one of claims 3-110, wherein the STGD disease is characterized by one or more mutations in ABCA4 gene and wherein the ABCA4 mutations optionally being autosomal recessive mutations.

112. The method of any one of claims 1-111, wherein the one or more nucleic acid-based agents comprise a ABCA4 gene or a functional fragment thereof, optionally wherein ABC4A gene is codon optimized.

113. The method of claim 112, wherein ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon-optimized form thereof.

114. A composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid, (ii) cholesterol, (iii) a helper lipid, and (iv) optionally, a PEGylated lipid.

115. A composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least about 80%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, wherein the ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of DB1 / 146899640.4 100SAL-043PC / 126933-5043 SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon- optimized form thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 35.7 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising about 49.8 mol % of the total lipid present, (iii) a helper lipid comprising about 9.6 mol % of the total lipid present, optionally being: DOPE comprising about 9.6 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 4.9 mol % of the total lipid present, optionally being PEG-2K-DMG.

116. A composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the nucleotide sequence of SEQ ID NO: 27, or a nucleotide sequence having at least about 80%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, wherein the ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon- optimized form thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 35.7 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising about 49.8 mol % of the total lipid present, (iii) a helper lipid comprising about 9.6 mol % of the total lipid present, optionally being: DOPE comprising about 9.6 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 4.9 mol % of the total lipid present, optionally being PEG-2K-DMG.

117. A composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence DB1 / 146899640.4 101SAL-043PC / 126933-5043 having at least about 80%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, wherein the ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon- optimized form thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 25 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising about 34.5 mol % of the total lipid present, (iii) a helper lipid comprising about 38 mol % of the total lipid present, optionally being: DOPE comprising about 38 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 2.5 mol % of the total lipid present.

118. A composition comprising: (a) one or more nucleic acid-based agents comprising a nucleic acid which encodes a mobile element enzyme that has the nucleotide sequence of SEQ ID NO: 27, or a nucleotide sequence having at least about 80%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, (b) a nucleic acid-based agent comprising an ABCA4 gene or functional fragment thereof, wherein the ABCA4 gene comprises at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 28 or a nucleic acid comprising a nucleotide sequence of SEQ ID NO: 10 or a codon- optimized form thereof, and (c) one or more lipids, the one or more lipids comprising: (i) a delivery lipid comprising about 25 mol % of the total lipid present, the delivery lipid being SS-OP, (ii) cholesterol comprising about 34.5 mol % of the total lipid present, (iii) a helper lipid comprising about 38 mol % of the total lipid present, optionally being: DOPE comprising about 38 mol % of the total lipid present, and (iv) a PEGylated lipid comprising about 2.5 mol % of the total lipid present. DB1 / 146899640.4 102

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