Arrdc1-mediated microvesicle-based treatment of age-related macular degeneration

Abstract

Described herein are compositions and methods for treatment of ocular disorders, e.g., wet AMD.

Description

[0001] Attorney Docket No.54926-0021WO1 ARRDC1-MEDIATED MICROVESICLE-BASED TREATMENT OF AGE-RELATED MACULAR DEGENERATION CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 699,652, filed September 26, 2024, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD Provided herein are compositions and methods for ARRDC1-mediated microvesicle-based editing of vascular endothelial growth factor A (VEGFA), as well as methods of treatment of ocular disorders, e.g., AMD, e.g., wet AMD. BACKGROUND Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. A need exists for new treatments for AMD. SUMMARY In its advanced stage, AMD occurs in two clinically distinguished forms (wet and dry), but only wet AMD is currently treatable. Current treatments of wet AMD require repeated ocular injections with vascular endothelial growth factor A (VEGFA) antagonists. These treatments at best stop disease progression and prevent or delay vision loss, but do not improve visual dysfunction. Furthermore, 15–40% of eyes fail to respond or only partially respond. Approximately 20 million people in the United States have AMD, nearly 1.5 million of whom have the advanced form of the disease. About 200,000 new cases of wet AMD are diagnosed each year in North America. Described herein are novel gene editing approaches for the treatment of AMD. A first approach is to selectively reduce pathogenic VEGFA isoforms while retaining anti- angiogenic isoforms (e.g., to knock down or knock out pathogenic forms selectively, e.g., by base editing at a splice site, e.g., as described herein). A second approach is to knock Attorney Docket No.54926-0021WO1 down or knock out all forms of VEGFA (e.g., through genome editing, e.g., to knock down or knock out of VEGFA). In vivo gene editing therapies such as these offer the transformative potential to cure, ameliorate, or prevent an array of diseases. However, broader therapeutic applications have been limited by the inability to efficiently and safely deliver gene editing technologies to disease-affected tissues and cell types, e.g., for the treatment of AMD (e.g., described herein). Thus, described herein are engineered human ARMMs (ARrestin-domain 1 Mediated Microvesicles) as a safe, targeted, and re-dosable therapeutic platform for the delivery of therapeutic cargo (e.g., gene editing protein and mRNA complexes) in vivo, e.g., to ocular cells, e.g., retinal pigment epithelium (RPE) cells, for the treatment of AMD (e.g., as described herein). Treatment of AMD using the ARMMs described herein, e.g., by reduction of pathogenic VEGFA, has the benefit of durability, eliminating the need for frequent injections. Moreover, it is effective for patients who do not respond or only partially respond to current therapies. The protein ARRDC1, which is the principal driver of ARMM formation, is used as a recruitment handle to actively load engineered vesicles. That therapeutic payload- loaded ARMMs are engineered versions of naturally existing vesicles enables this delivery system to overcome various limitations of existing delivery technologies, such as toxicity, low specificity, instability, and immunogenicity. This invention relates at least in part to the discovery that molecules, such as proteins and nucleic acids, including ribonucleic acids (RNAs), as well as small molecules, can be loaded into microvesicles, specifically ARRDC1-mediated microvesicles (ARMMs), and used to deliver gene editing compositions, for example, compositions for reduction of pathogenic VEGFA (e.g., by the gene editing approaches described herein). In addition, the ARMMs delivery systems, described herein, address limitations of current delivery systems that prevent the safe and efficient delivery of proteins and nucleic acids (e.g., RNA-guided proteins and gRNAs), e.g., to ocular cells, e.g., RPE cells. As ARMMs are derived from an endogenous budding pathway, they are unlikely to elicit a strong immune response, unlike viral delivery systems, which are known to trigger inflammatory responses. (See, Sen et al., “Cellular unfolded protein Attorney Docket No.54926-0021WO1 response against viruses used in gene therapy,” Front Microbiology, 5:250, 1-16 (2014)). Additionally, ARMMs allow for the specific packaging of many types and classes of potentially therapeutic molecules (e.g., biological molecules, such as a protein or nucleic acid (e.g., DNA plasmid, mRNA, miRNA, or shRNA), or small molecules). Thus, disclosed herein are compositions and methods for delivering therapeutic payloads (e.g., gene editing payloads described herein), e.g., to reduce pathogenic VEGFA, e.g., as described herein. Also disclosed herein are compositions and methods for targeting ARMMs, e.g., to an ocular cell, e.g., a RPE cell. ARMMs are microvesicles that are distinct from exosomes which, like budding viruses, are produced by direct plasma membrane budding (“DPMB”). DPMB is driven by a specific interaction of TSG101 with a tetrapeptide PSAP (SEQ ID NO: 39) motif of the arrestin-domain-containing protein ARRDC1 accessory protein, which is localized to the plasma membrane through its arrestin domain. ARMMs have been described in detail, for example, in PCT application number PCT / US2013 / 024839, filed February 6, 2013 (published as WO 2013 / 119602 A1 on August 15, 2013) by Lu, Q., et al., and entitled “Arrdc1-Mediated Microvesicles (ARMMs) and Uses Thereof,” as well as in U.S. Pat. Nos.: 9,737,480; 9,816,080; 10,260,055; and PCT Publication WO2018 / 067546; the entire contents of which are hereby incorporated by reference in their entirety. The ARRDC1 / TSG101 interaction results in the relocation of TSG101 from endosomes to the plasma membrane and mediates the release of microvesicles that contain TSG101, ARRDC1, and other cellular components as well as the molecule of interest. Molecules of interest, whether naturally or non-naturally occurring include, but are not limited to, proteins, nucleic acids, and small molecules that can preferably associate with one or more ARMM related proteins (e.g., ARRDC1), or can be modified to associate with more specifically, TSG101 or ARRDC1 or specific motif(s) therein. These associations facilitate the incorporation of the molecules into ARMMs, which in turn can be used to deliver the desired payload (molecule of interest) into a targeted cell. By way of example, but not limitation, a payload RNA can be fused to a trans-activation response (TAR) element, thereby allowing it to associate with an ARRDC1 protein that is fused to an RNA binding protein, such as a Tat protein (e.g., bovine TAT protein). Alternatively, a payload protein can be fused to one or more WW domains, which associate with the Attorney Docket No.54926-0021WO1 PPXY motif of ARRDC1. The association of the molecule to an ARMM-related protein (e.g., ARRDC1), facilitates the loading of the molecule into the ARRDC1-containing ARMM. Alternatively, the molecule can be fused to an ARMM protein (e.g., TSG101 or ARRDC1) to load the payload into the ARMM. The molecule can be fused to the ARMM protein (e.g., TSG101 or ARRDC1) via a linker that may be cleaved upon delivery to a target cell. Molecules of interest may also include a mixture of different types of molecules. For example, both protein and RNA molecules, e.g., as is the case for RNA- guided proteins such as Cas9 nucleases or base editors and gRNA(s). In some cases, the RNA-guided protein and gRNA(s) are in the form of a ribonucleoprotein. As another example, the delivery platform for ARMMs will enable delivery of molecule(s) of interest (e.g., therapeutic cargo) to target cells (e.g., ocular cells, e.g., RPE cells). Thus, provided herein are arrestin domain-containing protein 1 (ARRDC1)- mediated microvesicle(s) (ARMM(s)), comprising: a lipid bilayer; an ARRDC1 protein, fragment thereof, or variant thereof; an RNA-guided protein; and a gRNA targeting the VEGFA gene. Also provided herein are microvesicle producing cell(s) comprising: nucleic acid construct(s) encoding: an ARRDC1 protein, fragment thereof, or variant thereof; an RNA-guided protein; and a gRNA targeting the VEGFA gene. In some embodiments, the RNA-guided protein is a nuclease. In some embodiments, the nuclease is a Type II or Type V CRISPR Cas nuclease, optionally a Cas9 nuclease. In some embodiments, the RNA-guided protein is a base editor, optionally a cytosine base editor (CBE) or adenine base editor (ABE). In some embodiments, the gRNA, when complexed with the RNA-guided protein in a cell expressing VEGFA, introduces a mutation into the VEGFA gene that knocks down or knocks out expression of VEGFA mRNA and / or protein. In some embodiments, the mutation is a missense mutation or a nonsense mutation. In some embodiments, the mutation is a point mutation or an indel mutation. In some embodiments, the mutation is in an exon of the VEGFA gene. In some embodiments, the mutation is in an intron of the VEGFA gene. In some embodiments, the mutation is in a regulatory region of the VEGFA gene. Attorney Docket No.54926-0021WO1 In some embodiments, the RNA-guided protein is a base editor and the mutation is at the splice acceptor site of exon 8. In some embodiments, the base editor is an adenine base editor (ABE) and the mutation is an A->G mutation in the splice acceptor site of exon 8. In some embodiments, the gRNA comprises any one of the following targeting sequences: In some embodiments, the RNA-guided protein is a nuclease and the mutation is an indel. In some embodiments, the gRNA comprises any one of the following targeting sequences: Also provided herein are method(s) of treating an ocular disorder comprising: administering the ARMM or the microvesicle producing cell of any one of the preceding claims to a subject in need thereof. In some embodiments, the ocular disorder is AMD. In some embodiments, the ocular disorder is wet AMD. In some embodiments, the patient has choroidal neovascularization (CNV). In some embodiments, administering comprises intravitreal, subretinal, and / or suprachoroidal injection. Attorney Docket No.54926-0021WO1 Also provided herein are method(s) for delivering a payload to a cell comprising administering an ARMM or microvesicle described herein to a cell. Also provided herein are method(s) for knocking down or knocking out VEGFA in a cell, the method comprising administering an ARMM or microvesicle producing cell described herein to a cell. In some embodiments, knocking down or knocking out VEGFA in a cell comprises selectively knocking down or knocking out pathogenic exon 8a isoform(s) of VEGFA in a cell. In some embodiments, knocking down or knocking out VEGFA in a cell comprises non-selectively knocking down or knocking out VEGFA in a cell. In some embodiments, the cell is an RPE cell. Also provided herein are method(s) of treating an ocular disorder comprising: selectively knocking down or knocking out pathogenic exon 8a isoform(s) of VEGFA in a cell. In some embodiments, the method comprises editing the splice acceptor site of exon 8. In some embodiments, editing the splice acceptor site of exon 8 comprises introducing a point mutation into the splice acceptor site of exon 8. In some embodiments, the point mutation is an AàG point mutation within the splice acceptor site of exon 8. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DEFINITIONS The terms “ARRDC1-mediated microvesicle” or “ARMM,” as used herein, refers to a microvesicle comprising an ARRDC1 protein or variant thereof, and / or TSG101 Attorney Docket No.54926-0021WO1 protein, or variant thereof. ARMMs have been described in detail, for example, in PCT application number PCT / US2013 / 024839, filed February 6, 2013 (published as WO 2013 / 119602 A1 on August 15, 2013) by Lu et al., and entitled “Arrdc1-Mediated Microvesicles (ARMMs) and Uses Thereof,” as well as in U.S. Pat Nos.9,737,480; 9,816,080; 10,260,055, 10,945,954, 11,001,817, and PCT Publications WO2018 / 067546, WO2021 / 062196, and WO2021 / 252924; the entire contents of which are hereby incorporated by reference in their entirety. In some embodiments, the ARMM is shed from a cell (e.g., producer cell), and comprises an agent (payload), for example, a nucleic acid, protein, or small molecule, present in the cytoplasm or associated with the membrane of the cell. Exemplary payloads include, but are not limited to a nucleic acid, protein, or small molecule, present in the cytoplasm or associated with the membrane of the cell. In some embodiments, the ARMM is shed from a cell (e.g., a transgenic cell), and comprises an agent, for example, a nucleic acid, protein, or small molecule, present in the cytoplasm or associated with the membrane of the cell. In some embodiments, the ARMM is shed from a transgenic cell comprising a recombinant expression construct that includes a transgene, and the ARMM comprises a gene product, for example, an RNA transcript and / or a protein (e.g., an ARRDC1-Tat fusion protein and a TAR- payload RNA) encoded by the expression construct. In some embodiments, the ARMM is produced synthetically, for example, by contacting a lipid bilayer with an ARRDC1 protein or a variant thereof, or a variant thereof, in a cell-free system in the presence of TSG101, or a variant thereof. In other embodiments, the ARMM is synthetically produced by contacting a lipid bilayer with HECT domain ligase, and VPS4a. In some embodiments, an ARMM lacks a late endosomal marker. Some of the ARMMs provided herein do not include, or are negative for, one or more exosomal biomarkers. Exosomal biomarkers are known to those of skill in the art and include, but are not limited to, CD63, Lamp-1, Lamp-2, CD9, HSPA8, GAPDH, CD81, SDCBP, PDCD6IP, ENO1, ANXA2, ACTB, YWHAZ, HSP90AA1, ANXA5, EEF1A1, YWHAE, PPIA, MSN, CFL1, ALDOA, PGK1, EEF2, ANXA1, PKM2, HLA-DRA, and YWHAB. Certain ARMMs provided herein may include an exosomal biomarker. Accordingly, some ARMMs may be negative for one or more other exosomal biomarkers, but positive for one or more different exosomal biomarkers. For example, such an ARMM may be Attorney Docket No.54926-0021WO1 negative for CD63 and Lamp-1 but may include PGK1 or GAPDH; or may be negative for CD63, Lamp-1, CD9, and CD81, but may be positive for HLA-DRA. In some embodiments, ARMMs include an exosomal biomarker, but at a lower level than the level found in exosomes. For example, some ARMMs include one or more exosomal biomarkers at a level of less than about 1%, less than about 5%, less than about 10%, less than about 20%, less than about 30%, less than about 40%, or less than about 50% of the level of that biomarker found in exosomes. To give a non-limiting example, in some embodiments, an ARMM may be negative for CD63 and Lamp-1, include CD9 at a level of less than about 5% of the level of CD9 typically found in exosomes, and be positive for ACTB. Exosomal biomarkers in addition to those listed above are known in the art, and the invention is not limited in this regard. The term “cargo protein,” as used herein, refers to a protein that may be incorporated in an ARMM, for example, into the liquid phase of the ARMM or into the lipid bilayer of an ARMM. The term “cargo protein to be delivered” refers to any protein that can be delivered via its association with or inclusion in an ARMM to a subject, organ (e.g., liver, kidneys, heart, pancreas, brain, etc.), tissue, or cell. In some embodiments, the cargo protein is to be delivered to a target cell in vitro, in vivo, or ex vivo. In some embodiments, the cargo protein to be delivered is a biologically active agent, i.e., it has activity in a cell, organ, tissue, and / or subject. For instance, a protein that, when administered to a subject, has a biological effect on that subject, is considered biologically active. In certain embodiments, the cargo protein is an RNA binding protein (“RNB”), In some cases, the RNA binding protein is or comprises a Cas protein or variant thereof (e.g., a Cas protein (e.g., Cas9, C2c1, Cpf1, Cas12a, Cas13, Cas14) or variant thereof. In some cases, the RNA binding protein is or comprises a nuclease protein or variant thereof. In certain embodiments, the nuclease may be a Cas9 nuclease, a TALE nuclease, a zinc finger nuclease, or any variant thereof. Nucleases, including Cas9 proteins and their variants, are described in more detail elsewhere herein. In some embodiments, the Cas9 protein or variant thereof is associated with nucleic acid. For example, the cargo protein may be a Cas9 protein associated with a gRNA (e.g., as a ribonucleoprotein “RNP”). In some embodiments, a cargo protein to be delivered is a therapeutic agent. Attorney Docket No.54926-0021WO1 As used herein, the term “therapeutic agent” refers to any agent that, when administered to a subject has a beneficial effect. In some embodiments, the therapeutic agent comprises a small molecule, a protein (or peptide), one or more nucleic acids, or an agent associated with a small molecule. In some embodiments, the payload to be delivered is a diagnostic agent. In some embodiments, the agent to be delivered is a prophylactic agent. In some embodiments, the agent to be delivered is useful as an imaging agent. In some of these embodiments, the diagnostic or imaging agent is, and in others, it is not, biologically active. In some embodiments, the therapeutic agent comprises an agent that reduces (knocks down) the expression of one or more genes in an organism (e.g., a subject). In other embodiments, the therapeutic agent comprises an agent that inactivates or removes (knocks out) one or more specific genes in an organism (e.g., a subject). In some embodiments, the therapeutic agent to be delivered to a cell is a transcription factor, a tumor suppressor, a developmental regulator, a growth factor, a metastasis suppressor, a pro-apoptotic protein, a nuclease, or a recombinase. As used herein, the term “therapeutic effect” refers to a consequence of treatment, the results of which are judged to be desirable and beneficial. A therapeutic effect can include, directly or indirectly, the arrest, reduction, or elimination of a disease manifestation. A therapeutic effect can also include, directly or indirectly, the arrest reduction or elimination of the progression of a disease manifestation. As used herein, the term “transcription factor” refers to a DNA-binding protein that regulates the transcription of DNA into RNA, for example, by activation or repression of transcription. Some transcription factors affect the regulation of transcription alone, while others act in concert with other proteins. Some transcription factors can both activate and repress transcription under certain conditions. In general, transcription factors bind a specific target sequence or sequences highly similar to a specific consensus sequence in a regulatory region of a target gene. Transcription factors may regulate the transcription of a target gene alone or in a complex with other molecules. Examples of transcription factors include, but are not limited to, Sp1, NF1, CCAAT, GATA, HNF, PIT-1, MyoD, Myf5, Hox, Winged Helix, SREBP, p53, CREB, AP-1, Mef2, STAT, R-SMAD, NF-Κβ, Notch, TUBBY, and NFAT. Attorney Docket No.54926-0021WO1 The term “binding RNA,” as used herein, refers to a ribonucleic acid (RNA) that binds to an RNA binding protein, for example, any of the RNA binding proteins known in the art and / or described herein. In some embodiments, a binding RNA is an RNA that specifically binds to an RNA binding protein. A binding RNA that “specifically binds” to an RNA binding protein, binds to the RNA binding protein with greater affinity, avidity, more readily, and / or with greater duration than it binds to another protein, such as a protein that does not bind the RNA or a protein that weakly binds to the binding RNA. In some embodiments, the binding RNA is a naturally occurring RNA, or non-naturally occurring variant thereof, that binds to a specific RNA binding protein. For example, the binding RNA may be a TAR element, a Rev response element, an MS2 RNA, or any variant thereof that specifically binds an RNA binding protein. In some embodiments, the binding RNA may be a trans-activating response element (TAR element), or variant thereof, which is an RNA stem-loop structure that is found at the 5ʹ-ends of nascent HIV- 1 transcripts and specifically binds to the trans-activator of transcription (Tat) protein. In some embodiments, the binding RNA is a Rev response element (RRE), or variant thereof, that specifically binds to the accessory protein Rev (e.g., Rev from HIV-1). In some embodiments, the binding RNA is an MS2 RNA that specifically binds to a MS2 phage coat protein. The binding RNAs of the present disclosure may be designed to specifically bind a protein (e.g., an RNA binding protein fused to ARRDC1) to facilitate loading of the binding RNA (e.g., a binding RNA fused to a payload RNA) into an ARMM. The term “aptamer,” as used herein, refers to nucleic acids (e.g., RNA, DNA) that bind to a specific target molecule, e.g., an RNA binding protein. In some embodiments, nucleic acid (e.g., DNA or RNA) aptamers are engineered through repeated rounds of in vitro selection or alternatively, SELEX (systematic evolution of ligands by exponential enrichment) methodology, to bind to various molecular targets, for example, proteins, small molecules, macromolecules, metabolites, carbohydrates, metals, nucleic acids, cells, tissues, and organisms. Methods for engineering aptamers to bind to various molecular targets, such as proteins, are known in the art and include those described in U.S. Pat. Nos.6,376,19; and 9,061,043; Shui, B., et al., “RNA aptamers that functionally interact with green fluorescent protein and its derivatives,” Nucleic Acids Res., Mar; Attorney Docket No.54926-0021WO1 40(5): e39 (2012); Trujillo, U.H., et al., “DNA and RNA aptamers: from tools for basic research towards therapeutic applications,” Comb. Chem. High Throughput Screen, 9(8):619–32 (2006); Srisawat, C., et al., “Streptavidin aptamers: Affinity tags for the study of RNAs and ribonucleoproteins,” RNA, 7:632–641 (2001); and Tuerk and Gold, “Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase,” Science, (1990); the entire contents of each of which are hereby incorporated by reference in their entirety. The term “RNA binding protein,” as used herein, refers to a polypeptide molecule that binds to a binding RNA, for example, any of the binding RNAs known in the art and / or described herein. In some embodiments, an RNA binding protein is a protein that specifically binds to a binding RNA. An RNA binding protein that “specifically binds” to a binding RNA, binds to the binding RNA with greater affinity, avidity, more readily, and / or with greater duration than it binds to another RNA, such as a control RNA (e.g., an RNA having a random nucleic acid sequence) or an RNA that weakly binds to the RNA binding protein. In some embodiments, the RNA binding protein is a naturally occurring protein or a non-naturally occurring variant thereof, that binds to a specific RNA. For example, in some embodiments, the RNA binding protein may be a trans- activator of transcription (Tat) protein that specifically binds a trans-activating response element (TAR element). In some embodiments, the Tat protein is from a bovine. In some embodiments, the RNA binding protein is a regulator of virion expression (Rev) protein (e.g., Rev from HIV-1) or variant thereof, that specifically binds to a Rev response element (RRE). In some embodiments, the RNA binding protein is a coat protein of an MS2 bacteriophage that specifically binds to an MS2 RNA. The RNA binding proteins useful in the present disclosure (e.g., a binding protein fused to ARRDC1) may be designed to specifically bind a binding RNA (e.g., a binding RNA fused to a payload RNA) to facilitate loading of the binding RNA into an ARMM. The term “payload,” “payload protein,” “payload nucleic acid,” “payload DNA,” “payload RNA,” or “payload small molecule,” as used herein, refers to a protein, nucleic acid, including DNA or RNA, or a small molecule, respectively, that may be incorporated into an ARMM, for example, into the liquid phase of the ARMM or into the lipid bilayer of an ARMM. Types of payload protein, payload nucleic acid, payload DNA, payload Attorney Docket No.54926-0021WO1 RNA, and payload small molecule are known in the art and include those described in U.S. Pat. Nos.: 9,737,480; 9,816,080; 10,260,055; and PCT Publication WO2018 / 067546; the entire contents of each of which are hereby incorporated by reference in their entirety. In some cases, the payload is a gene editing payload described herein. The payload can be delivered via its association with or inclusion in an ARMM to a subject, organ, tissue, or cell. In some embodiments, the payload is to be delivered to a targeted cell in vitro, in vivo, or ex vivo. In some embodiments, the payload to be delivered is a biologically active agent, i.e., it has activity in a cell, organ, tissue, and / or subject. For instance, a protein, nucleic acid (e.g., DNA or RNA), or small molecule that, when administered to a subject, has a biological effect on that subject or is biologically active. In some embodiments, a payload to be delivered is a therapeutic agent. The term “linker,” as used herein, refers to a chemical moiety linking two molecules or moieties, e.g., an ARRDC1 protein and a Tat protein, a WW domain, and a Tat protein, or an ARRDC1 protein and an RNA-binding protein. Typically, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In some embodiments, the linker comprises an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker comprises a nucleotide (e.g., DNA or RNA) or a plurality of nucleotides (e.g., a nucleic acid). In some embodiments, the linker is an organic molecule, functional group, polymer, or other chemical moiety / moieties. In some embodiments, the linker is a cleavable linker, e.g., the linker comprises a bond that can be cleaved upon exposure to, for example, UV light or a hydrolytic enzyme, such as a protease or esterase. In some embodiments, the linker is any stretch of amino acids having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids). In other embodiments, the linker is a chemical bond (e.g., a covalent bond, amide bond, disulfide bond, ester bond, carbon-carbon bond, carbon-heteroatom bond, and the like). Attorney Docket No.54926-0021WO1 As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, the term “animal” refers to a human of either sex at any stage of development. In some embodiments, the term “animal” refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). Animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, a genetically engineered animal, or a clone. In some embodiments, the animal is a transgenic non- human animal, a genetically engineered non-human animal, or a non-human clone. As used herein, the terms “associated with,” “conjugated,” “linked,” “attached,” and the like, when used with respect to two or more entities, for example, with chemical moieties, molecules, and / or ARMMs, means that the entities are physically associated or connected with one another, either directly or via one or more additional moieties that serve as a linker, to form a structure that is sufficiently stable so that the entities remain physically associated under the conditions in which the structure is used, e.g., under physiological conditions. An ARMM microvesicle is typically associated with an agent, for example, a nucleic acid, protein, or small molecule, by a mechanism that involves a covalent (e.g., via an amide bond) or non-covalent association (e.g., between ARRDC1 and a WW domain, or between a Tat protein and a TAR element). In certain embodiments, the agent (e.g., a therapeutic agent, a payload protein, payload nucleic acid, or payload small molecule) is covalently bound to a molecule that associates non- covalently with a part of the ARMM that is fused to an ARRCD1 protein, a TSG101 protein or variant thereof, or a lipid bilayer-associated protein by a covalent bond (e.g., an amide bond), or variant thereof. In some embodiments, the association is via a linker, for example, a cleavable linker. In some embodiments, an entity (e.g., a payload protein, payload nucleic acid, or payload small molecule) is associated with an ARMM by inclusion in the ARMM, for example, by encapsulation of the molecule within the ARMM. For example, in some embodiments, a molecule (e.g., a therapeutic agent, a payload protein, payload nucleic acid, or payload small molecule) present in the cytoplasm of an ARMM-producing cell is associated with an ARMM by encapsulation of the cytoplasm with the agent in the ARMM upon ARMM budding. Similarly, a Attorney Docket No.54926-0021WO1 membrane protein or other molecule associated with the cell membrane of an ARMM producing cell may be associated with an ARMM produced by the cell by inclusion into the ARMM’s membrane upon budding. As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a cell, organ, tissue, and / or subject. For instance, a substance that when administered to an organism produces or elicits a biological effect on that organism is biologically active. As one example, a payload RNA may be considered biologically active if it increases or decreases the expression of a gene product when administered to a subject or cell. As another example, a nuclease payload protein may be considered biologically active if it increases or decreases the expression of a gene product when administered to a subject. As used herein, the term “conserved” refers to nucleotides or amino acid residues of a polynucleotide sequence or amino acid sequence, respectively, that are those that occur unaltered in the same position of two or more related sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences. In some embodiments, two or more sequences are said to be “completely conserved” if they are 100% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Attorney Docket No.54926-0021WO1 The term “engineered,” as used herein, refers to a protein, nucleic acid, complex, substance, or entity that has been designed, produced, prepared, synthesized, and / or manufactured by a human. Accordingly, an engineered product is a product that does not occur in nature. In some embodiments, an engineered protein or nucleic acid is a protein or nucleic acid that has been designed to meet requirements or to have desired features. For example, a payload RNA may be engineered to associate with the ARRDC1 by fusing one or more WW domains to a Tat protein and fusing the payload RNA to a TAR element to facilitate loading of the payload RNA into an ARMM. As another example, a payload RNA may be engineered to associate with the ARRDC1 by fusing a Tat protein to the ARRDC1 and by fusing the payload RNA to a TAR element to facilitate loading of the payload RNA into an ARMM. As another example, a payload protein may be engineered to associate with the ARRDC1 by fusing one or more WW domains to the payload protein to facilitate the loading of the payload protein into an ARMM. As used herein, the term “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA transcript from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and / or 3′ end processing); (3) translation of an RNA transcript into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein. The term “operably linked,” as used herein, refers to an arrangement of sequences or regions wherein the components are configured to perform their usual or intended function. Thus, a regulatory or control sequence operably linked to a coding sequence is capable of affecting the expression of the coding sequence. The regulatory or control sequences need not be contiguous with the coding sequence, so long as they function to direct the proper expression or polypeptide production. Thus, for example, intervening untranslated but transcribed sequences can be present between a promoter sequence and the coding sequence and the promoter sequence can still be considered operably linked to the coding sequence. A promoter sequence, as described herein, is a DNA regulatory region a short distance from the 5′ end of a gene that acts as the binding site for RNA polymerase. The promoter sequence may bind RNA polymerase in a cell and / or initiate transcription of a downstream (3′ direction) coding sequence. The promoter sequence may be a promoter capable of initiating transcription in prokaryotes or eukaryotes. Some Attorney Docket No.54926-0021WO1 non-limiting examples of eukaryotic promoters include the cytomegalovirus (CMV) promoter, the chicken β-actin (CBA) promoter, and a hybrid form of the CBA promoter (CBh). As used herein, a “fusion protein” includes a first protein moiety, e.g., an ARRDC1 protein or variant thereof, or a TSG101 protein or variant thereof, associated with a second protein moiety, for example, a protein to be delivered to a target cell through a peptide linkage. In certain embodiments, the fusion protein is encoded by a single fusion gene. As used herein, the term “gene” has its meaning as understood in the art. It will be appreciated by those of ordinary skill in the art that the term “gene” may include gene regulatory sequences (e.g., promoters, enhancers, etc.) and / or intron sequences. It will further be appreciated that the definition of a gene includes references to nucleic acids that do not encode proteins but rather encode functional RNA molecules, such as gRNAs, RNAi agents, ribozymes, tRNAs, etc. It should be noted that, as used in the present application, the term “gene” generally refers to a portion of a nucleic acid that encodes a protein; the term may optionally encompass regulatory sequences, as will be clear from context to those of ordinary skill in the art. This definition is not intended to exclude the application of the term “gene” to non-protein–coding expression units but rather to clarify that, in most cases, the term as used herein refers to a protein-coding nucleic acid. As used herein, the term “gene product” or “expression product” generally refers to an RNA transcribed from the gene (pre-and / or post-processing) or a polypeptide (pre- and / or post-modification) encoded by an RNA transcribed from the gene. As used herein, the term “green fluorescent protein” (GFP) refers to a protein originally isolated from the jellyfish Aequorea victoria that fluoresces green when exposed to blue light or a derivative of such a protein (e.g., an enhanced or wavelength- shifted version of the protein). The amino acid sequence of wild-type GFP is set forth in SEQ ID NO: 40. Proteins that are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% homologous to SEQ ID NO: 40 are also considered to be green fluorescent proteins. As used herein, the term “homology” refers to the overall relatedness between nucleic acids (e.g., DNA molecules and / or RNA molecules) or polypeptides. In some Attorney Docket No.54926-0021WO1 embodiments, nucleic acids or proteins are considered to be “homologous” to one another if their sequences are at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical. In some embodiments, nucleic acids or proteins are considered “homologous” to one another if their sequences are at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical. The term “homologous” necessarily refers to a comparison between at least two sequences (nucleotide sequences or amino acid sequences). In accordance with the invention, two nucleotide sequences are considered homologous if the polypeptides they encode are at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, or at least about 90% identical for at least one stretch of at least about 20 amino acids. In some embodiments, homologous nucleotide sequences are characterized by the ability to encode a stretch of at least 4–5 uniquely specified amino acids. Both the identity and the approximate spacing of these amino acids relative to one another must be considered for sequences to be considered homologous. For nucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. In accordance with the invention, two protein sequences are considered homologous if the proteins are at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, or at least about 90% identical for at least one stretch of at least about 20 amino acids. As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe). As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe). In some embodiments, a transgene comprising a sequence encoding an ARRDC1 protein, or a portion thereof, and one or more sequences encoding a therapeutic agent, cargo protein, or nucleic acid of interest is administered to an animal. In some of these embodiments, the animal receiving the administered transgene is preferably a mammal, and more preferably, a human subject. Attorney Docket No.54926-0021WO1 As used herein, the term “ex vivo” refers to events outside of the living body and thusly is understood to refer to medical procedures in which an organ, cells, or tissue is taken from a living body for a treatment or procedure, and then returned to the same, or another, living body. In certain embodiments, ex vivo therapy comprises inducing one or more genetic modifications in a patient’s cells outside of their body to produce therapeutic effects therein and the subsequent transfer (e.g., transplantation) of the cells back into the patient. As used herein, the term “isolated” refers to a substance or entity that has been: (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting); and / or (2) produced, prepared, and / or manufactured by the hand of man. Isolated substances and / or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated substances are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components. As used herein, the term “nucleic acid,” in its broadest sense, refers to a compound and / or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising individual nucleotides. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least two nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double-stranded DNA and / or complementary DNA (cDNA). Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, i.e., analogs having other than a phosphodiester backbone. For example, the so-called “peptide nucleic acids,” which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, are considered within the scope of the present Attorney Docket No.54926-0021WO1 invention. The term “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and / or encode the same amino acid sequence. Nucleotide sequences that encode proteins and / or RNA may include introns. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, backbone modifications, etc. A nucleic acid sequence is presented in the 5′ to 3′ direction unless otherwise indicated. The term “nucleic acid segment” is used herein to refer to a nucleic acid sequence that is a portion of a longer nucleic acid sequence. In many embodiments, a nucleic acid segment comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more residues. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2- thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2- aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl- uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2- thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5′-N-phosphoramidite linkages). In some embodiments, the present invention is specifically directed to “unmodified nucleic acids,” meaning nucleic acids (e.g., polynucleotides and residues, including nucleotides and / or nucleosides) that have not been chemically modified to facilitate or achieve delivery. As used herein, the term “protein” refers to a string of at least two amino acids linked to one another by one or more peptide bonds. Proteins may include moieties other than amino acids (e.g., may be glycoproteins) and / or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete protein chain as produced by a cell (with or without a signal sequence) or can Attorney Docket No.54926-0021WO1 be a functional portion thereof. Those of ordinary skill will further appreciate that a protein can sometimes include more than one protein chain, for example linked by one or more disulfide bonds or associated by other means. Proteins may containL-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., addition of a chemical entity such as a carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, an amide group, a terminal acetyl group, a linker for conjugation, functionalization, or other modification (e.g., alpha amidation), etc. In certain embodiments, the modifications of the protein lead to a more stable protein (e.g., greater half-life in vivo). These modifications may include cyclization of the protein, the incorporation of D-amino acids, etc. None of the modifications should substantially interfere with the desired biological activity of the protein. In certain embodiments, the modifications of the protein lead to a more biologically active protein. In some embodiments, proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, amino acid analogs, and combinations thereof. As used herein, the terms “subject,” or “patient” refer to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals, such as mice, rats, rabbits, production and farm animals, pets, non-human primates, and humans). In some embodiments, the subject is a patient having or suspected of having a disease or disorder (e.g, an ocular disorder described herein). In other embodiments, the subject is a healthy volunteer. As used herein, the terms "disease," and “disorder” refer to any condition, pathological condition, or disorder that damages or interferes with the normal function of a cell, tissue, or organ. As used herein, the terms “treating,” or "treatment" refer to partially or completely preventing, altering, and / or reducing the incidence of one or more symptoms or features of a particular disease or deleterious condition. In one sense of the invention, treatments can be performed either for prophylaxis or amelioration of a pathological condition in a subject. Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of Attorney Docket No.54926-0021WO1 any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. Treatment may be administered to a subject who does not exhibit signs or symptoms of a disease, disorder, condition, or to a subject who exhibits only early signs or symptoms of a disease, or condition for the purpose of decreasing the risk of developing or progressing to more severe effects associated with the disease, disorder, or condition. A treatment may prevent the onset of the disorder or a symptom of the disorder in a subject. A treatment can prevent physical deterioration (e.g., loss of vision, loss of visual acuity, low vision, blindness, decrease in ambulation, and more generally, any ameliorable morbidity) caused by a by preventing or reversing its progression. As used herein, the term “therapeutically effective amount” means an amount of an agent or payload to be delivered (e.g., nucleic acid, protein, drug, therapeutic agent, diagnostic agent, prophylactic agent, ARMM, or ARMM comprising a payload protein or payload RNA) that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, improve symptoms thereof, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. A therapeutically effective amount may be initially determined from preliminary in vitro studies and / or animal models. A therapeutically effective dose may also be determined from human data. The applied dose may be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other well-known methods is within the capabilities of the ordinarily skilled artisan. General principles for determining therapeutic effectiveness, which may be found in Chapter 1 of Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, McGraw-Hill (New York) (2001), incorporated herein by reference in its entirety. As used herein, the term "targeting ligand" refers to a ligand, or a function portion thereof, that binds to "a targeted receptor" that distinguishes the cell being targeted from other cells. The ligands may be capable of binding due to expression or preferential expression of a receptor for the ligand, accessible for ligand binding, on the target cells. Examples of such ligands include GE11 peptide, anti-EGFR nanobody, cRGD (cyclo Attorney Docket No.54926-0021WO1 (RGDfC), KE108 peptide, octreotide, prostate-specific membrane antigen (PSMA) aptamer, TRC105, chimeric monoclonal antibodies, tumor-specific monoclonal or polyclonal antibodies (e.g., Rituximab, Trastuzumab, Bevacizumab, Alemtuzumab, Panitumumab, etc., and bioequivalents and portions thereof), arginylglycylaspartic acid (“RGD”), DARPins, RNA aptamers, DNA aptamers, inteins, exteins, viral derived and nonviral derived cell-cell fusion protein (“fusogen(s)”) (e.g., VSV-G, syncytin-1, -2, HAP2, SNAREs (e.g., VAMP1, 2, 3, 4, 7, 8)), membrane proteins, such as tetraspanins (“TM4SF proteins”) (e.g., TSPAN1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33, and the like), peptide ligands identified from library screens, tumor-specific peptides, tumor-specific aptamers, Fab or scFv (i.e., a single chain variable region) fragments of antibodies such as, for example, an Fab fragment of an antibody directed to EphA2 or other proteins specifically expressed or uniquely accessible on metastatic cancer cells, growth factors, such as EGF, FGF, insulin, and insulin-like growth factors, and homologous polypeptides, somatostatin and its analogs, transferrin, lipoprotein complexes, Arg-Gly-Asp containing peptides, microtubule-associated sequence (MTAS), various galectins, δ-opioid receptor ligands, cholecystokinin A receptor ligands, ligands specific for angiotensin AT1 or AT2 receptors, peroxisome proliferator-activated receptor γ ligands, and other molecules that bind specifically to a receptor preferentially expressed on the surface of targeted cells or on an infectious organism, and fragments of any of these molecules. The term "a targeted receptor," as used herein, refers to a receptor expressed by a cell that can bind a cell targeting ligand. The receptor may be expressed on the surface of the cell. The receptor may be a transmembrane receptor. Examples of such targeted receptors include, but are not limited to, EGFR, αvβ3integrin, somatostatin receptor, folate receptor, prostate-specific membrane antigen, CD105, mannose receptor, estrogen receptor, GM1 ganglioside, and the like. In some embodiments, cell penetrating peptides may also be attached to one or more PEG terminal groups in place of or in addition to the targeting ligand. As used herein, the terms “cell penetrating peptide” (“CPP”), “protein transduction domain” (“PTD”), or “membrane translocating sequence,” refer to short peptides (e.g., from 4 to about 40 amino acids) that have the ability to translocate across a cellular membrane to Attorney Docket No.54926-0021WO1 gain access to the interior of a cell and to carry into the cells a variety of covalently and noncovalently conjugated cargoes, including proteins, and oligonucleotides. In preferred embodiments, CPPs comprise: 1) a high relative abundance of positively charged amino acids (e.g., lysine or arginine); 2) an amino acid sequence that comprises an alternating pattern of polar, charged amino acids and non-polar, hydrophobic amino acids; or 3) an amino acid sequence that comprises hydrophobic peptides (e.g., mostly apolar residues with low net charge or hydrophobic amino acid groups). (See, e.g., US Pat. Pub. No.: 20220177494; Oliveira, E.C, et al., “Predicting cell-penetrating peptides using machine learning algorithms and navigating in their chemical space,” Scientific Reports., 11(1):7628 (2021); Derakhshankhah, H., and Jafari, S., “Cell penetrating peptides: A concise review with emphasis on biomedical applications,” Biomedicine & Pharmacotherapy., 108:1090-1096 (2018); Milletti, F., “Cell-penetrating peptides: classes, origin, and current landscape,” Drug Discovery Today, 17(15–16):850-860 (2012); Stalmans, S., et al., “Chemical-functional diversity in cell-penetrating peptides,” PLOS ONE, 8(8):e71752 (2013); Wagstaff, K.M., and Jans, D.A., “Protein transduction: cell penetrating peptides and their therapeutic applications,” Current Medicinal Chemistry, 13(12):1371-1387 (2006), the entire contents of each of which are hereby incorporated by reference in their entirety). Examples of CPP peptides include, but are not limited to: TAT cell penetrating peptide; MAP; Penetratin or Antenapedia PTD; Penetratin-Arg; antitrypsin (358-374); Temporin L; Maurocalcine; pVEC (Cadherin-5); Calcitonin; Neurturin; Penetratin; TAT-HA2 Fusion Peptide; TAT (47-57); SynB1; SynB3; PTD-4; PTD-5; FHV Coat-(35-49); BMV Gag-(7-25); HTLV-II Rex-(4-16); HIV-1 Tat (48-60) or D-Tat; R9-Tat; Transportan; SBP or Human P1; FBP; MPG(δNLS); Pep-1 or Pep-1-Cysteamine; Pep-2; Periodic sequences, Polyarginines (RxN (4<N<17) chimera); Polylysines (KxN (4<N<17) chimera); (RAca)6R; (RAbu)6R; (RG)6R; (RM)6R; (RT)6R; (RS)6R; R10; (RA)6R; and R7. As used herein, a “vector” means any nucleic acid or nucleic acid-bearing particle, cell, or organism capable of being used to transfer a nucleic acid into a host cell. The term “vector” includes both viral and nonviral products and means for introducing the nucleic acid into a cell. A “vector” can be used in vitro, ex vivo, or in vivo. Vectors capable of directing the expression of operatively linked genes are referred to herein as Attorney Docket No.54926-0021WO1 “expression vectors.” Non-viral vectors include plasmids, cosmids, artificial chromosomes (e.g., bacterial artificial chromosomes or yeast artificial chromosomes), liposomes, electrically charged lipids (cytofectins), DNA-protein complexes, and biopolymers, for example. Viral vectors include, but are not limited to, retroviruses, lentiviruses, adeno-associated virus, pox viruses, baculovirus, reoviruses, vaccinia viruses, herpes simplex viruses, Epstein-Barr viruses, and adenovirus vectors, for example. Vectors can also comprise the entire genome sequence or recombinant genome sequence of a virus. A vector can also comprise a portion of the genome that comprises the functional sequences to produce a virus capable of infecting, entering, or being introduced to a cell to deliver nucleic acid therein. The term “WW domain” as used herein, refers to a protein domain having two basic residues at the C-terminus that mediates protein-protein interactions with short proline-rich or proline-containing motifs. WW domains are further described herein. The term “Cas9,” or “Cas9 protein,” or “Cas9 polypeptide” refers to an RNA- guided nuclease comprising a Cas9 protein as well as fusion proteins containing such Cas9 proteins and variants thereof (e.g., a protein comprising an active, inactive, or altered DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). In some embodiments, the fused proteins may include those that modify the epigenome or control transcriptional activity. The variants may include deletions or additions, such as, e.g., addition of one, two, or more nuclear localization sequences (such as from SV40 and others known in the art), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 such sequences or a range between and including any two of the foregoing values. In some embodiments, the Cas9 polypeptide is a Cas9 protein found in a type II CRISPR-associated system. Suitable Cas9 polypeptides that may be used in certain embodiments of the present invention include, but are not limited to, Cas9 protein from Streptococcus pyogenes (Sp. Cas9), F. novicida, S. aureus, S. thermophiles, N. meningitidis, and variants thereof. A Cas9 nuclease is also referred to sometimes as a casn1 nuclease or a CRISPR (clustered regularly interspaced short palindromic repeat)-associated nuclease. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (e.g., viruses, transposable elements, and conjugative plasmids). CRISPR clusters contain Attorney Docket No.54926-0021WO1 spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems correct processing of pre-crRNA requires a trans- encoded small RNA (tracrRNA), endogenous ribonuclease 3 (mc) and a Cas9 protein. The tracrRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tracrRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, then trimmed 3'-5' exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA,”, or simply “gRNA”) can be engineered so as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. (See, e.g., Jinek M., et al., Science, 337:816-821 (2012), the entire contents of which is hereby incorporated by reference). Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. Cas9 nuclease sequences and structures are well known to those of skill in the art. (See, e.g., Ferretti et al., “Complete genome sequence of an M1 strain of Streptococcus pyogenes,” Proc. Natl. Acad. Sci. U.S.A., 98:4658-4663 (2001); “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III,” Deltcheva E., et al., “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III,” Nature, 471:602-607 (2011); and Jinek, M., et al., “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity,” Science, 337:816-821 (2012), the entire contents of each of which are incorporated herein by reference). Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in the art. (See, e.g., Chylinski, Rhun, and Charpentier, “The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems,” RNA Biology, 10:5, 726-737 (2013); Karvelis, G., et al., “Harnessing the natural diversity and in vitro evolution of Cas9 to expand the genome editing toolbox,” Current Opinion in Microbiology, 37:88-94 (2017); Komor, A. C., et al., “CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes,” Cell, 168:20-36 (2017); and Murovec, J., et al., “New variants of CRISPR Attorney Docket No.54926-0021WO1 RNA-guided genome editing enzymes,” Plant Biotechnol. J., 15:917-26 (2017), the entire contents of each of which are incorporated herein by reference). In some embodiments, the Cas9 polypeptide is a wild-type Cas9, a nickase, or comprises a nuclease inactivated (“dCas9” for nuclease-"dead" Cas9) protein. Methods for generating a Cas9 protein (or a variant thereof) having an inactive DNA cleavage domain are known (See, e.g., Jinek et al., Science.337:816-821(2012); Qi et al., “Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression,” Cell, 28;152(5):1173-83 (2013), the entire contents of each of which are incorporated herein by reference). For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvC1 subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvC1 subdomain cleaves the non-complementary strand. Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations D10A and H841A completely inactivate the nuclease activity of S. pyogenes Cas9 (Jinek et al., Science, 337:816-821 (2012); Qi et al., Cell, 28;152(5):1173-83 (2013)). In some embodiments, proteins comprising variants of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or variants thereof are referred to as "Cas9 variants." A Cas9 variant shares homology to Cas9, or a variant thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to wild type Cas9. In some embodiments, the Cas9 variant comprises a variant of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to the corresponding variant of wild type Cas9. In some embodiments, wild type Cas9 protein corresponds to the Cas9 protein Attorney Docket No.54926-0021WO1 from Streptococcus pyogenes (SEQ ID NO: 41; single underline: HNH domain; double underline: RuvC domain). In some embodiments, wild type Cas9 corresponds to, or comprises SEQ ID NO: 42 (single underline: HNH domain; double underline: RuvC domain). In some embodiments, dCas9 corresponds to, or comprises in part or in whole, a Cas9 amino acid sequence having one or more mutations that inactivate the Cas9 nuclease activity. For example, in some embodiments, a dCas9 domain comprises mutation(s) at the amino acids corresponding to D10A and / or H820A of wild-type Cas9 (e.g., SEQ ID NO: 41). In other embodiments, dCas9 variants having mutations other than D10A and H820A are provided, which e.g., result in nuclease inactivated Cas9 (dCas9). Such mutations, by way of example, include other amino acid substitutions at D10 and H820, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and / or the RuvC1 subdomain). In some embodiments, variants or homologues of dCas9 (e.g., a protein comprising or consisting of the polynucleic acid sequence of SEQ ID NO: 41 with mutations D10A and / or H820A) are provided which are at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% to dCas9. In some embodiments, variants of dCas9 are provided having amino acid sequences which are shorter, or longer than dCas9, by about 5 amino acids, by about 10 amino acids, by about 15 amino acids, by about 20 amino acids, by about 25 amino acids, by about 30 amino acids, by about 40 amino acids, by about 50 amino acids, by about 75 amino acids, by about 100 amino acids or more. In some embodiments, Cas9 fusion proteins as provided herein comprise the full- length amino acid of a Cas9 protein, e.g., one of the sequences provided above. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only a fragment thereof. For example, in some embodiments, a Cas9 fusion protein provided herein comprises a Cas9 fragment, wherein the fragment binds crRNA and tracrRNA or sgRNA, but does not comprise a functional nuclease domain, e.g., in that it comprises only a truncated version of a nuclease domain or no nuclease Attorney Docket No.54926-0021WO1 domain at all. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of skill in the art. In some of these embodiments, the fusion protein comprises a transcriptional activator (e.g., VP64), a transcriptional repressor (e.g., KRAB, SID), a nuclease domain (e.g., FokI), base editors, prime editors, a recombinase domain (e.g., Hin, Gin, or Tn3), a deaminase (e.g., a cytidine deaminase or an adenosine deaminase) or an epigenetic modifier domain (e.g., TET1, p300). In some embodiments, Cas9 refers to Cas9 from: Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquisl (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1); Listeria innocua (NCBI Ref: NP 472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); or Neisseria meningitidis (NCBI Ref: YP_002342100.1). The term "deaminase" refers to an enzyme that catalyzes a deamination reaction. In some embodiments, the deaminase is a cytidine deaminase, catalyzing the hydrolytic deamination of cytidine or deoxycytidine to uracil or deoxyuracil, respectively. The terms "RNA-programmable nuclease" and "RNA-guided nuclease" are used interchangeably herein and refer to a nuclease that forms a complex with (e.g., binds or associates with) one or more RNA molecules that are not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease:RNA complex. RNA-programmable nucleases include Cas9 nucleases. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. gRNAs that exist as a single RNA molecule may be referred to as single-guide RNAs (sgRNAs), though "gRNA" is used interchangeably to refer to guide RNAs that exist as either single molecules or as two or more molecules. Typically, gRNAs that exist as single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (e.g., directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 Attorney Docket No.54926-0021WO1 protein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease / RNA complex to said target site and provides the sequence specificity of the nuclease:RNA complex. The term "recombinase," as used herein, refers to a site-specific enzyme that mediates the recombination of DNA between recombinase recognition sequences, which results in the excision, integration, inversion, or exchange (e.g., translocation) of DNA fragments between the recombinase recognition sequences. Recombinases can be classified into two distinct families: serine recombinases (e.g., resolvases and invertases) and tyrosine recombinases (e.g., integrases). Examples of serine recombinases include, without limitation, Hin, Gin, Tn3, β-six, CinH, ParA, γδ, Bxb1, φC31, TP901, TG1, φBT1, R4, φRV1, φFC1, MR11, A118, U153, and gp29. Examples of tyrosine recombinases include, without limitation, Cre, FLP, R, Lambda, HK101, HK022, and pSAM2. The serine and tyrosine recombinase names stem from the conserved nucleophilic amino acid residue that the recombinase uses to attack the DNA and which becomes covalently linked to the DNA during strand exchange. Recombinases have numerous applications, including the creation of gene knockouts / knock-ins and gene therapy applications. (See, e.g., Brown et al., “Serine recombinases as tools for genome engineering,” Methods, 53(4):372-379 (2011); Hirano et al., “Site-specific recombinases as tools for heterologous gene integration,” Appl. Microbiol. Biotechnol., 92(2):227-239 (2011); Chavez and Calos, “Therapeutic applications of the ΦC31 integrase system,” Curr. Gene Ther., 11(5):375-381 (2011); Turan and Bode, “Site-specific recombinases: from tag-and-target- to tag-and-exchange-based genomic modifications,” FASEB J., 25(12):4088-4107 (2011); Venken and Bellen, “Genome-wide manipulations of Drosophila melanogaster with transposons, Flp recombinase, and ΦC31 integrase,” Methods Mol. Biol., 859:203-228 (2012); Murphy, “Phage recombinases and their applications,” Adv. Virus Res., 83:367-414 (2012); Zhang et al., “Conditional gene manipulation: Cre-ating a new biological era,” J. Zhejiang Univ. Sci. B., 13(7):511-524 (2012); Karpenshif and Bernstein, “From yeast to mammals: recent advances in genetic control of homologous recombination,” DNA Repair (Amst), 1;11(10):781-788 (2012); the entire contents of each are hereby incorporated by reference in their entirety). The recombinases provided herein are not meant to be exclusive examples of recombinases Attorney Docket No.54926-0021WO1 that can be used in embodiments of the invention. The methods and compositions of the invention can be expanded by mining databases for new orthogonal recombinases or designing synthetic recombinases with defined DNA specificities. (See, e.g., Groth et al., “Phage integrases: biology and applications,” J. Mol. Biol., 335, 667-678 (2004); Gordley et al., “Synthesis of programmable integrases,” Proc. Natl. Acad. Sci. USA., 106, 5053-5058 (2009); the entire contents of each are hereby incorporated by reference in their entirety). Other examples of recombinases that are useful in the methods and compositions described herein are known to those of skill in the art, and any new recombinase that is discovered or generated is expected to be able to be used in the different embodiments of the invention. In some embodiments, a recombinase (or catalytic domain thereof) is fused to a Cas9 protein (e.g., dCas9). The terms “recombine” and “recombination,” in the context of a nucleic acid modification (e.g., a genomic modification), are used to refer to the process by which two or more nucleic acid molecules, or two or more regions of a single nucleic acid molecule, are modified by the action of a recombinase protein. Recombination can result in, inter alia, the insertion, inversion, excision, or translocation of a nucleic acid sequence, e.g., in or between one or more nucleic acid molecules. As used herein, the terms “approximately,” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (for example, when such number would exceed 100% of a possible value). DESCRIPTION OF DRAWINGS FIG.1 is a schematic of an example of ARMMs Cas9 / gRNA packaging and delivery to cells. FIG.2 shows isoforms of VEGFA. FIG.3A depicts an example editing strategy for human and mouse gRNA sequences for base editing of splice acceptor site AG at A6. A8 is a secondary adenine Attorney Docket No.54926-0021WO1 which will be subjected to conversion with the adenine base editor ABE8. Evaluation of base editing at the target sites A6 and A8 is shown by transfection of mouse Neuro2A or human HEK293T cells with ABE8 and the indicated gRNAs. A to G % conversion was quantified using next generation sequencing. FIG.3B shows the Human VEGFA 8a and 8b exons. FIG.4 shows example editing strategies for various species. FIG.5 depicts an editing and testing strategy for selective knockout / knockdown of exon 8a forms of VEGFA (“target-VEGFA”) and non-selective knockout / knockdown of VEGFA (“pan-VEGFA”) FIG.6 shows results of selective VEGFA knockout / knockdown. ARPE19 or Neuro2A cells were treated with 1e6 or 5e6 / cell engineered ARMMs loaded with the adenine base editor ABE8 and VEGFA gRNAs targeting the human or mouse sequences, respectively.48h after treatment, cells were harvested and genomic DNA were extracted and analyzed by next generation sequencing to quantify % A6 to G conversion at the target splice acceptor site.240523S and 240617L represent lot numbers of 2 batches of engineered ARMMs. FIG.7 shows results of selective VEGFA knockout / knockdown. Rat RPE-J cells were treated with 1e6 or 5e6 / cell engineered ARMMs loaded with the adenine base editor ABE8 and VEGFA gRNAs targeting the rat sequence.48h after treatment, cells were harvested and genomic DNA were extracted and analyzed by next generation sequencing to quantify % A6 to G conversion at the target splice acceptor site.240617S and 240712L represent lot numbers of 2 batches of engineered ARMMs. FIG.8 shows results of selective VEGFA knockout / knockdown. Human primary cells were treated with 1e6 or 5e6 / cell engineered ARMMs (lot# 240617L) loaded with the adenine base editor ABE8 and VEGFA gRNAs targeting the human sequence.48h after treatment, cells were harvested and genomic DNA were extracted and analyzed by next generation sequencing to quantify % A6 to G conversion at the target splice acceptor site. FIG 9 shows results of selective VEGFA knockout / knockdown. PCR was carried out on human genomic DNA using primers flanking the target base editing site after treatment with engineered ARMMs loaded with the adenine base editor ABE8. The band Attorney Docket No.54926-0021WO1 indicated with an arrow, which corresponds to the predicted PCR amplicon size, was excised and the resultant DNA was subjected to Sanger sequencing. Sequencing traces show successful modification of splicing to the next AG sequences leading to emergence of a new C-terminal sequence, annotated as 8new, and loss of the pro-angiogenic 8a form. FIG.10 depicts VEGFA editing strategies. FIG.11 shows results of selective VEGFA knockout / knockdown. Anti-VEGFA western blotting of lysates derived from mouse Neuro 2A cells 48h after treatment with 1e6 / cell of engineered ARMMs loaded with the adenine base editor ABE8 and the VEGFA base editing gRNA or mock treated (Control). An immunoreactive band corresponding to the larger VEGFA 8new form was observed in lysates from cells treated with engineered ARMMs. FIG.12 shows results of VEGFA knockout / knockdown. Mouse Neuro2A cells were treated with engineered ARMMs loaded with Cas9 / VEGFA gRNA or ABE8 / based editing gRNA.48h after treatment cell culture media (CM) were harvested and evaluated by Anti-VEGFA western blotting. An immunopositive VEGFA signal is observed in the mock treated control sample. After treatment with Cas9 loaded ARMMs, secreted VEGFA levels are not detectable. After treatment with ABE8 loaded ARMMs, a large immunopositive band is observed corresponding to VEGFA 8new. Left table shows editing efficiency after treatment of Neuro2A cells for 48 with engineered ARMMs loaded with Cas9 / pan-VEGFA gRNA or ABE8 / target-VEGFA gRNA. FIG.13 shows a VEGFA editing strategy. FIG.14 shows results of VEGFA knockout / knockdown. Rat RPE-J cells were treated with 1e6 or 5e6 / cell engineered ARMMs loaded with the genome editor Cas9 and VEGFA gRNAs targeting the rat sequence.48h after treatment, cells were harvested and genomic DNA were extracted and analyzed by Sanger sequencing to evaluate % insertions / deletions (indel).240711S and 240809L represent lot numbers of 2 batches of engineered ARMMs. FIG.15 shows results of VEGFA knockout / knockdown. Neuro2A cells were treated with 1e6 or 5e6 / cell engineered ARMMs loaded with the genome editor Cas9 and VEGFA gRNAs targeting the mouse sequence.48h after treatment, cells were harvested Attorney Docket No.54926-0021WO1 and genomic DNA were extracted and analyzed by Sanger sequencing to evaluate % insertions / deletions (indel).240711S and 240809L represent lot numbers of 2 batches of engineered ARMMs. Fig 16 shows results of VEGFA kockout / knockdown. Human HEK293T, A549, ARPE-19, or HRPE cells were treated with 1e6 or 5e6 / cell engineered ARMMs loaded with the genome editor Cas9 and VEGFA gRNAs targeting the human sequence.48h after treatment, cells were harvested and genomic DNA were extracted and analyzed by Sanger sequencing to evaluate % insertions / deletions (indel). DETAILED DESCRIPTION Provided herein are compositions and methods for the treatment of ocular disorders (e.g., AMD, e.g., wet AMD, e.g., as described herein) and their delivery via ARRDC1-mediated microvesicles. Also provided herein are methods of targeting ARRDC1-mediated microvesicles bearing a therapeutic payload to a specific cell type. In some embodiments, the cell is a RPE cell. VEGFA (VASCULAR ENDOTHELIAL GROWTH FACTOR A) The compositions and methods described herein find use, for example, in reduction of vascular endothelial growth factor A (VEGFA) (e.g., pathogenic VEGFA). The human VEGFA gene spans 16,272 bp of chromosome 6p12 and consists of eight exons and seven introns. Arcondeguy et al., “VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post- transcriptional level,” Nucleic Acids Research 41(17):1997–8010 (2013). A wide variety of isoforms are produced from alternative transcription start sites in the first exon and two alternative stop codons in the eighth exon—“a” and “b.” Alternative splicing at the exon 8 junction result in either the exon 8a form or the exon 8b form. Isoforms with exon 8a variant are pro-angiogenic (and are also referred to herein as pathogenic or pathological isoforms), while isoforms with exon 8b are anti-angiogenic. Id. Thus, the “8a” form protein ends with the sequence CDKPRR (SEQ ID NO: 11), whereas the “8b” form protein ends with the sequence SLTRKD (SEQ ID NO: 12). An example of this alternative splicing is shown below. Lowercase letters are intronic; uppercase letters are the beginning of exon 8. The 8a form results from splicing at the first bolded and underlined “ag” Attorney Docket No.54926-0021WO1 (positions 102-103 relative to SEQ ID NO: 10); the 8b form results from splicing at the second bolded and underlined “ag.” (positions 170-171 relative to SEQ ID NO: 10) The two alternate exon 8 stop codons are bolded (positions 124-126 and 192-194, respectively, relative to SEQ ID NO: 10). Reading frames resulting in the alternate C- terminal sequences (shown in the table below) are in [brackets]. SEQ ID NO: 10: ctgcagtgacccaggggcccccaggaatggggaggccgcctgcctcatcgccaggcctc ctcacttggccctaaccccagcctttgttttccatttccctcagA[TGTGACAAGCCGA GGCGGTGA]GCCGGGCAGGAGGAAGGAGCCTCCCTCAGGGTTTCGGGAACCagA[TCTC TCACCAGGAAAGACTGA]TACAGAACGATCGATACAGAAACCACGCTGCCGCCACCACA CCATCACCATCGACAGAACAGTCCTTAATCCAGAAACCTGAAATGAAGGAAGAGGAGAC TCTGCGCAGAGCACTTTGGGTCCGGAGGGCGAGACTCCGGCGGAAGCATTCCCGGGCGG GTGACCCAGCACGGTCCCTCTTGGAATTGGATTCG Isoforms VEGF-A 111, 121a, 145a, 148, 162, 165a, 183a, 189a, and 206 are all 8a isoforms (angiogenic), while isoforms VEGF-A 121b, 145b, 165b, 183b, and 189b are all 8b isoforms (anti-angiogenic). Id. All currently described isoforms contain exons 1–5 and 8 (either version 8a or 8b). Exons 6 and 7 encode heparin-binding domains, which are responsible for the diffusibility and extra cellular matrix (ECM) affinity of the alternative spliced isoforms. Id. VEGF-A isoform 121 (also referred to as 121a) is freely diffusible (as depicted in FIG.2). The subset of isoforms produced by use of the alternative upstream CUG codon give rise to long isoforms which have an N-terminal extension compared to the classical shorter AUG-initiated forms. These longer forms are post-translationally processed to produce an N-terminal N-VEGF chain and a C-terminal VEGFA chain. Attorney Docket No.54926-0021WO1 The compositions and methods described herein find use, for example, in the treatment of ocular disorders, e.g., AMD, by delivering therapeutic payloads that reduce expression of pathological forms of VEGFA (i.e., exon 8a isoforms of VEGFA), e.g., e.g., by delivering a payload, e.g., as described herein. In some cases, expression of the pathological form of VEGFA is selectively reduced (e.g., by editing the exon 8 splice site, e.g., as described herein). In some cases, expression of the pathological form of VEGFA is non-selectively reduced (e.g., by knock down or knock out of VEGFA irrespective of exon 8a form). Exemplary sequences of the human canonical isoform (long form isoform 189 (L- VEGF189)) and alternative isoforms are set forth below. SEQ ID NO: 13 >sp|P15692|VEGFA_HUMAN Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA PE=1 SV=3 MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQ DPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR SEQ ID NO: 14 >sp|P15692-1|VEGFA_HUMAN Isoform VEGF206 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPG PHPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR SEQ ID NO: 15 >sp|P15692-10|VEGFA_HUMAN Isoform VEGF111 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRCDKPRR SEQ ID NO: 16 >sp|P15692-11|VEGFA_HUMAN Isoform L-VEGF165 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM Attorney Docket No.54926-0021WO1 ERTCRCDKPRR SEQ ID NO: 17 >sp|P15692-12|VEGFA_HUMAN Isoform L-VEGF121 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKCDKPRR SEQ ID NO: 18 >sp|P15692-14|VEGFA_HUMAN Isoform L-VEGF206 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPG PHPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR SEQ ID NO: 19 >sp|P15692-15|VEGFA_HUMAN Isoform 15 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELN ERTCRSLTRKD SEQ ID NO: 20 >sp|P15692-16|VEGFA_HUMAN Isoform 16 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRPCGPCSERRKHLFVQDPQTCK CSCKNTDSRCKARQLELNERTCRCDKPRR SEQ ID NO: 21 >sp|P15692-17|VEGFA_HUMAN Isoform 17 of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD Attorney Docket No.54926-0021WO1 IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKM SEQ ID NO: 22 MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLG CSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWT GEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASET MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRCDKPRR SEQ ID NO: 23 MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQ DPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR SEQ ID NO: 24 MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELN ERTCRCDKPRR SEQ ID NO: 26 MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVCDKPRR Attorney Docket No.54926-0021WO1 SEQ ID NO: 28 >sp|P15692-8|VEGFA_HUMAN Isoform VEGF165B of Vascular endothelial growth factor A, long form OS=Homo sapiens OX=9606 GN=VEGFA MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELN ERTCRSLTRKD SEQ ID NO: 29 MNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVD IFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEM SFLQHNKCECRPKKDRARQEKCDKPRR The sequence of human VEGFA (GenBank Accession NG_008732.1) and its features are set forth in the “SEQUENCES” below. AGE RELATED MACULAR DEGENERATION (AMD) Compositions and methods are provided herein for the treatment of ocular disorders, e.g., age related macular degeneration (AMD), e.g., wet AMD. AMD is a progressive degeneration of photoreceptors and underlying retinal pigment epithelium (RPE) cells in the macula region of the retina. A hallmark of the disease is the accumulation of drusen, pale excrescences of variable size, and other deposits below the RPE on the Bruch membrane. As AMD advances, areas of geographic atrophy of the RPE can cause visual loss, or choroidal neovascularization (CNV) can occur to cause wet, or exudative, ARMD with accompanying central visual loss. VEGFA overexpression in the retinal pigment epithelium (RPE) leads to CNV. Currently, the only accepted therapies for wet AMD are antibodies against VEGFA and its receptor (e.g., aflibercept). These treatments, however, involve repeated intravitreal injections and are costly for patients and providers. ARMMS The present invention provides methods, systems, and compositions for ARRDC1-mediated microvesicles (“ARMMs”) delivery of molecule(s) of interest (e.g., therapeutic agents), also referred to as payloads (e.g., gene editing payloads described herein) to cells and tissues, e.g., ocular cells and tissues (e.g., as described herein). Attorney Docket No.54926-0021WO1 Molecules of interest, whether naturally or non-naturally, occurring include, but are not limited to, proteins, nucleic acids, and small molecules that can preferably associate with one or more ARMM related proteins (e.g., ARRDC1), or can be modified to associate with more specifically, TSG101 or ARRDC1 or specific motif(s) therein. These associations facilitate the incorporation of the molecules into ARMMs, which in turn can be used to deliver the desired payload (molecule of interest) into a targeted cell. By way of example, but not limitation, a payload RNA can be fused to a trans-activation response (TAR) element, thereby allowing it to associate with an ARRDC1 protein that is fused to an RNA binding protein, such as a Tat protein (e.g., bovine TAT protein). Alternatively, a payload protein can be fused to one or more WW domains, which associate with the PPXY motif of ARRDC1. The association of the molecule to an ARMM-related protein (e.g., ARRDC1), facilitates the loading of the molecule into the ARRDC1-containing ARMM. Alternatively, the molecule can be fused to an ARMM protein (e.g., TSG101 or ARRDC1) to load the payload into the ARMM. The molecule can be fused to the ARMM protein (e.g., TSG101 or ARRDC1) via a linker that may be cleaved upon delivery to a target cell. A schematic of the generation of engineered ARMMs loaded with a RNA-guided protein (for example, Cas9) / gRNA complex is provided in FIG.1. Examples of other RNA-guided protein cargos are described herein. The present invention further relates to compositions and methods of producing, testing, and administering ARMMs. More particularly, the present invention provides compositions and methods of producing, testing, and administering ARMMs comprising one or more therapeutic agents (e.g., biological molecules including, but not limited to, CRISPR / Cas9, and other similar endonucleases, base editors, small molecules, proteins, and nucleic acids (e.g., DNA, RNA, siRNA, mRNA, miRNA, and the like), for example, the gene editing payloads described herein. Also provided are methods of administering therapeutic agents associated with ARMMs (e.g., the gene editing payloads described herein), including, but not limited to, methods of treating or contacting cells and tissues in one or more exemplary dosing regimens (e.g., 1) in vivo administration of ARMMs to a patient; 2) ex vivo administration of ARMMs to target cells and implantation of the ARMMs treated cells to a / the patient; and 3) in vivo and ex vivo regimens). Additionally, the present invention relates to methods of manufacturing (e.g., culturing, clarifying, Attorney Docket No.54926-0021WO1 separating, and concentrating) the ARMMS compositions described herein, e.g., from stable producer cell lines and / or from transient cell cultures. Arrestin Domain Containing Protein 1 mediated microvesicles (“ARMMs”) are extracellular vesicles (“EVs”) that are distinct from exosomes. The budding of ARMMs requires ARRDC1, which is localized to the cytosolic side of the plasma membrane and, through a tetrapeptide motif, recruits the ESCRT-I complex protein TSG101 to the cell surface to initiate the outward membrane budding. Thus, in contrast to exosomes, the biogenesis of ARMMs occurs at the plasma membrane. ARMMs exhibit several additional features that make them potentially ideal vehicles for therapeutic delivery. ARRDC1 is not only necessary but also sufficient to drive ARMMs budding. Overexpression of the ARRDC1 protein increases the production of ARMMs in cells. This allows controlled production of ARMMs using modern biological manufacturing methods. Moreover, endogenous proteins such as cell surface receptors are actively recruited into ARMMs and can be delivered into recipient cells to initiate intercellular communication, suggesting that the exogenous payload molecules may be similarly packaged and delivered via ARMMs. In some cases, the ARMM further comprises a targeting moiety, e.g., that targets particular cell type(s), e.g., ocular cells, e.g., as described herein. In some embodiments, the targeting moiety is an antibody or antigen-binding fragment thereof. In some cases, the targeting moiety is a single-chain variable fragment (scFv), a VHH, or a nanobody. ARRDC1 In some embodiments, ARRDC1 is a protein that comprises a PSAP (SEQ ID NO: 39) motif and a PPXY motif in its C-terminus, and interacts with TSG101 as shown herein. It should be appreciated that the PSAP (SEQ ID NO: 39) motif and the PPXY motif are not required to be at the absolute C-terminal end of the ARRDC1. Rather, they may be at a C-terminal portion of the ARRDC1 protein (e.g., the C-terminal half of the ARRDC1). The disclosure also contemplates variants of ARRDC1, such as fragments of ARRDC1 and / or ARRDC1 proteins that have a degree of identity (e.g., 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% identity) to an ARRDC1 protein and are capable if interacting with TSG101. Accordingly, an ARRDC1 protein may be a protein that Attorney Docket No.54926-0021WO1 comprises a PSAP (SEQ ID NO: 39) motif and a PPXY motif and interacts with TSG101. In some embodiments, the ARRDC1 protein is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45, comprises a PSAP (SEQ ID NO: 39) motif and a PPXY motif, and interacts with TSG101. In some embodiments, the ARRDC1 protein has at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, at least 200, at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, at least 300, at least 310, at least 320, at least 330, at least 340, at least 350, at least 360, at least 370, at least 380, at least 390, at least 400, at least 410, at least 420, or at least 430 identical contiguous amino acids of any one of SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45, comprises a PSAP (SEQ ID NO: 39) motif and a PPXY motif, and interacts with TSG101. In some embodiments, the ARRDC1 protein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more mutations compared to any one of the amino acid sequences set forth in SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45, comprises a PSAP (SEQ ID NO: 39) motif and a PPXY motif, and interacts with TSG101. In some embodiments, the ARRDC1 protein comprises any one of the amino acid sequences set forth in SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45. Exemplary, non-limiting ARRDC1 protein sequences are provided herein, and additional, suitable ARRDC1 protein variants according to aspects of this invention are known in the art. It will be appreciated by those of skill in the art that this invention is not limited in this respect. Exemplary ARRDC1 sequences include SEQ ID NO: 43, SEQ ID NO: 44, and SEQ ID NO: 45 (PSAP and PPXY motifs are marked). TSG101 In certain embodiments, the inventive microvesicles further comprise TSG101 (tumor susceptibility gene 101). TSG101 belongs to a group of putative inactive homologs of ubiquitin-conjugating enzymes. The protein contains a coiled-coil domain that interacts with stathmin, a cytosolic phosphoprotein implicated in tumorigenesis. Attorney Docket No.54926-0021WO1 TSG101 is a protein that comprises a UEV domain and interacts with ARRDC1. As referred to herein, UEV refers to the Ubiquitin E2 variant domain of approximately 145 amino acids. The structure of the domain contains a α / β fold similar to the canonical E2 enzyme but has an additional N-terminal helix and further lacks the two C-terminal helices. Often found in TSG101 / Vps23 proteins, the UEV interacts with a ubiquitin molecule and is essential for the trafficking of a number of ubiquitylated payloads to multivesicular bodies (MVBs). Furthermore, the UEV domain can bind to Pro-Thr / Ser- Ala-Pro peptide ligands, a fact exploited by viruses such as HIV. Thus, the TSG101 UEV domain binds to the PTAP tetrapeptide motif in the viral Gag protein that is involved in viral budding. The disclosure also contemplates variants of TSG101, such as fragments of TSG101 and / or TSG101 proteins that have a degree of identity (e.g., 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% identity) to a TSG101 protein and are capable of interacting with ARRDC1. Accordingly, a TSG101 protein may be a protein that comprises a UEV domain and interacts with ARRDC1. In some embodiments, the TSG101 protein is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, comprises a UEV domain, and interacts with ARRDC1. In some embodiments, the TSG101 protein has at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, at least 200, at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, at least 300, at least 310, at least 320, at least 330, at least 340, at least 350, at least 360, at least 370, at least 380, or at least 390, and any integer between the numbers, identical contiguous amino acids of any one of SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, comprises a UEV domain and interacts with ARRDC1. In some embodiments, the TSG101 protein has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more mutations compared to any one of the amino acid sequences set forth in SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48 and comprises a UEV domain. In some embodiments, the ARRDC1 protein comprises any one of the amino acid sequences set forth in SEQ ID NO: 46, SEQ Attorney Docket No.54926-0021WO1 ID NO: 47, or SEQ ID NO: 48. Exemplary, non-limiting TSG101 protein sequences are provided herein, and additional, suitable TSG101 protein sequences, isoforms, and variants are known in the art. It will be appreciated by those of skill in the art that this invention is not limited in this respect. Exemplary TSG101 sequences include SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48 (the UEV domain in these sequences includes amino acids 1-145 and is underlined in the sequences). The structure of UEV domains is known to those of skill in the art. (See, e.g., Owen Pornillos et al., Structure and functional interactions of the Tsg101 UEV domain, EMBO J., 21(10): 2397–2406 (2002), the entire contents of which are incorporated herein by reference). WW Domains WW domains are protein domains having two basic residues at the C-terminus that mediates protein-protein interactions with short proline-rich or proline-containing motifs. It should be appreciated that the two basic residues (e.g., any two of: H, R, and K) of the WW domain are not required to be at the absolute C-terminal end of the WW protein domain. Rather, the two basic residues may be at a C-terminal portion of the WW protein domain (e.g., the C-terminal half of the WW protein domain). In some embodiments, the WW domain contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tryptophan (W) residues. In some embodiments, the WW domain contains at least two W residues. In some embodiments, the at least two W residues are spaced apart by from 15-25 amino acids. In some embodiments, the at least two W residues are spaced apart by from 19-23 amino acids. In some embodiments, the at least two W residues are spaced apart by from 20-22 amino acids. The WW domain possessing the two basic C-terminal amino acid residues may have the ability to associate with short proline-rich or proline-containing motifs (e.g., a PPXY motif). WW domains bind a variety of distinct peptide ligands including motifs with core proline-rich sequences, such as PPXY, which is found in ARRDC1. A WW domain may be a 30-40 amino acid protein interaction domain with two signature tryptophan residues spaced by 20-22 amino acids. The three-dimensional structure of WW domains shows that they generally fold into a three-stranded, antiparallel β sheet with two ligand-binding grooves. Attorney Docket No.54926-0021WO1 WW domains are found in many eukaryotes and are present in approximately 50 human proteins (Bork, P. & Sudol, M., “The WW domain: a signaling site in dystrophin?” Trends Biochem Sci., 19, 531-533 (1994)). WW domains may be present together with several other interaction domains, including membrane targeting domains, such as C2 in the NEDD4 family proteins, the phosphotyrosine-binding (PTB) domain in FE65 protein, FF domains in CA150 and FBPIl, and pleckstrin homology (PH) domains in PLEKHA5. WW domains are also linked to a variety of catalytic domains, including HECT E3 protein-ubiquitin ligase domains in NEDD4 family proteins, rotomerase or peptidyl prolyisomerase domains in Pinl, and Rho GAP domains in ArhGAP9 and ArhGAP12. The WW domain may be a WW domain that naturally possesses two basic amino acids at the C-terminus. In some embodiments, a WW domain or WW domain variant may be from the human ubiquitin ligase WWP1, WWP2, Nedd4-1, Nedd4-2, Smurf1, Smurf2, ITCH, NEDL1, or NEDL2. Exemplary amino acid sequences of WW domain containing proteins (and their WW domains) are set forth in SEQ ID NO: 49–SEQ ID NO: 58. It should be appreciated that any of the WW domains or WW domain variants of the exemplary proteins may be used in the invention, described herein, and are not meant to be limiting. In some embodiments, the WW domain consists essentially of a WW domain or WW domain variant. Consists essentially of means that a domain, peptide, or polypeptide consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues, for example, from about 1 to about 10 or so additional residues, typically from 1 to about 5 additional residues in the domain, peptide, or polypeptide. Alternatively, the WW domain may be a WW domain that has been modified to include two basic amino acids at the C-terminus of the domain. Techniques are known in the art and are described in the art, for example, in Sambrook et al., Molecular Cloning: a Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press (2001). Thus, a skilled person could readily modify an existing WW domain that does not normally have two C- terminal basic residues so as to include two basic residues at the C-terminus. Attorney Docket No.54926-0021WO1 Basic amino acids are amino acids that possess a side-chain functional group that has a pKa of greater than 7 and includes lysine, arginine, and histidine, as well as basic amino acids that are not included in the twenty α-amino acids commonly included in proteins. The two basic amino acids at the C-terminus of the WW domain may be the same basic amino acid or may be different basic amino acids. In one embodiment, the two basic amino acids are two arginines. The term WW domain also includes variants of a WW domain provided that any such variant possesses two basic amino acids at its C-terminus and maintains the ability of the WW domain to associate with the PPXY motif. A variant of such a WW domain refers to a WW domain that retains the ability of the variant to associate with the PPXY motif (i.e., the PPXY motif of ARRDC1 and that has been mutated at one or more amino acids, including point, insertion, and / or deletion mutations, but still retains the ability to associate with the PPXY motif. A variant or derivative, therefore, includes deletions, including truncations and fragments; insertions and additions, for example, conservative substitutions, site-directed mutants and allelic variants; and modifications, including one or more non-amino acyl groups (e.g., sugar, lipid, etc.) covalently linked to the peptide and post-translational modifications. In making such changes, substitutions of like amino acid residues can be made on the basis of relative similarity of side-chain substituents, for example, their size, charge, hydrophobicity, hydrophilicity, and the like, and such substitutions may be assayed for their effect on the function of the peptide by routine testing. The WW domain may be part of a longer protein. Thus, the protein, in various different embodiments, comprises the WW domain, consists of the WW domain, or consists essentially of the WW domain, as defined herein. The polypeptide may be a protein that includes a WW domain as a functional domain within the protein sequence. RNA-Guided Proteins In some cases, the ARMMs described herein comprise an RNA-guided protein. RNA-guided proteins such as Cas (e.g., Cas9) proteins, base editors, prime editors, and the like are described in the art. Attorney Docket No.54926-0021WO1 In some cases, the RNA-guided protein is a base editor (e.g., a protein comprising a fusion protein comprising a programmable DNA binding domain such as a Cas domain and a deaminase domain). In some cases, the deaminase is a cytodine deaminase and / or an adenosine deaminase. In some embodiments, the adenosine deaminase is TadA or a TadA variant. In some embodiments, the TadA is a TadA*8 or TadA*9. In some cases, the cytodine deaminase is APOBEC or an APOBEC variant. In some cases, the base editor is a cytosine base editor (CBE). In some cases, the base editor is an adenine base editor (ABE). In some cases, the base editor is ABE8. In some cases, the base editor is a base editor described in any one of WO2023023515A1, WO2023015223A2, WO2023009505A1, WO2023004409A1, WO2022256578A3, WO2022251687A3, WO2022246266A1, WO2022241270A3, WO2022221699A1, WO2022204574A1, WO2022204268A3, WO2022178307A1, WO2022159472A1, WO2022159463A1, WO2022159475A1, WO2022159421A1, WO2022140252A1, WO2022140239A1, WO2022140238A1, WO2022081890A1, WO2022067089A1, WO2022060871A1, WO2021207712A3, WO2021178725A1, WO2021163587A1, WO2021113494A1, WO2021062227A3, WO2021050512A1, WO2021050571A1, WO2021041885A3, WO2021041945A3, WO2020231863A1, WO2020150534A3, WO2020051561A1, WO2020051562A3, WO2020028823A1, WO2019217942A1, WO2019217943A1, WO2019217941A1, or WO2019079347A1, each of which is hereby incorporated by reference in its entirety. In some cases, the ARMMs described herein comprise a nucleic acid encoding an RNA-guided protein. In some cases, the nucleic acid is DNA and encodes an mRNA which, in turn, encodes the RNA-guided protein. In some cases, the nucleic acid is an mRNA which encodes the RNA-guided protein. gRNAs In some cases, the ARMMs comprise one or more gRNAs. gRNAs are described in the art. In some cases, the gRNA(s) are a single guide RNA (sgRNA). In some cases, the gRNA(s) are crisprRNA + tracrRNA. In some cases, the gRNA(s) are a combination of sgRNA(s) and crisprRNA + tracrRNA(s). Attorney Docket No.54926-0021WO1 Expression Constructs Some aspects of this invention provide expression constructs for encoding a gene product or gene products that induce or facilitate the generation of ARMMs in cells harboring such a construct. In some embodiments, the expression constructs described herein encode a fusion protein as described herein, such as ARRDC1 fusion proteins and TSG101 fusion proteins. In some embodiments, the expression constructs encode an ARRDC1 protein, or variant thereof, and / or a TSG101 protein, or variant thereof. In some embodiments, overexpression of either or both gene products in a cell increases the production of ARMMs in the cell, thus turning the cell into a microvesicle producing cell. In some embodiments, such an expression construct comprises at least one restriction or recombination site that allows in-frame cloning of a protein sequence to be fused, either at the C-terminus, or at the N-terminus of the encoded ARRDC1, or variant thereof. As another example, an expression construct comprises at least one restriction or recombination site that allows in-frame cloning of a protein sequence to be fused either at the C-terminus or at the N-terminus of one or more encoded WW domains. In some embodiments, the expression construct comprises (a) a nucleotide sequence encoding an ARRDC1 protein, or variant thereof, operably linked to a heterologous promoter, and (b) a restriction site or a recombination site positioned adjacent to the ARRDC1-encoding nucleotide sequence allowing for the insertion of a nucleotide sequencing encoding a payload protein, or an RNA binding protein or RNA binding protein variant sequence, in frame with the ARRDC1-encoding nucleotide sequence. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. Some aspects of this invention provide an expression construct comprising (a) a nucleotide sequence encoding a TSG101 protein, or variant thereof, operably linked to a heterologous promoter, and (b) a restriction site or a recombination site positioned adjacent to the TSG101-encoding nucleotide sequence allowing for the insertion of a nucleotide sequencing encoding a payload protein, or an RNA binding protein, DNA binding protein, or variant sequence thereof, in frame with the TSG101-encoding nucleotide sequence. In some embodiments, the heterologous promoter may be a Attorney Docket No.54926-0021WO1 constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. Some aspects of this invention provide an expression construct comprising (a) a nucleotide sequence encoding a WW domain, or variant thereof, operably linked to a heterologous promoter, and (b) a restriction site or a recombination site positioned adjacent to the WW domain-encoding nucleotide sequence allowing for the insertion of a payload protein or RNA binding protein, or a protein variant sequence thereof in frame with the WW domain-encoding nucleotide sequence. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. The expression constructs may encode a payload protein, or an RNA binding protein fused to at least one WW domain. In some embodiments, the expression constructs encode a payload protein or an RNA binding protein, or variant thereof, fused to at least one WW domain, or variant thereof. Any of the expression constructs, described herein, may encode any WW domain or variant thereof. In some embodiments, the heterologous promoter may be a constitutive promoter, in some embodiments, the heterologous promoter may be an inducible promoter. The expression constructs, described herein, may comprise any nucleic acid sequence capable of encoding a WW domain or variant thereof. For example, a nucleic acid sequence encoding a WW domain or WW domain variant may be from the human ubiquitin ligase WWP1, WWP2, Nedd4-1, Nedd4-2, Smurf1, Smurf2, ITCH, NEDL1, or NEDL2. Some aspects of this invention provide expression constructs that encode any of the proteins, nucleic acids, such as RNAs, or fusions thereof described herein. Nucleic acids encoding any of the proteins and / or nucleic acid (including RNA) described herein, may be in any number of nucleic acid vectors known in the art. Vectors suitable for use in the compositions and methods of the present invention include both viral and nonviral products and additional means for introducing nucleic acid(s) into cells. Expression of any of the proteins and / or nucleic acid (including RNA) described herein, may be controlled by any regulatory sequence (e.g., a promoter sequence) known Attorney Docket No.54926-0021WO1 in the art. Regulatory sequences, as described herein, are nucleic acid sequences that regulate the expression of a nucleic acid sequence. A regulatory or control sequence may include sequences that are responsible for expressing a particular nucleic acid or may include other sequences, such as heterologous, synthetic, or partially synthetic sequences. The sequences can be of eukaryotic, prokaryotic, or viral origin that stimulate or repress transcription of a gene in a specific or non-specific manner and in an inducible or non- inducible manner. Regulatory or control regions may include origins of replication, RNA splice sites, introns, chimeric or hybrid introns, promoters, enhancers, transcriptional termination sequences, poly A sites, locus control regions, signal sequences that direct the polypeptide into the secretory pathways of the target cell. A heterologous regulatory region is a regulatory region not naturally associated with the expressed nucleic acid it is linked to. Included among the heterologous regulatory regions are regulatory regions from a different species, regulatory regions from a different gene, hybrid regulatory sequences, and regulatory sequences that do not occur in nature, but which are designed by one of ordinary skill in the art. Exemplary Cells Producing ARMMs Containing Payload A microvesicle-producing cell of the present invention may be a cell containing any of the expression constructs, any of the fusion proteins, or any of the payloads of molecules (e.g., biological molecules, small molecules, proteins, and nucleic acids) described herein. For example, an inventive microvesicle-producing cell may contain one or more recombinant expression constructs encoding (1) an ARRDC1 protein, or PSAP (SEQ ID NO: 39) motif-containing variant thereof and (2) an RNA binding protein (e.g., a Tat protein), that is associated with the ARRDC1 protein, or PSAP (SEQ ID NO: 39) motif-containing variant thereof. In some embodiments, a microvesicle-producing cell may contain one or more recombinant expression constructs encoding (1) an ARRDC1 protein, or PSAP (SEQ ID NO: 39) motif-containing variant thereof, and (2) a payload protein, such as an RNA binding protein fused to at least one WW domain, or variant thereof, under the control of a heterologous promoter. In certain embodiments, the expression construct in the microvesicle producing cell encodes a payload protein with one or more WW domains or variants thereof. In certain embodiments, an expression Attorney Docket No.54926-0021WO1 construct in the microvesicle producing cell encodes a payload (e.g., a gene editing payload described herein) and / or a targeting moiety (e.g., a targeting moiety described herein, e.g., for targeted delivery of ARMMS to neurons). Any of the expression constructs, described herein, may be stably inserted into the genome of the cell. In some embodiments, the expression construct is maintained in the cell, but not inserted into the genome of the cell. In some embodiments, the expression construct is in a vector, for example, a plasmid vector, a cosmid vector, a viral vector, or an artificial chromosome. In some embodiments, the expression construct further comprises additional sequences or elements that facilitate the maintenance and / or the replication of the expression construct in the microvesicle-producing cell, or that improve the expression of the fusion protein in the cell. Such additional sequences or elements may include, for example, an origin of replication, an antibiotic resistance cassette, a polyA sequence, and / or a transcriptional isolator. Some expression constructs suitable for the generation of microvesicle producing cells according to aspects of this invention are described elsewhere herein. Methods and reagents for the generation of additional expression constructs suitable for the generation of microvesicle producing cells according to aspects of this invention will be apparent to those of skill in the art based on the present disclosure. In some embodiments, the microvesicle producing cell is a mammalian cell, for example, a mouse cell, a rat cell, a hamster cell, a rodent cell, or a nonhuman primate cell. In some embodiments, the microvesicle producing cell is a human cell. One skilled in the art may employ conventional techniques, such as molecular or cell biology, virology, microbiology, and recombinant DNA techniques. Exemplary techniques are explained fully in the literature. For example, one may rely on the following general texts to make and use the invention: Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, and Sambrook et al., Third Edition (2001); DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover ed.1985); Oligonucleotide Synthesis (M.J. Gaited.1984); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. (1985)); Transcription and Translation Hames & Higgins, eds. (1984); Animal Cell Culture (RI. Freshney, ed. (1986)); Immobilized Cells And Enzymes Attorney Docket No.54926-0021WO1 (IRL Press, (1986)); Gennaro et al., (eds.) Remington's Pharmaceutical Sciences, 18th edition; B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Ausubel et al., (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (updates through 2001), Coligan et al., (eds.), Current Protocols in Immunology, John Wiley & Sons, Inc.(updates through 2001); W. Paul et al., (eds.) Fundamental Immunology, Raven Press; E.J. Murray et al., (ed.) Methods in Molecular Biology: Gene Transfer and Expression Protocols, The Humana Press Inc. (1991)(especially vol.7); and J.E. Celis et al., Cell Biology: A Laboratory Handbook, Academic Press (1994). Delivery of ARMMs Containing Payload Molecules ARMMs containing any of the expression constructs and / or any of the payload of molecules described herein, may optionally further comprise a fusogen. The fusogen may result in the release of the contents of the ARMM into the cytoplasm of a specific targeted cell type. A fusogen may be a viral envelope protein, or portion thereof, that normally functions to aid viral attachment and entry into cells. In some cases, the fusogen is VSVG, or a portion thereof. Additional molecules, such as synthetic small molecules or natural products, can be modified to associate with an ARMM protein (e.g., TSG101 or ARRDC1) for the purpose of targeting. This association can facilitate their incorporation with ARMMs, which in turn can be used to augment delivery of ARMMs to target cells. The incorporation of a cleavable linker may be used to allow the small molecule to be released upon delivery in or to a target cell. As a non-limiting example, a small molecule can be linked to biotin, thereby allowing it to associate with an ARRDC1 protein which is fused to a streptavidin. As another non-limiting example, a small molecule can be linked to synthetic high affinity ligand that specifically binds to a mutant form of FKBP12 such as FKBP12(F36V) (Yang, W., et al., “Investigating protein-ligand interactions with a mutant FKBP possessing a designed specificity pocket” J. Med. Chem., 43(6):1135-1142 (2000)), which will associate with an ARRDC1 protein which is fused to FKBP12(F36V). The association of the small molecule to an ARMM protein (e.g., TSG101 or ARRDC1), facilitates the loading of the small molecule into the ARRDC1- containing ARMM. Attorney Docket No.54926-0021WO1 Some aspects of this invention relate to the recognition that ARMMs are taken up by target cells and ARMM uptake results in the release of the contents of the ARMM into the cytoplasm of the target cells. In some embodiments, the payload is an agent that affects a desired change in the target cell, for example, a change in cell survival, proliferation rate, a change in differentiation stage, a change in cell identity, a change in chromatin state, a change in the transcription rate of one or more genes, a change in the transcriptional profile, or a post-transcriptional change in gene compression of the target cell, and the like. It will be understood by those of skill in the art, that the agent to be delivered will be chosen according to the desired effect in the target cell. In some embodiments, cells from a subject are obtained and a payload is delivered to the cells by a system or method provided herein ex vivo. In some embodiments, the treated cells are selected for those cells in which a desired gene is expressed or repressed. In some embodiments, treated cells carrying a desired payload are returned to the subject they were obtained from. In some embodiments, the ARMMs further comprise a detectable label. In certain embodiments, detectably labeled ARMMs allow for the labeling of target cells without genetic manipulation. Detectable labels suitable for direct delivery to target cells are known in the art, and include, but are not limited to, fluorescent proteins, fluorescent dyes, membrane-bound dyes, and enzymes, for example, membrane-bound or cytosolic enzymes, catalyzing the reaction resulting in a detectable reaction product. Detectable labels suitable according to some aspects of this invention further include membrane- bound antigens, for example, membrane-bound ligands that can be detected with commonly available antibodies or antigen binding agents. Detectably labeled ARRMs find use in various diagnostic and analytical methods and applications. In some embodiments, ARMMs are provided that comprise a payload RNA that encodes a transcription factor, a transcriptional repressor, a fluorescent protein, a kinase, a phosphatase, a protease, a ligase, a chromatin modulator, a recombinase, and the like. In some embodiments, ARMMs are provided that comprise a payload RNA that inhibits the expression of a transcription factor, a transcriptional repressor, a fluorescent protein, a kinase, a phosphatase, a protease, a ligase, a chromatin modulator, or a recombinase. In some embodiments, the payload RNA is a therapeutic RNA. In some embodiments, the Attorney Docket No.54926-0021WO1 payload RNA is an RNA that affects a change in the state or identity of a target cell. For example, in some embodiments, the payload RNA encodes a reprogramming factor. Suitable transcription factors, transcriptional repressors, fluorescent proteins, kinases, phosphatases, proteases, ligases, chromatin modulators, recombinases, and reprogramming factors may be encoded by a payload RNA that is associated with a binding RNA to facilitate their incorporation into ARMMs and their function may be tested by any methods that are known to those skilled in the art, and the invention is not limited in this respect. Methods for isolating the ARMMs described herein are also provided. One exemplary method includes employing conventional techniques of collecting culture medium, or supernatant, from a cell culture comprising microvesicle-producing cells. In some embodiments, the cell culture comprises cells obtained from a subject, for example, cells suspected to exhibit a pathological phenotype, for example, a hyperproliferative phenotype. In some embodiments, the cell culture comprises genetically engineered cells producing ARMMs, for example, cells expressing a recombinant protein, for example, a recombinant ARRDC1 or TSG101 protein, such as an ARRDC1 or TSG101 protein, optionally fused to an RNA binding protein (e.g., a Tat protein) or variant thereof. In some embodiments, the supernatant is pre-cleared of cellular debris by centrifugation, for example, by two consecutive centrifugations of increasing G value (e.g., 500G and 2000G). In some embodiments, the method comprises passing the supernatant through a 0.2 µm filter, eliminating all large pieces of cell debris and whole cells. In some embodiments, the supernatant is subjected to ultracentrifugation, for example, at 120,000G for 2 hours, depending on the volume of centrifugate. The pellet obtained comprises microvesicles. In some embodiments, exosomes are depleted from the microvesicle pellet by staining and / or sorting (e.g., by FACS or MACS) using an exosome marker as described herein. Isolated or enriched ARMMs can be suspended in culture media or a suitable buffer, as described herein. Methods of ARMMs-Mediated Delivery of Payload to Cells Some aspects of this invention provide a method of delivering an agent (e.g., a therapeutic agent or agents) to a target cell. The target cell can be contacted with an Attorney Docket No.54926-0021WO1 ARMM in different ways. For example, a target cell may be contacted directly with an ARMM as described herein, or with an isolated ARMM from a microvesicle producing cell. The contacting can be done in vitro by administering the ARMM to the target cell in a culture dish, or in vivo by administering the ARMM to a subject. In some embodiments, the ARMMs are produced from cells obtained from a subject. In some embodiments, ARMMs that are produced from a cell obtained from a particular subject are administered to the same subject. Conversely, in some other embodiments, ARMMs produced from a cell that was obtained from the subject are administered to a different subject. As one example, a cell may be obtained from a subject and engineered to express one or more of the constructs provided herein (e.g., engineered to express a payload RNA associated with a binding RNA, an ARRDC1 protein, an ARRDC1 protein fused to an RNA binding protein, an RNA binding protein fused to a WW domain, a base editor or nuclease protein, guide and regulator sequences, and the like). Alternatively, a target cell can be contacted with a microvesicle producing cell as described herein, for example, contacted in vitro by co-culturing the target cell and the microvesicle producing cell, or contacted in vivo by administering a microvesicle producing cell to a subject harboring the target cell. Accordingly, the method may include contacting the target cell with a microvesicle, for example, an ARMM containing any of the payloads to be delivered, as described herein. The target cell may be contacted with a microvesicle-producing cell, as described herein, or with an isolated microvesicle that has a lipid bilayer, an ARRDC1 protein or variant thereof, a payload (e.g., a gene editing payload described herein). It should be appreciated that the target cell may be of any origin, for example, from an organism. In some embodiments, the target cell is a mammalian cell. Some non- limiting examples of a mammalian cell include, without limitation, a mouse cell, a rat cell, a hamster cell, a rodent cell, and a nonhuman primate cell. In some embodiments, the target cell is a human cell. It should also be appreciated that the target cell may be of any cell type. In other cases, the target cell may be any differentiated cell type found in a subject. In some embodiments, the target cell is a cell in vitro, and the method includes administering the microvesicle to the cell in vitro, or co-culturing the target cell with the microvesicle-producing cell in vitro. In some embodiments, the target cell is a cell in a Attorney Docket No.54926-0021WO1 subject, and the method comprises administering the microvesicle or the microvesicle- producing cell to the subject. In some embodiments, the subject is a mammalian subject, for example, a rodent, a mouse, a rat, a hamster, or a non-human primate. In some embodiments, the subject is a human subject. In some cases, the cell is an ocular cell, e.g., an RPE cell. In some embodiments, the microvesicle is associated with a binding agent that selectively binds an antigen on the surface of the target cell. In some embodiments, the compositions and methods of the present invention comprise one or more targeting ligands that associate (e.g., bind) to one or more targeting receptors. In some embodiments, the antigen of the target cell is a cell surface antigen. The choice of the binding agent will depend, of course, on the identity or the type of target cell. It will be appreciated that the present invention is not limited in this respect. Engineered ARMMs targeting ocular cells (e.g., as described herein) and methods of producing them are described herein. GENE EDITING PAYLOADS Thus, in some cases, the ARMMs described herein comprise a payload (e.g., as described herein) that is capable of editing a gene target (or expression product thereof, e.g., mRNA and / or protein). In some cases, the molecule(s) are capable of increasing the expression of a gene target. In some cases, the molecules(s) are capable of decreasing the expression of a gene target (e.g., knocking down or knocking out expression of the gene product (e.g., reducing expression of mRNA and / or protein). In some cases, the molecule(s) are capable of editing the gene target (or expression product thereof). In some cases, the molecule(s) are capable of editing the gene target so as to increase or decrease the expression of the gene target. In some cases, the molecule(s) are capable of editing the gene target to cause knock-out or knock-down of the expression of the gene target. In some cases, the molecule(s) are capable of editing the gene target so as to change the sequence of the expression of the gene target. In some cases, the gene target is a VEGFA gene (e.g., a human VEGFA gene, e.g., as described herein). In some cases, the gene editing is an edit (e.g., point mutation, or indel) within the gene sequence (e.g., the coding sequence or non-coding sequence). In some cases, the Attorney Docket No.54926-0021WO1 gene editing is an edit in a regulatory region (e.g., promoter, enhancer, silencer, or insulator). In some cases, the gene editing is epigenome editing. Examples of gene editing payloads targeting the VEGFA gene are described, for example, in the Examples that follow. In some cases, the increase or decrease in expression is compared to a reference expression level. In some cases, the reference expression level is the expression level in a control cell, e.g., that has not been delivered the payload. In some cases, the reference expression level is the expression level in cell(s) of an organism (e.g., a patient described herein). In some cases, the cell(s) of the organism are of the same tissue type and / or cell ontology. ADMINISTRATION AND METHODS OF TREATMENT Provided herein are methods of modulating the expression of a gene target (e.g., the VEGFA gene), by administering the ARMMs described herein to a cell, e.g., a cell of a patient described herein, e.g., an ocular cell, e.g., an RPE cell. Also provided herein are methods of treating a disease or disorder associated with mutation and / or dysregulation of a gene target (e.g., an ocular disorder, e.g., as described herein), by administering the ARMMs described herein to a patient in need thereof (e.g., a patient with or suspected to have a disease or disorder). Also provided herein are methods of delivering the ARMMs described herein to cell(s) (e.g., ocular cells, e.g., RPE cells, e.g., as described herein), methods of editing a gene target in said cell(s), and methods of decreasing expression of the gene target (e.g., pathogenic forms of VEGFA) in said cell(s). Administration The ARMMs can be administered to as subject by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, Attorney Docket No.54926-0021WO1 intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In some cases, the ARMMs are administered by intravitreal injection. In some cases, the ARMMs are administered by subretinal injection. In some cases, the ARMMs are administered by suprachoroidal injection. Disorders Compositions and methods disclosed herein find use in treating diseases or disorders such as ocular disorders described herein, e.g., AMD, e.g., wet AMD. Patients Suitable patients for the compositions and methods herein include those who are suffering from, who have been diagnosed with, or who are suspected of having an ocular disorder described herein, e.g., AMD, e.g., wet AMD. In some embodiments, the methods of treatment provided herein may be used to treat a subject (e.g., human, monkey, dog, cat, mouse) who is or has been diagnosed with, or is suspected of having, the disease / disorder. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. EXAMPLE 1: Selective Targeting of Pathogenic VEGFA 8a Isoforms To selectively target pathogenic VEGFA 8a isoforms, a base editing strategy was developed to edit the splice acceptor site of exon 8 (AàG at A6 and / or A8 of target sequence depicted in FIG.3A), such that the resulting protein would be spliced at the alternate site, leading to production of only the isoform 8b variant (as depicted in FIG. 3B) or another variant encoding an isoform that precludes those containing exon 8a. As Attorney Docket No.54926-0021WO1 shown in FIG.4, the splice acceptor site is conserved across species and can be targeted with gRNAs suited to each species. As shown in FIG.3A, this strategy resulted in base editing in vitro in both human and mouse cells, with two alternate gRNAs. gRNAs were designed for humans and non- human primates, mouse, rat, and rabbit, the targeting sequences of which are set forth in the table below. This base editing strategy was tested in vitro using ARMMs-based delivery (as depicted in FIG.5 and FIG.13, “target-VEGFA”). ARMMs were produced carrying ABE8 and gRNA cargos. The nucleotide and amino acid sequences of the base editor fusion protein (ARRDC1-ABE) are set forth in the “SEQUENCES” section, below. Cells in culture (ARPE-19 and human primary RPE for human, N2a for mouse, RPE-J for rat) were treated with the ARMMs and tested in vitro. As shown in FIG.6, ARMMs-delivered base editor cargos resulted in base editing in both human (ARPE-19) and mouse (N2a) cells. As shown in FIG.7, ARMMs- delivered base editor cargos resulted in base editing in rat cells. As shown in FIG.8, ARMMs-delivered base editor cargo resulted in base editing in human primary RPE cells. Results are shown in FIG.9 and FIG.10. Protein analysis results are shown in FIG.11 and FIG.12. mVEGF 164 antibody detects mouse VEGFA and VEGFA 8new in Western blots in lysates or in cell culture Attorney Docket No.54926-0021WO1 media after treatment with engineered ARMMs loaded with ABE8 / Target-VEGFA gRNA or mock treatment. EXAMPLE 2: Knockdown / Knockout of VEGFA In a second “pan-VEGFA” approach, ARMMs were produced carrying a payload of a Cas9 nuclease and a gRNA targeting VEGFA for knockout / knockdown. This gRNA sequence to knock out the VEGFA gene via Cas9 nuclease-mediated cleavage on the exon 3 site is conserved from human, NHP, minipig, rabbit to mouse and rat. They all share the same sequence: These ARMMs were tested in vitro in human, mouse, and rat cells for editing. mRNA and protein analysis were carried out in mouse cells. Editing was successful in all cell types, as shown in FIG.14 (rat), FIG.15 (mouse), and FIG.16 (human).

[0002] Attorney Docket No.54926-0021WO1 SEQUENCES SEQ ID NO: 39 (PSAP motif) PSAP SEQ ID NO: 40 (GFP) MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTFSYGVQCF SRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILGHKLE YNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSALSKDPNE KRDHMVLLEFVTAAGITHGMDELYK SEQ ID NO: 41 (WT spCas9) MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHSIKKNLIGALLFGSGETAEATRLKRTARRR YTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKL ADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQIYNQLFEENPINASRVDAKAILS ARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGD QYADLFLAAKNLSDAILLSDILRVNSEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQS KNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQ EDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDY FKKIECFDSVEISGVEDRFNASLGAYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDRGMIEERLKTY AHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQK AQVSGQGHSLHEQIANLAGSPAIKKGILQTVKIVDELVKVMGHKPENIVIEMARENQTTQKGQKNSRERMK RIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDSID NKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVET RQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGT ALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETN GETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSP TVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELEN GRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKR VILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQ SITGLYETRIDLSQLGGD SEQ ID NO: 42 MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRR YTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKL VDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILS Attorney Docket No.54926-0021WO1 ARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGD QYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQS KNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQ EDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDY FKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTY AHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQK AQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERM KRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSI DNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVE TRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVG TALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIET NGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDS PTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELE NGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSK RVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIH QSITGLYETRIDLSQLGGD SEQ ID NO: 43 (Human ARRDC1) >gi|22748653|ref|NP_689498.1| arrestin domain-containing protein 1 [Homo sapiens] MGRVQLFEISLSHGRVVYSPGEPLAGTVRVRLGAPLPFRAIRVTCIGSCGVSNKANDTAWVVEEGYFNSSL SLADKGSLPAGEHSFPFQFLLPATAPTSFEGPFGKIVHQVRAAIHTPRFSKDHKCSLVFYILSPLNLNSIP DIEQPNVASATKKFSYKLVKTGSVVLTASTDLRGYVVGQALQLHADVENQSGKDTSPVVASLLQKVSYKAK RWIHDVRTIAEVEGAGVKAWRRAQWHEQILVPALPQSALPGCSLIHIDYYLQVSLKAPEATVTLPVFIGNI PSLTPES SEQ ID NO: 44 (Mouse ARRDC1, isoform a) >gi|244798004|ref|NP_001155957.1| arrestin domain-containing protein 1 isoform a [Mus musculus] MGRVQLFEIRLSQGRVVYGPGEPLAGTVHLRLGAPLPFRAIRVTCMGSCGVSTKANDGAWVVEESYFNSSL SLADKGSLPAGEHNFPFQFLLPATAPTSFEGPFGKIVHQVRASIDTPRFSKDHKCSLVFYILSPLNLNSIP DIEQPNVASTTKKFSYKLVKTGNVVLTASTDLRGYVVGQVLRLQADIENQSGKDTSPVVASLLQKVSYKAK RWIYDVRTIAEVEGTGVKAWRRAQWQEQILVPALPQSALPGCSLIHIDYYLQVSMKAPEATVTLPLFVGNI Attorney Docket No.54926-0021WO1 SEQ ID NO: 45 (Mouse ARRDC1, isoform b) >gi|244798112|ref|NP_848495.2| arrestin domain-containing protein 1 isoform b [Mus musculus] MGRVQLFEIRLSQGRVVYGPGEPLAGTVHLRLGAPLPFRAIRVTCMGSCGVSTKANDGAWVVEESYFNSSL SLADKGSLPAGEHNFPFQFLLPATAPTSFEGPFGKIVHQVRASIDTPRFSKDHKCSLVFYILSPLNLNSIP DIEQPNVASTTKKFSYKLVKTGNVVLTASTDLRGYVVGQVLRLQADIENQSGKDTSPVVASLLQVSYKAKR WIYDVRTIAEVEGTGVKAWRRAQWQEQILVPALPQSALPGCSLIHIDYYLQVSMKAPEATVTLPLFVGNIA VNQTPLSPCPGRESSPGTLSLVVPSAPPQEEAEAVASGPHFSDPVSLSTKSHSQQQPLSAPLGSVSVTTTE PWVQVGSPARHSLHPPLCISIGATVPYFAEGSAGPVPTTSALILPPEYSSWGYPYEAPPSYEQSCGAAGTD LGLIPGS SEQ ID NO: 46 (Human TSG101) >gi|5454140|ref|NP_006283.1| tumor susceptibility gene 101 protein [Homo sapiens] MAVSESQLKKMVSKYKYRDLTVRETVNVITLYKDLKPVLDSYVFNDGSSRELMNLTGTIPVPYRGNTYNIP ICLWLLDTYPYNPPICFVKPTSSMTIKTGKHVDANGKIYLPYLHEWKHPQSDLLGLIQVMIVVFGDEPPVF SRPISASYPPYQATGPPNTSYMPGMPGGISPYPSGYPPNPSGYPGCPYPPGGPYPATTSSQYPSQPPVTTV GPSRDGTISEDTIRASLISAVSDKLRWRMKEEMDRAQAELNALKRTEEDLKKGHQKLEEMVTRLDQEVAEV DKNIELLKKKDEELSSALEKMENQSENNDIDEVIIPTAPLYKQILNLYAEENAIEDTIFYLGEALRRGVID LDVFLKHVRLLSRKQFQLRALMQKARKTAGLSDLY SEQ ID NO: 47 (Mouse TSG101) >gi|11230780|ref|NP_068684.1| tumor susceptibility gene 101 protein [Mus musculus] MAVSESQLKKMMSKYKYRDLTVRQTVNVIAMYKDLKPVLDSYVFNDGSSRELVNLTGTIPVRYRGNIYNIP ICLWLLDTYPYNPPICFVKPTSSMTIKTGKHVDANGKIYLPYLHDWKHPRSELLELIQIMIVIFGEEPPVF SRPTVSASYPPYTATGPPNTSYMPGMPSGISAYPSGYPPNPSGYPGCPYPPAGPYPATTSSQYPSQPPVTT VGPSRDGTISEDTIRASLISAVSDKLRWRMKEEMDGAQAELNALKRTEEDLKKGHQKLEEMVTRLDQEVAE VDKNIELLKKKDEELSSALEKMENQSENNDIDEVIIPTAPLYKQILNLYAEENAIEDTIFYLGEALRRGVI DLDVFLKHVRLLSRKQFQLRALMQKARKTAGLSDLY SEQ ID NO: 48 (Rat TSG101) >gi|48374087|ref|NP_853659.2| tumor susceptibility gene 101 protein [Rattus norvegicus] MAVSESQLKKMMSKYKYRDLTVRQTVNVIAMYKDLKPVLDSYVFNDGSSRELVNLTGTIPVRYRGNIYNIP ICLWLLDTYPYNPPICFVKPTSSMTIKTGKHVDANGKIYLPYLHDWKHPRSELLELIQIMIVIFGEEPPVF SRPTVSASYPPYTAAGPPNTSYLPSMPSGISAYPSGYPPNPSGYPGCPYPPAGPYPATTSSQYPSQPPVTT AGPSRDGTISEDTIRASLISAVSDKLRWRMKEEMDGAQAELNALKRTEEDLKKGHQKLEEMVTRLDQEVAE VDKNIELLKKKDEELSSALEKMENQSENNDIDEVIIPTAPLYKQILNLYAEENAIEDTIFYLGEALRRGVI DLDVFLKHVRLLSRKQFQLRALMQKARKTAGLSDLY Attorney Docket No.54926-0021WO1 SEQ ID NO: 49 (Human WWP1 amino acid sequence (uniprot.org / uniprot / Q9H0M0). The four underlined WW domains correspond to amino acids 349 – 382 (WW1), 381 – 414 (WW2), 456 – 489 (WW3), and 496 – 529 (WW4). MATASPRSDTSNNHSGRLQLQVTVSSAKLKRKKNWFGTAIYTEVVVDGEITKTAKSSSSSNPKWDEQLTVN VTPQTTLEFQVWSHRTLKADALLGKATIDLKQALLIHNRKLERVKEQLKLSLENKNGIAQTGELTVVLDGL VIEQENITNCSSSPTIEIQENGDALHENGEPSARTTARLAVEGTNGIDNHVPTSTLVQNSCCSYVVNGDNT PSSPSQVAARPKNTPAPKPLASEPADDTVNGESSSFAPTDNASVTGTPVVSEENALSPNCTSTTVEDPPVQ EILTSSENNECIPSTSAELESEARSILEPDTSNSRSSSAFEAAKSRQPDGCMDPVRQQSGNANTETLPSGW EQRKDPHGRTYYVDHNTRTTTWERPQPLPPGWERRVDDRRRVYYVDHNTRTTTWQRPTMESVRNFEQWQSQ RNQLQGAMQQFNQRYLYSASMLAAENDPYGPLPPGWEKRVDSTDRVYFVNHNTKTTQWEDPRTQGLQNEEP LPEGWEIRYTREGVRYFVDHNTRTTTFKDPRNGKSSVTKGGPQIAYERGFRWKLAHFRYLCQSNALPSHVK INVSRQTLFEDSFQQIMALKPYDLRRRLYVIFRGEEGLDYGGLAREWFFLLSHEVLNPMYCLFEYAGKNNY CLQINPASTINPDHLSYFCFIGRFIAMALFHGKFIDTGFSLPFYKRMLSKKLTIKDLESIDTEFYNSLIWI RDNNIEECGLEMYFSVDMEILGKVTSHDLKLGGSNILVTEENKDEYIGLMTEWRFSRGVQEQTKAFLDGFN EVVPLQWLQYFDEKELEVMLCGMQEVDLADWQRNTVYRHYTRNSKQIIWFWQFVKETDNEVRMRLLQFVTG TCRLPLGGFAELMGSNGPQKFCIEKVGKDTWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE SEQ ID NO: 50 (WW1 (349-382)) ETLPSGWEQRKDPHGRTYYVDHNTRTTTWERPQP SEQ ID NO: 51 (WW2 (381-414)) QPLPPGWERRVDDRRRVYYVDHNTRTTTWQRPTM SEQ ID NO: 52 (WW3 (456-489)) ENDPYGPLPPGWEKRVDSTDRVYFVNHNTKTTQWEDPRT SEQ ID NO: 53 (WW4 (496-529)) EPLPEGWEIRYTREGVRYFVDHNTRTTTFKDPRN SEQ ID NO: 54 (Human WWP2 amino acid sequence (uniprot.org / uniprot / O00308). The four underlined WW domains correspond to amino acids 300 – 333 (WW1), 330 – 363 (WW2), 405 – 437 (WW3), and 444 – 547 (WW4)) MASASSSRAGVALPFEKSQLTLKVVSAKPKVHNRQPRINSYVEVAVDGLPSETKKTGKRIGSSELLWNEII ILNVTAQSHLDLKVWSCHTLRNELLGTASVNLSNVLKNNGGKMENMQLTLNLQTENKGSVVSGGELTIFLD GPTVDLGNVPNGSALTDGSQLPSRDSSGTAVAPENRHQPPSTNCFGGRSRTHRHSGASARTTPATGEQSPG ARSRHRQPVKNSGHSGLANGTVNDEPTTATDPEEPSVVGVTSPPAAPLSVTPNPNTTSLPAPATPAEGEEP Attorney Docket No.54926-0021WO1 STSGTQQLPAAAQAPDALPAGWEQRELPNGRVYYVDHNTKTTTWERPLPPGWEKRTDPRGRFYYVDHNTRT TTWQRPTAEYVRNYEQWQSQRNQLQGAMQHFSQRFLYQSSSASTDHDPLGPLPPGWEKRQDNGRVYYVNHN TRTTQWEDPRTQGMIQEPALPPGWEMKYTSEGVRYFVDHNTRTTTFKDPRPGFESGTKQGSPGAYDRSFRW KYHQFRFLCHSNALPSHVKISVSRQTLFEDSFQQIMNMKPYDLRRRLYIIMRGEEGLDYGGIAREWFFLLS HEVLNPMYCLFEYAGKNNYCLQINPASSINPDHLTYFRFIGRFIAMALYHGKFIDTGFTLPFYKRMLNKRP TLKDLESIDPEFYNSIVWIKENNLEECGLELYFIQDMEILGKVTTHELKEGGESIRVTEENKEEYIMLLTD WRFTRGVEEQTKAFLDGFNEVAPLEWLRYFDEKELELMLCGMQEIDMSDWQKSTIYRHYTKNSKQIQWFWQ VVKEMDNEKRIRLLQFVTGTCRLPVGGFAELIGSNGPQKFCIDKVGKETWLPRSHTCFNRLDLPPYKSYEQ LREKLLYAIEETEGFGQE SEQ ID NO: 55 (WW1 (300-333)) DALPAGWEQRELPNGRVYYVDHNTKTTTWERPLP SEQ ID NO: 56 (WW2 (330-363)) PLPPGWEKRTDPRGRFYYVDHNTRTTTWQRPTA SEQ ID NO: 57 (WW3 (405-437)) HDPLGPLPPGWEKRQDNGRVYYVNHNTRTTQWEDPRT SEQ ID NO: 58 (WW4 (444-477)) PALPPGWEMKYTSEGVRYFVDHNTRTTTFKDPRP SEQ ID NO: 59 >NG_008732.1 Homo sapiens vascular endothelial growth factor A (VEGFA), RefSeqGene on chromosome 6 CGCCTGTAATCCCAGCACTCTGGGAGGCAGAGGTGGGCCGATCACTTGAGGTCAGGAGTTCGAGACCAGC CTGGGCAACATGGTGAAACACCATCTCTACTAAAAACACAAAAATTAGCCAGGTGTGGTGGCAGGCACCT GCAGTCCCAGCTACTCCGGAGGCTGAGGCAGGAGAATTGCTCGAACCTGGGAGGCAGGGGTTGCAGTGAG CCGACATGGCGCCACTGCACTCCAGTCTGGGCGACAGAGTGAGACCCTATCTCAAAAAAAAAAAAAAAAA AAAAAGACCCAACTCAAGTATCATCTCCAGGAAGCCTTCCCCTACTCCCAGCAATTAAATGCTCCTCAGA GAATTCCCATTTTTGGTTTACTCTTTGGTTTACCTCCAGACAGGAAGCCCCCACTGACACTGTTGTAGTC CCAGGGTGCAACACAAAGCAGAGATCACAAGCTGAGTTTAATAATTGCTTGTGGAATACATGTCCCAAGC CACCTCCTGCAGGAAGCCCTTCCAGATGCCCATTCTAGCCAGTCTGGCTCTTTGCTTCCATACCTTCACA ACACTTGTGCCTCCCCCAGGGCCTCTTTCTCATCTTGCTTTCTGGGGCAGCTGTGTGCACATTTGTCTGT GTGCAGCAACTCTCTAAGGCAGGGATTTTTACTCCTATTTTTGATGAGGGGAGCTGTGGCTCAGAGAGGT TGAATAACCTAAGGCCACACAGTGAGTGGCAGAGCCAGGAATGTGACTTGGGTCCATTTGAATCCAAAGT CCCTGTACTTTCCACTGCCCTACCTAGATGTCCCTGTACCTCCTATAAAATCAGCATGGAGCCTGGTGCC TGGTAGTCCCTACAAATATTCACAAATTGGAGCTTAGCTCAGCTCTCAGGCAAGGCCCAGGTCAAAAGGG CAGATACAGCTTTGGGACCTTAGTTGCCACCACATGCCATACCTTCTTCCCAGCAGAAGGACTCCCTCCA AGACAGGGTAGGGGTGGAGGATGTGAACAGGGGCAGAAATGGGCATGTTTTGGGGTCAGACTTGGAGGAA TAGCAGAGATTGGAGTGTCAGAAGGTGAGCATGCCTGGGGGTGTTGGGGAGATGCAATTCATCAGGGACA GCTTAGTGTCAGGGGATTAGACTGGGGCCCATGAAGGAGAGGCAGAGGCTGATGGGCCTAGGGGTGGTGT GGGTAGGTGAGCTTCCCCAGACAGTGACTCTGCCCTGCCCTCTCTCCAGCTAGGTCCTCTTCCCCATTCC Attorney Docket No.54926-0021WO1 TTCCCCCTTTCCTGACTGGATCCTCTTGGGAGAGTTACCCTCCTTGGCTTCCTCTGCTCCAATCTTTTTA TCAGTTGGCCATCATTACTTATCATTACCTCAAGTCAAACCTCCAGATCCACATGGGGCTAGGACATTGG CACTGGACCAAAGAGGCCCTTTCCTTTGCTTTCTCTTTGTCTTTTTAATGCTTTGTTGCAAAGACCTAGG CGGGGAGAGAGAGAGAGAGAGAGAGACAGAGATTGACCCACAGTCAGGGTCAGGGAATTGAGGGGAACCA ACCCAATTCTCTCTCCTTCAATTCACCAGGTTTGTATCCTGCCCTTCCTGCAGATCAGTGTCCTGCTAGT CACCTGGGGGTCAGGGGATGGAGTGAAGGACAAGACCTCCTTCCATTGCAGTGAAGCCACTTGGAGAAAT GTGTGGAAAACAGCAAGACCCAGTGACTCTCTCCTCACCTTCTTTCCAATCTCAGGAGAGATTTTGTCCC TTCATCCACCGGCTTCTAGATTAACCACCCACACCCACACAGGCGAGAGTTTCCCTGAATATTGGAGGTG ACAGGACATCAGGACAAAGTACAACTATTGTGCCTTGGCCCAATCACTACTTTCTTTGTCTGGGGCCGCC GCTGGCTCCTGGCTGCCTTTCGCACTTTTCTCCACCCCCACCCCTTTCTCCCCTTCCCCCTCACCTGGAA CACCTTCCCCTTCCTCCTTGGCTCCTTCTGAACTGCCTTCAGAGCCACAGACTGTGGGGAGTGGCCACTG CGCTCCCAAGGTGAGGCCCTCCAAGCGGGGCCGAGTTTGCCCCTCAACTGGGAGCCAGCATGACCTCTGT GTGGGCTGCTCTCTGCTTCACTGCCCCTTCCCCCAATCTGCTAGGTGACCCTGGGCCCCTTTGTGCCCTC TCTGGGCCTTCGGAGGATTCTTTGGGGAGACAGTCTGCTCTGACGCCCCTTCCCCTGCAGCAAGCAGCCT GGGGAGGGAGGTGAGGATAAGTGAAGTCAAGTTGTTCAGGGGGCTAAGCCCATGGAAGGGAAGATGCCAC AGAGATACATGTGGTCTTGTGATTGTTGTTTTGTGCTTTTTCCCCTTTTTTGAAAGCTCAGGTGACTAGG TGACTTGAGCTTTTAATTTGGTGACAATGTGGGCACTGGCTGAGTCCTTAAGAGTACATTGTTGTAAATG CCGGTGACAACACACTGGGGCATGGGATCCAGAGTTAACCCCTCCAGGTCACAGCCAGGTTATATCTCCA CAATGAAGGGGGGAGGTGGGCCATACTTTCTCGCCCTAATGAAGGTAGCTCAAAAACCCCTAGGCCAGGT TGTAATCCTAGCCTTATATAAAAGGAATTCTGTGCCCTCACTCCCCTGGATCCCTGGGCAAAGCCCCAGA GGGAAACACAAACAGGTTGTTGTAACACACCTTGCTGGGTACCACCATGGAGGACAGTTGGCTTATGGGG GTGGGGGGTGCCTGGGGCCACGGAGTGACTGGTGATGGCTATCCCTCCTTGGAACCCCTCCAGCCTCCTC TTAGCTTCAGATTTGTTTATTTGTTTTTTACTAAGACCTGCTCTTTCAGGTCTGTTGGCTCTTTTAGGGG CTGAAGAAGGCCGAGTTGAGAAGGGATGCAAGGGAGGGGGCCAGAATGAGCCCTTAGGGCTCAGAGCCTC CATCCTGCCCCAAGATGTCTACAGCTTGTGCTCCTGGGGTGCTAGAGGCGCACAAGGAGGAAAGTTAGTG GCTTCCCTTCCATATCCCGTTCATCAGCCTAGAGCATGGAGCCCAGGTGAGGAGGCCTGCCTGGGAGGGG GCCCTGAGCCAGGAAATAAACATTTACTAACTGTACAAAGACCTTGTCCCTGCTGCTGGGGAGCCTGCCA AGTGGTGGAGACAGGACTAGTGCACGAATGATGGAAAGGGAGGGTTGGGGTGGGTGGGAGCCAGCCCTTT TCCTCATAAGGGCCTTAGGACACCATACCGATGGAACTGGGGGTACTGGGGAGGTAACCTAGCACCTCCA CCAAACCACAGCAACATGTGCTGAGGATGGGGCTGACTAGGTAAGCTCCCTGGAGCGTTTTGGTTAAATT GAGGGAAATTGCTGCATTCCCATTCTCAGTCCATGCCTCCACAGAGGCTATGCCAGCTGTAGGCCAGACC CTGGCAAGATCTGGGTGGATAATCAGACTGACTGGTCCCACTCTTCCCACAGGCCTCAGAGCCCCAACTT TGTTCCCTGGGGCAGCCTGGAAATAGCCAGGTCAGAAACCAGCTAGGAATTTTTCCAAGCTGCTTCCTAT ATGCAAGAATGGGATGGGGCCTTTGGGAGCACTTAGGGAAGATGTGGAGAGTTGGAGGAAAAGGGGGCTT GGAGGTAAGGGAGGGGACTGGGGGAAGGATAGGGGAGAAGCTGTGAGCCTGGAGAAGTAGCCAAGGGATC CTGAGGGAATGGGGGAGCTGAGACGAAACCCCCATTTCTATTCAGAAGATGAGCTATGAGTCTGGGCTTG GGCTGATAGAAGCCTTGGCCCCTGGCCTGGTGGGAGCTCTGGGCAGCTGGCCTACAGACGTTCCTTAGTG CTGGCGGGTAGGTTTGAATCATCACGCAGGCCCTGGCCTCCACCCGCCCCCACCAGCCCCCTGGCCTCAG TTCCCTGGCAACATCTGGGGTTGGGGGGGCAGCAGGAACAAGGGCCTCTGTCTGCCCAGCTGCCTCCCCC TTTGGGTTTTGCCAGACTCCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTCCCTCCCAGTCACTGAC TAACCCCGGAACCACACAGCTTCCCGTTCTCAGCTCCACAAACTTGGTGCCAAATTCTTCTCCCCTGGGA AGCATCCCTGGACACTTCCCAAAGGACCCCAGTCACTCCAGCCTGTTGGCTGCCGCTCACTTTGATGTCT GCAGGCCAGATGAGGGCTCCAGATGGCACATTGTCAGAGGGACACACTGTGGCCCCTGTGCCCAGCCCTG GGCTCTCTGTACATGAAGCAACTCCAGTCCCAAATATGTAGCTGTTTGGGAGGTCAGAAATAGGGGGTCC AGGAGCAAACTCCCCCCACCCCCTTTCCAAAGCCCATTCCCTCTTTAGCCAGAGCCGGGGTGTGCAGACG GCAGTCACTAGGGGGCGCTCGGCCACCACAGGGAAGCTGGGTGAATGGAGCGAGCAGCGTCTTCGAGAGT GAGGACGTGTGTGTCTGTGTGGGTGAGTGAGTGTGTGCGTGTGGGGTTGAGGGCGTTGGAGCGGGGAGAA GGCCAGGGGTCACTCCAGGATTCCAATAGATCTGTGTGTCCCTCTCCCCACCCGTCCCTGTCCGGCTCTC CGCCTTCCCCTGCCCCCTTCAATATTCCTAGCAAAGAGGGAACGGCTCTCAGGCCCTGTCCGCACGTAAC CTCACTTTCCTGCTCCCTCCTCGCCAATGCCCCGCGGGCGCGTGTCTCTGGACAGAGTTTCCGGGGGCGG ATGGGTAATTTTCAGGCTGTGAACCTTGGTGGGGGTCGAGCTTCCCCTTCATTGCGGCGGGCTGCGGGCC AGGCTTCACTGAGCGTCCGCAGAGCCCGGGCCCGAGCCGCGTGTGGAAGGGCTGAGGCTCGCCTGTCCCC GCCCCCCGGGGCGGGCCGGGGGCGGGGTCCCGGCGGGGCGGAGCCATGCGCCCCCCCCTTTTTTTTTTAA AAGTCGGCTGGTAGCGGGGAGGATCGCGGAGGCTTGGGGCAGCCGGGTAGCTCGGAGGTCGTGGCGCTGG GGGCTAGCACCAGCGCTCTGTCGGGAGGCGCAGCGGTTAGGTGGACCGGTCAGCGGACTCACCGGCCAGG GCGCTCGGTGCTGGAATTTGATATTCATTGATCCGGGTTTTATCCCTCTTCTTTTTTCTTAAACATTTTT Attorney Docket No.54926-0021WO1 TTTTAAAACTGTATTGTTTCTCGTTTTAATTTATTTTTGCTTGCCATTCCCCACTTGAATCGGGCCGACG GCTTGGGGAGATTGCTCTACTTCCCCAAATCACTGTGGATTTTGGAAACCAGCAGAAAGAGGAAAGAGGT AGCAAGAGCTCCAGAGAGAAGTCGAGGAAGAGAGAGACGGGGTCAGAGAGAGCGCGCGGGCGTGCGAGCA GCGAAAGCGACAGGGGCAAAGTGAGTGACCTGCTTTTGGGGGTGACCGCCGGAGCGCGGCGTGAGCCCTC CCCCTTGGGATCCCGCAGCTGACCAGTCGCGCTGACGGACAGACAGACAGACACCGCCCCCAGCCCCAGC TACCACCTCCTCCCCGGCCGGCGGCGGACAGTGGACGCGGCGGCGAGCCGCGGGCAGGGGCCGGAGCCCG CGCCCGGAGGCGGGGTGGAGGGGGTCGGGGCTCGCGGCGTCGCACTGAAACTTTTCGTCCAACTTCTGGG CTGTTCTCGCTTCGGAGGAGCCGTGGTCCGCGCGGGGGAAGCCGAGCCGAGCGGAGCCGCGAGAAGTGCT AGCTCGGGCCGGGAGGAGCCGCAGCCGGAGGAGGGGGAGGAGGAAGAAGAGAAGGAAGAGGAGAGGGGGC CGCAGTGGCGACTCGGCGCTCGGAAGCCGGGCTCATGGACGGGTGAGGCGGCGGTGTGCGCAGACAGTGC TCCAGCCGCGCGCGCTCCCCAGGCCCTGGCCCGGGCCTCGGGCCGGGGAGGAAGAGTAGCTCGCCGAGGC GCCGAGGAGAGCGGGCCGCCCCACAGCCCGAGCCGGAGAGGGAGCGCGAGCCGCGCCGGCCCCGGTCGGG CCTCCGAAACCATGAACTTTCTGCTGTCTTGGGTGCATTGGAGCCTTGCCTTGCTGCTCTACCTCCACCA TGCCAAGGTAAGCGGTCGTGCCCTGCTGGCGCCGCGGGCCGCTGCGAGCGCCTCTCCCGGCTGGGGACGT GCGTGCGAGCGCGCGCGTGGGGGCTCCGTGCCCCACGCGGGTCCATGGGCACCAGGCGTGCGGCGTCCCC CTCTGTCGTCTTAGGTGCAGGGGGAGGGGGCGCGCGCGCTAGGTGGGAGGGTACCCGGAGAGAGGCTCAC CGCCCACGCGGGCCCTGCCCACCCACCGGAGTCACCGCACGTACGATCTGGGCCGACCAGCCGAGGGCGG GAGCCGGAGGAGGAGGCCGAGGGGGCTGGGCTTGCGTTGCCGCTGCCGGCTGAAGTTTGCTCCCGGCCGC TGGTCCCGGACGAACTGGAAGTCTGAGCAGCGGGGGCGGGAGCCAGAGACCAGTGGGCAGGGGGTGCTCG GACCTTGGACCGCGGGAGGGCAGAGAGCGTGGAGGGGGCAGGGCGCAGGAGGGAGAGGGGGCTTGCTGTC ACTGCCACTCGGTCTCTTCAGCCCTCGCCGCGAGTTTGGGAAAAGTTTTGGGGTGGATTGCTGCGGGGAC CCCCCCTCCCTGCTGGGCCACCTGCGCCGCGCCAACCCCGCCCGTCCCCGCTCGCGTCCCGCTCGGTGCC CGCCCTCCCCCGCCCGGCCGGGTGCGCGCGGCGCGGAGCCGATTACATCAGCCCGGGCCTGGCCGGCCGC GTGTTCCCGGAGCCTCGGCTGCCCGAATGGGGAGCCCAGAGTGGCGAGCGGCACCCCTCCCCCCGCCAGC CCTCCGCGGGAAGGTGACCTCTCGAGGTAGCCCCAGCCCGGGGATCCAGAGAACCATCCCTACCCCTTCC TACTGTCTCCAGACCCTACCTCTGCCCAGTGCTAGGAGGAATTTCCTGACGCCCCTTCTCTTCACCCATT TCCTTTTTAGCCTGGAGAGAAGCCCCTGTCACCCCGCTTATTTTCATTTCTCTCTGCGGAGAAGATCCAT CTAACCCCTTTCTGGCCCCAGAGTCCAGGGAAAGGATGATCACTGTCAGAAGTCGTGGCGCGGGAGCCCA CTGGGCGCTTTGTCACATTCCACCGAAAGTCCCGACTTGGTGACAGTGTGCTTCCCTTCCCTCGCCAACA GTTCCGAGTGAGCTGTGCTTTAGCTCTCGTGGGGGTGGGTCAAGGGAGGATTTGAAGAGTCATTGCCCCA CTTTACCCTTTTGGAGAAATGGCTTGAAATTTGCTGTGACACGGGCAGCATGGGAATAGTCCTTCCTGAA CCCTGGAAAGGAGCTCCTGCCAGCCTTGCACACACTTTGTCCTGGTGAAAGGCAGCCCTGGAGCAGGTGT TTTTTTGGAACTCCAAACCTGCCCACCCAACTTGCTTCTGAAAGGGACTCTAAAGGGTCCCTTTCCGCTC CTCTCTGACGCCTTCCCTCAGCCAGAATTCCCTTGGAGAGGAGGCAAGAGGAAAGCCATGGACAGGGGTC GCTGCTAACACCGCAAGTTCCTCAGACCCTGGCACAAAGGCCTTGGCTACAGGCCTCCAAGTAGGGAGGA GGGGGAGGAGTGGCTGCCTGGCCACAGTGTGACCTTCAGAGGCCCCCAGAGAAGGACACCTGGCCCCTGC CTGCCTAGAACCGCCCCTCCTGTGCTCCCTGGCCTTGGAAGGGGTATGAAATTTCCGTCCCCTTTCCTCC TTGGGGCCCAGGAGGAGTGGAGGGTCCCGGGAGAATATTGTCAGGGGGAAGGCAGGGGGTGTCATGGGAA TGGGTGAGGGGGCTGAGGTGCAGAATCCAGGGGGTCCCTGCAGGAGCCGCAGTGGTAAGCTGTCCAGCTG GAAGCCTGGTAACTGTTGTTTTCTCTTGAGAGGGGCTTCCTGTGACCTTGGCTGTCTCTGGGAGCAGGGC TGGGGTACCTGAGTGGGGTGCATTTGGGGTGTGTGGGAAGGAGAGGGAAAGAAAGATGGACAGTGGGACT CTCCCCTAGCAGGGTCTGGTGTTCCGTAGGCTAGAGTGCCCCTCTGCTCTGCGAGTGCTGGGCGGGAGGG GAGTTGGTGAGAGCTGGAGACCCCCAGGAAGGGCTGGCAGAAGCCTTTCCTTTTGGGTGCTGTCAGGTCC GCATGTCTTGGCGTGTTGACCTTCACAGCTTCTGGCGAGGGGAGGAATGATCTGATGCGGGTGGGGAGGG TTAGAGGAGGCCTCAGGCCTAAGGTGGTGCAGGGGGCCCCCTAGGGGCTGGGCAGTGCCAAGGCATAAAA GCCTTCCCTGGTCCCTGGTGGCATTTGAAGGTGCCCAGGTGAGAGGGGCTTGGCACCTCCTCACCCTGGG AGGGAGAAGAAACCAGGGAACAGGTAGGAGTGGGAGACAGGTGAGGCTTTGGAAATCTATTGAGGCTCTG GAGAGATTTGTGTAGAGAGGAAAATGTGGTTCTCCCCCAGGGTCTCCTCCTGGGTTTTTACCCTCTAAGC AACCTGTGGGCATGCTGGGTTATTCCTAAGGACTAGAAGAGCTTGGATGGGGGAGGGTGGTTGGTGCCCT TCGGTCCTCGGCACCCCCCTCCGTCTCCAACACCAGCTCACCCTGGTATTTGTCATGTCAGCAGGAGAAG GTCACCATGTTGTTTTTCTCGCCCCTAGTCCTTCCTTCCTGCCCCAGTCCAAATTTGTCCTCCTATTTGA CCTTAATACTTACCATGGCTTTGGACCAGGGAACTAGGGGGATAGTGAGAGCAGGGAGAGGGAAGTGTGG GGAAGGTACAGGGGACCTCGACAGTGAAGCATTCTGGGGTTTTCCTCCTGCATTTCGAGCTCCCCAGCCC CCAACATCTGGTTAGTCTTTAACTTCCTCGGGTTCATAACCATAGCAGTCCAGGAGTGGTGGGCATATTC TGTGCCCGTGGGGACCCCCGGTTGTGTCCTGTTCGACTCAGAAGACTTGGAGAAGCCAGAGGCTGTTGGT GGGAGGGAAGTGAGGAGGGAGGAGGGGCTGGGTGGCTGGGCCTGTGCACCCCAGCCCCTGCCCATGCCCA Attorney Docket No.54926-0021WO1 TGCCTTGCTCTCTTTCTGTCCTCAGTGGTCCCAGGCTGCACCCATGGCAGAAGGAGGAGGGCAGAATCAT CACGAAGGTGAGTCCCCCTGGCTGTTGGATGGGGTTCCCTGTCCTCTCAGGGGATGGGTGGATGGCCTAA TTCCTTTTTCTTCAGAACTGTGGGGAGGAAGGGGAAGGGGCACAGGAATATAAGGATCAAGAAAGAAAGA GCTGGGCACCACGAGGTTCACCCTCAGTTTCGTGAGGACTCTCCGCTGTTCAGGTCTCTGCTAGAAGTAG GACTTGTTGCCTTTTTCTTCTGCTCTTTCCAGTAAAATTTTATTTGGAGAAGGAGTCGTGCGCACAGAGC AGGAAGACAGTGTTCAGGGATCCTAGGTGTTGGGGGAAGTGTCCCTTGTTTCCCCTAGCTCCCAGGGGAG AGTGGACATTTAGTGTCATTTCCTATATAGACATGTCCCATTTGTGGGAACTGTGACCCTTCCTGTGTGA GCTGGAGGCACAGAGGGCTCAGCCTAATGGGATCTCTCCTCCCTTCCCTGGTTTGCATTCCTTTGGGGGT GGAGAAAACCCCATTTGACTATGTTCGGGTGCTGTGAACTTCCCTCCCAGGCCAGCAGAGGGCTGGCTGT AGCTCCCAGGCGCCCCGCCCCCCTGCCCAACCCCGAGTCCGCCTGCCTTTTGTTCCGTTGTGGTTTGGAT CCTCCCATTTCTCTGGGGACACCCTGGCTCTCCCCACCACTGACTGTGGCCTGTGCTCTCCACCTCTGGG GAGGGAAGGCCCTGGGGTCTTCCTTCCCGCGAGTTTCCCTGACCTAAATCTGGCGTGGCTGGGTAGTGGC CAGCAGTGGTGATGCCCAGCCTGTTCTGCCTCCTCCTTCCCCACCCCAGGAGCCCTTTCCTTGGCCTAGG ACCTGGCTTCTCAGCCACTGACCGGCCCCCTGCTTCCAGTGCGCCACTTACCCCTTCCAGCTTCCCAGTG GTCTCTGGTCTGGGAGAGGCAGGACAAAGGTCTTTGTTTGCTGGAGAAAAGGTTGTCTGCGATAAATAAG GAAAACCACGAAAGCCTGGTTGTTGGAGTGTACGTGTGTGCTCCCCCAGGCAGTGGAGGCCAGCCCTCCT TGGAGGGGCGGCTGCCTGATGAAGGATGCGGGTGAGGTTCCCCGCCTCCACCTCCCATGGGACTTGGGGA TTCATTCCAAGGGGAAGCTTTTTGGGGGAATTCCTACCCCAGGTCTTTTTACCCTCAGTTACCAACCCCT TGCCCAGGCCAGACCTTCCTGCTATCCCCTCCTGGGCCACAAGCCTGGCCCTCCTCTGTCCCAATTGTGA TGAAGGGGCAGTTCAAAACTTCTTGATTAGTCATCTTCTCCCCTATCGACTTGGCTTTAAAAAATGACCT TTTCAGACTTCTAGTCTCGTTCACTCTTTTTGATGATGCTTTGCCGTAACCCTTCGTGGGTAGAGAAGGA TTCTGTGCCCATTGGTGGTCTGGATAAAAGAAATAGAGACCTCACAGGAAGCAGTGGACTGGCCTGTTTC CCCACTGTTCTTTCTGTTTTCACACCTGTGGCCTTCTCCCCACCTTCTTCCCAATCAACCTATTGTGTAC ATAGCCCCCCTCATTGTCCTTTATTCTTCTGGAAAGCAGACCTTGGAGGGAGGAGTGAGGGGGAGGCTCA GCTGTGGTCTCTGGGGGGTGGGGGTTGGGAGCTGGGGTGGAAGTCCACGAAGCATACACTTAAGATGCTT TGGTGAAGTTCTAAACTTCATATTACCCAGGCTGAAAAAAGAGCACTTGTTCCTAGGGCTGGAAATGGAA GCCAAAACACCACCTTTTTCAGCCTGTTTCAGCATCTTTAGAGATCAGCCCAACCCACTTACACAGTTGA GCAGAGTTGGAGGCCTAGAGAGGGGAGGGACTGGCCCAAGGTCATACCAACTCATGGCCAGAGCCTGGGC CTCCTCACTGGCCAGGTGTTATTTCTTCCCTCTGGGTAGGGAACCTATTTCAGGGACAGGATTGCTATGT GGTAGTGGTGGTGGGGTGCGATAGGCGTGGCAGGCTGGGCCACAATTTGGAGTAGTCATGCCAGAGTCCT GCATTTATTTATTCTCAAGGGCCCCGCCTCTGTGGCCCAGAATTACCCCTTCATGCTCCAGTGCACCCCA GGCTTCGTGGCCAGCCTGGGAAACTGTCTCTACCCTGGTCTCCCTTCAGATCAGCTTCTAGAAATGTTTC GTGGCTACAGTGGCAGCACTGTTTTTTCCATGATGCAAGCAGTTTGCCCTCTTGGGCGGGGTTATCAGTG GCTGGCAGGGCTGGCACAGCGTGTCCGCCCACTGCCACCTGTGGGTTCCAGGAGGGCCCAGCCCCTGTGC TGATGCCCACCACCTTCTCAGCTCATGTCTGGGGAAGAGGACTGGCAGGGGGAAAGGTGCCTCCTCCTGA AAGGTGCCTCCTCTGTTTTTGCCTAATATAGGCTTGGGAACACTTTGATGTCAGCTAATTCTGACTCCTT TACTTACTAGCTGTGCGGCCTTGGGGCAACTTACTTAGCCTCTTTGAGCCTCCTGTTCCCCATCTGTAAA ATGGAATCTCAATAGTGTCTAATAGTACCATGTGGAGAAACTTGTGTGAAATGATAGCTGTGGACTACTG TACACAGTACTCAGGATGTAGTAAGTGCTCAATAAACAGCTGTTGGTATGGTTGACGTTATGGTAGTGGT TGTGGGGAGGACGTAGGAAACTGGAGACTAGCTTGGCAAAGCTGGCTCTTCCTCCTTTTAGGGAAAGCTT AGAGCATCCCCATGGGGTATACCCATACTCAGACTGTCCTCTGGCATCGAGGTTGGCCCAGGATTCAGTT CAGCTGTCACAGTGAGGTGGCGGGATCAGATGTGGCAGGCCATGTCCCTTGGAACTTGAGTACATCGTGT GATCTCTGGAATGAAAACAGGCCTTCACCAGTGTTGATGGTGGAAAGCTTAGGGAAGTGCTTCAAACACA GTAGGAGGGACTTACGTTAGATTTTGGAAGGACTTGCCTGATTCGGAAGCTCCAAAGAGTGGCATTACAG AGCTGGGTGGAGAGAGGGGCTAGCCATCTTTTGTGTCGCCCACCGGGCTCATGTGTCATCGCCTCTCATG CAGTGGTGAAGTTCATGGATGTCTATCAGCGCAGCTACTGCCATCCAATCGAGACCCTGGTGGACATCTT CCAGGAGTACCCTGATGAGATCGAGTACATCTTCAAGCCATCCTGTGTGCCCCTGATGCGATGCGGGGGC TGCTGCAATGACGAGGGCCTGGAGTGTGTGCCCACTGAGGAGTCCAACATCACCATGCAGGTGGGCATCT TTGGGAAGTGGGGCAAGGGGGGGATAGGGAGGGGGGTAACACTTTGGGAACAGGTGGTCCCAGGTCGTTT CCTGGCTAGATTTGCCTTGTCTGGCTCCTGCCCCTGAGTTGCACAGGGGAGGTATGGTGGGGTCTTGCCT TCTGTGGAGAAGATGCTTCATTCCCAGCCCAGGTTCCCAGCAAGCCCCAACCATCTCCTTCTCCCTGATG GTTGCCCATGGGCTCAGGAGGGGACAGATGGATGCCTGTGTCAGGAGCCCCTCTCTCCCTCTCTTGGAGA GAGTCCTGAGTGCCCCCCCTTCTTGGGGGCTTTGTTTGGGAAGCTGGATGAGCCTGGTCCATGGAGAGTT TAAAAAGTCTTTTGGTGTTACCTGGTAATGGGGCACATCTCAGCCCAGATAGGGTGGGAGGGAGCTGTGA AACACAGGGAGGGGGTTGCTTTCGGGTATCTACTAGGAGTCAGGGTGAAGCCTAGAGAGGATGAAAGAAG GGGAGGGGATGGGGAGTGGTAAGAACCTAGGATTTGAATTCCCAGCCTGGCCAACCCTTGCAGCCATGTC Attorney Docket No.54926-0021WO1 TTGGCCTCAAGTGGAACAAGGGCTCCTTGAGGCCAGCAGGGTTGGGGGAGTTGGGGTGGGCCTGAGCCTC TTTCCTGCTAGAGCTCTTGGTCCTCCCTGCCTCCACCACCCATCCCTGCTCTGCAGAACCCCTGGGTGCT GAGTGGCAGGAGCCCCAGGGTTGTCCCATCTGGGTATGGCTGGCTGGGTCACTAACCTCTGTGATCTGCT TCCTTCCTTTCCAGATTATGCGGATCAAACCTCACCAAGGCCAGCACATAGGAGAGATGAGCTTCCTACA GCACAACAAATGTGAATGCAGGTGAGGATGTAGTCACGGATTCATTATCAGCAAGTGGCTGCAGGGTGCC TGATCTGTGCCAGGGTTAAGCATGCTGTACTTTTTGGCCCCCGTCCAGCTTCCCGCTATGTGACCTTTGG CATTTTACTTCAATGTGCCTCAGTTTCTACATCTGTAAAATGGGCACAATAGTAGTATACTTCATAGCAT TGTTATAATGATTAAACAAGTTATATATGAAAAGATTAAAACAGTGTTGCTCCATAATAAATGCTGTTTT TACTGTGATTATTATTGTTGTTATCCCTATCATTATCATCACCATCTTAACCCTTCCCTGTTTTGCTCTT TTCTCTCTCCCTACCCATTGCAGACCAAAGAAAGATAGAGCAAGACAAGAAAAGTAAGTGGCCCTGACTT TAGCACTTCTCCCTCTCCATGGCCGGTTGTCTTGGTTTGGGGCTCTTGGCTACCTCTGTTGGGGGCTCCC ATAGCCTCCCTGGGTCAGGGACTTGGTCTTGTGGGGGACTTGTGGTGGCAGCAACAATGGGATGGAGCCA ACTCCAGGATGATGGCTCTAGGGCTAGTGAGAAAACATAGCCAGGAGCCTGGCACTTCCTTTGGAAGGGA CAATGCCTTCTGGGTCTCCAGATCATTCCTGACCAGGACTTGCTGTTTCGGTGTGTCAGGGGGCACTGTG GACACTGGCTCACTGGCTTGCTCTAGGACACCCACAGTGGGGAGAGGGAGTGGGTGGCAGAGAGGCCAGC TTTTGTGTGTCAGAGGAAATGGCCTCTTTTGGTGGCTGCTGTGACGGTGCAGTTGGATGCGAGGCCGGCT GGAGGGTGGTTTCTCAGTGCATGCCCTCCTGTAGGCGGCAGGCGGCAGACACACAGCCCTCTTGGCCAGG GAGAAAAAGTTGAATGTTGGTCATTTTCAGAGGCTTGTGAGTGCTCCGTGTTAAGGGGCAGGTAGGATGG GGTGGGGGACAAGGTCTGGCGGCAGTAACCCTTCAAGACAGGGTGGGCGGCTGGCATCAGCAAGAGCTTG CAGGGAAAGAGAGACTGAGAGAGAGCACCTGTGCCCTGCCCTTTCCCCCACACCATCTTGTCTGCCTCCA GTGCTGTGCGGACATTGAAGCCCCCACCAGGCCTCAACCCCTTGCCTCTTCCCTCAGCTCCCAGCTTCCA GAGCGAGGGGATGCGGAAACCTTCCTTCCACCCTTTGGTGCTTTCTCCTAAGGGGGACAGACTTGCCCTC TCTGGTCCCTTCTCCCCCTCCTTTCTTCCCTGTGACAGACATCCTGAGGTGTGTTCTCTTGGGCTTGGCA GGCATGGAGAGCTCTGGTTCTCTTGAAGGGGACAGGCTACAGCCTGCCCCCCTTCCTGTTTCCCCAAATG ACTGCTCTGCCATGGGGAGAGTAGGGGGCTCGCCTGGGCTCGGAAGAGTGTCTGGTGAGATGGTGTAGCA GGCTTTGACAGGCTGGGGAGAGAACTCCCTGCCAAGTACCGCCCAAGCCTCTCCTCCCCAGACCTCCTTA ACTCCCACCCCATCCTGCTGCCTGCCCAGGGCTCCAGGACACCCAGCCCTGCCTCCCAGTCCAGGTCGTG CTGAGCAGGCTGGTGTTGCTCTTGGTTCCGTGCCAGCTCCCAAGGTAGCCGCTTCCCCCACACCGGGATT CCCAGAGGTTCTGTCGCAGTTGCAAATGAAGGCACAAGGCCTGATACACAGCCCTCCCTCCCACTCCTGC TCCCCATCCAGGCAGGTCTCTGACCTTCTCCCCAAAGTCTGGCCTACCTTTTATCACCCCCGGACCTTCA GGGTCAGACTTGGACAGGGCTGCTGGGCAAAGAGCCTTCCCTCAGGCTTTGCCCCCTGCCGGGGACTGGG AGCCACTGTGAGTGTGGAGACCTTTGGGTCCTGTGCCCTCCACCCAGTCTCGGCTTCCCACCAAAGCCTT GTCAGGGGCTGGGTTTGCCATCCCATGGTGGGCAGCGTGAGGAGAAGAAAGAGCCATCGAGTGCTTGCTG CCCAGACACGCCTGTGTGCGCCCGCGCATGCCTCCCCAGAGACCACCTGCCTCCTGACACTTCCTCCGGG AAGCGGCCCTGTGTGGCTTTGCTTTGGTCGTTCCCCCATCCCTGCCCACCTTACCACTTCTTTTACTCCC CCCACCGCCCCCGCTCTCTCTCTGTCTCTGTTTTTTTATTTTCCAGAAAATCAGTTCGAGGAAAGGGAAA GGGGCAAAAACGAAAGCGCAAGAAATCCCGGTATAAGTCCTGGAGCGTGTACGTTGGTGCCCGCTGCTGT CTAATGCCCTGGAGCCTCCCTGGCCCCCAGTACAACCTCCGCCTGCCATTCCCTGTAACCCTGCCTCCCT CCCCTGGTCCTTCCCTGGCTCTCATCCTCCTGGCCCGTGTCTCTCTCTCACTCTCTCACTCCACTAATTG GCACCAACGGGTAGATTTGGTGGTGGCATTGCTGGTCCAGGGTTGGGGTGAATGGGGGTGCCGACTTGGC CTGGAGGATTAAGGGAGGGGACCCTGGCTTGGCTGGGCACCGATTTTCTCTCACCCACTGGGCACTGGTG GCGGGCCCATGTTGGCACAGGTGCCTGCTCACCCAACTGGTTTCCATTGCTCTAGGCTTCTGCACTCGTC TGGAAGCTGAGGGTGGTGGGGAGGGCAGACATGGCCCAAGAAGGGCTGTGAATGACTGGAGGCAGCTTGC TGAATGACTCCTTGGCTGAAGGAGGAGCTTGGGTGGGATCAGACACCATGTGGCGGCCTCCCTTCATCTG GTGGAAGTGCCCTGGCTCCTCACGGAGGTGGGGCCTCTGGAGGGGAGCCCCCTATTCCGGCCCAACCCAT GGCACCCACAGAGGCCTCCTTGCAGGGCAGCCTCTTCCTCTGGGTCGGAGGCTGTGGTGGGCCCTGCCCT GGGCCCTCTGGCCACCAGCGGCCTGGCCTGGGGACACCGCCTCCGGGCTTAGCCTCCCATCACACCCTAC TTTAGCCCACCTTGGTGGAAGGGCCTGGACATGAGCCTTGCACGGGGAGAAGGTGGCCCCTGATTGCCAT CCCCAGCAGGTGAAGAGTCAAGGCGTGCTCCGATGGGGGCAACAGCAGTTGGGTCCCTGTGGCCTGAGAC TCACCCTTGTCTCCCAGAGACACAGCATTGCCCCTTATGGCAGCCTCTCCCTGCACTCTCTGCCCGTCTG TGCCCGCCTCTTCCTGCGGCAGGTGTCCTAGCCAGTGCTGCCTCTTTCCGCCGCTCTCTCTGTCTTTTGC TGTAGCGCTCGGATCCTTCCAGGGCCTGGGGGCTGACCGGCTGGGTGGGGGTGCAGCTGCGGACATGTTA GGGGGTGTTGCATGGTGATTTTTTTTCTCTCTCTCTGCTGATGCTCTAGCTTAGATGTCTTTCCTTTTGC CTTTTTGCAGTCCCTGTGGGCCTTGCTCAGAGCGGAGAAAGCATTTGTTTGTACAAGATCCGCAGACGTG TAAATGTTCCTGCAAAAACACAGACTCGCGTTGCAAGGCGAGGCAGCTTGAGTTAAACGAACGTACTTGC AGGTTGGTTCCCAGAGGGCAAGCAAGTCAGAGAGGGGCATCACACAGAGATGGGGAGAGAGAGAGAGAAA Attorney Docket No.54926-0021WO1 GAGAGTGAGCGAGCGAGCGAGCGGGAGAGCGCCTGAGAGGGGCCAGCTGCTTGCTCAGTTTCTAGCTGCC TGCCTGGTGACTGCTGCCTTCTCTGCTTTTAAGGCCCCTGTGGTGGGCTGCAGGCACTGGTCCAGCCTGG CGGGGCCTGTTCCGAGGTTGCCCTGGTTGCCTGAGTGGTAGGCTGGTGTGGCTTAGTGTAGTGGTGTGGA CGCAAGCTGTGTGTTGTGTCCTGTGGTCCTTCTGCTCATAGTGGCTGTTGGTCCTGATGTTATTACTACC TCTGGTAGTAATGCTGAGAAGCTGAAAGCCGATTCCAGGTGTGGACAATGTCAACAAAGCACAGATGCTC TCGCTGGGGCCTTGCCTCGGCCCTTTGAAGTCTGCATGGCTGGGCTTCTCACTCACTCAGTGTTTCTTGC TGGGGGAAGGAATTGAGTCTCCCACTTCAGACTGGGCCTCCCTGAGGAAAGGGTTGTGTCTCCCCACTCA GACTGAGGTTCCCTGAGGGTAGGGCTGTGTCTCTCCCCTCCGACCTGGGCTCCCTGATAGGGCTGTCTCC CCGCTCAGACTGAGGCTCCCTCAGGCCAGGGCTATGTCTCCCTCCTCAGACTGGGGCTCTGAGGGCAAGG GGTCTGGCTGTTCGTTTAGGATGGGGCACTTTTGCCTACACACTGAAGGAGCTGTAGCATCCAAGAATAC TAGATACCTTTAATCCTCCACCAGTCATGGTGACAACCCCAAGCAGCCCACACATTTTCAAGTGCCCCCA GGATGCGTGGAGGGAGGGGTCTGTGCCCATTCTCCTGACATTAGCCTGTGAGCTCCGTAAGCCCGGGCCT CGTTTACGTACCTTTGTGAGCCCCGGGCATCTGTACCTCTTTCCTTTGCCCATACTGGGGACCAAGGAAG TGTCAAGTGCATGAGTGAATGTGTGACTCAGTTCAGAGGGTGAGGTCAGGAGCACAGGGTCGGGACAGGT GGCTGGCATCTTTTAATGCCTTAGCTTATGTTCTTTATACCAACTTGGCCTGTGCTCAGAGTGAGGGAGG CCCTGGGGGTCAGGGTAAGCGTCAGTCAGGGAGGCAAGACTTTGTGGGGATTTCCTAGACAGGGCCAAGG CACCCCCAGCTCACCCCGAGGCTGTGTTAGGGAAGTCCTTGGAGTGTCTCCCCTCCCCCAGCAATGTTCT TGTGGCTTGTGTGTGCTCAGGGGATGCTGGGAACCAGGCCTGGGTAGTTGGTGTGGGGTGCTGTCTGTCT TGGCCCTATGTGAAACCAAGAGGGCGTATATTAGTGCTGGGGTGGGGGCTCTGCCTAACTTCAGGGCTGG ATGAGGGGAGTCTCAGTTCCCCAGGGGTCCTTGGGAAAGATAAGGGACTTGACATTTTAGGGTTTTTAGG TGATTATTCTGCTGATGGGGGTTTGTGTGAAGTGACCTGGGAGCTAACTGAAGTTACTCTAACCTCCCAA TACCTTTACCCAACCCCCAAGCTGGCTGTATCTGGGAATATCAGTTTCCAAAATTGGAGGCTTAGGACTC CGTTTCGGGGCTCCCCAGAAGGGTAGGGCCTGTTCTGCCTCCTTCTCACAATCACCCAGGGGCAGGGGCA TGCTGAGAAAGTTCTTGGAGGCCCCCTTTGCTTCAGCTGGAGTAGTGAAGCCGCCGAATTGTCTCTCCCC ATCCTAAGTGAAGCAGCATATTTGAAAGGAAAGACAACCTGTTACCTGGGCCTGCAACCTCCAGGCAGCT CAAGAGAGATGAGGCCTACAGCCACAGTGGGAGGGGACATGGGGAATGGAGATGGTCCCTCACCTTCCTG GGGCCTCCTGCTCTACGCTACCCCCTCGGGAGCCTCCTGTCCCCAGGGCAGGCCCTTGCCATTGTTGGTC ACCCGGCCAAGCCTCTCTGCCTCAGGCGTTCTCCCAGAAGATCTGCCCACTCTCTTCCCCACACCAGCCC CTAGAGACTGAACTGAAAACCCTCCTCAGCAGGGAGCCTCTTCTGATTAACTTCATCCAGCTCTGGTCAC CCATCAGCTCTTAAAATGTCAAGTGGGGACTGTTCTTTGGTATCCGTTCATTTGTTGCTTTGTAAAGTGT TCCCATGTCCTTGTCTTGTCTCAAGTAGATTGCAAGCTCAGGAGGGTAGACTGGGAGCCCCTGAGTGGAG CTGCTGCTCAGGCCGGGGCTCCCTGAGGGCAGGGCTGGGGCTGTTCTCATACTGGGGCTTTCTGCCCCAG GACCACACCTTCCTGTCCTCTCTGCTCTTATGGTGCCGGAGGCTGCAGTGACCCAGGGGCCCCCAGGAAT GGGGAGGCCGCCTGCCTCATCGCCAGGCCTCCTCACTTGGCCCTAACCCCAGCCTTTGTTTTCCATTTCC CTCAGATGTGACAAGCCGAGGCGGTGAGCCGGGCAGGAGGAAGGAGCCTCCCTCAGGGTTTCGGGAACCA GATCTCTCACCAGGAAAGACTGATACAGAACGATCGATACAGAAACCACGCTGCCGCCACCACACCATCA CCATCGACAGAACAGTCCTTAATCCAGAAACCTGAAATGAAGGAAGAGGAGACTCTGCGCAGAGCACTTT GGGTCCGGAGGGCGAGACTCCGGCGGAAGCATTCCCGGGCGGGTGACCCAGCACGGTCCCTCTTGGAATT GGATTCGCCATTTTATTTTTCTTGCTGCTAAATCACCGAGCCCGGAAGATTAGAGAGTTTTATTTCTGGG ATTCCTGTAGACACACCCACCCACATACATACATTTATATATATATATATTATATATATATAAAAATAAA TATCTCTATTTTATATATATAAAATATATATATTCTTTTTTTAAATTAACAGTGCTAATGTTATTGGTGT CTTCACTGGATGTATTTGACTGCTGTGGACTTGAGTTGGGAGGGGAATGTTCCCACTCAGATCCTGACAG GGAAGAGGAGGAGATGAGAGACTCTGGCATGATCTTTTTTTTGTCCCACTTGGTGGGGCCAGGGTCCTCT CCCCTGCCCAGGAATGTGCAAGGCCAGGGCATGGGGGCAAATATGACCCAGTTTTGGGAACACCGACAAA CCCAGCCCTGGCGCTGAGCCTCTCTACCCCAGGTCAGACGGACAGAAAGACAGATCACAGGTACAGGGAT GAGGACACCGGCTCTGACCAGGAGTTTGGGGAGCTTCAGGACATTGCTGTGCTTTGGGGATTCCCTCCAC ATGCTGCACGCGCATCTCGCCCCCAGGGGCACTGCCTGGAAGATTCAGGAGCCTGGGCGGCCTTCGCTTA CTCTCACCTGCTTCTGAGTTGCCCAGGAGACCACTGGCAGATGTCCCGGCGAAGAGAAGAGACACATTGT TGGAAGAAGCAGCCCATGACAGCTCCCCTTCCTGGGACTCGCCCTCATCCTCTTCCTGCTCCCCTTCCTG GGGTGCAGCCTAAAAGGACCTATGTCCTCACACCATTGAAACCACTAGTTCTGTCCCCCCAGGAGACCTG GTTGTGTGTGTGTGAGTGGTTGACCTTCCTCCATCCCCTGGTCCTTCCCTTCCCTTCCCGAGGCACAGAG AGACAGGGCAGGATCCACGTGCCCATTGTGGAGGCAGAGAAAAGAGAAAGTGTTTTATATACGGTACTTA TTTAATATCCCTTTTTAATTAGAAATTAAAACAGTTAATTTAATTAAAGAGTAGGGTTTTTTTTCAGTAT TCTTGGTTAATATTTAATTTCAACTATTTATGAGATGTATCTTTTGCTCTCTCTTGCTCTCTTATTTGTA CCGGTTTTTGTATATAAAATTCATGTTTCCAATCTCTCTCTCCCTGATCGGTGACAGTCACTAGCTTATC TTGAACAGATATTTAATTTTGCTAACACTCAGCTCTGCCCTCCCCGATCCCCTGGCTCCCCAGCACACAT Attorney Docket No.54926-0021WO1 TCCTTTGAAATAAGGTTTCAATATACATCTACATACTATATATATATTTGGCAACTTGTATTTGTGTGTA TATATATATATATATGTTTATGTATATATGTGATTCTGATAAAATAGACATTGCTATTCTGTTTTTTATA TGTAAAAACAAAACAAGAAAAAATAGAGAATTCTACATACTAAATCTCTCTCCTTTTTTAATTTTAATAT TTGTTATCATTTATTTATTGGTGCTACTGTTTATCCGTAATAATTGTGGGGAAAAGATATTAACATCACG TCTTTGTCTCTAGTGCAGTTTTTCGAGATATTCCGTAGTACATATTTATTTTTAAACAACGACAAAGAAA TACAGATATATCTTAAAAAAAAAAAAGCATTTTGTATTAAAGAATTTAATTCTGATCTCAAAGCTCCTCT TGGTTTCTCCTTCTCCATTGAATCCTTGCTCTAGACTTCCTCCCGCCCCCTTTCCCTCTTCCTCTGGGGA ACATGGCATTTGTCTTGGGTCTGGGAAAGGTACGTCTAATGTGTAGGATATGGGGTGACCCACCTTGTTG TGCTGGGGGCAAAGTCCTTCCATTTTGGCTGAGCTGGTCCTGGGGGAACCCATCCATCCTGTCTTGATAT AGAAGGTGGGAAGCTCTGGGAATGGGTGGAGGGGGAGAAACAGCTTAGGAGCCAAGGGCCCTTGCAATTG GTAGTGCTGCCTTCAGGAATTAGATGATCCAGGCCCCTGTCCCTTAGCCAGGGAAAGAACTGGCCATGTC TCCAAGCTTGCTGCCCAGGAGACAGGAGAGAGCTGTTTTTGTCTGTGGGGGTCTTGTTGGCTGCAACAGG CTGGGAGTGGGAGGGGGATGCTGCTGGAGGGCTGTGACTCCAGGGTGTAACTTAATTTTACATAGTTTTA CACCCTGGAGTTCCTTGAGCCTCTGGAAGATGGACCCATAGGTTTGGTCACCACTGATGGGACACTCCCT GCCCCAGCTTGCCATAAGCTCTTCTCTCACGTCCTGCTCCTGGGTAAGGTGGCACCTATCCAGGTCTTTG ACACTGAAGGGCAGTGCTTCCAAATTCACTTCCTCTAGCCTCTCATTTATTCTTGCAAACCATAGATATG GCTTGAATAAATATTGAGCCAGTCATTGTGCTGCTATGAATAAGACACAATTCCACCCCTCAAGGATCTG GTGAGGATGGGTGGGTGGGGAGACCCAAAACTATAAATCCATGAGCAGAAAAATACATAAAATGTGCTGG GGGCATCTGATCTAGCTTGGGAGTGGGAGTTGTATTGGGGGTGGTGGCTGGGGGGTGGTGTCTTATGACA TTATCTCTAGGCTGCCACTTAAAGTATGGTTTGAAGACAGGGAGAACGGGGCGGCGGAGTGAAAGGGTTG AGGACATCCCAGGCAGAAGGGATAGTGTGAGCAAGGCATGAAGGTGGCACTTGGGCAGGGGCAGGGAGTG GGTGGGCAGGGTGGAGGCTGGAGACACGGGCAAGGGTTAGCTCCAAGGGAGCCTGCAGCACCATGCCAAG AGCCTAGGGCCTGTCAGGGATGAGCAGCAGCCGAGGGGTTTTAAACACTGAGCGGCTCAGTCAGATAGAC TTTTCCATAGGTGCCTGGCAACAGTATGGGAGGCAGAGAGGCCGGTAGAGGCTGTTGTGGTCTTCCAGGA GGAATTGTGCTGGTGGTGGGGAAGCACCTTTGGTGACTGGCAGTGCCGGCCATTGCAAGGTCTCAGCCTC AGGCAGCTTTTGGTCTAGTAAGTGCTCCTTTCCCAATCACTGACCACGTGCCGACCCCTACATTGGTTAA CACTGAATCTGCACAGCAGCCCTGGGAGGTAGGTGCTTTTTTTTTTTTTTTTTTTTTTTTGAGATGGAGT CTTGCTCTGTCACCCAGGCTGGAGTACAATGGTGCGATCTCGGGTCACTGCAACCTCCGCCTCCCAGGTT CAAGGGATTCTCCCTCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCACGCACCATCATGCCCGACTAAT TTTTGTGTTTTCGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGCCTCAAACCCTTGACCTCAGGTG ATCTGCCCGCCTTGGCCTCCCAAAGTGCTGGCATTACAGATGTGAGCCACCGCGCCCGGCAGGTAGGGGC TTTTTTCATCCCATCTGGATTTTTGCTGGAGCCTTTAAATTGGCCGCCTGGCTTCTCCTCTGGCCTTCCT TTAGTTGAATCTCACACAACTGCCAGAGTGAGCCTGTTAAAATGTGAGTTAAGTTTTGGCACCTTTTGAC TCAAAACCTTCCAGAGATAGTTTTACTCGGAGAAAAACCCAAATGGCCTTAAAAGGCCTGCACCATTTGG GCTGCCTCCCTGACTACTCAATGACTTCGGGC FEATURES Location / Qualifiers source 1..23272 / organism="Homo sapiens" / mol_type="genomic DNA" / db_xref="taxon:9606" / chromosome="6" / map="6p21.1" gene 4996..21272 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / note="vascular endothelial growth factor A" / db_xref="GeneID:7422" / db_xref="HGNC:HGNC:12680" / db_xref="MIM:192240" mRNA join(4996..6097,9126..9177,12254..12450,13245..13321, 13674..13703,15517..15639,16741..16872,19326..21272) / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" Attorney Docket No.54926-0021WO1 / product="vascular endothelial growth factor A, transcript variant 1" / transcript_id="NM_001025366.3" / db_xref="GeneID:7422" / db_xref="HGNC:HGNC:12680" / db_xref="MIM:192240" exon 4996..6097 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=1 CDS join(5492..6097,9126..9177,12254..12450,13245..13321, 13674..13703,15517..15639,16741..16872,19326..19347) / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / note="isoform a is encoded by transcript variant 1; non-AUG (CUG) translation initiation codon; vascular endothelial growth factor A165; vascular permeability factor; vascular endothelial growth factor A121; vascular endothelial growth factor A, long form" / codon_start=1 / product="vascular endothelial growth factor A, long form isoform a" / protein_id="NP_001020537.2" / db_xref="CCDS:CCDS34457.1" / db_xref="GeneID:7422" / db_xref="HGNC:HGNC:12680" / db_xref="MIM:192240" / translation="MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEG VGARGVALKLFVQLLGCSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKE EERGPQWRLGARKPGSWTGEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPP HSPSRRGSASRAGPGRASETMNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHH EVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVP TEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRK RKKSRYKSWSVYVGARCCLMPWSLPGPHPCGPCSERRKHLFVQDPQTCKCSCKNTDSR CKARQLELNERTCRCDKPRR" misc_feature 5645..5647 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / note="Region: alternative non-AUG (CUG) translation initiation site" misc_feature 5666..5668 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / note="Region: alternative non-AUG (CUG) translation Attorney Docket No.54926-0021WO1 initiation site" misc_feature 5906..5908 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / note="Region: alternative non-AUG (CUG) translation initiation site" misc_feature 6032..6034 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / note="start of isoform i precursor; Region: alternative AUG translation initiation site" exon 9126..9177 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=2 exon 12254..12450 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=3 exon 13245..13321 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=4 exon 13674..13703 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=5 exon 15517..15639 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=6 exon 16741..16872 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=7 exon 19326..21272 / gene="VEGFA" / gene_synonym="MVCD1; VEGF; VPF" / inference="alignment:Splign:2.1.0" / number=8 SEQ ID NO: 60 DNA sequence of ARRDC1-ABE (ARRDC1 in Bold (1-1299), ABE8 in Italics (1525- 6306), Linker underlined (1300-1524)) Attorney Docket No.54926-0021WO1 atggggcgagtgcagctcttcgagatcagcctgagccacggccgcgtcgtctacagccccggggagccgtt ggctgggaccgtgcgcgtgcgcctgggggcaccgctgccgttccgagccatccgggtgacctgcataggttc ctgcggggtctccaacaaggctaatgacacagcgtgggtagtggaggagggttacttcaacagttccctgtc gctggcagacaaggggagcctgcccgctggagagcacagcttccccttccagttcctgcttcctgccactgc acccacgtcctttgagggtcctttcgggaagatcgtgcaccaggtgagggccgccatccacacgccacggtt ttccaaggatcacaagtgcagcctcgtgttctatatcttgagccccttgaacctgaacagcatcccagacatt gagcaacccaacgtggcctctgccaccaagaagttctcctacaagctggtgaagacgggcagcgtggtcct cacagccagcactgatctccgcggctatgtggtggggcaggcactgcagctgcatgccgacgttgagaacc agtcaggcaaggacaccagccctgtggtggccagtctgctgcagaaagtgtcctataaggccaagcgctgg atccacgacgtacggaccattgcggaggtggagggtgcgggcgtcaaggcctggcggcgggcgcagtggc acgagcagatcctggtgcctgccttgccccagtcggccctgccgggctgcagcctcatccacatcgactac tacttacaggtctctctgaaggcgccggaagctactgtgaccctcccggtcttcattggcaatattgctgtgaa ccatgccccagtgagcccccggccaggcctggggctgcctcctggggccccacccctggtggtgccttccg caccaccccaggaggaggctgaggctgaggctgcggctggcggcccccacttcttggaccccgtcttcctc tccaccaagagccattcgcagcggcagcccctgctggccaccttgagttctgtgcctggtgcgccggagcc ctgccctcaggatggcagccctgcctcacacccgctgcaccctcccttgtgcatttcaacaggtgccactgt cccctactttgcagagggctccggggggccagtgcccactaccagcaccttgattcttcctccagagtacag ttcttggggctacccctatgaggccccaccgtcttatgagcagagctgcggcggcgtggaacccagcctgac ccctgagagctctggtggcggaggctcgggcggaggtgggtcgggtggcggcggatcatctagagaaaacctgta ttttcagggcgtcgactctggtggcggaggctcgggcggaggtgggtcgggtggcggcggatcactcgagatggagg agccgcagcggccgctaatacgactcactatagggagagccgccaccatgaaacggacagccgacggaagcg agttcgagtcaccaaagaagaagcggaaagtctctgaggtggagttttcccacgagtactggatgagacatgccct gaccctggccaagagggcacgggatgagagggaggtgcctgtgggagccgtgctggtgctgaacaatagagtgat cggcgagggctggaacagagccatcggcctgcacgacccaacagcccatgccgaaattatggccctgagacag ggcggcctggtcatgcagaactacagactgattgacgccaccctgtacgtgacattcgagccttgcgtgatgtgcgc cggcgccatgatccactctaggatcggccgcgtggtgtttggcgtgaggaactcaaaaagaggcgccgcaggctc cctgatgaacgtgctgaactaccccggcatgaatcaccgcgtcgaaattaccgagggaatcctggcagatgaatgt gccgccctgctgtgcgatttctatcggatgcctagacaggtgttcaatgctcagaagaaggcccagagctccatca actccggaggatctagcggaggctcctctggctctgagacacctggcacaagcgagagcgcaacacctgaaagc agcgggggcagcagcggggggtcagacaagaagtacagcatcggcctggccatcggcaccaactctgtgggctg ggccgtgatcaccgacgagtacaaggtgcccagcaagaaattcaaggtgctgggcaacaccgaccggcacagc atcaagaagaacctgatcggagccctgctgttcgacagcggcgaaacagccgaggccacccggctgaagagaa ccgccagaagaagatacaccagacggaagaaccggatctgctatctgcaagagatcttcagcaacgagatggc caaggtggacgacagcttcttccacagactggaagagtccttcctggtggaagaggataagaagcacgagcggca ccccatcttcggcaacatcgtggacgaggtggcctaccacgagaagtaccccaccatctaccacctgagaaag aaactggtggacagcaccgacaaggccgacctgcggctgatctatctggccctggcccacatgatcaagttccgg ggccacttcctgatcgagggcgacctgaaccccgacaacagcgacgtggacaagctgttcatccagctggtgca gacctacaaccagctgttcgaggaaaaccccatcaacgccagcggcgtggacgccaaggccatcctgtctgcc Attorney Docket No.54926-0021WO1 agactgagcaagagcagacggctggaaaatctgatcgcccagctgcccggcgagaagaagaatggcctgttcgg aaacctgattgccctgagcctgggcctgacccccaacttcaagagcaacttcgacctggccgaggatgccaaac tgcagctgagcaaggacacctacgacgacgacctggacaacctgctggcccagatcggcgaccagtacgccga cctgtttctggccgccaagaacctgtccgacgccatcctgctgagcgacatcctgagagtgaacaccgagatcac caaggcccccctgagcgcctctatgatcaagagatacgacgagcaccaccaggacctgaccctgctgaaagct ctcgtgcggcagcagctgcctgagaagtacaaagagattttcttcgaccagagcaagaacggctacgccggctac attgacggcggagccagccaggaagagttctacaagttcatcaagcccatcctggaaaagatggacggcaccga ggaactgctcgtgaagctgaacagagaggacctgctgcggaagcagcggaccttcgacaacggcagcatcccc caccagatccacctgggagagctgcacgccattctgcggcggcaggaagatttttacccattcctgaaggacaac cgggaaaagatcgagaagatcctgaccttccgcatcccctactacgtgggccctctggccaggggaaacagcag attcgcctggatgaccagaaagagcgaggaaaccatcaccccctggaacttcgaggaagtggtggacaagggcg cttccgcccagagcttcatcgagcggatgaccaacttcgataagaacctgcccaacgagaaggtgctgcccaag cacagcctgctgtacgagtacttcaccgtgtataacgagctgaccaaagtgaaatacgtgaccgagggaatgaga aagcccgccttcctgagcggcgagcagaaaaaggccatcgtggacctgctgttcaagaccaaccggaaagtgac cgtgaagcagctgaaagaggactacttcaagaaaatcgagtgcttcgactccgtggaaatctccggcgtggaagat cggttcaacgcctccctgggcacataccacgatctgctgaaaattatcaaggacaaggacttcctggacaatgag gaaaacgaggacattctggaagatatcgtgctgaccctgacactgtttgaggacagagagatgatcgaggaacgg ctgaaaacctatgcccacctgttcgacgacaaagtgatgaagcagctgaagcggcggagatacaccggctgggg caggctgagccggaagctgatcaacggcatccgggacaagcagtccggcaagacaatcctggatttcctgaagt ccgacggcttcgccaacagaaacttcatgcagctgatccacgacgacagcctgacctttaaagaggacatccag aaagcccaggtgtccggccagggcgatagcctgcacgagcacattgccaatctggccggcagccccgccattaa gaagggcatcctgcagacagtgaaggtggtggacgagctcgtgaaagtgatgggccggcacaagcccgagaaca tcgtgatcgaaatggccagagagaaccagaccacccagaagggacagaagaacagccgcgagagaatgaagc ggatcgaagagggcatcaaagagctgggcagccagatcctgaaagaacaccccgtggaaaacacccagctgc agaacgagaagctgtacctgtactacctgcagaatgggcgggatatgtacgtggaccaggaactggacatcaacc ggctgtccgactacgatgtggaccatatcgtgcctcagagctttctgaaggacgactccatcgacaacaaggtgct gaccagaagcgacaagaaccggggcaagagcgacaacgtgccctccgaagaggtcgtgaagaagatgaagaa ctactggcggcagctgctgaacgccaagctgattacccagagaaagttcgacaatctgaccaaggccgagagag gcggcctgagcgaactggataaggccggcttcatcaagagacagctggtggaaacccggcagatcacaaagca cgtggcacagatcctggactcccggatgaacactaagtacgacgagaatgacaagctgatccgggaagtgaaag tgatcaccctgaagtccaagctggtgtccgatttccggaaggatttccagttttacaaagtgcgcgagatcaacaac taccaccacgcccacgacgcctacctgaacgccgtcgtgggaaccgccctgatcaaaaagtaccctaagctgg aaagcgagttcgtgtacggcgactacaaggtgtacgacgtgcggaagatgatcgccaagagcgagcaggaaatc ggcaaggctaccgccaagtacttcttctacagcaacatcatgaactttttcaagaccgagattaccctggccaacg gcgagatccggaagcggcctctgatcgagacaaacggcgaaaccggggagatcgtgtgggataagggccgggat tttgccaccgtgcggaaagtgctgagcatgccccaagtgaatatcgtgaaaaagaccgaggtgcagacaggcggc ttcagcaaagagtctatcctgcccaagaggaacagcgataagctgatcgccagaaagaaggactgggaccctaa gaagtacggcggcttcgacagccccaccgtggcctattctgtgctggtggtggccaaagtggaaaagggcaagtc Attorney Docket No.54926-0021WO1 caagaaactgaagagtgtgaaagagctgctggggatcaccatcatggaaagaagcagcttcgagaagaatccca tcgactttctggaagccaagggctacaaagaagtgaaaaaggacctgatcatcaagctgcctaagtactccctgtt cgagctggaaaacggccggaagagaatgctggcctctgccggcgaactgcagaagggaaacgaactggccctg ccctccaaatatgtgaacttcctgtacctggccagccactatgagaagctgaagggctcccccgaggataatgag cagaaacagctgtttgtggaacagcacaagcactacctggacgagatcatcgagcagatcagcgagttctccaag agagtgatcctggccgacgctaatctggacaaagtgctgtccgcctacaacaagcaccgggataagcccatcag agagcaggccgagaatatcatccacctgtttaccctgaccaatctgggagcccctgccgccttcaagtactttgac accaccatcgaccggaagaggtacaccagcaccaaagaggtgctggacgccaccctgatccaccagagcatc accggcctgtacgagacacggatcgacctgtctcagctgggaggtgactctggcggctcaaaaagaaccgccga cggcagcgaattcgagcccaagaagaagaggaaagtctaa SEQ ID NO: 61 Amino acid sequence of ARRDC1-ABE (ARRDC1 in Bold (1-433), ABE8 in Italics (509-2101), Linker Underlined (434-508)) MGRVQLFEISLSHGRVVYSPGEPLAGTVRVRLGAPLPFRAIRVTCIGSCGVSNKANDTA WVVEEGYFNSSLSLADKGSLPAGEHSFPFQFLLPATAPTSFEGPFGKIVHQVRAAIHTPR FSKDHKCSLVFYILSPLNLNSIPDIEQPNVASATKKFSYKLVKTGSVVLTASTDLRGYVVG QALQLHADVENQSGKDTSPVVASLLQKVSYKAKRWIHDVRTIAEVEGAGVKAWRRAQ WHEQILVPALPQSALPGCSLIHIDYYLQVSLKAPEATVTLPVFIGNIAVNHAPVSPRPGL GLPPGAPPLVVPSAPPQEEAEAEAAAGGPHFLDPVFLSTKSHSQRQPLLATLSSVPGAP EPCPQDGSPASHPLHPPLCISTGATVPYFAEGSGGPVPTTSTLILPPEYSSWGYPYEAPP SYEQSCGGVEPSLTPESSGGGGSGGGGSGGGGSSRENLYFQGVDSGGGGSGGGGSG GGGSLEMEEPQRPLIRLTIGRAATMKRTADGSEFESPKKKRKVSEVEFSHEYWMRHALTLA KRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATL YVTFEPCVMCAGAMIHSRIGRVVFGVRNSKRGAAGSLMNVLNYPGMNHRVEITEGILADE CAALLCDFYRMPRQVFNAQKKAQSSINSGGSSGGSSGSETPGTSESATPESSGGSSGGS DKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLK RTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAY HEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQT YNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKS NFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPL SASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPIL EKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKI LTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPN EKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKED YFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMI Attorney Docket No.54926-0021WO1 EERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNF MQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRH KPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQ NGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVK KMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRM NTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYP KLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETN GETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWD PKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVK KDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNE QKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTN LGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSGGSKRTADGSEF EPKKKRKV- SEQ ID NO: 62 The sequence of ARRDC1-Cas9 DNA sequence of ARRDC1-ABE (ARRDC1 in Bold (1-1299), Cas9 in Italics (1351- 5619), Linker Underlined (1300-1350)) atggggcgagtgcagctcttcgagatcagcctgagccacggccgcgtcgtctacagccccggggagccgtt ggctgggaccgtgcgcgtgcgcctgggggcaccgctgccgttccgagccatccgggtgacctgcataggttc ctgcggggtctccaacaaggctaatgacacagcgtgggtagtggaggagggttacttcaacagttccctgtc gctggcagacaaggggagcctgcccgctggagagcacagcttccccttccagttcctgcttcctgccactgc acccacgtcctttgagggtcctttcgggaagatcgtgcaccaggtgagggccgccatccacacgccacggtt ttccaaggatcacaagtgcagcctcgtgttctatatcttgagccccttgaacctgaacagcatcccagacatt gagcaacccaacgtggcctctgccaccaagaagttctcctacaagctggtgaagacgggcagcgtggtcct cacagccagcactgatctccgcggctatgtggtggggcaggcactgcagctgcatgccgacgttgagaacc agtcaggcaaggacaccagccctgtggtggccagtctgctgcagaaagtgtcctataaggccaagcgctgg atccacgacgtacggaccattgcggaggtggagggtgcgggcgtcaaggcctggcggcgggcgcagtggc acgagcagatcctggtgcctgccttgccccagtcggccctgccgggctgcagcctcatccacatcgactac tacttacaggtctctctgaaggcgccggaagctactgtgaccctcccggtcttcattggcaatattgctgtgaa ccatgccccagtgagcccccggccaggcctggggctgcctcctggggccccacccctggtggtgccttccg caccaccccaggaggaggctgaggctgaggctgcggctggcggcccccacttcttggaccccgtcttcctc tccaccaagagccattcgcagcggcagcccctgctggccaccttgagttctgtgcctggtgcgccggagcc ctgccctcaggatggcagccctgcctcacacccgctgcaccctcccttgtgcatttcaacaggtgccactgt cccctactttgcagagggctccggggggccagtgcccactaccagcaccttgattcttcctccagagtacag ttcttggggctacccctatgaggccccaccgtcttatgagcagagctgcggcggcgtggaacccagcctgac Attorney Docket No.54926-0021WO1 ccctgagagctctggtggcggaggctcgggcggaggtgggtcgggtggcggcggatcaatggactataaggacca cgacggagactacaaggatcatgatattgattacaaagacgatgacgataagatggccccaaagaagaagcgga aggtcggtatccacggagtcccagcagccgacaagaagtacagcatcggcctggacatcggcaccaactctgtg ggctgggccgtgatcaccgacgagtacaaggtgcccagcaagaaattcaaggtgctgggcaacaccgaccggc acagcatcaagaagaacctgatcggagccctgctgttcgacagcggcgaaacagccgaggccacccggctgaa gagaaccgccagaagaagatacaccagacggaagaaccggatctgctatctgcaagagatcttcagcaacgag atggccaaggtggacgacagcttcttccacagactggaagagtccttcctggtggaagaggataagaagcacgag cggcaccccatcttcggcaacatcgtggacgaggtggcctaccacgagaagtaccccaccatctaccacctgag aaagaaactggtggacagcaccgacaaggccgacctgcggctgatctatctggccctggcccacatgatcaagtt ccggggccacttcctgatcgagggcgacctgaaccccgacaacagcgacgtggacaagctgttcatccagctgg tgcagacctacaaccagctgttcgaggaaaaccccatcaacgccagcggcgtggacgccaaggccatcctgtct gccagactgagcaagagcagacggctggaaaatctgatcgcccagctgcccggcgagaagaagaatggcctgtt cggaaacctgattgccctgagcctgggcctgacccccaacttcaagagcaacttcgacctggccgaggatgcca aactgcagctgagcaaggacacctacgacgacgacctggacaacctgctggcccagatcggcgaccagtacgc cgacctgtttctggccgccaagaacctgtccgacgccatcctgctgagcgacatcctgagagtgaacaccgagat caccaaggcccccctgagcgcctctatgatcaagagatacgacgagcaccaccaggacctgaccctgctgaaa gctctcgtgcggcagcagctgcctgagaagtacaaagagattttcttcgaccagagcaagaacggctacgccggc tacattgacggcggagccagccaggaagagttctacaagttcatcaagcccatcctggaaaagatggacggcac cgaggaactgctcgtgaagctgaacagagaggacctgctgcggaagcagcggaccttcgacaacggcagcatc ccccaccagatccacctgggagagctgcacgccattctgcggcggcaggaagatttttacccattcctgaaggac aaccgggaaaagatcgagaagatcctgaccttccgcatcccctactacgtgggccctctggccaggggaaacag cagattcgcctggatgaccagaaagagcgaggaaaccatcaccccctggaacttcgaggaagtggtggacaagg gcgcttccgcccagagcttcatcgagcggatgaccaacttcgataagaacctgcccaacgagaaggtgctgccc aagcacagcctgctgtacgagtacttcaccgtgtataacgagctgaccaaagtgaaatacgtgaccgagggaatg agaaagcccgccttcctgagcggcgagcagaaaaaggccatcgtggacctgctgttcaagaccaaccggaaagt gaccgtgaagcagctgaaagaggactacttcaagaaaatcgagtgcttcgactccgtggaaatctccggcgtgga agatcggttcaacgcctccctgggcacataccacgatctgctgaaaattatcaaggacaaggacttcctggacaat gaggaaaacgaggacattctggaagatatcgtgctgaccctgacactgtttgaggacagagagatgatcgaggaa cggctgaaaacctatgcccacctgttcgacgacaaagtgatgaagcagctgaagcggcggagatacaccggctg gggcaggctgagccggaagctgatcaacggcatccgggacaagcagtccggcaagacaatcctggatttcctga agtccgacggcttcgccaacagaaacttcatgcagctgatccacgacgacagcctgacctttaaagaggacatc cagaaagcccaggtgtccggccagggcgatagcctgcacgagcacattgccaatctggccggcagccccgcca ttaagaagggcatcctgcagacagtgaaggtggtggacgagctcgtgaaagtgatgggccggcacaagcccgag aacatcgtgatcgaaatggccagagagaaccagaccacccagaagggacagaagaacagccgcgagagaatg aagcggatcgaagagggcatcaaagagctgggcagccagatcctgaaagaacaccccgtggaaaacacccag ctgcagaacgagaagctgtacctgtactacctgcagaatgggcgggatatgtacgtggaccaggaactggacatc aaccggctgtccgactacgatgtggaccatatcgtgcctcagagctttctgaaggacgactccatcgacaacaag gtgctgaccagaagcgacaagaaccggggcaagagcgacaacgtgccctccgaagaggtcgtgaagaagatga Attorney Docket No.54926-0021WO1 agaactactggcggcagctgctgaacgccaagctgattacccagagaaagttcgacaatctgaccaaggccgag agaggcggcctgagcgaactggataaggccggcttcatcaagagacagctggtggaaacccggcagatcacaa agcacgtggcacagatcctggactcccggatgaacactaagtacgacgagaatgacaagctgatccgggaagtg aaagtgatcaccctgaagtccaagctggtgtccgatttccggaaggatttccagttttacaaagtgcgcgagatcaa caactaccaccacgcccacgacgcctacctgaacgccgtcgtgggaaccgccctgatcaaaaagtaccctaa gctggaaagcgagttcgtgtacggcgactacaaggtgtacgacgtgcggaagatgatcgccaagagcgagcagg aaatcggcaaggctaccgccaagtacttcttctacagcaacatcatgaactttttcaagaccgagattaccctggc caacggcgagatccggaagcggcctctgatcgagacaaacggcgaaaccggggagatcgtgtgggataagggc cgggattttgccaccgtgcggaaagtgctgagcatgccccaagtgaatatcgtgaaaaagaccgaggtgcagaca ggcggcttcagcaaagagtctatcctgcccaagaggaacagcgataagctgatcgccagaaagaaggactggga ccctaagaagtacggcggcttcgacagccccaccgtggcctattctgtgctggtggtggccaaagtggaaaaggg caagtccaagaaactgaagagtgtgaaagagctgctggggatcaccatcatggaaagaagcagcttcgagaaga atcccatcgactttctggaagccaagggctacaaagaagtgaaaaaggacctgatcatcaagctgcctaagtact ccctgttcgagctggaaaacggccggaagagaatgctggcctctgccggcgaactgcagaagggaaacgaactg gccctgccctccaaatatgtgaacttcctgtacctggccagccactatgagaagctgaagggctcccccgaggat aatgagcagaaacagctgtttgtggaacagcacaagcactacctggacgagatcatcgagcagatcagcgagttc tccaagagagtgatcctggccgacgctaatctggacaaagtgctgtccgcctacaacaagcaccgggataagcc catcagagagcaggccgagaatatcatccacctgtttaccctgaccaatctgggagcccctgccgccttcaagta ctttgacaccaccatcgaccggaagaggtacaccagcaccaaagaggtgctggacgccaccctgatccaccag agcatcaccggcctgtacgagacacggatcgacctgtctcagctgggaggcgacaaaaggccggcggccacga aaaaggccggccaggcaaaaaagaaaaagtaa SEQ ID NO: 63 Amino acid sequence of ARRDC1-ABE (ARRDC1 in Bold (1-433), Cas9 in Italics (450-1872), Linker Underlined (434-449)) MGRVQLFEISLSHGRVVYSPGEPLAGTVRVRLGAPLPFRAIRVTCIGSCGVSNKANDTA WVVEEGYFNSSLSLADKGSLPAGEHSFPFQFLLPATAPTSFEGPFGKIVHQVRAAIHTPR FSKDHKCSLVFYILSPLNLNSIPDIEQPNVASATKKFSYKLVKTGSVVLTASTDLRGYVVG QALQLHADVENQSGKDTSPVVASLLQKVSYKAKRWIHDVRTIAEVEGAGVKAWRRAQ WHEQILVPALPQSALPGCSLIHIDYYLQVSLKAPEATVTLPVFIGNIAVNHAPVSPRPGL GLPPGAPPLVVPSAPPQEEAEAEAAAGGPHFLDPVFLSTKSHSQRQPLLATLSSVPGAP EPCPQDGSPASHPLHPPLCISTGATVPYFAEGSGGPVPTTSTLILPPEYSSWGYPYEAPP SYEQSCGGVEPSLTPESSGGGGSGGGGSGGGGSMDYKDHDGDYKDHDIDYKDDDDK MAPKKKRKVGIHGVPAADKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKN LIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEE DKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGD Attorney Docket No.54926-0021WO1 LNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKN GLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLS DAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAG YIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILR RQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGA SAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIV DLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEEN EDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQS GKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGI LQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEH PVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRS DKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQ LVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHH AHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFF KTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESI LPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSS FEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFL YLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHR DKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ LGGDKRPAATKKAGQAKKKK- OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.54926-0021WO1 WHAT IS CLAIMED IS:

1. An arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicle (ARMM), comprising: a lipid bilayer; an ARRDC1 protein, fragment thereof, or variant thereof; an RNA-guided protein; and a gRNA targeting the VEGFA gene.

2. A microvesicle producing cell comprising: nucleic acid construct(s) encoding: an ARRDC1 protein, fragment thereof, or variant thereof; an RNA-guided protein; and a gRNA targeting the VEGFA gene.

3. The ARMM or microvesicle producing cell of any one of the preceding claims, wherein the RNA-guided protein is a nuclease.

4. The ARMM or microvesicle producing cell of claim 3, wherein the nuclease is a Type II or Type V CRISPR Cas nuclease, optionally a Cas9 nuclease.

5. The ARMM or microvesicle producing cell of claim 3, wherein the RNA- guided protein is a base editor, optionally a cytosine base editor (CBE) or adenine base editor (ABE).

6. The ARMM or microvesicle producing cell of any one of the preceding claims, wherein the gRNA, when complexed with the RNA-guided protein in a cell expressing VEGFA, introduces a mutation into the VEGFA gene that knocks down or knocks out expression of VEGFA mRNA and / or protein.Attorney Docket No.54926-0021WO1 7. The ARMM or microvesicle producing cell of claim 6, wherein the mutation is a missense mutation or a nonsense mutation.

8. The ARMM or microvesicle producing cell of claim 6 or claim 7, wherein the mutation is a point mutation or an indel mutation.

9. The ARMM or microvesicle producing cell of any one of claims 6–8, wherein the mutation is in an exon of the VEGFA gene.

10. The ARMM or microvesicle producing cell of any one of claims 6–8, wherein the mutation is in an intron of the VEGFA gene.

11. The ARMM or mivrovesicle producing cell of any one of claims 6–8, wherein the mutation is in a regulatory region of the VEGFA gene.

12. The ARMM or microvesicle producing cell of claim 6, wherein the RNA- guided protein is a base editor and the mutation is at the splice acceptor site of exon 8.

13. The ARMM or microvesicle producing cell of claim 12, wherein the base editor is an adenine base editor (ABE) and the mutation is an A->G mutation in the splice acceptor site of exon 8.

14. The ARMM or microvesicle producing cell of claim 13, wherein the gRNA comprises a target sequence set forth in any one of SEQ ID NOs 30-37.

15. The ARMM or microvesicle producing cell of claim 6, wherein the RNA- guided protein is a nuclease and the mutation is an indel.

16. The ARMM or microvesicle producing cell of claim 15, wherein the gRNA comprises a target sequence set forth in SEQ ID NO: 38.Attorney Docket No.54926-0021WO1 17. A method of treating an ocular disorder, the method comprising: administering the ARMM or the microvesicle producing cell of any one of the preceding claims to a subject in need thereof.

18. The method of claim 17, wherein the ocular disorder is AMD.

19. The method of claim 18, wherein the ocular disorder is wet AMD.

20. The method of any one of claims 17–19, wherein the patient has choroidal neovascularization (CNV).

21. The method of any one of claims 17–20, wherein administering comprises intravitreal, subretinal, and / or suprachoroidal injection.

22. A method for delivering a payload to a cell, the method comprising administering the ARMM or microvesicle producing cell of any one of claims 1–16 to a cell.

23. A method for knocking down or knocking out VEGFA in a cell, the method comprising administering the ARMM or microvesicle producing cell of any one of claims 1–16 to a cell.

24. The method of claim 23, wherein the knocking down or knocking out VEGFA in a cell comprises selectively knocking down or knocking out pathogenic exon 8a isoform(s) of VEGFA in a cell.

25. The method of claim 23, wherein the knocking down or knocking out VEGFA in a cell comprises non-selectively knocking down or knocking out VEGFA in a cell.Attorney Docket No.54926-0021WO1 26. The method of any one of claims 21–25, wherein the cell is an RPE cell.

27. A method of treating an ocular disorder, the method comprising: selectively knocking down or knocking out pathogenic exon 8a isoform(s) of VEGFA in a cell.

28. The method of claim 27, wherein the method comprises editing the splice acceptor site of exon 8.

29. The method of claim 28, wherein editing the splice acceptor site of exon 8 comprises introducing a point mutation into the splice acceptor site of exon 8.

30. The method of claim 29, wherein the point mutation is an AàG point mutation within the splice acceptor site of exon 8.

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