Photoreceptor specific promotors for use in gene therapies for treatment of retinal degeneration

Abstract

Aspects of the disclosure relate to methods and compositions for gene therapies for treating ocular disease, including conditions associated with retinal degeneration and advanced stages of retinal regeneration, using photoreceptor-specific promoters.

Description

[0001]PHOTORECEPTOR SPECIFIC PROMOTORS FOR USE IN GENE THERAPIES FOR TREATMENT OF RETINAL DEGENERATION CROSS-REFERENCE TO RELATED APPLICATION This application claims priority of US Provisional application numbers 63 / 642,473 filed May 3, 2024, and 63 / 683,967, filed August 16, 2024 the entire contents of each being incorporated herein by reference as though set forth in full. GOVERNMENT INTEREST STATEMENT This invention was made with government support under EY033049, EY006855, and EY017549 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED IN ELECTRONIC FORM The Contents of the electronic sequence listing (UPN-24-10755-PCT.xml; Size: 34,832 bytes; and Date of Creation: May 5, 2025) is herein incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Gene therapy holds immense promise as a treatment for many inherited retinal degenerative diseases (IRD)1,2. The first gene therapy for a form of Leber Congenital Amaurosis (LCA)3due to mutations in the RPE65 gene (voritegene-neparvovec4or Luxturna) was approved by FDA in 2017, and gene therapies for several other IRDs are in clinical trials5,6. Despite promising preclinical data, not all clinical trials have resulted in successful therapies7. Preclinical proof-of-concept retinal gene therapy studies are frequently conducted either before or shortly after the onset of degeneration when many of the primary target cells, the photoreceptors (PR), still remain. However, human patients with progressive retinal degeneration are often diagnosed after a significant number of PRs are already lost8. At these advanced stages of disease, the retina undergoes structural and cellular remodeling, as well as transcriptional changes9-11. Such changes may affect the efficiency of viral vector mediated transduction and / or the activity of cell specific promoters. Indeed, several currently used PR-specific promoters drive transgene expression with high efficiency and specificity in rods and / or cones early in the course of degeneration, but only promote modest structural and functional rescue of PRs when the treatment is delivered in animal models at advanced stages of degeneration12-14. What is needed are additional promoters that target photoreceptors. SUMMARY OF THE INVENTION Provided herein, in a first aspect, are expression cassettes comprising a nucleic acid having promoter activity in photoreceptor cells operably linked to a transgene, wherein the nucleic acid having promoter activity comprises a cis regulatory element (CRE) from PRL, TPH1, GNGT2, IMPG2 or PDE6H, or a sequence sharing at least 80% identity therewith. In certain embodiments, the nucleic acid having promoter activity has cone and / or rod cell- specific promoter activity. In certain embodiments, the nucleic acid having promoter activity is a human sequence or a canine sequence. In certain embodiments, the nucleic acid having promoter activity comprises any one of SEQ ID NO: 1-22, or a sequence sharing at least 80% identity with any one of SEQ ID NO: 1-22. In certain embodiments, the nucleic acid having promoter activity has a length of less than 1 kb. In certain embodiments, the transgene encodes a therapeutic protein, a reporter protein, a gene silencing tool (eg., shRNA) or a gene editing tool. In certain embodiments, the therapeutic protein is associated with a retinal disease or disorder. In certain embodiments, the therapeutic protein is selected from ADIPOR1, ABCA4, ABCC6, ABHD12, ACBD5, ACO2, ADAM9, ADAMTS18, ADGRA3, ADGRV1, ADIPOR1, AFG3L2, AGBL5, AHI1, AHR, AIPL1, ALMS1, ARHGEF18, ARL2BP, ARL3, ARL6, ARMS2, ARSG, ASRGL1, ATF6, ATXN7, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BEST1, C12orf65, C1QTNF5, C2, C21orf2, C3, C8orf37, CA4, CABP4, CACNA1F, CACNA2D4, CAPN5, CC2D2A, CCT2, CDH23, CDH3, CDHR1, CEP164, CEP19, CEP250, CEP290, CEP78, CERKL, CFB, CFH, CHM, CIB2, CLCC1, CLN3, CLRN1, CLUAP1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL2A1, COL9A1, COQ2, COQ4, COQ5, CRB1, CRX, CSPP1, CTNNA1, CWC27, CYP4V2, DHDDS, DHX38, DMD, DRAM2, DTHD1, DYNC2H1, DYNC2I2, EFEMP1, ELOVL1, ELOVL4, EMC1, ENSA, ERCC6, ESPN, EXOSC2, EYS, FAM161A, FBLN5, FLVCR1, FSCN2, FZD4, GDF6, GNAT1, GNAT2, GNB3, GNPTG, GPR179, GRK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HARS, HGSNAT, HK1, HMCN1, HMX1, HTRA1, IDH3B, IFT140, IFT172, IFT27, IFT81, IMPDH1, IMPG1, IMPG2, INPP5E, INVS, IQCB1, ITM2B, JAG1, KCNJ13, KCNV2, KIAA1549, KIF11, KIF3B, KIZ, KLHL7, KSS, LAMA1, LCA5, LHON, LRAT, LRIT3, LRP5, LRRTM4, LZTFL1, MAK, MAPKAPK3, MERTK, MFN2, MFRP, MFSD8, MIEF1, MIR204, MKKS, MKS1, MT-ATP6, MT-TH, MT-TL1, MTTP, MT-TP, MT-TS2, MVK, MYO7A, NBAS, NDP, NEK2, NEUROD1, NMNAT1, NPHP1, NPHP3, NPHP4, NR2E3, NR2F1, NRL, NYX, OAT, OFD1, OPA1, OPA3, OPN1LW, OPN1MW, OPN1SW, OTX2, PANK2, PAX2, PCARE, PCDH15, PCYT1A, PDE6A, PDE6B, PDE6C, PDE6G, PDE6H, PDSS1, PDZD7, PEX1, PEX2, PEX7, PGK1, PHYH, PITPNM3, PLA2G5, PLK4, PNPLA6, POC1B, POC5, POMGNT1, PPT1, PRCD, PRDM13, PROM1, PROS1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, PRPS1, RAB28, RAX2, RB1, RBP3, RBP4, RCBTB1, RD3, RDH11, RDH12, RDH5, REEP6, RGR, RGS9, RGS9BP, RHO, RIMS1, RIMS2, RLBP1, ROM1, RP1, RP1L1, RP2, RP9, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, RTN4IP1, SAG, SAMD11, SDCCAG8, SEMA4A, SLC24A1, SLC25A46, SLC37A3, SLC39A12, SLC4A7, SLC66A1, SLC7A14, SNRNP200, SPATA7, SPP2, TEAD1, TIMM8A, TIMP3, TLR3, TLR4, TMEM126A, TMEM216, TMEM237, TOPORS, TREX1, TRIM32, TRNT1, TRPM1, TSPAN12, TTC8, TTLL5, TTPA, TUB, TUBGCP4, TUBGCP6, TULP1, UNC119, USH1C, USH1G, USH2A, VCAN, WDPCP, WDR19, WFS1, WHRN, ZNF408, ZNF423, or ZNF513. In certain embodiments, the reporter protein is selected from the group consisting of a fluorescent protein, a calcium indicator, alkaline phosphatase, beta-galactosidase, beta- lactamase, and horseradish peroxidase. In certain embodiments, the transgene is an siRNA, shRNA, RNAi, miRNA, antisense RNA, ribozyme, or deoxyribozyme. Certain aspects of the invention comprise vectors or lipid nanoparticles (LNPs) comprising the expression cassette described herein. In certain embodiments, the vector is a recombinant viral vector. In certain embodiments, the vector is a recombinant adeno- associated virus. In certain embodiments, the rAAV has an AAV2, AAV5, AAV7m8, AAV9, or AAV8 capsid. In another aspect of the invention, cells transformed with the expression cassettes, the vectors, the rAAVs, or the LNPs described herein are provided. In certain embodiments, is a rod photoreceptor cell or a cone photoreceptor cell. Also provided herein are pharmaceutical compositions comprising the expression cassettes, the vectors, the rAAVs, or the LNPs described herein with a pharmaceutically acceptable excipient. In another aspect of the invention, uses of the expression cassettes, the vectors, the rAAVs, the LNPs, or pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of ocular disease are provided herein. In certain embodiments, the ocular disease is a disease associated with degeneration of photoreceptor cells. In certain embodiments, the disease associated with photoreceptor degeneration is age-related macular degeneration, Bardet-Biedl syndrome, chorioretinal atrophy, congenital stationary night blindness, oculo-retinal developmental disease, optic atrophy, usher syndrome, retinopathy of prematurity, achromatopsia, leber's hereditary optic neuropathy, cone-rod dystrophy, leber's congenital amaurosis, Stargardt disease, diabetic retinopathy, retinal detachment, best's disease, retinitis pigmentosa, choroideremia, or retinal blanket degeneration. In another aspect of the invention, methods of treating an ocular disease in a subject in need thereof, the methods comprising administering the expression cassettes, the vectors, the rAAVs, the LNPs, or pharmaceutical compositions described herein are provided. In certain embodiments, wherein the composition is administered via subretinal injection. In certain embodiments, the effective amount 1x108to 1x1014vg / mL. In certain embodiments, the ocular disease is age-related macular degeneration, Bardet-Biedl syndrome, chorioretinal atrophy, congenital stationary night blindness, oculo-retinal developmental disease, optic atrophy, usher syndrome, retinopathy of prematurity, achromatopsia, leber's hereditary optic neuropathy, cone-rod dystrophy, leber's congenital amaurosis, stargardt disease, diabetic retinopathy, retinal detachment, best's disease, retinitis pigmentosa, choroideremia, or retinal blanket degeneration. In certain embodiments, the subject has advanced stage disease. In certain embodiments, the subject has lost about 50% or more of their rod or cone photoreceptor cells. Other aspects and advantages of the invention will be readily apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Fig.1: An illustration of Massively Parallel Reporter Assay (MPRA). Fig.2: Flowchart depicting gene selection process. Identification of promoter candidate genes with specific expression in PR of retinas based on transcriptomic analysis comparing gene expression in mutant versus normal retinas. Fig.3A-3H: Identification and validation of ONL-enriched genes. (Fig.3A) The purity of the three retinal layers (Outer Nuclear Layer and Inner Segments, ONL / IS; Inner Nuclear Layer, INL; and Ganglion Cell Layer, GCL) isolated by laser capture microdissection confirmed by analyzing the expression of layer-specific marker genes using qPCR analysis. The fold enrichment is calculated by comparing the expression levels of these markers in each layer to their levels in the whole retina. (Fig.3B) Enrichment of six of the candidate genes within the ONL confirmed by qPCR analysis. The Inset: Fold change for the gene in mutant retinas compared to normal retinas. Data are presented as mean ± standard deviation, with n = 3 dogs per group. ONL specific gene expression was validated using RNA-in situ hybridization (RNA-ISH) performed using RNAscope probes specific for canine: (Fig.3C) VCAN, (Fig.3D) PRL, (Fig.3E) TPH1, (Fig.3F) IMPG2, (Fig.3G) PDE6H, and (Fig.3H) GNGT2 transcripts. Calibration bar: 40 µm. Fig.4A-4B: Design and in vitro testing of Cis-Regulatory Regions (CREs) of selected canine genes. (Fig.4A) A total of 2 CREs were identified for the canine PDE6H gene; 3 for canine IMPG2; 2 for canine GNGT2; 2 for canine PRL and 2 for canine TPH1. These sequences contained TATA boxes, GC-rich sequences, and putative transcription factor (TF) binding sites centered around the transcription start sites identified by 5’-RACE. Nucleotide positions correspond to the annotations in the CanFam3 genome assembly (Fig.4B) Promoter activity of all CREs were assessed using Dual Luciferase Assays performed in HEK293 and Y79 cells. Results are presented as Relative Response Ratios, with n = 3 independent experiments and 4 replicates per CRE in each assay. Error bars indicate + 1 standard deviation. Statistical significance is denoted by * for p-value ≤ 0.05 and ** for p-value ≤ 0.005. Statistical significance was first evaluated using ANOVA to assess differences across multiple groups. Variance equality between groups was then assessed using an F-test. For pairwise comparisons, Student’s t-test was used for data with equal variances (p > 0.05 from F-test), while Welch’s t-test was applied when variances were significantly different (p < 0.05 from F-test). Statistical significance is denoted by p ≤ 0.05 (*) and p ≤ 0.005 (**). Fig.5A-5B: Cell cluster identification in normal and mutant retinas following MPRA screening for promoters. Retinal cell clusters were identified and annotated based on the expression of known cell-type specific marker genes. Fig.6A-6B: Identification of major retinal cell classes and GFP expression in single cell RNA sequencing data from canine retina following Massively Parallel Reporter Assay (MPRA). UMAP visualization of the cell clusters in the canine retina, color-coded by major cell classes. Feature plots depict GFP expression across cell clusters in normal and mutant retinas after MPRA using (Fig.6A) the canine promoter pool and (Fig.6B) the human promoter pool. GFP expression patterns highlight promoter activity across different retinal cell types. Fig.7A-7C: Massively Parallel Reporter Assay (MPRA) for promoter candidate screening in canine retinas. MPRA results assessing the efficiency and cell-type specificity of five lead candidate promoters in (Fig.7A) normal, (Fig.7B) PDE6β-RCD1 (late-stage, 22 weeks), and (Fig.7C) RPGR-XLPRA2 retinas (late stage, 40 weeks). Each plot displays GFP expression driven by individual promoters across distinct retinal cell types. The percentage of GFP-positive cells per cell-type is represented by bar plots, while the mean GFP expression (transcript count) indicated by an orange line. Fig.8A-8B: Massively Parallel Reporter Assay (MPRA) for promoter candidate screening in normal canine retinas. MPRA results assessing the efficiency and specificity for (Fig.8A) the canine promoter pool and (Fig.8B) the human promoter pool. Each plot represents GFP expression driven by individual promoters across retinal cell types. The percentage of GFP-positive cells per cell-type is shown as green bars, while the mean GFP expression is depicted as an orange line. Two normal dogs were used in the assay, one for evaluating each promoter pool. Fig.9A-9B: Massively Parallel Reporter Assay (MPRA) for promoter candidate screening in PDE6β-RCD1 retinas. MPRA results assessing the efficiency and specificity for (Fig.9A) the canine promoter pool and (Fig.9B) the human promoter pool. Each plot represents GFP expression driven by individual promoters across retinal cell types. The percentage of GFP-positive cells per cell-type is shown as light blue bars, while the mean GFP expression is depicted as an orange line. Two PDE6β-RCD1 (late stage: 22 weeks) dogs were used in the assay, one for evaluating each promoter pool. Fig.10A-10B: Massively Parallel Reporter Assay (MPRA) for promoter candidate screening in RPGR-XLPRA2 retinas. MPRA results assessing the efficiency and specificity for (Fig.10A) the canine promoter pool and (Fig.10B) the human promoter pool. Each plot represents GFP expression driven by individual promoters across retinal cell types. The percentage of GFP-positive cells per cell-type is shown as dark blue bars, while the mean GFP expression is depicted as an orange line. Two RPGR-XLPRA2 (late stage: 40 weeks) dogs were used in the assay, one for evaluating each promoter pool. Fig.11A-11D: GFP expression driven by individual promoters in PDE6β-RCD1 and RPGR-XLPRA2 canine retina at mid-stages of retinal degeneration. Promoter specificity was evaluated for each promoter 6 weeks after subretinal delivery of AAV5-promoter-GFP at 9 weeks and 16 weeks of age in PDE6β-RCD1 and RPGR-XLPRA2 dogs, respectively. Immunohistochemical staining for was performed for rods (RHO, red), cones (ARR3, magenta) and GFP (green), in retinas expressing GFP driven by (Fig.11A) cGNGT2p1, (Fig. 11B) hGNGT2p1, (Fig, 11C) cIMPG2p1, and (D1-4) cPDE6Hp1 promoters. ONL: Outer nuclear layer; INL: Inner nuclear layer, GCL: Ganglion cell layer; RPE: Retinal Pigment Epithelium. Fig.12A-12D: GFP expression driven by individual promoters in PDE6β-RCD1 and RPGR-XLPRA2 canine retina at late-stages of retinal degeneration. Promoter specificity was evaluated for each promoter 6 weeks after subretinal delivery of AAV5-promoter-GFP at 12 weeks and 40 weeks of age in PDE6β-RCD1 and RPGR-XLPRA2 dogs, respectively. Immunohistochemical staining for rods (RHO, cones (ARR3, magenta) and GFP (green) in retinas expressing GFP driven by (Fig.12A) cGNGT2p1, (Fig.12B) hGNGT2p1, (Fig.12C) cIMPG2p1, and (Fig.12D) cPDE6Hp1 promoters. ONL: Outer nuclear layer; INL: Inner nuclear layer, GCL: Ganglion cell layer; RPE: Retinal Pigment Epithelium. Fig.13A-13D: GFP expression driven by individual promoters in normal canine retinas. Promoter specificity was evaluated for the promoters 6 weeks after subretinal delivery of AAV5-promoter-GFP in normal dogs. Immunohistochemical staining for rods (RHO, cones (ARR3, magenta) and GFP (green) in retinas expressing GFP driven by (Fig. 13A) cGNGT2p1, (Fig.13B) hGNGT2p1, (Fig.13C) cIMPG2p1, and (Fig.13D) cPDE6Hp1 promoters. ONL: Outer nuclear layer; INL: Inner nuclear layer, GCL: Ganglion cell layer; OS: outer segments; IS: inner segments; RPE: Retinal Pigment Epithelium. Fig.14A-14D: GFP expression driven by GRK1 promoter 6 weeks after subretinal delivery in (Fig.14A) Normal, (Fig.14B) RPGR-XLPRA2 at mid-stage disease, (Fig.14C) RPGR-XLPRA2 at late-stage disease, and (Fig.14D) PDE6 / 3-RCD1 at late-stage disease. lmmunohistochemical staining was performed for rods (RHO, red), cones (ARR3, magenta) and GFP (green). ONL: outer nuclear layer; INL: inner nuclear layer, IS: inner segment, OS: outer segment, RPE: retinal pigment epithelium. Fig.15: Retinal cell-type specificity of lead promoter candidates in normal and degenerating canine retinas. Schematic illustration of the specificity of lead promoter candidates in normal retinas and in mutant dogs at mid and late stages of degeneration. Each cell contains schematic representations of rod photoreceptors, cone photoreceptors, and / or retinal pigment epithelial (RPE) cells, depicting the targeted expression profile of each promoter. Fig 16: Photoreceptor-specific genes are downregulated in advanced stages of retinal degenerative disease. Fold change in expression of photoreceptor-specific genes, data from RNAseq analysis of normal, PDE6β-RCD1 and RPGR-XLPRA2 retinas with >50% photoreceptor loss20. RHO: Rhodopsin, GRK1: G-Protein-Coupled Receptor Kinase-1, CNGA1: Cyclic Nucleotide Gated Channel Alpha 1, CNGB1: Cyclic Nucleotide Gated Channel Beta 1, SAG: S-Antigen Visual Arrestin, PDE6A: Phosphodiesterase 6A, PDE6B: Phosphodiesterase 6B, ARR3: Arrestin 3, RDH8: Retinol Dehydrogenase 8 (All-Trans), IRBP / RBP3: Retinol Binding Protein 3, NPHP5 / IQCB1: IQ Motif containing B1, PRPH2: Peripherin 2, CRX:Cone-Rod Homeobox. DETAILED DESCRIPTION OF THE INVENTION As used herein, “disease”, “disorder”, and “condition” are used interchangeably, to indicate an abnormal state in a subject. The term “expression” is used herein in its broadest meaning and comprises the production of RNA, of protein, or of both RNA and protein. With respect to RNA, the term “expression” or “translation” relates in particular to the production of peptides or proteins. Expression may be transient or may be stable. “Patient” or “subject”, as used herein interchangeably, means a male or female mammalian animal, including a human, a veterinary or farm animal, a domestic animal or pet, and animals normally used for clinical research such as canines, non-human primates, and mice. In certain embodiments, the subject is a human patient. In certain embodiments, the subject has or is suspected of having one or more conditions, diseases, or disorders of the eye. It is to be noted that the term “a” or “an” refers to one or more. As such, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein. While various embodiments in the specification are presented using “comprising” language, under other circumstances, a related embodiment is also intended to be interpreted and described using “consisting of” or “consisting essentially of” language. The words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively. The words “consist”, “consisting”, and its variants, are to be interpreted exclusively, rather than inclusively. As used herein, the term “about” means a variability of 10 % from the reference given, unless otherwise specified. Nucleic Acids and Expression Cassettes As used herein, an “expression cassette” refers to a nucleic acid molecule which comprises a biologically useful nucleic acid sequence for directing expression of therapeutic proteins to photoreceptors (e.g., encodes a photoreceptor promoter sequence) and regulatory sequences operably linked thereto which direct or modulate transcription, translation, and / or expression of the nucleic acid sequence. Such an expression cassette may be administered to a subject for therapeutic purposes. Expression cassettes can also be used for generating a viral vector for therapeutic delivery of the nucleotide sequences described. As used herein, the term “regulatory sequence”, or “expression control sequence” refers to nucleic acid sequences, such as initiator sequences, enhancer sequences, and promoter sequences, which induce, repress, or otherwise control the transcription of protein encoding nucleic acid sequences to which they are operably linked. As used herein, “operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest. The expression cassettes described herein contain a cell-specific promoter sequence as part of the expression control sequences. The term “cell-specific” means that the particular promoter selected for the recombinant vector can direct expression of the transgene in a particular ocular cell type, such as photoreceptor cells. In certain embodiments, the promoter is a “photoreceptor-specific promoter” which directs expression of the transgene in a photoreceptor cell. In certain embodiments the photoreceptor cell is a rod photoreceptor cell or a cone photoreceptor cell. In certain embodiments, the photoreceptor-specific promoter directs expression of the transgene in both rod and cone photoreceptor cells. In certain embodiments, a photoreceptor-specific promoter for ocular cells is selected. For example, the promoter may be a cis regulatory element (CRE) from PRL (SEQ ID NO: 12, 13, or 19), TPH1 (SEQ ID NO: 5, 10, 11, or 16), GNGT2 (SEQ ID NO: 1, 4, 8, 9, 17, or 18), IMPG2 (SEQ ID NO: 2, 6, 14, 20, or 21), or PDE6H (SEQ ID NO: 3, 7, 15, or 22), or a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity therewith. In other embodiments, the promoter selected from the photoreceptor-specific genes is identified in Figures 3, 4, 7-10, 16 or Table 3. TABLE 3: Sequences for Canine (c) and Human (h) Promoters In one embodiment, the promoter has the sequence of SEQ ID NO: 1, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 1. In one embodiment, the promoter has the sequence of SEQ ID NO: 2, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 2. In one embodiment, the promoter has the sequence of SEQ ID NO: 3, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 3. In one embodiment, the promoter has the sequence of SEQ ID NO: 4, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 4. In one embodiment, the promoter has the sequence of SEQ ID NO: 5, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 5. In one embodiment, the promoter has the sequence of SEQ ID NO: 6, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 6. In one embodiment, the promoter has the sequence of SEQ ID NO: 7, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 7. In one embodiment, the promoter has the sequence of SEQ ID NO: 8, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 8. In one embodiment, the promoter has the sequence of SEQ ID NO: 9, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 9. In one embodiment, the promoter has the sequence of SEQ ID NO: 10, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 10. In one embodiment, the promoter has the sequence of SEQ ID NO: 11, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 11. In one embodiment, the promoter has the sequence of SEQ ID NO: 12, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 12. In one embodiment, the promoter has the sequence of SEQ ID NO: 13, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 13. In one embodiment, the promoter has the sequence of SEQ ID NO: 14, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 14. In one embodiment, the promoter has the sequence of SEQ ID NO: 15, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 15. In one embodiment, the promoter has the sequence of SEQ ID NO: 16, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 16. In one embodiment, the promoter has the sequence of SEQ ID NO: 17, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 17. In one embodiment, the promoter has the sequence of SEQ ID NO: 18, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 18. In one embodiment, the promoter has the sequence of SEQ ID NO: 19, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 19. In one embodiment, the promoter has the sequence of SEQ ID NO: 20, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 20. In one embodiment, the promoter has the sequence of SEQ ID NO: 21, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 21. In one embodiment, the promoter has the sequence of SEQ ID NO: 22, or a sequence sharing at least 80% identity therewith. In one embodiment, the promoter has a sequence sharing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity with SEQ ID NO: 22. In certain embodiments, fragments of the promoter sequences are provided. Suitable fragments are at least about 15 nucleotides in length, and encompass functional fragments, i.e., fragments which are of biological interest. For example, a functional fragment of the promoter sequences described herein can initiate the transcription of a gene. Such fragments include 5’ and 3’ truncations of the promoter sequences listed in the tables herein. In certain embodiments, the suitable fragments have 5’ and / or 3’ truncations of about 1-800, 1-775, 1- 750, 1-725, 1-700, 1-675, 1-650, 1-625, 1-600, 1-575, 1-550, 1-525, 1-500, 1-475, 1-450, 1- 425, 1-400, 1-375, 1-350, 1-325, 1-300, 1-275, 1-250, 1-225, 1-200, 1-175.1-150, 1-125, 1- 100, 1-75, 1-50, 1-25, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, or 800 nucleotides, based upon the nucleotide number provided in SEQ ID NOs: 1-22. Other suitable fragments include shorter internal, 5’ end, or 3’ end fragments. Other suitable fragments may be readily identified by one of skill in the art. In addition to a promoter a vector may contain one or more other appropriate transcription initiation, termination, enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation (poly A) signals; sequences that stabilize cytoplasmic mRNA for example WPRE; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance secretion of the encoded product. An example of a suitable enhancer is the CMV enhancer. Other suitable enhancers include those that are appropriate for desired target tissue indications. In one embodiment, the expression cassette comprises one or more expression enhancers. In one embodiment, the expression cassette contains two or more expression enhancers. These enhancers may be the same or may differ from one another. For example, an enhancer may include a CMV immediate early enhancer. This enhancer may be present in two copies which are located adjacent to one another. Alternatively, the dual copies of the enhancer may be separated by one or more sequences. In still another embodiment, the expression cassette further contains an intron, e.g., the chicken beta-actin intron. Other suitable introns include those known in the art, e.g., such as are described in WO 2011 / 126808. Examples of suitable poly A sequences include, e.g., rabbit beta globin, SV40, SV50, bovine growth hormone (bGH), human growth hormone, HSV TK, and synthetic poly As. Optionally, one or more sequences may be selected to stabilize mRNA. An example of such a sequence is a modified WPRE sequence, which may be engineered upstream of the poly A sequence and downstream of the coding sequence (see, e.g., MA Zanta-Boussif, et al, Gene Therapy (2009) 16: 605-619). As described herein, regulatory elements comprise but not limited to: promoter; enhancer; transcription factor; transcription terminator; efficient RNA processing signals such as splicing and polyadenylation signals (poly A); sequences that stabilize cytoplasmic mRNA, for example Woodchuck Hepatitis Virus (WHP) Posttranscriptional Regulatory Element (WPRE); sequences that enhance translation efficiency (i.e., Kozak consensus sequence). In certain embodiments, the nucleic acids provided include small interfering nucleic acids (e.g., RNAs) that target genes involved in retinal degeneration. The majority of these genes are expressed in the photoreceptors. Exemplary genes involved in retinal degeneration include, without limitation, the genes listed in Table 1. In certain embodiments, the gene involved in retinal degeneration is selected from ABCA4, PROM1, PRPH2, UNC119, CDHR1, CNGA3, CNGB3, PDE6B, PDE6H, RHO, RPGR, GNAT1 and GNAT2. Other genes involved in retinal degeneration are known to those skilled in the art and include the 250 genes identified on the RetNex site at https: / / web.sph.uth.edu / RetNet / sum- dis.htm?csrt=5192481961881097950#A-genes. In certain embodiments, interfering RNAs that digest mRNA are provided. Interfering RNA includes, but is not limited to, RNA enzymes (ribozymes), small interfering RNA (siRNA), small hairpin RNA (shRNA), or artificial microRNAs (miRNA). In certain embodiments, the sequence encodes a short hairpin RNAs (shRNAs) driven by a promoter (e.g., an RNA polymerase III promoter or other suitable constitutive or inducible promoter), an artificial microRNAs (miRNAs) driven by a promoter (e.g., using an RNA polymerase II promoter or other suitable constitutive or inducible promoter), or an siRNA driven by a promoter (e.g., an RNA polymerase III promoter or other suitable constitutive or inducible promoter). A “self-complementary nucleic acid” refers to a nucleic acid capable of hybridizing with itself (i.e., folding back upon itself) to form a single-stranded duplex structure, due to the complementarity (e.g., base-pairing) of the nucleotides within the nucleic acid strand. Self-complementary nucleic acids can form a variety of secondary structures, such as hairpin loops, loops, bulges, junctions and internal bulges. Certain self-complementary nucleic acids (e.g., miRNA or a-miRNA (artificial miRNA)) perform regulatory functions, such as gene silencing. The terms “sequence identity”, “percent sequence identity”, or “percent identical” in the context of nucleic acid sequences refers to the residues in the two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over the full-length of the genome, the full-length of a gene coding sequence, or a fragment of at least about 500 to 5000 nucleotides, is desired. However, identity among smaller fragments, e.g. of at least about nine nucleotides, usually at least about 20 to 24 nucleotides, at least about 28 to 32 nucleotides, at least about 36 or more nucleotides, may also be desired. Similarly, “percent sequence identity” may be readily determined for amino acid sequences, over the full-length of a protein, or a fragment thereof. Suitably, a fragment is at least about 8 amino acids in length and may be up to about 700 amino acids. Examples of suitable fragments are described herein. Generally, when referring to “identity”, “homology”, or “similarity” between two different sequences, “identity”, “homology” or “similarity” is determined in reference to “aligned” sequences. “Aligned” sequences or “alignments” refer to multiple nucleic acid sequences or protein (amino acids) sequences, often containing corrections for missing or additional bases or amino acids as compared to a reference sequence. Alignments are performed using any of a variety of publicly or commercially available Multiple Sequence Alignment Programs. Examples of such programs include, “Clustal Omega”, “Clustal W”, “CAP Sequence Assembly”, “MAP”, and “MEME”, which are accessible through Web Servers on the internet. Other sources for such programs are known to those of skill in the art. Alternatively, Vector NTI utilities are also used. There are also a number of algorithms known in the art that can be used to measure nucleotide sequence identity, including those contained in the programs described above. As another example, polynucleotide sequences can be compared using Fasta™, a program in GCG Version 6.1. Fasta™ provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences. For instance, percent sequence identity between nucleic acid sequences can be determined using Fasta™ with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) as provided in GCG Version 6.1, herein incorporated by reference. Multiple sequence alignment programs are also available for amino acid sequences, e.g., the “Clustal Omega”, “Clustal X”, “MAP”, “PIMA”, “MSA”, “BLOCKMAKER”, “MEME”, and “Match-Box” programs. Generally, any of these programs are used at default settings, although one of skill in the art can alter these settings as needed. Alternatively, one of skill in the art can utilize another algorithm or computer program which provides at least the level of identity or alignment as that provided by the referenced algorithms and programs. See, e.g., J. D. Thomson et al, Nucl. Acids. Res., “A comprehensive comparison of multiple sequence alignments”, 27(13):2682-2690 (1999). It should be understood that the expression cassettes described herein are intended to be applied to the compositions and methods described across the Specification. Gene-Editing / Disruption of genes involved in retinal degeneration In certain embodiments, provided herein are expression cassettes that include a nucleic acid sequence encoding one or more elements of a gene editing system that targets and / or disrupts expression of a gene involved in retinal degeneration. In certain embodiments, the gene is selected from Table 1. As used herein, “gene editing system” refers to technologies or molecular machinery for modifying genetic material, typically with specificity for a particular gene or nucleic acid sequence (including, e.g., target sequences or motifs). Such gene editing systems are designed to modify a target site in the genome or introduce a mutation. As used herein, a “mutation” or “modification”, unless otherwise stated, can refer to any alteration of a genomic sequence, including but not limited to small nucleotide insertions or deletions (indels) or a larger deletion, insertion, or inversion. In certain embodiments, the introduction a mutation or modification is referred to as “editing” or “gene editing”. Terms such as “target site” and “target sequence”, unless indicated otherwise, are used herein to refer to a sequence that is recognized by one or more elements of a gene- editing system. For example, a sgRNA includes a sequence that binds (i.e., is complementary to) a target site or target sequence in the genome. In certain embodiments, the gene editing system is a Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) system that edits the sequence of a gene involved in retinal degeneration. In one embodiment, provided herein is a CRISPR / Cas dual vector system (see, e.g. WO 2016 / 176191, which is incorporated herein by reference). Alternatively, in certain embodiments, a suitable gene editing system includes a zinc-finger nuclease (ZFN) to induce DNA double-strand breaks, which may or may not be in conjunction with delivery of an exogenous DNA donor substrate (See, e.g., Ellis et al, Gene Therapy (epub January 2012) 20:35-42 which is incorporated herein by reference). In other embodiments, a suitable gene editing system includes a meganuclease (see, e.g., in US Patent 8,445,251; US 9,340,777; US 9,434,931; US 9,683,257, and WO 2018 / 195449, each of which is incorporated herein by reference) or transcription activator‐like (TAL) effector nucleases (TALENs). In certain embodiments, a suitable CRISPR gene editing system includes, at a minimum, a Cas9 enzyme and an sgRNA specific for a target site in the sequence of a gene involved in retinal degeneration. Accordingly, in one embodiment, the gene editing vector comprises a Cas9 gene as the editing enzyme and an sgRNA which is at least 20 nucleotides in length and specifically binds to a selected site in a gene involved in retinal degeneration 5 ' to a protospacer- adjacent motif (PAM) that is specifically recognized by the Cas9. In certain embodiments, the expression cassette or vector genome includes a nucleic acid sequence encoding the sgRNA molecule and a nucleic acid sequence encoding a Cas9 enzyme. In certain embodiments, the gene editing system also includes a donor or repair template. The expression cassette providing the donor template may be the same as the expression cassettes encoding the sgRNA and Cas9, or a different expression cassette. Thus, in certain embodiments, a dual-vector system (as described for example in WO 2016 / 176191) is provided, wherein the gene editing system includes an expression cassette comprising a Cas9 gene under control of regulatory sequences which direct its expression and a second expression cassette comprising a sgRNA and a donor template. “Cas9” (CRISPR associated protein 9) refers to family of RNA-guided DNA endonucleases which is characterized by two signature nuclease domains, RuvC (cleaves non-coding strand) and HNH (coding strand). Suitable bacterial sources of Cas9 include Staphylococcus aureus (SaCas9), Stapylococcus pyogenes (SpCas9), and Neisseria meningitides (KM Estelt et al, Nat Meth, 10:1116-21 (2013)). The wild-type coding sequences may be utilized in the constructs described herein. Alternatively, bacterial codons are optimized for expression in humans, e.g. using any of a variety of known human codon optimizing algorithms. Other endonucleases with similar properties may optionally be substituted. See, e.g., the public CRISPR database (db) accessible at crispr.u-psud.fr / crispr. CRISPR / Cas9 gene targeting requires a single guide RNA (sgRNA) that contains a targeting sequence (crRNA sequence) and a Cas9 nuclease-recruiting sequence (tracrRNA). The crRNA region is a 20-nucleotide sequence that is homologous to a target site and will direct Cas9 nuclease activity. Strategies for identifying suitable target sites in the genome while also eliminating off target effects are known to those of skill in the art (see, e.g., ChopChop available online at chopchop.cbu.uib.no / ). In another embodiment, the CRISPR nuclease may be Cpf1 (CRISPR from Prevotella and Francisella). Cpf1's preferred PAM is 5 '-TTN; this contrasts with that of SpCas9 (5'- NGG) and SaCas9 (5 '-NNGRRT; N=any nucleotide; R=adenine or guanine) in both genomic location and GC-content. While at least 16 Cpf1 nucleases have been identified, two humanized nucleases (AsCpf1 and LbCpf1) are particularly useful. See, www.addgene.Org / 69982 / sequences / #depositor-full (AsCpf1 sequences; and www.addgene.Org / 69988 / sequences / #depositor-full (LbCpf1 sequences), which are incorporated herein by reference. Further, Cpfl1 does not require a tracrRNA; allowing use of shorter guide RNAs (about 42 nucleotides) as compared to Cas9. Plasmids may be obtained from Addgene, a public plasmid database. As described herein, a gene editing system is utilized to introduce a mutation in a gene involved in retinal degeneration in target cell. In some embodiments, the target polynucleotide sequence is cleaved such that a double-strand break results. In some embodiments, the target polynucleotide sequence is cleaved such that a single-strand break results. In certain embodiments, the alteration is an insertion or deletion (indel), which can result in random insertion / deletion mutations at the site of junction as a result of non- homologous end joining. Indel mutations occurring within the coding region of a gene can result in frame-shift and a premature stop codon, and disrupt transcription. In certain embodiments, the gene editing system one or more elements of an RNA- targeting CRISPR system, such as a member of the Cas13 enzyme family and / or crRNA construct. The diverse Cas13 family contains at least four known subtypes, including Cas13a (formerly C2c2), Cas13b, Cas13c, and Cas13d. The Cas13 family is the only family of class 2 Cas enzymes known to exclusively target single-stranded RNA. Cas13 enzymes and systems are known in the art, see, e.g., US Patent No.10,362,616, Abudayyeh, et al, C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353, aaf5573 (2016); S. Shmakov, et al, Discovery and functional characterization of diverse class 2 CRISPR-Cas systems. Mol. Cell 60, 385–397 (2015); S. Shmakov, et al, Diversity and evolution of class 2 CRISPR-Cas systems. Nat. Rev. Microbiol.15, 169–182 (2017). A. A. Smargon, et al, Cas13b is a type VI-B CRISPR-associated RNA-guided RNase differentially regulated by accessory proteins Csx27 and Csx28. Mol. Cell 65, 618–630.e7 (2017); J. S. Gootenberg, et al, Nucleic acid detection with CRISPR-Cas13a / C2c2. Science 356, 438–442 (2017); O. O. Abudayyeh, et al, RNA targeting with CRISPR-Cas13. Nature 550, 280–284 (2017). Each of these documents is incorporated herein. A Cas13 protein uses a short crRNA that interacts with the Cas13 molecule through a stem loop and facilitates target binding and cleavage through a series of conformational changes in the Cas13 molecule. In certain embodiments, the Cas13 protein is Cas13a, Cas13b, Cas13c, or Cas13d. In one embodiment, the Cas13 comprises one or more mutations the HEPN domain(s). The Cas13d protein is a Class 2, Type VI CRISPR effector guided by a crRNA. Two higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domains have been found in the Cas13d, flanking a helical domain. See, for example, WO 2019 / 010384 Al, US 2019 / 0169595A1, Zhang C, et al. (2018). Structural Basis for the RNA-Guided Ribonuclease Activity of CRISPR-Cas13d. Cell 175, 212–223.e217, golden.com / wiki / CRISPR-Cas13d, and zlab.bio / cas13, which publication is incorporated herein by reference in its entirety. While the term Class 2, Type VI is a broader genus, of which Cas13d is exemplary, throughout the Specification, one of skill in the art would appreciate that the use of the terms “Cas13d” or “Cas13d and a variant thereof” also encompass other Class 2, Type VI proteins, and the terms can be interchangeable. Cas13d and a variant thereof includes, e.g., a wild type or naturally occurring Cas13d protein, an ortholog of a Cas13d, a functional variant thereof, or another modified variant as disclosed. Orthologs are genes in different species that evolved from a common ancestral gene by speciation. Normally, orthologs retain the same function in the course of evolution. In some embodiments, the Cas13d is selected from a RfxCas13d from Ruminococcus flavefaciens strain XPD3002, an AdmCas13d from Anaerobic digester metagenome 15706, EsCas13d from Eubacterium siraeum DSM15702, P1E0Cas13d from Gut metagenome assembly P1E0-k21, UrCas13d from Uncultured Ruminoccocus sp., RffCas13d from Ruminoccocus flavefaciens FD1, and RaCas13d from Ruminoccocus albus. In one embodiment, the Cas13d protein is a RfxCas13d or a variant thereof. The amino acid sequences of the Cas13d orthologs are publicly available. In one embodiment, the Cas13d has an amino acid sequence as provided by a Protein Data Bank (PDB) accession number 6OAW_B or 6OAW_A or 6E9F_A or 6E9E_A or 6IV9_A, or an amino acid sequence as provided by the UniProtKB identifier B0MS50 (B0MS50_9FIRM) or A0A1C5SD84 (A0A1C5SD84_9FIRM). Each of the sequences of these references is incorporated by reference herein in its entirety. The term “target RNA” refers to an RNA polynucleotide being or comprising the target sequence, including coding and non-coding transcripts. In other words, the target RNA may be an RNA polynucleotide or a part of a RNA polynucleotide to which a part of a clustered regularly interspaced short palindromic repeats (CRISPR) RNA (crRNA) is designed to have complementarity and to which the effector function mediated by the complex comprising CRISPR enzyme and a guide RNA (gRNA) is to be directed. In certain embodiments, a viral vector is used to deliver one more elements of a gene editing system. While the examples below describe use of AAV vectors and the following discussion focuses on AAV vectors, it will be understood that a different, partially or wholly integrating vector or virus may be used in the system in place of the gene editing vector and / or the vector carrying template. See, e.g., Jinek, M.; Chilynksi, K.; Fonfara, I.,; Hauer, M.,; Doudna, J.,; Charpentier, E., (August 17, 2012). “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity”. Science.337 (6069): 816–821. Bibcode:2012 Sci..337..816J. doi:10.1126 / science.1225829. PMID 22745249; US Patent 8,697,359; US 9,909,122, US 2017 / 0051312; US 2017 / 0137801; US 2017 / 0166893; US2017 / 0360048; US 2018 / 0002682, which are incorporated by reference in their entirety. In certain embodiments, a viral vector delivers one or more components of a genome editing system, such as CRISPR / Cas9 or CRISPR / Cas13. In another embodiment, a combination or dual AAV vector system is provided to deliver the components of the CRISPR system when co-administered to a subject (see, e.g. WO 2016 / 176191, which is incorporated by reference herein in its entirety). The vectors may be formulated together or separately and delivered essentially simultaneously, preferably by the same route. Expression cassettes can be delivered via any suitable delivery system. Suitable non- viral delivery systems are known in the art (see, e.g., Ramamoorth and Narvekar. J Clin Diagn Res.2015 Jan; 9(1):GE01-GE06, which is incorporated herein by reference) and can be readily selected by one of skill in the art and may include, e.g., naked DNA, naked RNA, dendrimers, PLGA, polymethacrylate, an inorganic particle, a lipid particle (e.g., a lipid nanoparticle or LNP), or a chitosan-based formulation. In certain embodiments, the vector is a non-viral plasmid that comprises an expression cassette described thereof, e.g., “naked DNA”, “naked plasmid DNA”, RNA, and mRNA; coupled with various compositions and nano particles, including, e.g., micelles, liposomes, cationic lipid - nucleic acid compositions, poly-glycan compositions and other polymers, lipid and / or cholesterol-based - nucleic acid conjugates, and other constructs such as are described herein. See, e.g., X. Su et al, Mol. Pharmaceutics, 2011, 8 (3), pp 774–787; web publication: March 21, 2011; WO2013 / 182683, WO 2010 / 053572 and WO 2012 / 170930, all of which are incorporated herein by reference. In certain embodiments, one or more nucleic acid sequences provided herein are delivered to ocular cells by a vector or a viral vector, of which many are known and available in the art. In one embodiment, provided is a vector comprising an expression cassette as described herein. In one embodiment, the vector is a non-viral vector. In a further embodiment, the non-viral vector is a plasmid. In another embodiment, the vector is a viral vector. Viral vectors include any virus suitable for gene therapy, including but not limited to a bocavirus, adenovirus, adeno-associated virus (AAV), herpes virus, lentivirus, retrovirus, or parvovirus. However, for ease of understanding, the adeno-associated virus is referenced herein as an exemplary viral vector. A “vector” as used herein is a biological or chemical moiety comprising a nucleic acid sequence which can be introduced into an appropriate target cell for replication or expression of a nucleic acid sequence. Examples of a vector include but are not limited to a recombinant virus, a plasmid, Lipoplexes, a Polymersome, Polyplexes, a dendrimer, a cell penetrating peptide (CPP) conjugate, a magnetic particle, or a nanoparticle. In one embodiment, a vector is a nucleic acid molecule having an exogenous or heterologous engineered nucleic acid encoding a functional gene product, which can then be introduced into an appropriate target cell. Such vectors preferably have one or more origins of replication, and one or more site into which the recombinant DNA can be inserted. Vectors often have means by which cells with vectors can be selected from those without, e.g., they encode drug resistance genes. Common vectors include plasmids, viral genomes, and “artificial chromosomes”. Conventional methods of generation, production, characterization, or quantification of the vectors are available to one of skill in the art. As used herein, a recombinant viral vector is any suitable viral vector which targets the desired cell(s). Thus, the recombinant viral vectors described herein preferably target one or more of the cells and tissues affected by an ocular condition, including rods and / or cones of the eye. The examples provide illustrative recombinant adeno-associated viruses (rAAV). However, other suitable viral vectors may include, e.g., a recombinant adenovirus, a recombinant parvovirus such a recombinant bocavirus, a hybrid AAV / bocavirus, a recombinant herpes simplex virus, a recombinant retrovirus, or a recombinant lentivirus. In preferred embodiments, these recombinant viruses are replication-defective. As used herein, the terms “recombinant AAV”, “rAAV”, and “AAV vector” used interchangeably, mean, without limitation, an AAV vector comprising a capsid protein and a vector genome packaged therein, wherein the vector genome comprises a nucleic acid heterologous to the AAV. In one embodiment, the capsid protein is a non-naturally occurring capsid. Such an artificial capsid may be generated by any suitable technique, using a selected AAV sequence (e.g., a fragment of a vp1 capsid protein) in combination with heterologous sequences which may be obtained from a different selected AAV, non-contiguous portions of the same AAV, from a non-AAV viral source, or from a non-viral source. An artificial AAV may be, without limitation, a pseudotyped AAV, a chimeric AAV capsid, a recombinant AAV capsid, or a “humanized” AAV capsid. Pseudotyped vectors, wherein the capsid of one AAV is replaced with a heterologous capsid protein, are useful in the invention. In one embodiment, AAV2 / 5 and AAV2 / 8 are exemplary pseudotyped vectors. The selected genetic element may be delivered by any suitable method, including transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. The methods used to make such constructs are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Green and Sambrook, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY (2012). A “replication-defective” virus or viral vector refers to a synthetic or artificial viral particle in which an expression cassette containing a gene of interest is packaged in a viral capsid or envelope, where any viral genomic sequences also packaged within the viral capsid or envelope are replication-deficient; i.e., they cannot generate progeny virions but retain the ability to infect target cells. In one embodiment, the genome of the viral vector does not include genes encoding the enzymes required to replicate (the genome can be engineered to be “gutless” - containing only the gene of interest flanked by the signals required for amplification and packaging of the artificial genome), but these genes may be supplied during production. Therefore, it is deemed safe for use in gene therapy since replication and infection by progeny virions cannot occur except in the presence of the viral enzyme required for replication. Such replication-defective viruses may be adeno-associated viruses (AAV), adenoviruses, lentiviruses (integrating or non-integrating), or another suitable virus source. “Plasmid” or “plasmid vector” generally is designated herein by a lower-case p preceded and / or followed by a vector name. Plasmids, other cloning and expression vectors, properties thereof, and constructing / manipulating methods thereof that can be used in accordance with the present invention are readily apparent to those of skill in the art. In certain embodiments, the expression cassettes described herein are engineered into a suitable genetic element (a vector) useful for generating viral vectors and / or for delivery to a host cell, e.g., naked DNA, phage, transposon, cosmid, episome, etc., which transfers the sequences carried thereon. The selected vector may be delivered by any suitable method, including transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. The methods used to make such constructs are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY. As used herein, the term “host cell” may refer to the packaging cell line in which a vector (e.g., a recombinant AAV) is produced from a production plasmid. In the alternative, the term “host cell” may refer to any target cell in which expression an expression cassette or a miRNA or modified snRNA described herein is desired, i.e., a photoreceptor cell. Thus, a “host cell,” refers to a prokaryotic or eukaryotic cell that contains exogenous or heterologous DNA that has been introduced into the cell by any means, e.g., electroporation, calcium phosphate precipitation, microinjection, transformation, viral infection, transfection, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. In certain embodiments herein, the term “host cell” refers to cultures of cells of various mammalian species for in vitro assessment of the compositions described herein. In other embodiments herein, the term “host cell” refers to the cells employed to generate and package the viral vector or recombinant virus. As used herein, a “vector genome” refers to the nucleic acid sequence packaged inside a viral vector. In one example, a vector genome contains, at a minimum, from 5’ to 3’, a vector-specific sequence, a nucleic acid sequence as provided herein for reducing gene expression in a target cell, where the vector-specific sequence may be a terminal repeat sequence that specifically packages the vector genome into a viral vector capsid or envelope protein. In certain embodiments, the vector genome contains, at a minimum, from 5’ to 3’, a 5’ AAV ITR sequence, an expression cassette, and a 3’ AAV inverted terminal repeat (ITR) sequence, including intervening sequences. In certain embodiments, for example, AAV inverted terminal repeats are utilized for packaging into AAV and certain other parvovirus capsids. Lentivirus long terminal repeats may be utilized where packaging into a lentiviral vector is desired. Similarly, other terminal repeats (e.g., a retroviral long terminal repeat), or the like may be selected. An AAV vector is an AAV nuclease (e.g., DNase)-resistant particle having an AAV protein capsid into which is packaged expression cassette flanked by AAV inverted terminal repeat sequences (ITRs) for delivery to target cells. A nuclease-resistant recombinant AAV (rAAV) indicates that the AAV capsid has fully assembled and protects these packaged vector genome sequences from degradation (digestion) during nuclease incubation steps designed to remove contaminating nucleic acids which may be present from the production process. In many instances, the rAAV described herein is DNase resistant. An AAV capsid is composed of 60 capsid (cap) protein subunits, VP1, VP2, and VP3, that are arranged in an icosahedral symmetry in a ratio of approximately 1:1:10 to 1:1:20, depending upon the selected AAV. Various AAVs may be selected as sources for capsids of AAV vectors as identified above. See, e.g., US Published Patent Application No.2007- 0036760-A1; US Published Patent Application No.2009-0197338-A1; EP 1310571. See also, WO 2003 / 042397 (AAV7 and other simian AAV), US Patent 7790449 and US Patent 7282199 (AAV8), WO 2005 / 033321 and US 7,906,111 (AAV9), and WO 2006 / 110689, and WO 2003 / 042397 (AAVrh10). These documents also describe other AAV which may be selected for generating AAV and are incorporated by reference. Among the AAVs isolated or engineered from human or non-human primates (NHP) and well characterized, human AAV2 is the first AAV that was developed as a gene transfer vector; it has been widely used for efficient gene transfer experiments in different target tissues and animal models. Unless otherwise specified, the AAV capsid, ITRs, and other selected AAV components described herein, may be readily selected from among any AAV, including, without limitation, the AAVs commonly identified as AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV8bp, AAV7m8 and AAVAnc80. See, e.g., WO 2005 / 033321, which is incorporated herein by reference. The rAAV particles provided herein may be of any AAV serotype, including any derivative or pseudotype (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 2 / 1, 2 / 5, 2 / 8, or 2 / 9). As used herein, the serotype of an rAAV viral vector (e.g., an rAAV particle) refers to the serotype of the capsid proteins of the recombinant virus. In some embodiments, the rAAV particle is not AAV2. In certain embodiments, the rAAV particle is AAV2. In some embodiments, the rAAV particle is AAV6. In some embodiments, the rAAV particle is an AAV6 serotype comprising an rAAV capsid protein as described herein. Non-limiting examples of derivatives and pseudotypes include rAAV2 / l , rAAV2 / 5, rAAV2 / 8, rAAV2 / 9, AAV2-AAV3 hybrid, AAVrh.10, AAVhu.14, AAV3a / 3b, AAVrh32.33, AAV-HSC15, AAV-HSC17, AAVhu.37, AAVrh.8, CHt-P6, AAV2.5, AAV6.2, AAV2i8, AAV-HSC15 / 17, AAVM41, AAV9.45, AAV6(Y445F / Y731F), AAV2.5T, AAV-HAE1 / 2, AAV clone 32 / 83, AAVShHIO, AAV2 (Y->F), AAV8 (Y733F), AAV2.15, AAV2.4, AAVM41, and AAVr3.45. Such AAV serotypes and derivatives / pseudotypes, and methods of producing such derivatives / pseudotypes are known in the art (see, e.g., Mol Ther.2012 Apr;20(4):699- 708. doi: 10.1038 / mt.2011.287. Epub 2012 Jan 24. The AAV vector toolkit: poised at the clinical crossroads. Asokan Al, Schaffer DV, Samulski RJ.). In certain embodiments, the rAAV particle is a pseudotyped rAAV particle, which comprises (a) a nucleic acid vector comprising ITRs from one serotype (e.g., AAV2) and (b) a capsid comprised of capsid proteins derived from another serotype (e.g., AAVl, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, or AAV10). Methods for producing and using pseudotyped rAAV vectors are known in the art (see, e.g., Duan et al., J. Virol., 75:7662-7671, 2001; Halbert et al., J. Virol., 74: 1524-1532, 2000; Zolotukhin et al., Methods, 28: 158-167, 2002; and Auricchio et al., Hum. Molec. Genet., 10:3075-3081, 2001). As used herein, a “stock” of rAAV refers to a population of rAAV. Despite heterogeneity in their capsid proteins due to deamidation, rAAV in a stock are expected to share an identical vector genome. A stock can include rAAV having capsids with, for example, heterogeneous deamidation patterns characteristic of the selected AAV capsid proteins and a selected production system. The stock may be produced from a single production system or pooled from multiple runs of the production system. A variety of production systems, including but not limited to those described herein, may be selected. As used herein, relating to AAV, the term “variant” means any AAV sequence which is derived from a known AAV sequence, including those sharing at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or greater sequence identity over the amino acid or nucleic acid sequence. In another embodiment, the AAV capsid includes variants which may include up to about 10% variation from any described or known AAV capsid sequence. That is, the AAV capsid shares about 90% identity to about 99.9% identity, about 95% to about 99% identity or about 97% to about 98% identity to an AAV capsid provided herein and / or known in the art. In one embodiment, the AAV capsid shares at least 95% identity with an AAV capsid. When determining the percent identity of an AAV capsid, the comparison may be made over any of the variable proteins (e.g., vp1, vp2, or vp3). In one embodiment, the AAV capsid shares at least 95% identity with the AAV8 vp3. In another embodiment, a self-complementary AAV is used. The ITR sequences or other AAV components may be readily isolated or engineered using techniques available to those of skill in the art from an AAV. Such AAV may be isolated, engineered, or obtained from academic, commercial, or public sources (e.g., the American Type Culture Collection, Manassas, VA). Alternatively, the AAV sequences may be engineered through synthetic or other suitable means by reference to published sequences such as are available in the literature or in databases such as, e.g., GenBank, PubMed, or the like. AAV vectors may be engineered by conventional molecular biology techniques, making it possible to optimize these particles for cell specific delivery of nucleic acid sequences, for minimizing immunogenicity, for tuning stability and particle lifetime, for efficient degradation, for accurate delivery to the nucleus, etc. In one aspect, provided herein is an AAV vector comprising an AAV capsid and an expression cassette, wherein the expression cassette comprises a nucleic acid sequence that encodes an RNA interference construct (e.g., siRNA, shRNA, or miRNA) for inhibiting or reducing gene expression or activity in a target cell. In certain embodiments, an AAV vector comprises an AAV capsid and an expression cassette, wherein the expression cassette comprises one or more components of a gene editing system (e.g., CRISPR / Cas enzyme, guide RNA, crRNA) for inhibiting or reducing gene expression or activity in a target cell. The nucleic acid packaged in the AAV capsid sequence includes AAV ITR sequences flanking the expression cassette. The expression cassette comprises a photoreceptor cell specific promoter, as described herein. The ITRs are the genetic elements responsible for the replication and packaging of the genome during vector production and are the only viral cis elements required to generate rAAV. In one embodiment, the ITRs are from an AAV different than that supplying a capsid. In a preferred embodiment, the ITR sequences from AAV2, or the deleted version thereof (ΔITR), which may be used for convenience and to accelerate regulatory approval. However, ITRs from other AAV sources may be selected. Where the source of the ITRs is from AAV2 and the AAV capsid is from another AAV source, the resulting vector may be termed pseudotyped. Typically, AAV vector genome comprises an AAV 5’ ITR, the nucleic acid sequences encoding the gene product(s) and any regulatory sequences, and an AAV 3’ ITR. However, other configurations of these elements may be suitable. In one embodiment, a self- complementary AAV is provided. A shortened version of the 5’ ITR, termed ΔITR, has been described in which the D-sequence and terminal resolution site (trs) are deleted. In certain embodiments, the vector genome includes a shortened AAV2 ITR of 130 base pairs, wherein the external “a” element is deleted. The shortened ITR is reverted back to the wild-type length of 145 base pairs during vector DNA amplification using the internal A element as a template. In other embodiments, the full-length AAV 5’ and 3’ ITRs are used. In certain embodiments, the regulatory sequences are selected such that the total rAAV vector genome is about 2.0 to about 5.5 kilobases in size. In certain embodiments, the regulatory sequences are selected such that the total rAAV vector genome is about 2.9 to about 5.5 kilobases in size. In certain embodiments, the regulatory sequences are selected such that the total rAAV vector genome is about 2.9 kb in size. In certain embodiments, it is desirable that the rAAV vector genome approximate the size of the native AAV genome. Thus, in certain embodiments, the regulatory sequences are selected such that the total rAAV vector genome is about 4.7 kb in size. In certain embodiments, the total rAAV vector genome is less about 5.2 kb in size. The size of the vector genome may be manipulated based on the size of the regulatory sequences including the promoter, enhancer, intron, poly A, etc. See, Wu et al., Mol Ther, Jan 2010, 18(1):80-6, which is incorporated herein by reference. The recombinant adeno-associated virus (AAV) described herein may be generated using techniques which are known. See, e.g., WO 2003 / 042397; WO 2005 / 033321, WO 2006 / 110689; US 7588772 B2. Such a method involves culturing a host cell which contains a nucleic acid sequence encoding an AAV capsid; a functional rep gene; an expression cassette as described herein flanked by AAV inverted terminal repeats (ITRs); and sufficient helper functions to permit packaging of the expression cassette into the AAV capsid protein. Also provided herein is the host cell which contains a nucleic acid sequence encoding an AAV capsid; a functional rep gene; a vector genome as described; and sufficient helper functions to permit packaging of the vector genome into the AAV capsid protein. In one embodiment, the host cell is a HEK 293 cell. These methods are described in more detail in WO2017160360 A2, which is incorporated by reference herein. Other methods of producing rAAV available to one of skill in the art may be utilized. Suitable methods may include without limitation, baculovirus expression system or production via yeast. See, e.g., Robert M. Kotin, Large-scale recombinant adeno-associated virus production. Hum Mol Genet.2011 Apr 15; 20(R1): R2–R6. Published online 2011 Apr 29. doi: 10.1093 / hmg / ddr141; Aucoin MG et al., Production of adeno-associated viral vectors in insect cells using triple infection: optimization of baculovirus concentration ratios. Biotechnol Bioeng.2006 Dec 20;95(6):1081-92; SAMI S. THAKUR, Production of Recombinant Adeno-associated viral vectors in yeast. Thesis presented to the Graduate School of the University of Florida, 2012; Kondratov O et al. Direct Head-to-Head Evaluation of Recombinant Adeno-associated Viral Vectors Manufactured in Human versus Insect Cells, Mol Ther.2017 Aug 10. pii: S1525-0016(17)30362-3. doi: 10.1016 / j.ymthe.2017.08.003. [Epub ahead of print]; Mietzsch M et al, OneBac 2.0: Sf9 Cell Lines for Production of AAV1, AAV2, and AAV8 Vectors with Minimal Encapsidation of Foreign DNA. Hum Gene Ther Methods.2017 Feb;28(1):15-22. doi: 10.1089 / hgtb.2016.164.; Li L et al. Production and characterization of novel recombinant adeno-associated virus replicative-form genomes: a eukaryotic source of DNA for gene transfer. PLoS One.2013 Aug 1;8(8):e69879. doi: 10.1371 / journal.pone.0069879. Print 2013; Galibert L et al, Latest developments in the large-scale production of adeno-associated virus vectors in insect cells toward the treatment of neuromuscular diseases. J Invertebr Pathol.2011 Jul;107 Suppl:S80-93. doi: 10.1016 / j.jip.2011.05.008; and Kotin RM, Large- scale recombinant adeno-associated virus production. Hum Mol Genet.2011 Apr 15;20(R1):R2-6. doi: 10.1093 / hmg / ddr141. Epub 2011 Apr 29. Conventional methods for characterization or quantification of rAAV are available to one of skill in the art. To calculate empty and full particle content, VP3 band volumes for a selected sample (e.g., in examples herein an iodixanol gradient-purified preparation where # of GC = # of particles) are plotted against GC particles loaded. The resulting linear equation (y = mx+c) is used to calculate the number of particles in the band volumes of the test article peaks. The number of particles (pt) per 20 µL loaded is then multiplied by 50 to give particles (pt) / mL. Pt / mL divided by GC / mL gives the ratio of particles to genome copies (pt / GC). Pt / mL–GC / mL gives empty pt / mL. Empty pt / mL divided by pt / mL and x 100 gives the percentage of empty particles. Generally, methods for assaying for empty capsids and AAV vector particles with packaged genomes have been known in the art. See, e.g., Grimm et al., Gene Therapy (1999) 6:1322-1330; Sommer et al., Molec. Ther. (2003) 7:122-128. To test for denatured capsid, the methods include subjecting the treated AAV stock to SDS- polyacrylamide gel electrophoresis, consisting of any gel capable of separating the three capsid proteins, for example, a gradient gel containing 3-8% Tris-acetate in the buffer, then running the gel until sample material is separated, and blotting the gel onto nylon or nitrocellulose membranes, preferably nylon. Anti-AAV capsid antibodies are then used as the primary antibodies that bind to denatured capsid proteins, preferably an anti-AAV capsid monoclonal antibody, most preferably the B1 anti-AAV-2 monoclonal antibody (Wobus et al., J. Viral. (2000) 74:9281-9293). A secondary antibody is then used, one that binds to the primary antibody and contains a means for detecting binding with the primary antibody, more preferably an anti-IgG antibody containing a detection molecule covalently bound to it, most preferably a sheep anti-mouse IgG antibody covalently linked to horseradish peroxidase. A method for detecting binding is used to semi-quantitatively determine binding between the primary and secondary antibodies, preferably a detection method capable of detecting radioactive isotope emissions, electromagnetic radiation, or colorimetric changes, most preferably a chemiluminescence detection kit. For example, for SDS-PAGE, samples from column fractions can be taken and heated in SDS-PAGE loading buffer containing reducing agent (e.g., DTT), and capsid proteins were resolved on pre-cast gradient polyacrylamide gels (e.g., Novex). Silver staining may be performed using SilverXpress (Invitrogen, CA) according to the manufacturer's instructions or other suitable staining method, i.e. SYPRO ruby or Coomassie stains. In one embodiment, the concentration of AAV vector genomes (vg) in column fractions can be measured by quantitative real time PCR (Q-PCR). Samples are diluted and digested with DNase I (or another suitable nuclease) to remove exogenous DNA. After inactivation of the nuclease, the samples are further diluted and amplified using primers and a TaqMan™ fluorogenic probe specific for the DNA sequence between the primers. The number of cycles required to reach a defined level of fluorescence (threshold cycle, Ct) is measured for each sample on an Applied Biosystems Prism 7700 Sequence Detection System. Plasmid DNA containing identical sequences to that contained in the AAV vector is employed to generate a standard curve in the Q-PCR reaction. The cycle threshold (Ct) values obtained from the samples are used to determine vector genome titer by normalizing it to the Ct value of the plasmid standard curve. End-point assays based on the digital PCR can also be used. In one aspect, an optimized q-PCR method is used which utilizes a broad-spectrum serine protease, e.g., proteinase K (such as is commercially available from Qiagen). More particularly, the optimized qPCR genome titer assay is similar to a standard assay, except that after the DNase I digestion, samples are diluted with proteinase K buffer and treated with proteinase K followed by heat inactivation. Suitably samples are diluted with proteinase K buffer in an amount equal to the sample size. The proteinase K buffer may be concentrated to 2-fold or higher. Typically, proteinase K treatment is about 0.2 mg / mL, but may be varied from 0.1 mg / mL to about 1 mg / mL. The treatment step is generally conducted at about 55 °C for about 15 minutes, but may be performed at a lower temperature (e.g., about 37 °C to about 50 °C) over a longer time period (e.g., about 20 minutes to about 30 minutes), or a higher temperature (e.g., up to about 60 °C) for a shorter time period (e.g., about 5 to 10 minutes). Similarly, heat inactivation is generally at about 95 °C for about 15 minutes, but the temperature may be lowered (e.g., about 70 to about 90 °C) and the time extended (e.g., about 20 minutes to about 30 minutes). Samples are then diluted (e.g., 1000 fold) and subjected to TaqMan analysis as described in the standard assay. Additionally, or alternatively, droplet digital PCR (ddPCR) may be used. For example, methods for determining single-stranded and self-complementary AAV vector genome titers by ddPCR have been described. See, e.g., M. Lock et al, Hu Gene Therapy Methods, Hum Gene Ther Methods.2014 Apr;25(2):115-25. doi: 10.1089 / hgtb.2013.131. Epub 2014 Feb 14. It should be understood that the vectors described herein are intended to be applied to other compositions and methods described across the Specification. Pharmaceutical Compositions In certain embodiments, the compositions provided herein are included in a final formulation suitable for delivery to a subject, e.g., is an aqueous liquid suspension buffered to a physiologically compatible pH and salt concentration. Optionally, one or more surfactants are present in the formulation. In another embodiment, the composition may be transported as a concentrate which is diluted for administration to a subject. In other embodiments, the composition may be lyophilized and reconstituted at the time of administration. In certain embodiments, the suspension further comprises a surfactant, preservative, excipients, and / or buffer dissolved in the aqueous suspending liquid. In one embodiment, the buffer is PBS. Various suitable solutions are known including those which include one or more of: buffering saline, a surfactant, and a physiologically compatible salt or mixture of salts adjusted to an ionic strength equivalent to about 100 mM sodium chloride (NaCl) to about 250 mM sodium chloride, or a physiologically compatible salt adjusted to an equivalent ionic concentration. A suitable surfactant, or combination of surfactants, may be selected from among Poloxamers, i.e., nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol. In one embodiment, the formulation contains a poloxamer. The pH may be in the range of 6.5 to 8.5, or 7 to 8.5, or 7.5 to 8. As the pH of the cerebrospinal fluid is about 7.28 to about 7.32, for intrathecal delivery, a pH within this range may be desired; whereas for intravenous delivery, a pH of 6.8 to about 7.2 may be desired. However, other pHs within the broadest ranges and these subranges may be selected for other routes of delivery. Additionally provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a vector comprising a nucleotide sequence encoding an miRNA or modified siRNA operatively linked to a photoreceptor cell-specific promoter as described herein. As used herein, “carrier” includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions. The phrase “pharmaceutically-acceptable” refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a host. Delivery vehicles such as liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles, and the like, may be used for the introduction of the compositions of the present invention into suitable host cells. Suitable carriers may be readily selected by one of skill in the art in view of the indication for which the vector is directed. For example, one suitable carrier includes saline, which may be formulated with a variety of buffering solutions (e.g., phosphate buffered saline). Other exemplary carriers include sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil, and water. The selection of the carrier is not a limitation of the present invention. Other conventional pharmaceutically acceptable carrier, such as preservatives, or chemical stabilizers. Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, and parachlorophenol. Suitable chemical stabilizers include gelatin and albumin. As used herein, the term “dosage” or “amount” can refer to the total dosage or amount delivered to the subject in the course of treatment, or the dosage or amount delivered in a single unit (or multiple unit or split dosage) administration. The aqueous suspension or pharmaceutical compositions described herein are designed for delivery to subjects in need thereof by any suitable route or a combination of different routes. The pharmaceutical compositions described herein are designed for delivery to subjects in need thereof by any suitable route or a combination of different routes. In one aspect, provided herein is a pharmaceutical composition comprising a dosage of a vector as described herein in a formulation buffer. As used herein, the term “dosage” can refer to the total dosage delivered to the subject in the course of treatment, or the amount delivered in a single unit (or multiple unit or split dosage) administration. The pharmaceutical virus compositions can be formulated in dosage units to contain an amount of replication- defective AAV vector carrying a nucleic acid sequences as described herein that is in the range of about 1.0 x 109vg (vector genomes) / mL to about 1.0 x 1015vg / mL including all integers or fractional amounts within the range. In one embodiment, the compositions are formulated to contain at least 1x109, 2x109, 3x109, 4x109, 5x109, 6x109, 7x109, 8x109, or 9x109vg / mL including all integers or fractional amounts within the range. In another embodiment, the compositions are formulated to contain at least 1x1010, 2x1010, 3x1010, 4x1010, 5x1010, 6x1010, 7x1010, 8x1010, or 9x1010vg / mL including all integers or fractional amounts within the range. In another embodiment, the compositions are formulated to contain at least 1x1011, 2x1011, 3x1011, 4x1011, 5x1011, 6x1011, 7x1011, 8x1011, or 9x1011vg / mL including all integers or fractional amounts within the range. In another embodiment, the compositions are formulated to contain at least 1x1012, 2x1012, 3x1012, 4x1012, 5x1012, 6x1012, 7x1012, 8x1012, or 9x1012vg / mL including all integers or fractional amounts within the range. In another embodiment, the compositions are formulated to contain at least 1x1013, 2x1013, 3x1013, 4x1013, 5x1013, 6x1013, 7x1013, 8x1013, or 9x1013vg / mL including all integers or fractional amounts within the range. In another embodiment, the compositions are formulated to contain at least 1x1014, 2x1014, 3x1014, 4x1014, 5x1014, 6x1014, 7x1014, 8x1014, or 9x1014vg / mL including all integers or fractional amounts within the range. In another embodiment, the compositions are formulated to contain at least 1x1015, 2x1015, 3x1015, 4x1015, 5x1015, 6x1015, 7x1015, 8x1015, or 9x1015vg / mL including all integers or fractional amounts within the range. In one embodiment, for human application the dose can range from 1x1010to about 1x1012vg / mL including all integers or fractional amounts within the range. All dosages may be measured by any known method, including as measured by oqPCR or digital droplet PCR (ddPCR) as described in, e.g., M. Lock et al, Hum Gene Ther Methods. 2014 Apr;25(2):115-25. doi: 10.1089 / hgtb.2013.131, which is incorporated herein by reference. These above doses may be administered in a variety of volumes of carrier, excipient or buffer formulation, ranging from about 25 to about 1000 microliters, including all numbers within the range, depending on the size of the area to be treated, the viral titer used, the route of administration, and the desired effect of the method. In one embodiment, the volume of carrier, excipient or buffer is at least about 25 µL. In one embodiment, the volume is about 50 µL. In another embodiment, the volume is about 75 µL. In another embodiment, the volume is about 100 µL. In another embodiment, the volume is about 125 µL. In another embodiment, the volume is about 150 µL. In another embodiment, the volume is about 175 µL. In yet another embodiment, the volume is about 200 µL. In another embodiment, the volume is about 225 µL. In yet another embodiment, the volume is about 250 µL. In yet another embodiment, the volume is about 275 µL. In yet another embodiment, the volume is about 300 µL. In yet another embodiment, the volume is about 325 µL. In another embodiment, the volume is about 350 µL. In another embodiment, the volume is about 375 µL. In another embodiment, the volume is about 400 µL. In another embodiment, the volume is about 450 µL. In another embodiment, the volume is about 500 µL. In another embodiment, the volume is about 550 µL. In another embodiment, the volume is about 600 µL. In another embodiment, the volume is about 650 µL. In another embodiment, the volume is about 700 µL. In another embodiment, the volume is about 800 µL. In another embodiment, the volume is about or at least 100 µL. In another embodiment, the volume is between about 100 to 250 µL. In another embodiment, the volume is between about 150 and 800 µL. In another embodiment, the volume is between about 700 and 1000 µL. In another embodiment, the volume is between about 250 and 500 µL. In the case of AAV vectors, quantification of the genome copies (“GC”), vector genomes (“VG”), or virus particles may be used as the measure of the dose contained in the formulation or suspension. Any method known in the art can be used to determine the genome copy (GC) number of the replication-defective virus compositions of the invention. One method for performing AAV GC number titration is as follows: Purified AAV vector samples are first treated with DNase to eliminate un-encapsidated AAV genome DNA or contaminating plasmid DNA from the production process. The DNase resistant particles are then subjected to heat treatment to release the genome from the capsid. The released genomes are then quantitated by real-time PCR using primer / probe sets targeting specific region of the viral genome (usually the transgene or the poly A signal). See, e.g.,S.K. McLaughlin et al, 1988 J. Virol., 62:1963, which is incorporated by reference in its entirety. In certain embodiments, nucleic acid compositions described herein are formulated in a nanoparticle. In certain embodiments, nucleic acid compositions described herein are formulated in a lipid nanoparticle. In certain embodiments, nucleic acid compositions described herein are formulated in a lipid-polycation complex, referred to as a cationic lipid nanoparticle. The formation of the lipid nanoparticle may be accomplished by methods known in the art and / or as described in U.S. Pub. No.20120178702, herein incorporated by reference in its entirety. As a non-limiting example, the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyomithine and / or polyarginine and the cationic peptides described in International Pub. No. WO 2012 / 013326 or US Patent Pub. No. US 2013 / 0142818; each of which is herein incorporated by reference in its entirety. In certain embodiments, nucleic acid compositions described herein are formulated in a lipid nanoparticle that includes a non-cationic lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE). It should be understood that the pharmaceutical compositions described herein are intended to be applied to other compositions and methods described across the Specification. Methods In certain embodiments, an expression cassette, nucleic acid, or a viral or non-viral vector comprising a photoreceptor-cell specific promoter as described herein is used in preparing a medicament. In certain embodiments, uses of the same for treatment of an ocular disease in a subject in need thereof are provided. As used herein, the term “treatment” or “treating” is defined encompassing administering to a subject one or more compositions described herein for the purposes of amelioration of one or more symptoms of an ocular disease. “Treatment” can thus include one or more of reducing onset or progression of disease, preventing disease, reducing the severity of the disease symptoms, retarding their progression, removing the disease symptoms, delaying progression of disease, or increasing efficacy of therapy in a given subject. The desired result will depend upon the active agent being administered. For example, an effective amount of a rAAV particle may be an amount of the particle that is capable of transferring a heterologous nucleic acid to a host organ, tissue, or cell. A “therapeutically effective amount” of a composition provided herein is delivered to a subject to achieve a desired result or to reach a therapeutic goal. By “administering” or “route of administration” is delivery of a therapy described herein (e.g. a rAAV comprising an RNA interference sequence), with or without a pharmaceutical carrier or excipient, of the subject. In certain embodiments, the administration is repeated periodically. In certain embodiments, a composition is administered direct to an eye. In certain embodiments, the route of administration is ocular delivery, subretinal injection, intra-retinal injection, or intravitreal injection. Routes of administration may be combined, if desired. In certain embodiments, the methods provide herein include administration of nucleic acid molecules and / or vectors described herein in a single composition or multiple compositions. Optionally, two or more different AAV may be delivered, or multiple viruses [see, e.g., WO202011 / 126808 and WO 2013 / 049493]. In another embodiment, multiple viruses may contain different replication-defective viruses (e.g., AAV and adenovirus), alone or in combination with proteins. In another embodiment, the amount of the vectors, the virus and the replication- defective virus described herein are administered in a range of about 1.0 x 107vector genomes (VG) per eye to about 1.0 x 1015VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x107, 2x107, 3x107, 4x107, 5x107, 6x107, 7x107, 8x107, or 9x107VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x108, 2x108, 3x108, 4x108, 5x108, 6x108, 7x108, 8x108, or 9x108VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x109, 2x109, 3x109, 4x109, 5x109, 6x109, 7x109, 8x109, or 9x109VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x1010, 2x1010, 3x1010, 4x1010, 5x1010, 6x1010, 7x1010, 8x1010, or 9x1010VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x1011, 2x1011, 3x1011, 4x1011, 5x1011, 6x1011, 7x1011, 8x1011, or 9x1011VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x1012, 2x1012, 3x1012, 4x1012, 5x1012, 6x1012, 7x1012, 8x1012, or 9x1012VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x1013, 2x1013, 3x1013, 4x1013, 5x1013, 6x1013, 7x1013, 8x1013, or 9x1013VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x1014, 2x1014, 3x1014, 4x1014, 5x1014, 6x1014, 7x1014, 8x1014, or 9x1014VG per eye including all integers or fractional amounts within the range. In one embodiment, the amount thereof is at least 1x1015, 2x1015, 3x1015, 4x1015, 5x1015, 6x1015, 7x1015, 8x1015, or 9x1015VG per eye including all integers or fractional amounts within the range. In certain embodiments, the method comprises delivery of a dose ranging from 1x109to about 1x1013VG per eye per dose including all integers or fractional amounts within the range. In certain embodiments, the method comprises delivery of the vector in an aqueous suspension. In another embodiment, the method comprises administering the rAAV described herein in a dosage of from about 1 x 1012to 1 x 1013VG in a volume about or at least 150 microliters. As used herein, the term “ocular cells” refers to any cell in, or associated with the function of, the eye. The term may refer to any one of photoreceptor cells, including rod, cone and photosensitive ganglion cells or retinal pigment epithelium (RPE) cells. In certain embodiments, the ocular cells are the photoreceptor cells. In certain embodiments the photoreceptor cells are rod photoreceptor cells or cone photoreceptor cells In other embodiments, the ocular cells are cones, rods, or cones and rods. In certain embodiments, the compositions provided herein are administered to a subject in need of treatment. In certain embodiments, the subject has or is suspected of having one or more conditions, diseases, or disorders of the eye. In certain embodiments, the subject has, or is at risk of developing retinitis pigmentosa (autosomal dominant, autosomal recessive, or X-linked), Leber's congenital amaurosis, cone or cone-rod dystrophy, Usher syndrome, macular degeneration, Stargardt's disease, age-related macular degeneration, trauma-induced retinal degeneration, or retinal detachment. In certain embodiments, the subject has been identified as having expression of a gene involved in retinal degeneration in cells of the eye. In certain embodiments, the composition is administered before disease onset. In another embodiment, the composition is administered prior to the initiation of vision impairment or loss. In another embodiment, the composition is administered after initiation of vision impairment or loss. In certain embodiments, the composition is readministered at a later date. Optionally, more than one readministration is permitted. Such readministration may be with the same type of vector, a different viral vector, or via non-viral delivery as described herein. In certain embodiments, the vector is readministered to the patient to a different portion of the initially injected retina. In one embodiment, the vector is readministered to the patient to the same portion of the initially injected retina. In certain embodiments, the subject has about 10% or more photoreceptor damage / loss. In another embodiment, the subject has about 20% or more photoreceptor damage / loss. In another embodiment, the subject has about 30% or more photoreceptor damage / loss. In another embodiment, the subject has about 40% or more photoreceptor damage / loss. In another embodiment, the subject has about 50% or more photoreceptor damage / loss. In another embodiment, the subject has about 60% or more photoreceptor damage / loss. In another embodiment, the subject has about 70% or more photoreceptor damage / loss. In another embodiment, the subject has about 80% or more photoreceptor damage / loss. In another embodiment, the subject has about 90% or more photoreceptor damage / loss. In certain embodiments, the subject has, or is at risk of developing, a retinal degeneration and more particularly, an advanced stage retinal degeneration. In another embodiment, the subject is a “carrier” for a mutation in a gene involved in retinal degeneration. In another embodiment, the subject has shown clinical signs of the ocular disease. Clinical signs of retinal degeneration include, but are not limited to, decreased peripheral vision, decreased central (reading) vision, decreased night vision, loss of color perception, reduction in visual acuity, decreased photoreceptor function, pigmentary changes. In another embodiment, the subject has been diagnosed with ocular disease. In yet another embodiment, the subject has not yet shown clinical signs of ocular disease. In certain embodiments, the method includes delivery of a nucleic acid sequence that reduces or inhibits expression of a gene involved in retinal degeneration and a nucleic acid sequence encoding a functional gene product, or fragment thereof. The nucleic acid sequences may be delivered in a single construct (e.g., a vector genome wherein the sequences are operably linked) or in separated constructs that may be delivered using more than one vector delivered by one or more routes of administration. In certain embodiments, the subject has been previously treated with a gene therapy, specifically a gene augmentation therapy, prior to administration of a composition for delivery of a nucleic acid sequence that reduces or inhibits expression a gene involved in retinal degeneration. In certain embodiments, the subject is administered of a composition for delivery of a nucleic acid sequence that reduces or inhibits expression a gene involved in retinal degeneration prior to administration of a gene augmentation therapy. In certain embodiments, treatment of a subject having an ocular disease with a composition described herein to reducing or inhibiting expression of a gene involved in retinal degeneration or activity does not require re-administration. The methods of treatment described herein may be used in conjunction with other treatments (secondary therapy), i.e., the standard of care for the subject’s diagnosis and condition. As used herein, the term “secondary therapy” refers to the therapy that could be combined with the gene therapy described herein for the treatment of an ocular disease. In certain embodiments, the methods of treatment described herein may be used in conjunction with other gene therapies. In certain embodiments, the method of treatment reduces COS elongation, thinning, and / or curving. In another embodiment, the treatment reduces ROS elongation, thinning, and / or curving. In another embodiment, the treatment reduces glial activation. In another embodiment, the treatment reduces ELM-RPE distance, in another embodiment, treatment reduces accumulation of retinal debris. In another embodiment, treatment reduces abnormal POS-RPE apposition and microarchitecture of RPE-PR interface. In another embodiment, treatment reduces subretinal debris at RPE apical surface, or within subretinal space. In another embodiment, treatment reduces compromised IPM and defective ELM. In another embodiment, treatment reduces fluctuation of ONL thickness associated with reactive gliosis and cell migration. In another embodiment, treatment reduces schistic changes in the inner / outer retina. In another embodiment, treatment reduces formation of subretinal & intraretinal scars. In another embodiment, treatment reduces RPE monolayer hypertrophy. In another embodiment, treatment reduces occasional severe deformation of individual RPE cells associated with ONL & INL thickness fluctuations. In another embodiment, treatment reduces and Muller Glial trunks / projections penetrating ONL layer. In one embodiment, treatment reduces gross macular lesion. In yet another embodiment, treatment reduces bullous detachment. In certain embodiments, it is desirable to perform non-invasive retinal imaging and functional studies to identify areas of the retina to be targeted for therapy and / or to evaluate efficacy of treatment. In certain embodiments, clinical diagnostic tests are employed to determine the precise location(s) for one or more subretinal injection(s). The non-invasive retinal imaging and functional studies may include electroretinography (ERG), perimetry, topographical mapping of the layers of the retina and measurement of the thickness of its layers by means of confocal scanning laser ophthalmoscopy (cSLO) and optical coherence tomography (OCT), topographical mapping of cone density via adaptive optics (AO), functional eye exam, etc., depending upon the species of the subject being treated, their physical status and health and treatment. In view of the imaging and functional studies, in some embodiments one or more injections are performed in the same eye in order to target different areas of the affected eye. The volume and viral titer of each injection is determined individually, as further described herein, and may be the same or different from other injections performed in the same, or contralateral, eye. In another embodiment, a single, larger volume injection is made in order to treat the entire eye. In one embodiment, the volume and concentration of the rAAV composition is selected so that only the region of damaged ocular cells is impacted. In another embodiment, the volume and / or concentration of the rAAV composition is a greater amount, in order reach larger portions of the eye, including non-damaged ocular cells. In another embodiment, the method includes performing additional studies, e.g., functional and imaging studies to determine the efficacy of the treatment. For examination in animals, such tests include retinal and visual function assessment via electroretinograms (ERGs) looking at rod and cone photoreceptor function, optokinetic nystagmus, pupillometry, water maze testing, light-dark preference, optical coherence tomography (to measure thickness of various layers of the retina), histology (retinal thickness, rows of nuclei in the outer nuclear layer, immunofluorescence to document transgene expression, cone photoreceptor counting, staining of retinal sections with peanut agglutinin - which identifies cone photoreceptor sheaths). Specifically for human subjects, following administration of a dosage of a composition described in this specification, the subject is tested for efficacy of treatment using electroretinograms (ERGs) to examine rod and cone photoreceptor function, pupillometry visual acuity, contrast sensitivity color vision testing, visual field testing (Humphrey visual fields / Goldmann visual fields), perimetry mobility test (obstacle course), and reading speed test. Other useful post-treatment efficacy test to which the subject is exposed following treatment with a pharmaceutical composition described herein are functional magnetic resonance imaging (fMRI), full-field light sensitivity testing, retinal structure studies including optical coherence tomography, fundus photography, fundus autofluorescence, adaptive optics laser scanning ophthalmoscopy, mobility testing, test of reading speed and accuracy, microperimetry and / or ophthalmoscopy. These and other efficacy tests are described in US Patent No.8,147,823; in co-pending International patent application publication WO 2014 / 011210 or WO 2014 / 124282, incorporated by reference. In certain embodiments, provided are methods of generating a recombinant rAAV comprises obtaining a plasmid containing an AAV expression cassette as described above and culturing a packaging cell carrying the plasmid in the presence of sufficient viral sequences to permit packaging of the AAV viral genome into an infectious AAV envelope or capsid. Specific methods of rAAV vector generation are described above and may be employed in generating an rAAV vector that can deliver the sequences of the expression cassettes and genomes described above and in the examples below. It should be understood that the methods of treatment described herein are intended to be applied to other compositions and methods described across the Specification. The invention is now described with reference to the following examples. These examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these examples but rather should be construed to encompass any and all variations that become evident as a result of the teaching provided herein. EXAMPLES Example 1: Materials and Methods Candidate Gene Selection A flowchart depicting the gene selection process is shown in Fig.1. Candidate genes for developing photoreceptor-specific promoters were identified from transcriptomic profiling studies performed on PDE6β-RCD1 (age: 22 weeks) and RPGR-XLPRA2 (age: 40 weeks) at a stage of retinal degeneration with greater than 50% photoreceptor cell loss (advanced stage disease).22Genes were selected in two categories: 1) the top 50 genes whose expression was upregulated (Expression Upregulated) and 2) 190 genes whose expression varied less than two-fold compared to normal (Expression Unchanged). Photoreceptor- specific genes from among the list of genes with upregulated expression were shortlisted for further analysis based on the following two criteria: a) gene expression was upregulated in both PDE6β-RCD1 and RPGR-XLPRA2; b) gene expression had been previously identified in retina, even if retinal cellular layer-specificity was unknown. The genes with unchanged expression were selected based on the following 2 criteria: a) gene expression was not significantly different from normal retina in both disease models, and b) gene expression had been identified specifically in the photoreceptors. Laser capture microdissection (LCM) and pPCR analysis Posterior eye cups from normal (age: 26 weeks, n = 3), PDE6β-RCD1 (age: 22 weeks, n = 3) and RPGR-XLPRA2 (age: 40 weeks, n = 3) dogs were dissected along the four quadrants and embedded in optimal cutting temperature (OCT) compound (Sakura Finetek, Torrance, CA, USA) under RNase-free conditions without fixation or cryopreservation. For LCM, 12 µm-thick retinal sections were cut and collected on PEN membrane slides (Zeiss, Göttingen, Germany) and stained using hematoxylin as described before.41Each retinal cellular layer (outer nuclear layer, ONL; inner nuclear layer, INL; and ganglion cell layer, GCL) and the full retinal section was isolated using a laser microdissection system (LMD 7000, Leica Microsystems, Deerfield, IL, USA) and collected individually in AdhesiveCap 500 clear tubes (Carl Zeiss, Fisher Scientific). Total RNA was isolated from the microdissected sections using RNeasy Plus Micro kit (Qiagen, Germantown, MD, USA). First-strand cDNA was synthesized using Superscript III (Life Technologies, ThermoFisher Scientific), followed by second strand cDNA synthesis using DNA polymerase I and T4 DNA polymerase (Life Technologies, ThermoFisher Scientific). A single round of linear antisense RNA amplification was performed using MEGAScript T7 transcription kit (Life Technologies, ThermoFisher Scientific), yielding a 1000-fold increase in transcripts, followed again by cDNA synthesis. Quantitative real-time PCR was performed on ViiA 7 Real Time PCR system (384-well format) (Applied Biosystems, ThermoFisher Scientific, Waltham, MA) using SYBR Green kit and gene-specific primers. To determine the cellular layer specificity for each gene, the fold change was calculated by comparing the Ct value in a layer with that in the total retina (all layers). RNA in situ hybridization (ISH) Retinal layer-specific localization of transcripts was visualized using the RNAscope RNA-ISH assay as previously described23. Briefly, 10 µm-thick sections from normal and mutant retinas were pretreated following the RNAscope pre-treatment protocol for fresh frozen tissues. After binding canine specific RNA probes, RNA-ISH was performed using the RNAscope 2.5 HD Assay-Red (Advanced Cell Diagnostics, Newark, CA, USA), following manufacturer’s protocol. Images were captured using a bright field microscope (Axioplan, Carl Zeiss Meditec GmbH, Oberkochen, Germany) with a 40X objective. Identification of Cis Regulatory Elements (CREs) The transcriptional start sites (TSSs) for the selected genes were identified using rapid amplification of cDNA ends (5'-RACE) (SMARTer RACE kit, Takara Bio, San Jose, CA, USA). Gene specific primers were designed within the third or the fourth exons for each of the genes following guidelines in the RACE manual. First strand RACE ready cDNA was synthesized from retinal RNA obtained from normal and mutant (PDE6β-RCD1 and RPGR- XLPRA2) canine retinas.5′-RACE products were amplified from the cDNA using 5′ RACE CDS Primer A and gene- specific primers. Amplicons were purified using the Nucleospin Gel and PCR Clean up kit (Takara Boi) and cloned into linearized pRACE plasmid. After transformation and culturing on LB agar- ampicillin plates, plasmids were isolated from bacterial colonies and sequenced using M13Forward and M13Reverse primers. Sequences were aligned to canine (Broad CanFam3.1 / canFam3)42genome using the Blat43 tool from UCSC Genome browser. Following identification of TSS, up to 2000 bp regions upstream and downstream of the TSS were analyzed for sequence motifs characteristic of promoters such as TATA box and GC-box. Canine genomic regions were aligned to human, mouse, rat, cat and cattle sequences using CLUSTAL omega and T-Coffee to identify conserved sequences.44,45Additionally, any regions already identified as a potential promoter in Ensembl was included. Sequence repeats inferred as involved in transcriptional regulation were identified using GPMiner and MEME suite.46,47Finally, all the conserved sequences and patterns were annotated on the probing interval, using an additive score for each hit (overlapping sequences marked as consensus). Contiguous sequence regions with majority of hits were identified as candidate cis regulatory elements. Sequences / intervals with a degree of conservation with the human genome (hg38) were also identified by sequence alignment as well as by following Ensembl and UCSC annotations. Dual Luciferase Assay Putative CREs identified using in silico approaches were amplified from canine genomic DNA and cloned into the promoterless NanoLuc-luciferase reporter plasmid vector (NLuc) (Promega, Madison, WI, USA) to generate NLuc promoter constructs. Human retinoblastoma Y79 cells and human embryonic kidney HEK293 cells (ATCC) were cultured under standard conditions (37°C, 5% CO2) in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and DMEM medium with 10% FBS, respectively. For the transfection, 5 femtomoles of NLuc-promoter-NanoLuc-luciferase plasmid and 200 nanograms of carrier DNA (Promega) were co-transfected with 5 fmols of a control plasmid containing firefly luciferase under TK promoter (pGL4-TK-firefly-luciferase) using the Neon Transfection system (ThermoFisher Scientific). The cells were plated in 96 well plates following transfection. Firefly and Renilla Luciferase activities were measured after addition of passive lysis buffer 24 hours post transfection. The promoter activity was assessed by Nano-Glo Dual Luciferase Reporter Assay system (Promega) according to the manufacturer’s instructions. Luminescence was recorded on the Envision Xcite multi-mode plate reader (PerkinElmer, Shelton, CT, USA). Firefly luciferase activity served as an internal control to normalize transfection efficiency. Fold induction of NanoLuc luciferase activity and the efficiency of the promoters were measured by comparison to, respectively, a promoterless NanoLuc luciferase vector. Data were presented as mean ± standard deviation from three independent experiments. Differences in promoter activity between the two cell lines were analyzed using one-s way ANOVA followed by post-hoc T-test in Excel. A p-value <0.05 was considered statistically significant. Massively Parallel Reporter Assay (MPRA) and Single Cell RNAseq Analysis An illustration of the MPRA assay is shown in Fig.2. A series of plasmids with unique 25 bp barcodes downstream of the eGFP reporter gene driven by the ubiquitous CAG promoter were used for MPRA screen. The CAG promoter was replaced with each of the promoters to be tested using AgeI and KpnI restriction sites. Four rod and / or cone specific promoters currently used in AAV based retinal gene therapy [hRHO48(536 bps), hGRK115,18(292 bps), PR2.125(~2100 bps), hIRBP49(241 bps)] and the ubiquitous CAG promoter (1720 bps) were also included as controls. Each plasmid was sequenced after cloning and the barcode corresponding to each promoter verified. All plasmids were packaged in AAV2 / 5 vector using a triple transfection method.50The fraction of each promoter-containing vector in the pool was determined through deep sequencing on an Illumina iSeq platform. Pooled AAV capsids were denatured at 98°C for 2 minutes to release AAV genomes, and then GFP barcodes were PCR amplified from the pool, using primer / adapters that allowed for direct Illumina sequencing following PCR amplification.51PCR amplifications were performed in technical triplicates and then pooled. The amplicons were gel purified and concentrated and then sequenced with a 150-cycle single-read run on an Illumina iSeq system. Barcodes were then counted using custom code written in Python and the balance of barcodes representing each promoter was determined. Two AAV5 pools were created, one with the canine promoters and the other with the human promoters, consisting of 14 AAV5-promoter-eGFP constructs, including the control promoters. Each AAV5 promoter pool was injected subretinally in both eyes of one normal, one PDE6β-RCD1 (age: 22 weeks) and one RPGR-XLPRA2 (age: 40 weeks) dog (see Supplementary Table 2). The dogs were maintained on an anti-inflammatory protocol consisting of oral prednisone (started at 1 mg / kg BID) on the day of dosing that was gradually tapered over the course of 4 weeks, subconjunctival injection of triamcinolone acetonide (4 mg on day of dosing and 5 weeks post-injection), as well as a topical administration of prednisolone acetate (1%) tapered over the course of 4 weeks. Following euthanasia and enucleation, a single 5 mm diameter punch of neuroretinal tissue was collected within the injected region (taking care to include the area centralis) from one of the eyes of each dog and placed in Hibernate-A medium. The tissue was then immediately processed for single cell RNAseq. The contralateral eye was processed for immunohistochemistry as described in the next section. The neuroretinal punch was incubated in 0.25% Trypsin at 37°C and then dissociated into single cells using the Miltenyi Biotec Neural Tissue Dissociation kit - Postnatal Neurons (Cat. No.130-094-802, Miltenyi Biotec, Inc., Auburn, CA, USA). Following dissociation, the cell count was determined by both manual counting with a hemocytometer and automated counting with the Luna-FL dual fluorescence cell counter. For each sample, 10,000 cells were loaded onto the 10X Genomics Chromium Next GEM Chip G. The library was then prepared using the Chromium Next GEM Single Cell 3’ kit v3.1 (10X Genomics, Pleasanton, CA, USA). These libraries were pooled and sequenced on an Illumina Novaseq 2000 platform (Illumina, San Deigo, CA, USA). The sequencing data were processed using the 10X Genomics Cell Ranger pipeline, which generated gene expression matrices for further analysis. These matrices were then integrated and analyzed using the Seurat v3 R package.52,53Retinal cell clusters were identified by their expression of a predefined panel of cell-specific marker genes. After clustering, each dataset from the individual dogs was analyzed separately. GFP transcripts in each dataset were sorted by their promoter-specific barcodes, assigned to their respective cell clusters, and quantified. The efficiency and cell type specificity of each promoter were evaluated by calculating the mean expression level of the barcoded GFP transcript within each cell cluster and determining the percentage of cells in each cluster that expressed the GFP barcode. For comparative analysis of promoter activity, all promoter efficiencies were normalized against the promoter exhibiting the highest GFP expression within each dataset. This approach allowed for a precise comparison of promoter performance across different cell types within each dog retina. Subretinal Injection of Individual Promoter Vectors and Immunohistochemistry Four of the top performing promoter constructs, identified through the MPRA assay, were packaged individually in an AAV5 vector (Ocular Gene Therapy Core, University of Florida, Gainesville, FL, USA). These vectors were then subretinally injected at a titer of 1.5 x 1011vg / mL into the superior-temporal or the superior-nasal quadrants in normal adult dogs, PDE6β-RCD1 dogs at 9 weeks of age (mid-stage disease) and at 12 weeks of age (late-stage disease), and in RPGR-XLPRA2 dogs at 16 weeks of age (mid-stage disease) and at 40 weeks of age (late-stage disease) (Table 2). Six weeks post-injection, the dogs were euthanized, and their eyes were carefully processed for morphologic and immunohistochemical analysis. Following enucleation, the posterior eyecups were fixed in 4% paraformaldehyde (PFA) for 3 hours and then in 2% PFA for 24 hours. This was followed by cryopreservation through sequential immersion in 15% and 30% sucrose / PBS solutions for 24 hours each. Each eye was dissected into four quadrants and embedded in OCT compound. For immunohistochemical analysis 10 µm-thick cryosections were prepared and treated with primary antibodies against rhodopsin (MAB5316, 1:200, Millipore, Burlington, MA, USA), human cone arrestin (courtesy of C.Craft, University of Southern California, LUMIF, 1:200) and GFP (AB3080, 1:500, Chemicon, Millipore Sigma). Briefly, the sections were permeabilized with 0.25% Triton X- 100 in PBS for 5 min and blocked for 1 hour at room temperature in a buffer containing 5% BSA and 4.5% fish gelatin in PBS. The sections were then incubated overnight at 4°C with the primary antibodies diluted in the same blocking buffer. Antigen-antibody complexes were visualized using Alexa Fluor-conjugated secondary antibodies (Invitrogen, ThermoFisher Scientific). Cell nuclei were counterstained with Hoechst 33342 stain (Thermo Fisher Scientific). Slides were mounted in Gelvatol mounting medium and examined with an epifluorescence microscope (Axioplan, Carl Zeiss Meditec GmbH). Images were acquired using Stellaris 8 Falcon FLIM microscope (Leica Microsystems, Wetzlar, Germany) and a 40X objective. Images were processed using Leica Application Suite X (LAS X) and further refined in Adobe Photoshop and Illustrator for display. Example 2: Identification of Photoreceptor-Specific Promoters for Gene Therapy at Advanced Stages of Retinal Degeneration Photoreceptor (PR)-specific promoters used in current retinal gene therapies were developed following validation in normal retinas. While most drive transgene expression with high efficiency and specificity in rods and / or cones early during retinal degeneration (RD), results have been more variable with intervention at later stages. At these advanced stages of disease, the retina undergoes structural and cellular remodeling, as well as transcriptional changes that may affect the efficiency of viral vector mediated transduction and / or the activity of cell specific promoters. In a previous study comparing the retinal transcriptomic profile from two non-allelic early onset IRDs in dogs (PDE6β-RCD1 and RPGR-XLPRA2) at advanced stages of disease (>50% PR loss) with that of normal dogs11, we identified that the expression of several PR- specific transcripts was severely downregulated in both diseases. Notably, the promoters derived from a number of these genes (e.g. RHO, ARR3, GRK1, PR2.1, PR1.7, and IRBP promoters) are currently used for retinal gene therapy15-20.Thus, our results indicate that these promoters are less efficient when used at more clinically relevant advanced stages of retinal diseases. Accordingly, we developed novel PR-specific promoters for efficient expression of therapeutic transgenes at advanced stages of inherited RDs. Identification of candidate genes for developing Photoreceptor-specific promoters: To identify potent promoters that can efficiently drive transgene expression in photoreceptors during advanced stages of retinal disease, we first focused on genes that were upregulated in a transcriptomic dataset of PDE6β-RCD1 and RPGR-XLPRA2 retinas that had > 50% loss of photoreceptors.22 A literature survey (conducted in 2018) identified several genes that were known to express in retina, although their cell-specificity was not well-defined. Of the top 50 upregulated genes in the dataset, 13 were shortlisted for further testing for potential photoreceptor-specificity: Prolactin 23 (PRL23), Solute Carrier Family 22 Member 14 (SLC22A14), G Protein-Coupled Receptor 37 Like 1 (GPR37L1), Wnt Family Member 4 (WNT4), Tryptophan Hydroxylase 1 (TPH1), ELOVL Fatty Acid Elongase 5 (ELOVL5), Moesin (MSN), Interleukin 17 Receptor E Like (IL17REL), Proline Rich 29 (PRR29), Fibroblast Growth Factor Receptor 1 (FGFR1), Versican (VCAN), Sulfatase 2 (SULF2), and Desmin (DES). Next, we identified 290 genes in the dataset whose retinal expression levels varied less than 2-fold between the two mutant models and that of normal dogs. After a thorough review of published literature, 13 genes were identified as having expression in either rod or cone cells: Carboxypeptidase E (CPE), Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1), Interphotoreceptor Matrix Proteoglycan 2 (IMPG2), Calcium Voltage-Gated Channel Auxiliary Subunit Alpha2delta 4 (CACNA2D4), Phosphodiesterase 6H (PDE6H), Cadherin Related Family Member 1 (CDHR1), Inosine Monophosphate Dehydrogenase 1 (IMPDH1), Discs Large MAGUK Scaffold Protein 4 (DLG4), Family With Sequence Similarity 169 Member A (FAM169A), Synaptic Vesicle Glycoprotein 2B (SV2B), Proline Rich Coiled-Coil 2A (PRRC2A), G Protein Subunit Gamma Transducin 2 (GNGT2), and Synaptophysin (SYP). To determine whether the selected genes were specifically expressed or upregulated only in the photoreceptors of diseased retinas, laser capture microdissection (LCM) was used to isolate individual cellular layers - outer nuclear layer and inner segments, ONL / IS; inner nuclear layer, INL; ganglion cell layer, GCL - from PDE6β-RCD1, RPGR-XLPRA2 and normal retinas. The expression of the selected genes was then analyzed using qPCR. The purity of each dissected layer was verified by testing for the expression of layer-specific markers: Rhodopsin (RHO) for ONL / IS, CABP5 (Calcium Binding Protein 5) for INL, SNCG (Synuclein Gamma) for GCL, and RPE65 to determine the level of retinal pigment epithelium (RPE) contamination (Fig.3A). Of the 13 upregulated genes, three were found to have ONL-specific expression: Versican (VCAN), Prolactin (PRL), and Tryptophan hydroxylase 1 (TPH1). Among the 13 genes with expression levels unaltered by disease, three exhibited ONL-specific expression that remained unchanged between normal and diseased retinas: Interphotoreceptor matrix proteoglycan 2 (IMPG2), Phosphodiesterase 6H (PDE6H), and G Protein Subunit Gamma Transducin 2 (GNGT2) (Fig.3B). The photoreceptor-specificity of the selected genes was verified by RNA-in situ hybridization (RNA-ISH). Our analysis confirmed that VCAN and PRL (Fig.3C and 3D) were exclusively expressed in the ONL of diseased retina. TPH1 mRNA showed a cone- restricted expression in the normal ONL that increased in the diseased retinas but was also expressed in some INL cells (Fig.3E). IMPG2 mRNA was observed in both rods and cones (Fig.3F) whereas PDE6H and GNGT2 mRNA were present only in cones and their expressions sustained in the diseased retinas (Fig.3G and 3H). In summary, we identified a total of six genes - VCAN, TPH1, PRL, IMPG2, PDE6H, and GNGT2 - with increased or sustained expression in photoreceptors during late stages of retinal degeneration across two non-allelic diseases, and these were selected as candidates for the development of novel photoreceptor-specific promoters. Identification of the upstream retina specific cis regulatory elements (CREs) To delineate the 5’ CREs of the six genes, the transcriptional start sites (TSS) were identified using the rapid amplification of cDNA ends (5’RACE) protocol. For five of the genes - VCAN, TPH1, IMPG2, PDE6H, and GNGT2 - the TSS were located as expected in the region upstream of exon 1. However, for PRL, an alternative TSS positioned downstream of the annotated exon 1 was found. Using sequence alignment and pattern recognition methods multiple overlapping candidate promoter sequences were identified for each of these canine genes (Fig.4A). The promoter region for VCAN was found to be particularly complex and extended over a large genomic region, leading to its exclusion from further analysis (data not shown). Consequently, we focused on the remaining five genes, identifying a total of 11 potential CRE sequences in the canine genome. Comparing these regions with the human genome showed that the aligned human sequences already contained defined CREs, indicating that there is conservation across species. A total of 7 CRE sequences were selected for the five genes in the human genome. In vitro assessment of promoter activity To assess promoter activity, the CREs were cloned into a NanoLuc-luciferase reporter plasmid and tested using dual luciferase assays. The relative response ratio of NanoLuc luciferase activity was measured in both human retinoblastoma Y79 and human embryonic kidney HEK293 cells, with higher values indicating stronger promoter activity. A set of photoreceptor-specific promoters commonly utilized in AAV-based retinal gene therapy, including hRHO, PR2.1 (derived from human red cone-opsin gene), hGRK1, and hIRBP, were included as controls. Statistical analysis using two-way ANOVA showed that on average, the activity of the promoters differed significantly between HEK293 and Y79 cell lines (p < 0.0001). Of the 11 canine CREs tested, 7 (cIMPG2p2, cPDE6Hp1, cGNGT2p1, cGNGT2p2, cTPH1p1, cTPH1p2, and cPRLp1) exhibited high relative response ratios in Y79 cells, indicating robust promoter activity. Additionally, all the human promoters tested showed significantly higher relative response ratios in Y79 cells compared to HEK293 cells, underscoring their potential for driving targeted gene expression in retinal cells (Fig.4B). Importantly, all promoters identified in this assay were under 1000 bp, making them ideal candidates for AAV-based gene therapy. In summary, we identified several promoters that have in vivo photoreceptor-specificity. The sequences for the 7 canine and the 6 human promoters are provided in Table 3. In vivo screening of promoters using massively parallel reporter assay To assess the transcriptional activity and cell type specificity of candidate promoter sequences, we employed a massively parallel reporter assay (MPRA) in normal and mutant (PDE6β-RCD1 and RPGR-XLPRA2) retinas at late stages of degeneration, followed by single-cell RNAseq (scRNAseq) analysis. Two distinct MPRA libraries were created: one consisting of AAV carrying the GFP reporter gene under the control of canine promoters, and another with human promoters. Both libraries included AAV constructs containing commonly used retinal gene therapy promoters (hRHO, hGRK1, PR2.1, hIRBP, and CAG). These AAV-promoter libraries were injected subretinally into normal dogs and in mutant dogs at 22 weeks (PDE6β-RCD1) and at 40 weeks (RPGR-XLPRA2), corresponding to late disease stages. Six-weeks post injection, neuroretinal punches were harvested, dissociated into single cells, and subjected to scRNAseq. This analysis enabled identification of all major retinal cell types based on the expression of specific marker genes (Fig.5) GFP expression analysis revealed that the highest expression was generally localized in the rod and cone photoreceptors, although some expression was also observed in glial cells and other retinal cell types (Fig.6). Promoter efficiency was assessed by measuring the mean GFP expression and the fraction of cells expressing GFP in each retinal cell type. Data for the top-performing promoters is consolidated in Figure 7, while Figures 8-10 present data for all tested promoters. In normal retinas, both ubiquitous (CAG) and photoreceptor-specific (hRHO, PR2.1, hGRK1, and hIRBP) control promoters showed higher efficiency but lacked absolute specificity, driving GFP expression across various retinal cell types at low levels (Figs.8A, 8B). Surprisingly, overall GFP expression from all promoters in the canine promoter pool was low in RPGR-XLPRA2 retina for unknown reasons (Fig.10A). Among the novel promoters, the GNGT2 promoters (cGNGT2p1, hGNGT2p1 and hGNGT2p2) stood out, exhibiting the highest GFP expression in mutant retinas, predominantly in the cones but also at lower levels in rods, making them capable of targeting both photoreceptor types in retinal degeneration (Figs 7B, 7C). Additionally, the cIMPG2p2 promoter performed well in the PDE6β-RCD1 retina, with strong expression in both rods and cones. Conversely, the cPDE6Hp1 promoter exhibited cone-dominant expression in the mutant retinas but with lower efficiency compared to the GNGT2 promoters (Figs 7B, 7C). The PRL and the TPH1 promoters performed poorly across all retinal types (Figs.8-10). In summary, transcriptomic analysis of the MPRA identified several promoters as capable of targeted gene expression in photoreceptors in the context of retinal degeneration. While many of the promoters showed higher GFP expression in cones during the MPRA screen, it is important to note that at the late stage of degeneration, very few rods remain, and those that remain are not healthy. As a result, the majority of the photoreceptors in these retinas are cones, which may explain the higher GFP expression observed in cones. This observation highlights the relevance of cone-targeted promoters in late stages of retinal degeneration, where the preservation and functionality of cones are of primary therapeutic interest. In vivo validation of top performing promoters for GFP expression in photoreceptors To validate the transcriptional activity and cell-type specificity of the top-performing promoters identified in the MPRA screen, four lead candidates - cGNGT2p1(581 bp), hGNGT2p1 (481 bp), cIMPG2p2 (745 bp), and cPDE6Hp1 (840 bp) - were individually packaged into AAV5 vectors and delivered subretinally at equal viral doses (1.5 x 1011vg / mL, ~150 µL). Although hGNGT2p2 (797 bp) exhibited similar efficacy and specificity to hGNGT2p1 (481 bp), it was not selected for individual screening. In the PDE6β-RCD1 model, subretinal injections were performed at 9 and 12 weeks of age, corresponding to mid- and late-stage degeneration, respectively. In the RPGR-XLPRA2 model, injections were conducted at 16 and 40 weeks of age to assess promoter activity at comparable stages of disease progression as in the PDE6β-RCD1 dogs. The same promoters were also evaluated in normal dog retinas. Five weeks post-injection, GFP expression efficiency and specificity were assessed via immunohistochemistry. When delivered to the PDE6β-RCD1 retina at mid-stage degeneration, cGNGT2p1 and hGNGT2p1 promoters demonstrated robust GFP expression in rod and cone cells, as confirmed by co-localization with rhodopsin (RHO) and cone arrestin (ARR3), respectively (Fig.11A, 11B). A similar pattern was observed in the RPGR-XLPRA2 mid-stage degeneration, where both promoters exhibited strong photoreceptor-specific expression (Fig. 11A, 11B), reinforcing their potential for gene therapy applications in mid-stages of retinal degeneration. Importantly, neither promoter showed detectable GFP expression in RPE cells, indicating strong specificity for photoreceptors. The cIMPG2p2 promoter was largely rod- specific when delivered at mid-stage disease in both PDE6β-RCD1 (Fig.11C) and RPGR- XLPRA2 (Fig.11C) retinas, with only occasional GFP-positive RPE cells. In contrast, cPDE6Hp1 was cone-specific across both models but exhibited reduced specificity, as GFP expression was also detected in RPE cells (Fig.11D). When delivered at late stages of degeneration, cGNGT2p1 and hGNGT2p1 continued to drive GFP expression in rods and cones in both PDE6β-RCD1 and RPGR-XLPRA2 models (Fig.12A, 12B). Similarly, both cIMPG2p2 and cPDE6Hp1 drove GFP expression in both classes of photoreceptors, but also in the RPE (Fig.12C, 12D). Comparisons with normal retinas revealed similar GFP expression patterns from these promoters as observed for mid-stage disease (Fig.13A, 13B, 13C, 13D). Notably, the hGRK1 promoter, which is commonly used to drive transgene expression in both rods and cones, exhibited weaker GFP expression in both normal and mutant retinas compared to these novel promoters, indicating their superior efficiency in targeting photoreceptors (Fig.12A, 12B, 12C, 12D). Overall, cGNGT2p1 and hGNGT2p1 demonstrated strong and sustained expression in rods and cones across all stages of degeneration, with high specificity and no detectable expression in RPE, making them ideal for gene therapy targeting photoreceptors at any stage of disease progression. In contrast, cIMPG2p2 was highly effective for targeting rods at mid- stages but lost specificity at late stages where it also drove transgene expression in cones. Similarly, cPDE6Hp1 was well-suited for cone-targeted gene therapy in mid-disease stage, with some expression also observed in RPE cells, but when used at late stage it also drove expression in rods. These observations are summarized in Fig.15. These findings underscore the importance of selecting promoters based on the disease stage at the time of intervention and the targeted cell type, with cGNGT2p1 and hGNGT2p1 emerging as the most versatile options for photoreceptor-directed gene therapy. Discussion Our study addresses a critical gap in gene therapy for IRDs by developing novel promoters to drive optimal gene expression in mid-to-late stages of retinal degeneration. While much of the existing research has concentrated on early-stage retinal degeneration, therapies targeted at more advanced stages of the disease are significantly underexplored, despite their clinical relevance for therapeutic intervention. Late-stage degeneration presents unique challenges due to the loss of photoreceptor cells and the potential for altered gene expression profiles. Therefore, designing promoters that maintain specificity and drive high levels of expression in these later stages is essential for the success of gene therapy and for overcoming the limitations of current therapeutic approaches. Novel promoters for mid-stage retinal disease Among the promoters identified herein, the promoters derived from the GNGT2 gene show significant potential for targeting both rods and cones. The cGNGT2p1 and hGNGT2p1 promoters maintain high expression levels irrespective of the stage of degeneration and do not drive expression in RPE cells. Notably, our findings demonstrate that the GNGT2 promoter outperforms the widely used GRK1 promoter in driving gene expression in both rods and cones during advanced stages of degeneration. Supporting this, a larger human GNGT2-derived promoter (1197 bp) has been reported to drive robust cone-dominant expression of GFP in adult mouse retina following both intravitreal and subretinal delivery, although it also induced GFP expression in rods.24This highlights the unique advantage of the smaller cGNGT2p1 (581 bp) and hGNGT2p1 (481 bp) promoters identified in our study. Their compact size and high specificity make them superior alternatives to existing promoters, which either present size constraints or lack photoreceptor specificity. The ability of these promoters to drive robust gene expression in both photoreceptor types make them highly valuable for treating diseases that impact rods and cones or for conditions where cone preservation is critical after extensive rod loss. While the GNGT2 can target both rods and cones, the cPDE6Hp1 promoter offers more focused specificity for cone-targeted therapies. Highly cone-specific in both normal and mutant retinas, cPDE6Hp1 is ideal for cone-targeted gene therapy for treating diseases that primarily affect cones like achromatopsia and cone-rod dystrophies. Current therapies often use the PR1.7 promoter – a shorter version of the PR2.1 promoter – but their large sizes (1700 bp and 2100 bp, respectively)17,25limit their utility in AAV-based vectors, which have a limited packaging capacity of ~ 4.7kb. Smaller alternatives, such as the 500 bp mouse and human ARR3 promoters (mCAR and hCAR) show non-specific gene expression in rods and RPE cells, reducing their effectiveness for targeted therapies.26In contrast, the cPDE6Hp1 promoter is both compact (840 bp) and cone-specific in degenerating retinas. A larger human PDE6H promoter (2005 bp) reported by Korecki et al. shows cone-restricted expression, although the large size makes it unsuitable for AAV-based gene therapies.24In addition to cone-targeted strategies, rod-specific promoters are also of critical importance for diseases where rod preservation is a priority. The cIMPG2p2 promoter (745 bp) is primarily rod-specific in normal and mid-stage degenerating mutant retinas. This characteristic makes it a promoter for treating diseases where rod preservation is a primary goal. This adaptability may be beneficial for treating progressive retinal diseases where rod cell death precedes cone degeneration. Enhancing Promoter Specificity to Reduce Immune Response in Gene Therapy While promoter specificity is critical for ensuring targeted expression, achieving high levels of transgene expression while minimizing viral vector particle dosage remains a challenge in gene therapy. High doses of AAVs can provoke immune responses, compromising the efficacy of gene therapy.13,33Historically, retinal gene therapy has relied on ubiquitous promoters such as the cytomegalovirus (CMV) promoter and the chicken beta- actin (CBA) promoter often coupled with a CMV immediate-early enhancer (CAG), to drive transgene expression. Many clinical trials continue to utilize the ubiquitous promoters, and the only FDA-approved retinal gene therapy for LCA and RP caused by biallelic mutations in RPE65, Voretigene neparvovec-rzyl (Luxturna), uses the CAG promoter to drive RPE65 expression.33,34While ubiquitous promoters are known for achieving robust transgene expression, their specificity can vary depending on the vector serotype and target tissue. For example, studies in RPE65-deficient dogs demonstrated that RPE65 transgene expression from AAV2-CBA was primarily restricted to RPE cells, with only minimal off-target expression in photoreceptors.35However, when delivered subretinally with other AAV serotypes, ubiquitous promoters have been reported to drive expression beyond the intended target cells (photoreceptors and RPE), such as Müller glia and astrocytes.13,36This raises concern that non-specific expression in glial cells could potentially trigger inflammatory and immune responses, exacerbating retinal damage and undermining the therapeutic benefits. Notably, it remains unclear whether lesions of chorioretinal atrophy reported in RPE65- LCA2 patients treated with Voretigene neparvovec-rzyl could have been triggered by transgene expression in non-RPE cells.37In contrast, transgene expression with photoreceptor- and RPE-specific promoters have been shown to have little to no immunogenicity when used at low AAV doses.38In our MPRA screen performed at the late stage disease, we observed GFP mRNA expression driven by supposedly cell-specific promoters like the cone-specific PR2.1, as well as the ubiquitous CAG promoter, in a small but significant subset of glial cells (Figs.8-10). However, the cell-specific promoters developed in our study showed minimal to no transgene expression in glial cells. While transcript detection does not necessarily correlate with protein expression, even transient GFP expression in non-target cells could contribute to immune activation.38,39Given the role of glial cells - particularly microglia and astrocytes - in immune surveillance, unintended transgene expression in these cells may heighten inflammatory responses. By enhancing transcriptional specificity, our optimized promoters could improve the safety profile of gene therapies, ensuring that therapeutic genes are predominantly expressed in the intended cell types while reducing the risk of immune activation or cellular dysfunction, ultimately maximizing treatment efficacy. Conclusions Herein, four novel photoreceptor-specific promoters suitable for mid-to-late-stage retinal diseases with enhanced efficacy and specificity for AAV-based gene therapy interventions were identified. 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Cideciyan, A.V., Sudharsan, R., Dufour, V.L., Massengill, M.T., Iwabe, S., Swider, M., Lisi, B., Sumaroka, A., Marinho, L.F., Appelbaum, T., Rossmiller, B., et al. (2018). Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector. Proc Natl Acad Sci U S A 115, E8547-E8556.10.1073 / pnas.1805055115. 49. Yokoyama, T., Liou, G.I., Caldwell, R.B., and Overbeek, P.A. (1992). Photoreceptor- specific activity of the human interphotoreceptor retinoid-binding protein (IRBP) promoter in transgenic mice. Exp Eye Res 55, 225-233.10.1016 / 0014-4835(92)90186-v. 50. Grieger, J.C., Choi, V.W., and Samulski, R.J. (2006). Production and characterization of adeno-associated viral vectors. Nat Protoc 1, 1412-1428.10.1038 / nprot.2006.207. 51. Ozturk, B.E., Johnson, M.E., Kleyman, M., Turunc, S., He, J., Jabalameli, S., Xi, Z., Visel, M., Dufour, V.L., Iwabe, S., Pompeo Marinho, L.F.L., et al. (2021). scAAVengr, a transcriptome-based pipeline for quantitative ranking of engineered AAVs with single-cell resolution. Elife 10.10.7554 / eLife.64175. 52. Satija, R., Farrell, J.A., Gennert, D., Schier, A.F., and Regev, A. (2015). Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33, 495-502. 10.1038 / nbt.3192. 53. Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W.M., 3rd, Hao, Y., Stoeckius, M., Smibert, P., and Satija, R. (2019). Comprehensive Integration of Single-Cell Data. Cell 177, 1888-1902 e1821.10.1016 / j.cell.2019.05.031. Embodiments 1. An expression cassette comprising a nucleic acid having promoter activity in photoreceptor cells operably linked to a transgene, wherein the nucleic acid having promoter activity comprises a cis regulatory element (CRE) from PRL, TPH1, GNGT2, IMPG2 or PDE6H, or a sequence sharing at least 80% identity therewith. 2. The expression cassette of embodiment 1, wherein the nucleic acid having promoter activity has cone and / or rod cell-specific promoter activity. 3. The expression cassette of embodiment 1 or 2, wherein the nucleic acid having promoter activity is a human sequence or a canine sequence. 4. The expression cassette of any one of embodiments 1 to 3, wherein the nucleic acid having promoter activity comprises any one of SEQ ID NO: 1-22, or a sequence sharing at least 80% identity with any one of SEQ ID NO: 1-22. 5. The expression cassette of any one of embodiments 1 to 4, wherein the nucleic acid having promoter activity has a length of less than 1 kb. 6. The expression cassette of any one of embodiments 1 to 5, wherein the transgene encodes a therapeutic protein, a reporter protein, a gene silencing tool (eg. shRNA) or a gene editing tool. 7. The expression cassette of embodiment 6, wherein the therapeutic protein is associated with a retinal disease or disorder. 8. The expression cassette of embodiment 6 or 7, wherein the therapeutic protein is selected from ADIPOR1, ABCA4, ABCC6, ABHD12, ACBD5, ACO2, ADAM9, ADAMTS18, ADGRA3, ADGRV1, ADIPOR1, AFG3L2, AGBL5, AHI1, AHR, AIPL1, ALMS1, ARHGEF18, ARL2BP, ARL3, ARL6, ARMS2, ARSG, ASRGL1, ATF6, ATXN7, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BEST1, C12orf65, C1QTNF5, C2, C21orf2, C3, C8orf37, CA4, CABP4, CACNA1F, CACNA2D4, CAPN5, CC2D2A, CCT2, CDH23, CDH3, CDHR1, CEP164, CEP19, CEP250, CEP290, CEP78, CERKL, CFB, CFH, CHM, CIB2, CLCC1, CLN3, CLRN1, CLUAP1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL2A1, COL9A1, COQ2, COQ4, COQ5, CRB1, CRX, CSPP1, CTNNA1, CWC27, CYP4V2, DHDDS, DHX38, DMD, DRAM2, DTHD1, DYNC2H1, DYNC2I2, EFEMP1, ELOVL1, ELOVL4, EMC1, ENSA, ERCC6, ESPN, EXOSC2, EYS, FAM161A, FBLN5, FLVCR1, FSCN2, FZD4, GDF6, GNAT1, GNAT2, GNB3, GNPTG, GPR179, GRK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HARS, HGSNAT, HK1, HMCN1, HMX1, HTRA1, IDH3B, IFT140, IFT172, IFT27, IFT81, IMPDH1, IMPG1, IMPG2, INPP5E, INVS, IQCB1, ITM2B, JAG1, KCNJ13, KCNV2, KIAA1549, KIF11, KIF3B, KIZ, KLHL7, KSS, LAMA1, LCA5, LHON, LRAT, LRIT3, LRP5, LRRTM4, LZTFL1, MAK, MAPKAPK3, MERTK, MFN2, MFRP, MFSD8, MIEF1, MIR204, MKKS, MKS1, MT-ATP6, MT-TH, MT-TL1, MTTP, MT-TP, MT-TS2, MVK, MYO7A, NBAS, NDP, NEK2, NEUROD1, NMNAT1, NPHP1, NPHP3, NPHP4, NR2E3, NR2F1, NRL, NYX, OAT, OFD1, OPA1, OPA3, OPN1LW, OPN1MW, OPN1SW, OTX2, PANK2, PAX2, PCARE, PCDH15, PCYT1A, PDE6A, PDE6B, PDE6C, PDE6G, PDE6H, PDSS1, PDZD7, PEX1, PEX2, PEX7, PGK1, PHYH, PITPNM3, PLA2G5, PLK4, PNPLA6, POC1B, POC5, POMGNT1, PPT1, PRCD, PRDM13, PROM1, PROS1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, PRPS1, RAB28, RAX2, RB1, RBP3, RBP4, RCBTB1, RD3, RDH11, RDH12, RDH5, REEP6, RGR, RGS9, RGS9BP, RHO, RIMS1, RIMS2, RLBP1, ROM1, RP1, RP1L1, RP2, RP9, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, RTN4IP1, SAG, SAMD11, SDCCAG8, SEMA4A, SLC24A1, SLC25A46, SLC37A3, SLC39A12, SLC4A7, SLC66A1, SLC7A14, SNRNP200, SPATA7, SPP2, TEAD1, TIMM8A, TIMP3, TLR3, TLR4, TMEM126A, TMEM216, TMEM237, TOPORS, TREX1, TRIM32, TRNT1, TRPM1, TSPAN12, TTC8, TTLL5, TTPA, TUB, TUBGCP4, TUBGCP6, TULP1, UNC119, USH1C, USH1G, USH2A, VCAN, WDPCP, WDR19, WFS1, WHRN, ZNF408, ZNF423, or ZNF513. 9. The expression cassette of embodiment 6, wherein the reporter protein is selected from the group consisting of a fluorescent protein, a calcium indicator, alkaline phosphatase, beta-galactosidase, beta-lactamase, and horseradish peroxidase. 10. The expression cassette of any one of embodiments 1 to 5, wherein the transgene is an siRNA, shRNA, RNAi, miRNA, antisense RNA, ribozyme, or deoxyribozyme. 11. A vector comprising the expression cassette of any one of embodiments 1 to 10. 12. The vector of embodiment 11, wherein the vector is a recombinant viral vector. 13. A recombinant adeno-associated virus (rAAV) comprising the expression cassette of any one of embodiments 1 to 10. 14. The rAAV of embodiment 13, wherein the rAAV has an AAV2, AAV5, AAV7m8, AAV9, or AAV8 capsid. 15. A cell transformed with the expression cassette of any one of embodiments 1 to 10, the vector of any one of embodiments 11 or 12 or the rAAV of any one of embodiments 13 or 14. 16. The cell of embodiment 15 which is a rod photoreceptor cell or a cone photoreceptor cell. 17. The cell of embodiment 15 which is a photoreceptor cell. 18. A lipid nanoparticle (LNP) comprising the expression cassette of any one of embodiments 1 to 10. 19. A pharmaceutical composition comprising the expression cassette of any one of embodiments 1 to 10, the vector of any one of embodiments 11 or 12, the rAAV of any one of embodiments 13 or 14, the cell of embodiment 16 or 17, or the LNP of embodiment 18 and a pharmaceutically acceptable excipient. 20. Use of an expression cassette according to any one of embodiments 1 to 10, the vector of any one of embodiments 11 or 12, the rAAV of any one of embodiments 13 or 14, the cell of embodiment 16 or 17, the LNP of embodiment 18, or a pharmaceutical composition according to embodiment 19 for the manufacture of a medicament for the treatment of an ocular disease. 21. The use of embodiment 20, wherein the ocular disease is a disease associated with degeneration of photoreceptor cells. 22. The use of embodiment 20, wherein the disease associated with photoreceptor degeneration is age-related macular degeneration, Bardet-Biedl syndrome, chorioretinal atrophy, congenital stationary night blindness, oculo-retinal developmental disease, optic atrophy, usher syndrome, retinopathy of prematurity, achromatopsia, leber's hereditary optic neuropathy, cone-rod dystrophy, leber's congenital amaurosis, Stargardt disease, diabetic retinopathy, retinal detachment, best's disease, retinitis pigmentosa, choroideremia, or retinal blanket degeneration. 23. A method of treating an ocular disease in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition according to embodiment 19 to the eye of the subject. 24. The method of embodiment 23, wherein the composition is administered via subretinal injection. 25. The method of embodiment 23 or 24, wherein the effective amount is 1x108to 1x1014vg / mL. 26. The method of any one of embodiments 23 to 25, wherein the ocular disease is age-related macular degeneration, Bardet-Biedl syndrome, chorioretinal atrophy, congenital stationary night blindness, oculo-retinal developmental disease, optic atrophy, usher syndrome, retinopathy of prematurity, achromatopsia, leber's hereditary optic neuropathy, cone-rod dystrophy, leber's congenital amaurosis, stargardt disease, diabetic retinopathy, retinal detachment, best's disease, retinitis pigmentosa, choroideremia, or retinal blanket degeneration. 27. The method of any one of embodiments 23 to 26, wherein the subject has advanced stage disease. 28. The method of any one of embodiments 23 to 26, wherein the subject has lost about 50% or more of their rod or cone cells. Each and every patent, patent application, and publication cited in this specification is incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. An expression cassette comprising a nucleic acid having promoter activity in photoreceptor cells operably linked to a transgene, wherein the nucleic acid having promoter activity comprises a cis regulatory element (CRE) from PRL, TPH1, GNGT2, IMPG2 or PDE6H, or a sequence sharing at least 80% identity therewith.

2. The expression cassette of claim 1, wherein the nucleic acid having promoter activity has cone and / or rod cell-specific promoter activity.

3. The expression cassette of claim 1, wherein the nucleic acid having promoter activity is a human sequence or a canine sequence.

4. The expression cassette of claim 1, wherein the nucleic acid having promoter activity comprises any one of SEQ ID NO: 1-22, or a sequence sharing at least 80% identity with any one of SEQ ID NO: 1-22.

5. The expression cassette of claim 1, wherein the nucleic acid having promoter activity has a length of less than 1 kb.

6. The expression cassette of claim 1, wherein the transgene encodes a therapeutic protein, a reporter protein, a gene silencing tool, or a gene editing tool.

7. The expression cassette of claim 6, wherein the therapeutic protein is associated with a retinal disease or disorder.

8. The expression cassette of claim 6, wherein the therapeutic protein is selected from ADIPOR1, ABCA4, ABCC6, ABHD12, ACBD5, ACO2, ADAM9, ADAMTS18, ADGRA3, ADGRV1, ADIPOR1, AFG3L2, AGBL5, AHI1, AHR, AIPL1, ALMS1, ARHGEF18, ARL2BP, ARL3, ARL6, ARMS2, ARSG, ASRGL1, ATF6, ATXN7, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BEST1, C12orf65, C1QTNF5, C2, C21orf2, C3, C8orf37, CA4, CABP4, CACNA1F, CACNA2D4, CAPN5, CC2D2A, CCT2, CDH23, CDH3, CDHR1, CEP164, CEP19, CEP250, CEP290, CEP78, CERKL, CFB, CFH, CHM, CIB2, CLCC1, CLN3, CLRN1, CLUAP1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL2A1, COL9A1, COQ2, COQ4, COQ5, CRB1, CRX, CSPP1, CTNNA1,CWC27, CYP4V2, DHDDS, DHX38, DMD, DRAM2, DTHD1, DYNC2H1, DYNC2I2, EFEMP1, ELOVL1, ELOVL4, EMC1, ENSA, ERCC6, ESPN, EXOSC2, EYS, FAM161A, FBLN5, FLVCR1, FSCN2, FZD4, GDF6, GNAT1, GNAT2, GNB3, GNPTG, GPR179, GRK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HARS, HGSNAT, HK1, HMCN1, HMX1, HTRA1, IDH3B, IFT140, IFT172, IFT27, IFT81, IMPDH1, IMPG1, IMPG2, INPP5E, INVS, IQCB1, ITM2B, JAG1, KCNJ13, KCNV2, KIAA1549, KIF11, KIF3B, KIZ, KLHL7, KSS, LAMA1, LCA5, LHON, LRAT, LRIT3, LRP5, LRRTM4, LZTFL1, MAK, MAPKAPK3, MERTK, MFN2, MFRP, MFSD8, MIEF1, MIR204, MKKS, MKS1, MT- ATP6, MT-TH, MT-TL1, MTTP, MT-TP, MT-TS2, MVK, MYO7A, NBAS, NDP, NEK2, NEUROD1, NMNAT1, NPHP1, NPHP3, NPHP4, NR2E3, NR2F1, NRL, NYX, OAT, OFD1, OPA1, OPA3, OPN1LW, OPN1MW, OPN1SW, OTX2, PANK2, PAX2, PCARE, PCDH15, PCYT1A, PDE6A, PDE6B, PDE6C, PDE6G, PDE6H, PDSS1, PDZD7, PEX1, PEX2, PEX7, PGK1, PHYH, PITPNM3, PLA2G5, PLK4, PNPLA6, POC1B, POC5, POMGNT1, PPT1, PRCD, PRDM13, PROM1, PROS1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, PRPS1, RAB28, RAX2, RB1, RBP3, RBP4, RCBTB1, RD3, RDH11, RDH12, RDH5, REEP6, RGR, RGS9, RGS9BP, RHO, RIMS1, RIMS2, RLBP1, ROM1, RP1, RP1L1, RP2, RP9, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, RTN4IP1, SAG, SAMD11, SDCCAG8, SEMA4A, SLC24A1, SLC25A46, SLC37A3, SLC39A12, SLC4A7, SLC66A1, SLC7A14, SNRNP200, SPATA7, SPP2, TEAD1, TIMM8A, TIMP3, TLR3, TLR4, TMEM126A, TMEM216, TMEM237, TOPORS, TREX1, TRIM32, TRNT1, TRPM1, TSPAN12, TTC8, TTLL5, TTPA, TUB, TUBGCP4, TUBGCP6, TULP1, UNC119, USH1C, USH1G, USH2A, VCAN, WDPCP, WDR19, WFS1, WHRN, ZNF408, ZNF423, or ZNF513.

9. The expression cassette of claim 6, wherein the reporter protein is selected from the group consisting of a fluorescent protein, a calcium indicator, alkaline phosphatase, beta- galactosidase, beta-lactamase, and horseradish peroxidase.

10. The expression cassette of claim 1, wherein the transgene is an siRNA, shRNA, RNAi, miRNA, antisense RNA, ribozyme, or deoxyribozyme.

11. A vector comprising the expression cassette of claim 1 to 10.

12. The vector of claim 11, wherein the vector is a recombinant viral vector.

13. A recombinant adeno-associated virus (rAAV) comprising the expression cassette of any one of claims 1 to 10.

14. The rAAV of claim 13, wherein the rAAV has an AAV2, AAV5, AAV7m8, AAV9, or AAV8 capsid.

15. A cell transformed with the expression cassette of claims 1 to 10.

16. The cell of claim 15 which is a rod photoreceptor cell or a cone photoreceptor cell.

17. The cell of claim 15 which is a photoreceptor cell.

18. A lipid nanoparticle (LNP) comprising the expression cassette of any one of claims 1 to 10.

19. A pharmaceutical composition comprising the expression cassette of any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

20. Use of an expression cassette according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of an ocular disease.

21. The use of claim 20, wherein the ocular disease is a disease associated with degeneration of photoreceptor cells.

22. The use of claim 20, wherein the disease associated with photoreceptor degeneration is age-related macular degeneration, Bardet-Biedl syndrome, chorioretinal atrophy, congenital stationary night blindness, oculo-retinal developmental disease, optic atrophy, usher syndrome, retinopathy of prematurity, achromatopsia, leber's hereditary optic neuropathy, cone-rod dystrophy, leber's congenital amaurosis, Stargardt disease, diabetic retinopathy, retinal detachment, best's disease, retinitis pigmentosa, choroideremia, or retinal blanket degeneration.

23. A method of treating an ocular disease in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition according to claim 19 to the eye of the subject.

24. The method of claim 23, wherein the composition is administered via subretinal injection.

25. The method of claim 23, wherein the effective amount is 1x108to 1x1014vg / mL.

26. The method of claims 23, wherein the ocular disease is age-related macular degeneration, Bardet-Biedl syndrome, chorioretinal atrophy, congenital stationary night blindness, oculo-retinal developmental disease, optic atrophy, usher syndrome, retinopathy of prematurity, achromatopsia, leber's hereditary optic neuropathy, cone-rod dystrophy, leber's congenital amaurosis, stargardt disease, diabetic retinopathy, retinal detachment, best's disease, retinitis pigmentosa, choroideremia, or retinal blanket degeneration.

27. The method of claim 23, wherein the subject has advanced stage disease.

28. The method of claim 23, wherein the subject has lost about 50% or more of their rod or cone cells.

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