Gene-mediated conditions

Abstract

The present disclosure relates to nucleic acids, vectors and related compositions and methods for treating Pre-mRNA Processing Factor 31 (PRPF31) gene-mediated conditions. The present disclosure provides nucleic acids that bind to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre- mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, expression vectors and methods of use thereof.

Description

[0001] GENE-MEDIATED CONDITIONS

[0002] RELATED APPLICATION DATA

[0003] The present application claims priority from Australian Patent Application No. 2023902730 filed on 25 August 2023 entitled “Gene-mediated conditions”, the entire contents of which is hereby incorporated by reference.

[0004] SEQUENCE LISTING

[0005] The present application is filed together with a Sequence Listing in electronic form. The entire contents of the Sequence Listing are hereby incorporated by reference.

[0006] FIELD

[0007] The present disclosure relates to nucleic acids, vectors and related compositions and methods for treating Pre-mRNA Processing Factor 31 (PRPF31) gene-mediated conditions.

[0008] BACKGROUND

[0009] Retinitis pigmentosa (RP) is aphenotypically linked group of related degenerative eye diseases that cause severe vision impairment. Retinitis pigmentosa is a rare disease that affects approximately one out of every 4,000 individuals (more than 1.5 million people worldwide). In a majority of cases, retinitis pigmentosa is inherited however rarely it can be the result of miscoding during DNA division.

[0010] Retinitis pigmentosa is commonly caused by the progressive degeneration of the rod photoreceptor cells. However, the retinal pigment epithelium and cone photoreceptor cells may also degenerate during progression of the disease. This degeneration may also be accompanied by abnormal deposits of pigment in the rods of the retina.

[0011] Retinitis pigmentosa may be: (1) non-syndromic, that is, it occurs alone, without any other clinical findings, (2) syndromic, with other neurosensory disorders, developmental abnormalities, or complex clinical findings, or (3) secondary to other systemic genetic diseases, such as Usher syndrome. Symptoms usually start in childhood, and most people eventually lose most of their sight.

[0012] Several genes have been identified that can cause the RP phenotype when mutated. Inheritance patterns of retinitis pigmentosa have been identified as autosomal dominant, autosomal recessive, X-linked, and maternally (mitochondrially) acquired, and are dependent on the specific retinitis pigmentosa gene mutations present in the parental generation. Of the familial RP cases, 30%-40% show autosomal-dominant genetic inheritance.

[0013] There is currently no approved therapy to treat or prevent the development of retinitis pigmentosa or to improve vision following the onset of the disease. Current strategies being investigated for treatment of retinitis pigmentosa include vitamin supplementation (e.g., vitamin A palmitate), bone marrow derived stem cell transplantation, retinal prosthesis, and adeno-associated virus (AAV)-mediated gene therapy with, for example, insertion of RPE65, RPGR or PRPF31. Unfortunately, whilst these strategies may delay disease, degradation of retinal photoreceptors continues to progress.

[0014] Accordingly, there is an ongoing need to provide new treatments and preventative measures for ocular diseases, such as retinitis pigmentosa.

[0015] SUMMARY

[0016] In producing the present invention, the inventors identified regulators of expression of Pre-mRNA Processing Factor 31 (PRPF31) as potential targets for pharmacological intervention for treating or preventing retinitis pigmentosa. The inventors have identified several non-coding RNA (ncRNA) sequences that overlay, in part or in full, the PRPF31 pre-mRNA or mRNA that may be regulated to influence the expression of PRPF31 mRNA and PRPF31 protein in a cell and / or tissue.

[0017] The inventors have identified oligonucleotides that bind to a PRPF31 pre-mRNA or mRNA or a ncRNA that is complementary to a portion of a PRPF31 pre-mRNA or mRNA and that rely on any of a variety of mechanisms of action to upregulate PRPF31 expression. For example, oligonucleotides identified by the inventors increase PRPF31 mRNA and / or PRPF31 protein expression by reducing specific binding of a microRNA (miRNA) to the PRPF31 mRNA and / or by reducing function or expression of a ncRNA that negatively regulates PRPF31 expression. In addition, oligonucleotides identified by the inventors increase PRPF31 mRNA and / or PRPF31 expression by reducing the complexity of the secondary structures and / or steric blocking upstream open reading frames (uORFs) that reduce the translation efficiency of PRPF31 protein

[0018] Accordingly, the findings by the inventors provide the basis for a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA.

[0019] The findings by the inventors also provide the basis for a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA. The present disclosure further provides a nucleic acid that binds to:

[0020] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0021] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 {PRPF31') pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0022] Accordingly, the present disclosure provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre- mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA.

[0023] The present disclosure further provides a nucleic acid that binds to:

[0024] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0025] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0026] The present disclosure also provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA.

[0027] The present disclosure further provides a nucleic acid that binds to:

[0028] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0029] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0030] The present disclosure further provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre- mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA.

[0031] The present disclosure further provides a nucleic acid that binds to:

[0032] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 PRPF31') pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0033] The present disclosure provides a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0034] The present disclosure provides a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0035] The present disclosure further provides a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0036] The present disclosure provides a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0037] In one example, the nucleic acid binds to a targeted portion of the 3 ’ untranslated region (UTR) or the 5’ UTR of PRPF31 pre-mRNA or mRNA.

[0038] In one example, the nucleic acid binds to a targeted portion of the 3 ’ UTR of PRPF31 pre-mRNA or mRNA.

[0039] In one example, the nucleic acid binds to a targeted portion of the 5 ’ UTR of PRPF31 pre-mRNA or mRNA.

[0040] The present disclosure also provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell. The present disclosure also provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0041] The present disclosure also provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0042] The present disclosure also provides a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0043] The findings by the inventors additionally provide the basis for methods of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject.

[0044] Accordingly, the present disclosure provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to:

[0045] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0046] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0047] The present disclosure also provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to:

[0048] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 PRPF31') pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0049] The present disclosure further provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to:

[0050] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0051] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0052] The present disclosure provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to:

[0053] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0054] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0055] The present disclosure provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to atargeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0056] The present disclosure provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to atargeted portion of Pre-mRNA Processing Factor 31 (PRPF31 ) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0057] The present disclosure also provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0058] The present disclosure further provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0059] The present disclosure further provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0060] The present disclosure further provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0061] The present disclosure further provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0062] The present disclosure further provides a method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0063] In one example, the disease or condition is an ocular condition. For example, the ocular condition is retinitis pigmentosa.

[0064] The present disclosure further provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to:

[0065] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0066] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0067] The present disclosure further provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to:

[0068] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0069] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0070] The present disclosure further provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to: (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0071] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 PRPF31') pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0072] The present disclosure further provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to:

[0073] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0074] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0075] The present disclosure provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0076] The present disclosure provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0077] The present disclosure provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0078] The present disclosure provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0079] The present disclosure also provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0080] The present disclosure also provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0081] The present disclosure also provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0082] The present disclosure also provides a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0083] In one example, the vector comprises a retinal cell type-selective or tissue- selective promoter for driving expression of the nucleic acid in the mammalian cell.

[0084] In one example, the retinal cell type-selective or tissue-selective promoter is selective for expression in a retinal cell and / or tissue selected from the group consisting of retina, retinal pigment epithelium, Muller glial cells, endothelial cells, glial cells, astrocytes, photoreceptors, bipolar cells, horizontal cells, ganglion cells, amacrine cells and combinations thereof.

[0085] In one example, the vector comprises an inducible promoter.

[0086] In one example, the vector is a non-viral vector.

[0087] The present disclosure also provides a composition comprising the non-viral vector according to the disclosure and a transfection agent. In one example, the vector is a viral vector. For example, the viral vector is a recombinant virus selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus and anellovirus.

[0088] In one example, upon binding of the nucleic acid to the PRPF31 pre-mRNA or RNA in the cell the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0089] In one example, the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0090] In one example, upon binding of the nucleic acid to the PRPF31 pre-mRNA or RNA in the cell the level of PRPF31 mRNA in the cell is increased.

[0091] In one example, the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein is increased by about 1. 1 to about 10-fold in the cell.

[0092] In one example, the level of PRPF31 mRNA in the cell is increased. For example, the level of PRPF31 mRNA in the cell is increased by about 1. 1 to about 10-fold in the cell. For example, the level of PRPF31 mRNA in the cell and / or the tissue is increased by about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5 -fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1. 1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9- fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold. For example, the level of PRPF31 mRNA in the cell and / or the tissue is increased by at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold.

[0093] In one example, the amount of functional PRPF31 protein is increased. For example, the amount of functional PRPF31 protein is increased by about 1.1 to about 10- fold in the cell. For example, the amount of functional PRPF31 protein in the cell and / or the tissue is increased by about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5 -fold, about 1.1 to about 6- fold, about 1 .1 to about 7-fold, about 1.1 to about 8-fold, about 1. 1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8- fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold. For example, the amount of functional PRPF31 protein in the cell and / or the tissue is increased by at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold.

[0094] In one example, the cell and / or tissue is selected from the group consisting of an ocular tissue, retinal pigment epithelium (RPE) cells, Muller glial cells, endothelial cells, glial cells, astrocytes, photoreceptors, bipolar cells, horizontal cells, ganglion cells, amacrine cells and combinations thereof. For example, the cell and / or tissue is selected from the group consisting of the retina, RPE cells and combinations thereof.

[0095] In one example, the nucleic acid binds near or within a targeted portion of:

[0096] (i) a P RPF31 gene pre -mRNA intron;

[0097] (ii) a PRPF31 gene pre-mRNA exon; and / or

[0098] (iii)a PRPF31 gene mRNA exon-exon junction.

[0099] In one example, the nucleic acid binds near or within a targeted portion of a PRPF31 gene pre-mRNA intron.

[0100] In one example, the nucleic acid binds near or within a targeted portion of a PRPF31 gene pre-mRNA exon.

[0101] In one example, the nucleic acid binds near or within a targeted portion of a PRPF31 gene mRNA exon-exon junction.

[0102] In one example, binding of the nucleic acid to the targeted portion of the PRPF31 pre-mRNA or mRNA reduces specific binding of a microRNA (miRNA) to the PRPF31 mRNA.

[0103] In one example, binding of the nucleic acid to the targeted portion reduces specific binding of the miR-1251 -5p family miRNAs and / or miR-129-3p family miRNAs to the 3 ’UTR of a PRPF31 mRNA.

[0104] In one example, binding of the nucleic acid to the targeted portion reduces specific binding of the miR-129-3p family miRNAs to the 3 ’UTR of a PRPF31 mRNA. For example, binding of the nucleic acid reduces specific binding of hsa-miR-129-l-3p and / or hsa-miR-129-2-3p to the 3’UTR of a PRPF31 mRNA.

[0105] In one example, binding of the nucleic acid to the targeted portion reduces specific binding of the miR-1251-5p family miRNAs to the 3’UTR of a PRPF31 mRNA.

[0106] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and increases translation of PRPF31 mRNA.

[0107] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and sterically inhibits translation from upstream Open Reading Frames (uORF) start site and / or sterically inhibits secondary structure in the 5' UTR.

[0108] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA corresponding to SEQ ID NO: 1. In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862.

[0109] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA corresponding to SEQ ID NO: 41861.

[0110] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA corresponding to SEQ ID NO: 41862.

[0111] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and is complementary to a sequence corresponding to SEQ ID NO: 1.

[0112] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 6 to 18193.

[0113] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 6 to 18193 or 41833 to 41860.

[0114] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 6 to 9098.

[0115] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 9099 to 18193.

[0116] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41833 to 41860.

[0117] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41833 to 41849.

[0118] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41833 to 41843.

[0119] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41844 to 41849.

[0120] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125, 16126, 41833, 41835 to 41840, 41842, 41843, 41846 or 41849. In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125, 16126, 41846, 41848 or 41849.

[0121] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125, 16126, 41846 or 41849.

[0122] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125, 16126 or 41846.

[0123] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125 or 41849.

[0124] In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 16125. For example, the nucleic acid comprises a sequence CCAGAACCCGATCCTAGCCCTTCAG (SEQ ID NO: 16125).

[0125] In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 16126. For example, the nucleic acid comprises a sequence CTGCCAGAACCCGATCCTAGCCCTT (SEQ ID NO: 16126).

[0126] In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 41846. For example, the nucleic acid comprises a sequence AGAACCCGATCCTAGCCCTTCAGAA (SEQ ID NO: 41846).

[0127] In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 41849. For example, the nucleic acid comprises a sequence TCTTTTCAAAAAATCTCCTTTCTCA (SEQ ID NO: 41849).

[0128] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16106, 16116, 16176, 41844, 41845, or 41847 to 41849.

[0129] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41835- 41840, 41842, 41843 or 10870, 10862 or 10843.

[0130] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 10870, 10862 or 10843.

[0131] In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 10843. For example, the nucleic acid comprises a sequence AACAACTTTATTAGCACCTGGCACT (SEQ ID NO: 10843). In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 10862. For example, the nucleic acid comprises a sequence GGCAAAGCTACTCTCTGATTGGTCC (SEQ ID NO: 10862).

[0132] In one example, the nucleic acid comprises a sequence set forth in SEQ ID NO: 10870. For example, the nucleic acid comprises a sequence GTCTCACTCTCGCGCCGTTATAGAG (SEQ ID NO: 10870).

[0133] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA, wherein the targeted portion is within the nucleotide sequence corresponding to SEQ ID NO: 1 and / or SEQ ID NO: 41861.

[0134] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA, wherein the targeted portion is within the nucleotide sequence corresponding to SEQ ID NO: 41861.

[0135] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 7008 to 7103, 16098 to 16201, or 41844 to 41849.

[0136] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16106, 16116, 16176, 41844, 41845, or 41847 to 41849.

[0137] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125, 16126, 41846, 41848 or 41849.

[0138] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 16125 or 41849.

[0139] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 16116. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence GGACTGGACCTCTGTGTCCCTTCAG (SEQ ID NO: 16116).

[0140] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 16125. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence CCAGAACCCGATCCTAGCCCTTCAG (SEQ ID NO: 16125).

[0141] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 16126. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence CTGCCAGAACCCGATCCTAGCCCTT (SEQ ID NO: 16126). In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 16176. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence TCTCAGTTAAAAAAGACAAGGCATG (SEQ ID NO: 16176).

[0142] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 41844. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence TTCAGTGGGAAGCCACCTTGGACAC (SEQ ID NO: 41844).

[0143] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 41845. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence TCTGTGTCCCTTCAGTGGGAAGCCA (SEQ ID NO: 41845).

[0144] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 41846. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence AGAACCCGATCCTAGCCCTTCAGAA (SEQ ID NO: 41846).

[0145] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 41847. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence AAAAGACAAGGCATGATGAAGACCT (SEQ ID NO: 41847).

[0146] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 41848. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence AAATCTCCTTTCTCAGTTAAAAAAG (SEQ ID NO: 41848).

[0147] In one example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence set forth in SEQ ID NO: 41849. For example, the nucleic acid binds within a targeted portion of the 3 ’UTR of PRPF31 mRNA and comprises a sequence TCTTTTCAAAAAATCTCCTTTCTCA (SEQ ID NO: 41849).

[0148] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 1672 to 1796, 10765 to 10886 or 41833-41843.

[0149] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA, wherein the targeted portion is within the nucleotide sequence corresponding to SEQ ID NO: 1 and / or SEQ ID NO: 41862. In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA, wherein the targeted portion is within the nucleotide sequence corresponding to SEQ ID NO: 41862.

[0150] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 1672 to 1796, 10765 to 10886 or 41833-41843.

[0151] In one example, the nucleic acid binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 10843, 10862, 10870, 41833, 41835 to 41840, 41842 or 41843.

[0152] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 10843, 10862 or 10870.

[0153] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 10843. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence AACAACTTTATTAGCACCTGGCACT (SEQ ID NO: 10843).

[0154] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 10862. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence GGCAAAGCTACTCTCTGATTGGTCC (SEQ ID NO: 10862).

[0155] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 10870. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence GTCTCACTCTCGCGCCGTTATAGAG (SEQ ID NO: 10870).

[0156] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41833. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence CACTGTTTCTAGCGTTAGTC (SEQ ID NO: 41833).

[0157] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41835. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence CACTCTCGCGCCGTTATAGA (SEQ ID NO: 41835).

[0158] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41836. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence CACTCTCGCGCCGTTATACT (SEQ ID NO: 41836). In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41837. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence AGCTACTCTCTGATTGGTCC (SEQ ID NO: 41837).

[0159] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41838. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises a sequence AGCTACTCTCTGATTGGTGG (SEQ ID NO: 41838).

[0160] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41839. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises the sequence CAACTTTATTAGCACCTGGC (SEQ ID NO: 41839).

[0161] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41840. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises the sequence CAACTTTATTAGCACCTGCG (SEQ ID NO: 41840).

[0162] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41842. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises the sequence ACTGGTTGCGGCGTTAGACA (SEQ ID NO: 41843).

[0163] In one example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises SEQ ID NO: 41843. For example, the nucleic acid binds within a targeted portion of the 5 ’UTR of PRPF31 mRNA and comprises the sequence ACTGGTTGCGGCGTTAGAGU (SEQ ID NO: 41843).

[0164] In one example, binding of the nucleic acid to the targeted portion of the ncRNA that is complementary to a portion of a PRPF31 pre-mRNA or mRNA: reduces function of the ncRNA; and / or modulates splicing of the ncRNA. For example, the nucleic acid reduces function of the ncRNA. In another example, the nucleic acid modulates splicing of the ncRNA.

[0165] In one example, the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

[0166] In one example, the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 2.

[0167] In one example, the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 3. In one example, the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 4.

[0168] In one example, the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 5.

[0169] In one example, the nucleic acid binds within a targeted portion of ncRNA and is complementary to a sequence corresponding to any one of SEQ ID NOs: 2 to 5.

[0170] In one example, the nucleic acid binds within a targeted portion of ncRNA and is complementary to a sequence corresponding to SEQ ID NO: 2.

[0171] In one example, the nucleic acid binds within a targeted portion of ncRNA and is complementary to a sequence corresponding to SEQ ID NO: 3.

[0172] In one example, the nucleic acid binds within a targeted portion of ncRNA and is complementary to a sequence corresponding to SEQ ID NO: 4.

[0173] In one example, the nucleic acid binds within a targeted portion of ncRNA and is complementary to a sequence corresponding to SEQ ID NO: 5.

[0174] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 18194 to 41831 .

[0175] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 18194 to 27282.

[0176] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 27283 to 36362.

[0177] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 36363 to 37743.

[0178] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 37744 to 39121.

[0179] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 39122 to 39876.

[0180] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 39877 to 40628.

[0181] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 40629 to 41231.

[0182] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41232 to 41831.

[0183] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41850 to 41860. In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 31223, 41850, 41852, 41854, or 41855.

[0184] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 31223, 41850, 41852, or 41854.

[0185] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in SEQ ID NO: 31223. For example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence CAGCAAGGCGCTTCTTTTCTTTAAG (SEQ ID NO: 31223).

[0186] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in SEQ ID NO: 41850. For example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence CAACAACCTGACCGTGGAGAT (SEQ ID NO: 41850).

[0187] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in SEQ ID NO: 41852. For example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence GAATACCGCGTCATCGTGGAT (SEQ ID NO: 41852).

[0188] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in SEQ ID NO: 41854. For example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence TCACACCCATGCCTCCGTGTC (SEQ ID NO: 41854).

[0189] In one example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence set forth in SEQ ID NO: 41855. For example, the nucleic acid binds within a targeted portion of ncRNA and comprises a sequence GATTTAGATACTCACACCCATG (SEQ ID NO: 41855).

[0190] In one example, the nucleotide sequence is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the nucleotide sequence of the targeted portion over the length of the nucleic acid.

[0191] In one example, the nucleic acid is:

[0192] (i) an antisense oligonucleotide;

[0193] (ii) a small interfering RNA (siRNA);

[0194] (iii) a short hairpin RNA (shRNA);

[0195] (iv) a guide RNA (gRNA); and / or

[0196] (v) a nucleic acid encoding a DNA endonuclease or an endonuclease system. In one example, the nucleic acid is an antisense oligonucleotide (ASO). For example, the ASO is a gapmer ASO.

[0197] In one example, the nucleic acid is a siRNA.

[0198] In one example, the nucleic acid is a shRNA.

[0199] In one example, the nucleic acid is a gRNA.

[0200] In one example, the antisense oligonucleotide comprises a phosphorodiamidate morpholino moiety.

[0201] In one example, the nucleic acid is a nucleic acid encoding a DNA endonuclease or an endonuclease system. For example, the endonuclease system is a meganuclease, a zinc finger nuclease (ZFN), a transcription-activator like effector nuclease (TALEN) and / or a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas nuclease.

[0202] In one example, the ASO or siRNA comprises a backbone modification. For example, the backbone modification comprises a phosphorothioate linkage or a phosphorodiamidate linkage. In one example, the ASO or siRNA comprises a phosphorothioate linkage. For example, the ASO or siRNA comprises a phosphorothioate linkage In another example, the ASO or siRNA comprises a phosphorodiamidate linkage. For example, the ASO or siRNA comprises a phosphorodiamidate linkage.

[0203] In one example, the ASO or siRNA comprises a phosphorodiamidate morpholino, a locked nucleic acid, an unlocked nucleic acid, a glycol nucleic acid, a peptide nucleic acid, a 2'-O-methyl, a 2' -Fluoro, a 2'-O-methoxyethyl, a 2'-deoxy-2'-fluoro-P-D- arabinonucleic acid (FANA), or a O-alkyl nucleic acid moiety. For example, the ASO or siRNA comprises a phosphorodiamidate morpholino moiety. In another example, the ASO or siRNA comprises a locked nucleic acid. In a further example, the ASO or siRNA comprises an unlocked nucleic acid. In one example, the nucleic acid comprises a glycol nucleic acid. In another example, the ASO or siRNA comprises a peptide nucleic acid. In a further example, the ASO or siRNA comprises a 2'-O-methyl moiety. In one example, the ASO or siRNA comprises a 2' -Fluoro moiety. In another example, the ASO or siRNA comprises a 2'-O-methoxyethyl moiety. In a further example, the ASO or siRNA comprises a 2'-deoxy-2'-fluoro-P-D-arabinonucleic acid (FANA) moiety. In one example, the ASO or siRNA comprises a O-alkyl nucleic acid moiety.

[0204] In one example, the ASO or siRNA comprises at least one modified sugar moiety. For example, each sugar moiety in the antisense oligonucleotide or siRNA is a modified sugar moiety. In one example, the ASO or siRNA comprises a 2'-O-methoxyethyl moiety. For example, each nucleotide of the ASO or siRNA comprises a 2'-O-methoxyethyl moiety.

[0205] In one example, the nucleotide sequence of the ASO or siRNA consists of 10 to 50 nucleotides, 15 to 40 nucleotides, 18 to 40 nucleotides, 16 to 20 nucleotides, 17 to 25 nucleotides, 19 to 23 nucleotides, 20 to 35 nucleotides, 20 to 30 nucleotides, 22 to 30 nucleotides, 22 to 28 nucleotides, 24 to 30 nucleotides, 25 to 30 nucleotides, or 26 to 30 nucleotides. In one example, the nucleotide sequence of the ASO or siRNA consists of 16 to 20 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 16 nucleotides. In one example, the nucleotide sequence of the ASO or siRNA consists of 19 to 23 nucleotides. In one example, the nucleotide sequence of the ASO or siRNA consists of 20 to 30 nucleotides. For example, the nucleotide sequence of the ASO or siRNA consists of 17 nucleotides. In one example, the nucleotide sequence of the ASO or siRNA consists of 19 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 21 nucleotides. In a further example, the nucleotide sequence of the ASO or siRNA consists of 22 nucleotides. In one example, the nucleotide sequence of the ASO or siRNA consists of 23 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 24 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 25 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 26 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 27 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 28 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 29 nucleotides. In another example, the nucleotide sequence of the ASO or siRNA consists of 30 nucleotides.

[0206] In one example, the ASO or siRNA comprises one or more phosphorodiamidate morpholino moieties.

[0207] In one example of any method described herein, the ASO or siRNA is linked to a functional moiety. The functional moiety can be covalently linked or non-covalently linked to the ASO or siRNA. The functional moiety can be at the 5' end and / or 3' end of the ASO.

[0208] In some examples, the functional moiety comprises a delivery moiety. For example, the delivery moiety is selected from the group consisting of lipids, peptides, carbohydrates, and antibodies. An exemplary delivery moiety comprises a cellpenetrating peptide (CPP), e.g., as described in WO2021 / 119756. In one example, the CPP comprises the sequence RRSRTARAGRPGRNSSRPSAPR (SEQ ID NO: 41832), optionally wherein any amino acid other than glycine is a D amino acid. In one example, the CPP consists of a sequence set forth in SEQ ID NO: 41832. In another example, the CPP comprises the sequence RASARRASARRANARRANARRSGGR (SEQ ID NO: 41863). In one example, the CPP consists of a sequence sequence forth in SEQ ID NO: 41863.

[0209] The present disclosure additionally contemplates delivery moieties such as a N- acetylgalactosamine (GalNAc) moiety, a fatty acid moiety, or a lipid moiety.

[0210] In some examples, the functional moiety comprises a stabilising moiety.

[0211] In some examples, the functional moiety comprises a half-life extending moiety. For example, the half-life extending moiety is a polyethylene glycol (PEG) or an albumin binding protein. Other suitable half-life extending moieties will be apparent to the skilled person and / or described herein.

[0212] In one example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 6 to 41831 or 41833 to 41860.

[0213] In one example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 6 to 41831.

[0214] In one example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 6 to 18193. For example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 6 to 9098. In another example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 9099 to 18193. In a further example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 18194 to 41831. For example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 18194 to 27282. In one example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 27283 to 36362. In another example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 36363 to 37743. In a further example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 37744 to 39121. In one example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 39122 to 39876. In another example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 39877 to 40628. In a further example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 40629 to 41231. In one example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 41232 to 41831. In another example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 41833 to 41849. For example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 41833 to 41843. In another example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 41844 to 41849. In another example, the nucleotide sequence of the antisense oligonucleotide corresponds to a sequence set forth in any one of SEQ ID NOs: 41850 to 41860.

[0215] In one example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 6 to 18193 or 41833 to 41849. In one example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 6 to 18193. For example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 6 to 9098. In another example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre- mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 9099 to 18193. In a further example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41833 to 41849. In one example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41833 to 41843. In another example, the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41844 to 41849.

[0216] In one example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 18194 to 41831 or 41850 to 41860. In one example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 18194 to 41831. In another example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 18194 to 27282. In one example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 27283 to 36362. In another example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 36363 to 37743. In a further example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 37744 to 39121. In one example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 39122 to 39876. In another example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 39877 to 40628. In a further example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 40629 to 41231. In one example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41232 to 41831. In one example, the antisense oligonucleotide binds within a targeted portion of ncRNA and comprises a sequence set forth in any one of SEQ ID NOs: 41850 to 41860.

[0217] The present disclosure additionally provides a pharmaceutical composition comprising a nucleic acid of the disclosure, and a pharmaceutically acceptable excipient, for use in any method of the disclosure.

[0218] In one example, the nucleic acid is complexed with a delivery nanocarrier. For example, the delivery nanocarrier is selected from the group consisting of: lipoplexes, liposomes, exosomes, inorganic nanoparticles, and DNA nanostructures. In one example, the delivery nanocarrier comprises a lipid nanoparticle (LNP) encapsulating the antisense oligonucleotide.

[0219] In one example of any method described herein, the nucleic acid is formulated for a route of administration selected from the group consisting of intravitreal, suprachoroidal, subretinal, ciliary intramuscular, intravenous, intra-arterial, subcutaneous, and topical routes.

[0220] The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to:

[0221] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0222] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell. The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to:

[0223] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0224] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0225] The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, wherein the nucleic acid binds to:

[0226] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0227] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0228] The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3P) gene mediated disease or condition in a subject, wherein the nucleic acid binds to:

[0229] (i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or

[0230] (ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell. The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0231] The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0232] The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0233] The present disclosure also provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0234] The present disclosure further provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell. The present disclosure further provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0235] The present disclosure further provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell.

[0236] The present disclosure further provides use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0237] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862.

[0238] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 1

[0239] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41861

[0240] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41862

[0241] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862.

[0242] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 1

[0243] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41861

[0244] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41862

[0245] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862.

[0246] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 1.

[0247] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41861.

[0248] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41862.

[0249] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862. The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 1

[0250] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41861

[0251] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to SEQ ID NO: 41862.

[0252] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

[0253] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 6 to 18193.

[0254] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 6 to 9098.

[0255] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 9099 to 18193.

[0256] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 41833 to 41843.

[0257] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 41844 to 41849.

[0258] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

[0259] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

[0260] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

[0261] The present disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

[0262] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 2.

[0263] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 2.

[0264] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 2.

[0265] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 2.

[0266] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 3.

[0267] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 3.

[0268] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 3.

[0269] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 3.

[0270] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 4.

[0271] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 4.

[0272] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 4.

[0273] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 4.

[0274] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 5.

[0275] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 5.

[0276] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 5.

[0277] In one example, the disclosure provides an antisense oligonucleotide that binds to a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to SEQ ID NO: 5.

[0278] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 18194 to 41831 or 41850 to 41860.

[0279] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 18194 to 41831.

[0280] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 18194 to 27282.

[0281] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 27283 to 36362.

[0282] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 36363 to 37743.

[0283] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 37744 to 39121.

[0284] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 39122 to 39876. In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 39877 to 40628.

[0285] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 40629 to 41231.

[0286] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 41232 to 41831.

[0287] In one example, the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 41850 to 41860.

[0288] The disclosure also provides a modified cell comprising a nucleic acid of the disclosure for use in any method described herein. For example, the modified cell is a mammalian cell, such as a human cell.

[0289] The present disclosure also provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, or a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0290] The present disclosure also provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, or a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell is increased.

[0291] The present disclosure also provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, or a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased. The present disclosure also provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, or a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0292] The present disclosure provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more double-strand breaks within or near a DNA sequence encoding Pre- mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0293] The present disclosure provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more double-strand breaks within or near a DNA sequence encoding Pre- mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell is increased.

[0294] The present disclosure provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more double-strand breaks within or near a DNA sequence encoding Pre- mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0295] The present disclosure provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more double-strand breaks within or near a DNA sequence encoding Pre- mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased. The present disclosure further provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0296] The present disclosure further provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell is increased.

[0297] The present disclosure further provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0298] The present disclosure further provides a method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single -strand breaks or one or more double -strand breaks within or near a DNA sequence encoding a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0299] In one example, the genetic modification is selected from the group consisting of:

[0300] (i) small insertions and deletions (indels);

[0301] (ii) insertion and / or deletion and / or replacement of one or more nucleotide bases within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA; (iii) insertion of a RNA destabilizing element near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;

[0302] (iv) deletion of one or more exons within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;

[0303] (v) deletion of one or more introns within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;

[0304] (vi) deletion of one or more miRNA binding sites within or near the targeted portion of the PRPF31 pre-mRNA and / or mRNA; and

[0305] (vii) combinations thereof.

[0306] In one example, the genetic modification is an indel.

[0307] In one example, the genetic modification is an insertion and / or deletion and / or replacement of one or more nucleotide bases within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA. In one example, the genetic modification is an insertion and / or deletion and / or replacement of one or more nucleotide bases within or near the targeted portion of the PRPF31 pre-mRNA or mRNA. In one example, the genetic modification is an insertion and / or deletion and / or replacement of one or more nucleotide bases within or near the targeted portion of the ncRNA.

[0308] In one example, the genetic modification is an insertion of a RNA destabilizing element near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA. In one example, the genetic modification is an insertion of a RNA destabilizing element near the targeted portion of the PRPF31 pre-mRNA or mRNA. In one example, the genetic modification is an insertion of a RNA destabilizing element near the targeted portion of the PRPF31 ncRNA. For example, the RNA destabilizing element is a microRNA binding site and / or a polyadenylation site upstream of the ncRNA transcriptional start site.

[0309] In one example, the genetic modification is a deletion of one or more exons within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA. In one example, the genetic modification is a deletion of one or more exons within or near the targeted portion of the PRPF31 pre-mRNA or mRNA. In one example, the genetic modification is a deletion of one or more exons within or near the targeted portion of the PRPF31 ncRNA.

[0310] In one example, the genetic modification is a deletion of one or more introns within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA. In one example, the genetic modification is a deletion of one or more introns within or near the targeted portion of the PRPF31 pre-mRNA or mRNA. In one example, the genetic modification is a deletion of one or more introns within or near the targeted portion of the PRPF31 ncRNA.

[0311] In one example, the genetic modification is a deletion of one or more miRNA binding sites within or near the targeted portion of the PRPF31 pre-mRNA and / or mRNA.

[0312] In one example, the genetic modification is:

[0313] (i) deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;

[0314] (ii) deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA; and / or

[0315] (iii) deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA.

[0316] In one example, the genetic modification is deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA.

[0317] In one example, the genetic modification is deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA.

[0318] In one example, the genetic modification is deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA.

[0319] In one example, the genetic modification is:

[0320] (i) deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;

[0321] (ii) deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA; and / or

[0322] (iii) deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA; wherein

[0323] (i) the PRPF31 pre-mRNA or mRNA comprises a sequence set forth in SEQ ID NO: 1; and / or

[0324] (ii) the ncRNA comprises a sequence set forth in any one of SEQ ID NOs: 2 to 5.

[0325] In one example, the genetic modification is:

[0326] (i) deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA or mRNA; (ii) deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA or mRNA; and / or

[0327] (iii) deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 pre-mRNA or mRNA; wherein the PRPF31 pre-mRNA or mRNA comprises a sequence set forth in SEQ ID NO: 1.

[0328] In one example, the genetic modification is deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA or mRNA, wherein the PRPF31 pre-mRNA or mRNA comprises a sequence set forth in SEQ ID NO: 1.

[0329] In one example, the genetic modification is deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 pre-mRNA or mRNA, wherein the PRPF31 pre-mRNA or mRNA comprises a sequence set forth in SEQ ID NO: 1.

[0330] In one example, the genetic modification is deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 pre-mRNA or mRNA, wherein the PRPF31 pre-mRNA or mRNA comprises a sequence set forth in SEQ ID NO: 1.

[0331] In one example, the genetic modification is:

[0332] (i) deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 ncRNA;

[0333] (ii) deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 ncRNA; and / or

[0334] (iii) deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 ncRNA; wherein the ncRNA comprises a sequence set forth in any one of SEQ ID NOs: 2 to 5.

[0335] In one example, the genetic modification is deletion of an intronic sequence or part thereof within or near the targeted portion of the PRPF31 ncRNA, wherein the ncRNA comprises a sequence set forth in any one of SEQ ID NOs: 2 to 5.

[0336] In one example, the genetic modification is deletion of an exon sequence or part thereof within or near the targeted portion of the PRPF31 ncRNA, wherein the ncRNA comprises a sequence set forth in any one of SEQ ID NOs: 2 to 5.

[0337] In one example, the genetic modification is deletion of an exon-exon boundary or part thereof within or near the targeted portion of the PRPF31 ncRNA, wherein the ncRNA comprises a sequence set forth in any one of SEQ ID NOs: 2 to 5. In one example, the DNA endonuclease or endonuclease system is selected from the group consisting of a meganuclease, a zinc finger nuclease (ZFN), a transcriptionactivator like effector nuclease (TALEN) and a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas nuclease.

[0338] In one example, the DNA endonuclease or endonuclease system is encoded in a viral vector selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus and anellovir.

[0339] In one example, the genetic modification increases or decreases function of the PRPF31 pre-mRNA, mRNA and / or ncRNA. For example, the genetic modification increases or decreases function of the PRPF31 pre-mRNA or mRNA. In one example, the genetic modification increases function of the PRPF31 pre-mRNA or mRNA. In another example, the genetic modification decreases function of the PRPF31 pre-mRNA or mRNA. In one example, the genetic modification increases or decreases function of the PRPF31 ncRNA. For example, the genetic modification increases function of the PRPF31 ncRNA. In another example, the genetic modification decreases function of the PRPF31 ncRNA.

[0340] The present disclosure provides a method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more double-strand breaks within or near a DNA sequence comprising a miRNA binding site within a 3 ’untranslated region (UTR) of a gene encoding the PRPF31 pre-mRNA or mRNA in a cell, such that the miRNA binding site or part thereof is deleted, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0341] In one example, the DNA endonuclease or endonuclease system is selected from the group consisting of a meganuclease, a zinc finger nuclease (ZFN), a transcriptionactivator like effector nuclease (TALEN) and a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas nuclease.

[0342] In one example, the DNA endonuclease or endonuclease system is encoded in a viral vector selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus and anellovir.

[0343] The present disclosure further provides a method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising deleting a miRNA binding site or part thereof within a 3 ’untranslated region (UTR) of a gene encoding the PRPF31 pre- mRNA or mRNA in a cell, such that the miRNA is no longer able to bind to the miRNA binding site and wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0344] The present disclosure also provides a method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising preventing a miRNA binding to a miRNA binding site within a 3 ’untranslated region (UTR) of a gene encoding the PRPF31 pre- mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0345] In one example, the miRNA binding site is a binding site of a miR-129-3p and / or a miR-1251-5p.

[0346] In one example, the miRNA binding site is a binding site of a miR-129-3p microRNA family member. For example, the miR-129-3p microRNA family member is hsa-miR-129-l-3p and / or hsa-miR-129-2-3p. In one example, the miR-129-3p microRNA family member is hsa-miR-129-l-3p. In another example, the miR-129-3p microRNA family member is hsa-miR-129-2-3p. In a further example, the miR-129-3p microRNA family member is hsa-miR-129-l-3p and hsa-miR-129-2-3p.

[0347] In one example, the miRNA binding site is a binding site of a miR-1251-5p microRNA family member. In one example, the miR-1251-5p microRNA family member is hsa-miR-1251-5p.

[0348] The present disclosure also provides a method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising sterically inhibiting translation from an upstream Open Reading Frames (uORF) start site and / or sterically inhibiting a secondary structure in the 5' UTR, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

[0349] KEY TO SEQUENCE LISTING

[0350] SEQ ID NO: 1 PRPF31 sense strand

[0351] SEQ ID NO: 2 PRPF31 antisense strand

[0352] SEQ ID NO: 3 PRPF31 antisense strand - spliced

[0353] SEQ ID NO: 4 PRPF31 antisense strand - spliced

[0354] SEQ ID NO: 5 PRPF31 antisense strand - spliced

[0355] SEQ ID NOs: 6-9098 ASOs (16mers) complementary to SEQ ID NO: 1

[0356] SEQ ID NOs: 9099-18193 ASOs (25mers) complementary to SEQ ID NO: 1

[0357] SEQ ID NOs: 18194-27282 ASOs (16mers) complementary to SEQ ID NO: 2

[0358] SEQ ID NOs: 27283-36362 ASOs (25mers) complementary to SEQ ID NO: 2

[0359] SEQ ID NOs: 36363-37743 ASOs (16mers) complementary to SEQ ID NO: 3

[0360] SEQ ID NOs: 37744-39121 ASOs (25mers) complementary to SEQ ID NO: 3

[0361] SEQ ID NOs: 39122-39876 ASOs (16mers) complementary to SEQ ID NO: 4

[0362] SEQ ID NOs: 39877-40628 ASOs (25mers) complementary to SEQ ID NO: 4

[0363] SEQ ID NOs: 40629-41231 ASOs (16mers) complementary to SEQ ID NO: 5

[0364] SEQ ID NOs: 41232-41831 ASOs (25mers) complementary to SEQ ID NO: 5

[0365] SEQ ID NO: 41832 Amino acid sequence of a cell penetrating peptide

[0366] SEQ ID NO: 41833-41843 ASOs targeting 5’UTR of PRPF31

[0367] SEQ ID NO: 41844-41849 ASOs targeting 3 ’UTR of PRPF31

[0368] SEQ ID NO: 41850-41860 ASOs targeting NAT of PRPF31

[0369] SEQ ID NO: 41861 Nucleotide sequence of PRPF31 3 ’UTR

[0370] SEQ ID NO: 41862 Nucleotide sequence of PRPF31 5’UTR

[0371] SEQ ID NO: 41863 Amino acid sequence of a cell penetrating peptide

[0372] BRIEF DESCRIPTION OF THE DRAWINGS

[0373] Figure 1 is a graphical representation showing the different regions for upregulation of the PRPF31 transcription and / or PRPF31 protein and the location of the ncRNA transcripts relative to the canonical PRPF31 gene.

[0374] Figure 2 is a graphical representation showing miRNA modulation of PRPF31 transcript levels. A significant decrease in PRPF31 expression was observed with pre- miR-129-2-3p, 48 hours following lipofectamine transfection of ARPE-19 cells with pre- miRNA (miR-129-3p and miR-1251-5p). PRPF31 mRNA expression was assessed in PPMO treated RP11 derived iPSC-RPE cells using a ddPCR assay. UT= untreated cells. miR-NC = negative control. Bars = Mean ± S.D. Statistics were generated via 2-way ANOVA using Dunnett’s multiple comparisons test. P-values: ** P < 0.01, *** P <0.001. Figure 3 is a schematic representation showing the PRPF31 transcript and ASO target region within the 3' UTR. (A) PRPF31 transcript model (gene id ENSG00000105618. 14 from Gencode v45. Exons and intronsare indicated in dark color and 5' and 3' UTRs indicated in lighter color. (B) Seed sequence of hsa-mir- 129-1 -3p is indicated in bold. ASOs (black line with SEQ ID number indicated) were designed to target the 3 ' UTR of PRPF31 transcript (SEQ ID NO: 41861) and (C) inhibit or alter the binding of target microRNA binding to the PRPF31 3 'UTR to mediate upregulation of PRPF31 gene expression.

[0375] Figure 4 is a graphical representation showing PRPF31 mRNA expression in PPMO (SEQ ID NO. 16125, 16126, 41846) treated RPl l-derived iPSC-RPE cells harbouring PRPF31 C.1205C>A heterozygous mutation using a ddPCR assay. A scrambled negative control (JKP-GTC), predicted not to hybridize to human transcripts, was included as a negative control. Bar graph represents mean + S.D. n=3 technical replicates per experiment. UT = untreated cells. JKP-GTC = scrambled negative control PPMO.

[0376] Figure 5 is a series of graphical representations showing expression levels of PRPF31 mRNA and PRPF31 protein in WT and PRPF31+ / - hTERT-RPEl cell lines.

[0377] (A) Relative PRPF31 mRNA expression in wild-type (WT) and PRPF3 U7- hTERT- RPEl, assessed using one-step RT-digital droplet PCR. PRPF31 transcript expression was normalised to the housekeeping genes SENP5 and HPRT1. n=l biological replicate.

[0378] (B) Relative PRPF31 protein expression in WT and PRPF31+ / - hTERT-RPEl, assessed using western blot assay. The expression of PRPF31 was normalised to total protein expression. (C) Western blot gel image showing the PRPF31 protein band at ~55 kDa and total protein staining was used a loading control.

[0379] Figure 6 is a graphical representation showing PRPF31 mRNA expression in PRPF31+ / " RPE1 cells 72 hours following ASO transfection using a PRPF31 ddPCR assay. A scrambled negative control (GTC), predicted not to hybridize to human transcripts, was included as a negative control. Bar graph represents mean + S.D. n=3 technical replicates per experiment. UT = untreated cells. Utz = vehicle transfected untreated cells. GTC = GeneTools negative control. Figure 7 is a schematic representation showing the 5 ' UTR of PRPF31 transcript (SEQ ID NO. 41862) in HMC3 and HEK293 cells. PRPF31 transcript models from probe-enriched long read sequenced compared to GENCODE annotation. PRPF31 transcript models from HMC3 and HEK293 cell samples obtained by probe -enriched RNA long sequencing are shown above the current gene annotation from GENCODE (v46) for this locus. Gray shadowing boxes mark the transcripts using the protein coding canonical exons of PRPF31 and is labelled as PRPF31-201 in GENCODE annotation. The black box highlights the difference in length of exon 1 which is the first part of the PRPF31 5' UTR that continues in exon 2. The length of exon 1 in long read sequencing is observed in both samples, HMC3 and HEK293 cells, with the same transcript model, which is not the case in the GENCODE transcripts. The transcript model PRPF31-203 with the longest exon 1 exhibits the retention of the second last intron (marked with a *).

[0380] Figure 8 is a series of graphical representations showing the PRPF31 transcript and ASO design to target the 5 ' UTR of PRPF31 transcript. (A) PRPF31 transcript model (gene id ENSG00000105618.14 from GENCODE v45) is depicted, with exons and introns shown in dark color and the 5' and 3' UTRs in a lighter color. (B) The 5' UTR sequence corresponds to SEQ ID NO: 41862. The predicted upstream open reading frame (uORF) is highlighted in bold, and the canonical initiation codon is bolded and underlined. A black line indicates the target sequences of ASOs, which are intended to upregulate PRPF31 gene expression by (C) altering the secondary structure of mRNA or (D) preventing the initiation of protein translation of the uORF. The number represents the SEQ ID number of respective ASO.

[0381] Figure 9 is a graphical representation showing PRPF31 transcript levels in ASO transfected PRPF31+ / ’ RPE1 cells (SEQ ID NOs: 41833 to 41843). PRPF31 mRNA expression was assessed 72 hours following ASO transfection (2.5 and 5 pM) using a PRPF31 ddPCR assay. A scrambled negative control (GeneTools negative control, GTC), predicted not to hybridize to human transcripts, was included as a negative control. Bar graph represents mean + S.D. n=3 technical replicates per experiment. UT = untreated cells. Utz = vehicle transfected untreated cells. GTC = GeneTools negative control.

[0382] Figure 10 is a graphical representation showing PRPF31 protein in ASO transfected PRPF3 I1’ RPE1 cells (SEQ ID NO: 41833 to 41843). PRPF31 protein expression was assessed 6 days following Neon™ transfection using a PRPF31 ELISA assay. A GeneTools negative control (GTC), predicted not to hybridize to human transcripts, was included as a negative control. Bar graph represents mean + S.D. n=3 technical replicates per experiment. UT = untreated cells. Utz = vehicle transfected untreated cells.

[0383] Figure 11 is an evaluation of PPMO effect on PRPF31 protein in PRPF31+ / " RPE1 cells. PPMO treated PRPF31+ / - RPE1 cells (SEQ ID NOs: 41851 to 41854). PRPF31 protein expression using an ELISA assay was assessed 6 days following Neon™ transfection. A non-targetting control (negative control), predicted not to hybridize to human transcripts, was included as a negative control. Bar graph represents mean + S.D. n=2-3 technical replicates per experiment. UT = untreated cells.

[0384] Figure 12 is showing knockdown effect of NAT on PRPF31 transcript levels usinf gapmer ASOs. Gapmer ASO were transfected PRPF31+ / " RPE1 cells (SEQ ID NOs: 41856-41860) and incubated for 72 hours. Subsequently, samples were harvested for assessment of PRPF31 expression levels using a ddPCR assay. Bar graph represents mean + S.D. n=3 technical replicates per experiment. UT = untreated cells. Utz = vehicle transfected untreated cells.

[0385] Figure 13 is showing ASO effect on PRPF31 transcript levels in PRPF31+ / - RPE1 cells. ASO transfected PRPF31+ / " RPE1 cells (SEQ ID NOs: 31223, 41850 to 41855). PRPF31 mRNA expression was assessed 72 hours following ASO transfection using a PRPF31 ddPCR assay. A scrambled negative control (GeneTools negative control, GTC), predicted2not to hybridize to human transcripts, was included as a negative control . Bar graph represents mean + S.D. n=3 technical replicates per experiment. UT = untreated cells. Utz = vehicle transfected untreated cells. GTC = GeneTools negative control.

[0386] DETAILED DESCRIPTION

[0387] General

[0388] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms “a”, “an” and “the” include plural aspects unless the context clearly dictates otherwise. For example, reference to “a” includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to “the” includes a single as well as two or more and so forth.

[0389] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0390] The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the present disclosure.

[0391] Any example of the present disclosure herein shall be taken to apply mutatis mutandis to any other example of the disclosure unless specifically stated otherwise. Stated another way, any specific example of the present disclosure may be combined with any other specific example of the disclosure (except where mutually exclusive).

[0392] Any example of the present disclosure disclosing a specific feature or group of features or method or method steps will be taken to provide explicit support for disclaiming the specific feature or group of features or method or method steps.

[0393] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for example, molecular biology, microbiology, virology, recombinant DNA technology, peptide synthesis in solution, solid phase peptide synthesis, and immunology).

[0394] Unless otherwise indicated, the conventional techniques of molecular biology, microbiology, virology, recombinant DNA technology, peptide synthesis in solution, solid phase peptide synthesis, and immunology utilized in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al. Molecular Cloning: A Uaboratory Manual, Cold Spring Harbour Uaboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRE Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and J.E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present).

[0395] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0396] The term “about”, unless stated to the contrary, refers to + / - 20%, more preferably + / - 10%, of the designated value. For the avoidance of doubt, the term “about” followed by a designated value is to be interpreted as also encompassing the exact designated value itself (for example, “about 10” also encompasses 10 exactly).

[0397] Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0398] All publications cited herein are hereby incorporated by reference in their entirety. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0399] Any discussion of documents, acts, materials, devices, articles or the like that has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

[0400] Selected Definitions

[0401] As used herein, the term “non-coding RNA” or “ncRNA” refers to a type of RNA that is not translated into a protein. The term ncRNA includes short non-coding RNA (sncRNA) that are less than 200 nucleotides in length and long non-coding RNA (IncRNA) that are greater than 200 nucleotides in length. Exemplary sncRNAs include microRNAs, siRNAs, piRNAs, snoRNAs, snRNAs, exRNAs, scaRNAs. transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). Exemplary IncRNA include natural antisense transcripts (NATs), intronic, intergenic and overlapping bidirectional transcripts.

[0402] The term “precursor mRNA” or “pre-mRNA” refers to the primary transcript, which is the single-stranded RNA product synthesized by transcription of the genomic DNA sequence of the transcription unit for a particular gene, and generally encompasses the nucleotide sequence between a transcription start site and a termination signal.

[0403] The term “antisense oligonucleotide” “antisense oligomer” or “ASO,” as used herein, encompasses oligonucleotides and any other oligomeric molecule that comprises nucleobases capable of hybridizing to a complementary sequence on a target RNA transcript, but does not comprise a sugar moiety, such as in the case of a peptide nucleic acid (PNA). Preferably, the ASO is an ASO that is resistant to nuclease cleavage or degradation.

[0404] The phrase “binds to a targeted portion” or “binds within a targeted portion,” in reference to an ASO, as used herein, refers to specific hybridization between the ASO nucleotide sequence and a target nucleotide sequence that is complementary within the ranges set forth herein. In some examples, specific hybridization occurs where, under ex vivo conditions, the hybridization occurs under high stringency conditions. By "high stringency conditions" is meant that the ASO, under such ex vivo conditions, hybridize to a target sequence in an amount that is detectably stronger than non-specific hybridization. High stringency conditions, then, are conditions that distinguish a polynucleotide with an exact complementary sequence, or one containing only a few scattered mismatches from a random sequence that happened to have a few small regions (e.g., 1-5 bases) that matched the probe. Such small regions of complementarity are more easily melted than a full-length complement of 12-17 or more bases, and moderate stringency hybridization makes them easily distinguishable. In one example, high stringency conditions include, for example, low salt and / or high temperature conditions, such as provided by about 0.02-0,1 M NaCl or the equivalent, at temperatures of about 50-70 °C. The skilled person will appreciate that under in vivo conditions, the specificity of hybridization between an ASO and its target sequence is defined in terms of the level of complementarity between the ASO and the target sequence to which it hybridizes within a cell.

[0405] As used herein, a “target” or “targeted portion” refers to a stretch of polynucleotides within a pre-mRNA, mRNA and / or ncRNA transcript sequence or to which an ASO of the disclosure is substantially complementary (or complementary) and able to hybridise (e.g., under physiological conditions).

[0406] The term “peptide” is intended to include compounds composed of amino acid residues linked by amide bonds. A peptide may be natural or unnatural, ribosome encoded or synthetically derived. Typically, a peptide will consist of between 2 and 200 amino acids. For example, the peptide may have a length in the range of 10 to 20 amino acids or 10 to 30 amino acids or 10 to 40 amino acids or 10 to 50 amino acids or 10 to 60 amino acids or 10 to 70 amino acids or 10 to 80 amino acids or 10 to 90 amino acids or 10 to 100 amino acids, including any length within said range(s). The peptide may comprise or consist of fewer than about 150 amino acids or fewer than about 125 amino acids or fewer than about 100 amino acids or fewer than about 90 amino acids or fewer than about 80 amino acids or fewer than about 70 amino acids or fewer than about 60 amino acids or fewer than about 50 amino acids.

[0407] Peptides, as referred to herein, include "inverso" peptides in which all L-amino acids are substituted with the corresponding D-amino acids, "retro-inverso" peptides in which the sequence of amino acids is reversed and all L-amino acids are replaced with D-amino acids.

[0408] Peptides may comprise amino acids in both L- and / or D-form. For example, both L- and D-forms may be used for different amino acids within the same peptide sequence. In some examples the amino acids within the peptide sequence are in L-form, such as natural amino acids. In some examples the amino acids within the peptide sequence are a combination of L- and D-form. Further, peptides may comprise unusual, but naturally occurring, amino acids including, but not limited to, hydroxyproline (Hyp), beta-alanine, citrulline (Cit), ornithine (Om), norleucine (Nle), 3 -nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr). Peptides may also incorporate unnatural amino acids including, but not limited to, homo amino acids, N-methyl amino acids, alpha-methyl amino acids, beta (homo) amino acids, gamma amino acids, and N-substituted glycines. Peptides may be linear peptides or cyclic peptides.

[0409] The term “protein” shall be taken to include a single polypeptide chain, i.e., a series of contiguous amino acids linked by peptide bonds or a series of polypeptide chains covalently or non-covalently linked to one another (i.e., a polypeptide complex). For example, the series of polypeptide chains can be covalently linked using a suitable chemical bond or a disulfide bond. Examples of non-covalent bonds include hydrogen bonds, ionic bonds, Van der Waals forces, and hydrophobic interactions.

[0410] Percentage amino acid sequence identity with respect to a given amino acid sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Amino acid sequence identity may be determined using the EMBOSS Pairwise Alignment Algorithms tool available from The European Bioinformatics Institute (EMBL-EBI), which is part of the European Molecular Biology Laboratory. This tool is accessible at the website located at www.ebi.ac.uk / Tools / emboss / align / . This tool utilizes the Needleman- Wunsch global alignment algorithm (Needleman and Wunsch, 1970). Default settings are utilized which include Gap Open: 10.0 and Gap Extend 0.5. The default matrix “Blosum62” is utilized for amino acid sequences and the default matrix.

[0411] The term “cell penetrating peptide” (CPP) refers to a peptide that is capable of crossing a cellular membrane. In one example, a CPP is capable of translocating across a mammalian cell membrane and entering into a cell. In another example, a CPP may direct a conjugate to a desired subcellular compartment. Thus, a CPP may direct or facilitate penetration of a molecule of interest across a phospholipid, mitochondrial, endosomal, lysosomal, vesicular, or nuclear membrane. A CPP may be translocated across the membrane with its amino acid sequence complete and intact, or alternatively partially degraded.

[0412] A CPP may direct a molecule of interest, such as an antisense oligonucleotide disclosed herein, from outside a cell through the plasma membrane, and into the cytoplasm or a desired subcellular compartment. Alternatively, or in addition, a CPP may direct a molecule of interest across the blood-brain, trans-mucosal, hematoretinal, skin, gastrointestinal and / or pulmonary barriers.

[0413] The term “peptide ligand” or “receptor binding domain” refers to a peptide that is capable of binding to a membrane surface receptor to enable translocation of the peptide across a cellular membrane. In one example a peptide ligand may enable translocation across the cellular membrane via the natural endocytosis of the targeted receptor. In another example the peptide ligand may utilise a complementary mechanism of translocation across the cellular membrane including utilising a conjugated CPP. In one example, a peptide ligand is capable of translocating across a mammalian cell membrane and to enter a cell. In another example, a peptide ligand may direct a conjugate to a desired subcellular compartment. Thus, a peptide ligand may direct or facilitate cellular uptake of a molecule of interest across a phospholipid, mitochondrial, endosomal, lysosomal, vesicular, or nuclear membrane. A peptide ligand may be translocated across the membrane with its amino acid sequence complete and intact, or alternatively partially degraded.

[0414] A peptide ligand via its binding to a target receptor may direct a molecule of interest, such as an ASO disclosed herein, from outside a cell through the plasma membrane, and into the cytoplasm or a desired subcellular compartment. Alternatively, or in addition, a peptide ligand via its binding to a target receptor may direct a molecule of interest across a relevant biological barrier, e.g., the blood-brain, trans-mucosal, hematoretinal, skin, gastrointestinal, and / or pulmonary barriers. As used herein, the term “subject” shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to humans and non-human primates. For example, the subject is a human.

[0415] As used herein, the terms “treating”, “treat” or “treatment” include administering a protein described herein to thereby reduce or eliminate at least one symptom of a specified disease or condition or to slow progression of the disease or condition.

[0416] As used herein, the terms “preventing”, “prevent” or “prevention” include administering a compound of the disclosure to thereby stop or hinder the development of at least one symptom of a condition.

[0417] Compositions for Increasing PRPF31 Protein Levels

[0418] Pre-mRNA processing factor 31 PRPF31) (also known as PRP31, RP11, SNRNP61, and NY-BR-99) encodes an essential pre-mRNA splicing factor required for the assembly and recycling of the U4 / U6 RNA complex, which catalyses the splicing of pre-messenger RNAs (pre-mRNAs) to remove introns and produce mature mRNAs. For the purposes of nomenclature only and not limitation, exemplary sequences of human PRPF31 are set out in NCBI Gene ID 26121 and NCBI transcript accession number NM_015629.4. Additionally, the PRPF31 gene is identified by Ensembl ID ENSG00000105618 and the canonical PRPF31 transcript is identified by the Ensembl ID ENST00000321030.9. The PRPF31 gene is 16.3 kb located at chromosome 19ql3.42 and encodes 9 different transcripts, 6 of which are protein coding. The largest, most widely expressed transcript consists of 14 exons; 1 non-coding and 13 coding, which produces a 499 amino acid PRPF31 protein of 55 kDa in size. The PRPF31 protein contains several important functional domains; the flexible loop (residues 256-265), Nop domain (residues 222-254 and 278-307), coiled-coil domain and tip (residues 85-120 and 181-215). Additional sequence of PRPF31 gene, transcripts and proteins can be determined using sequences provided herein and / or in publicly available databases and / or determined using standard techniques (e.g., as described in Ausubel et al., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley- Interscience (1988, including all updates until present) or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989)).

[0419] As described herein, several transcripts associated with microRNA (miRNA) binding sites have been identified in PRPF31 pre-mRNAs and / or mRNAs encoding PRPF31.

[0420] MicroRNAs (miRNAs) are a family of short (19 to 23 nucleotide) non-coding single stranded labile RNAs. Although they can bind to any part of target mRNA, their main mode of action is to bind to complimentary RNA sequences in the 3' untranslated region (3' UTR) and regulate gene expression by stimulating either mRNA degradation or translational repression. Both mechanisms lead to diminished expression of the target gene.

[0421] While not wishing to be bound by theory, it is believed that a nucleic acid at least partly complementary to the binding sites for microRNAs located within the PRPF31 mRNA 3' UTR will hybridize to the PRPF31 3' UTR and sterically hinder (“mask”) access of these miRNAs to their binding sites on the PRPF31 3' UTR, ultimately allowing increases in PRPF31 protein levels.

[0422] Accordingly, disclosed herein is a nucleic acid that binds to a targeted portion of the PRPF31 pre-mRNA or mRNA (z.e., a target PRPF31 transcript), wherein binding of the nucleic acid to the targeted portion increases the level of PRPF31 protein. In one example, the nucleic acid hybridizes to a targeted portion of the 3' UTR of PRPF31 pre- mRNA or mRNA, whereby one or more miRNAs are unable to hybridize to their specific target sequences and consequently, increased levels of PRPF31 protein.

[0423] As described herein, the present disclosure provides nucleic acids, expression vectors, and related compositions and methods to increase PRPF31 protein levels by modulating the post-transcriptional or translational regulation of the 3' UTR of PRPF31 mRNA, e.g., by blocking specific binding of mirR-129-3p family miRNAs (e.g., hsa- miR-129-l-3p and hsa-miR-129-2-3p) and / or miR-1251-5p family miRNAs to their cognate binding sites.

[0424] As described herein, the present disclosure provides nucleic acids, expression vectors, and related compositions and methods to increase PRPF31 protein levels by modulating the post-transcriptional or translational regulation of the 3' UTR of PRPF31 mRNA, e.g., by blocking specific binding of mirR-129-3p family miRNAs (e.g., hsa- miR-129-l-3p and hsa-miR-129-2-3p) to their cognate binding sites.

[0425] Accordingly, in one example provided herein is a nucleic acid (e.g., an antisense oligonucleotide) that binds to a targeted portion of the 3' UTR of a PRPF31 mRNA, wherein binding of the nucleic acid to the targeted portion increases the level of PRPF31 protein.

[0426] As described herein, the present disclosure provides nucleic acids, expression vectors, and related compositions and methods to increase PRPF31 protein levels by sterically inhibiting translation from upstream Open Reading Frames (uORF) start site and / or sterically inhibiting secondary structures in the 5' UTR.

[0427] Accordingly, in one example provided herein is a nucleic acid (e.g., an antisense oligonucleotide) that binds to a targeted portion of the 5' UTR of a PRPF31 mRNA, wherein binding of the nucleic acid to the targeted portion increases the level of PRPF31 protein.

[0428] Furthermore, as described herein, several ncRNA transcripts (i.e., PRPF31 ncRNA transcripts) have been identified that have complementary sequences to PRPF31 pre-mRNAs and / or mRNAs encoding PRPF31 protein.

[0429] Without being bound by theory or mode of action, the nucleic acids according to any example herein, bind or hybridize to the targeted ncRNA sequence to reduce transcript levels or induce degradation of the transcript or downregulate the ncRNA. This occurs by knockdown of the ncRNA, specific splice variants of the ncRNA and / or premature termination of transcription of the ncRNA.

[0430] Without being bound by theory or mode of action, the nucleic acids according to any example, hybridize with the targeted ncRNA sequence to thereby block access of the ncRNA to the corresponding sequence / binding sites in the PRPF31 pre-mRNA or mRNA. In other words, the nucleic acids herein, by hybridizing with target sequences in a ncRNA, in effect act as ‘decoys’ to inhibit binding of a ncRNA comprising one or more corresponding complementary sequences to a PRPF31 pre-mRNA or mRNA.

[0431] Accordingly, disclosed herein is a method for increasing the amount of functional PRPF31 protein in a cell, the method comprising a cell up taking a nucleic acid that binds to a targeted portion of a ncRNA that is complementary to a portion of a PRPF31 pre- mRNA or mRNA to reduce or prevent binding of the ncRNA to the PRPF31 pre-mRNA or mRNA, wherein the amount of functional PRPF31 protein in the cell is increased.

[0432] Without being bound by theory or mode of action, the nucleic acids according to any example increase expression of PRPF31 protein through one or more of steric inhibition of 3’ end transcript features (e.g., polyadenylation) to prevent accumulation of mature and non-functional transcripts and / or steric inhibition of functional domains and / or secondary structure in the 3 ’ UTR and / or steric inhibition of miRNA binding to prevent transcript degradation and translational repression.

[0433] Without being bound by theory or mode of action, the nucleic acids according to any example that encode gene editing nucleic acids may increase expression of PRPF31 by introducing indels or upstream poly(A) sites, resulting in knockdown of the ncRNA transcript; or alternately excising exons or miRNA binding sites, resulting in upregulation of PRPF31 protein.

[0434] Without being bound by theory or mode of action, the nucleic acids according to any example increase expression of PRPF31 protein through one or more of steric inhibition of secondary structures in the 5 ’UTR and / or steric inhibition of translation from uORFs. Antisense Oligonucleotides (ASOs)

[0435] In some examples, of the compositions and methods described herein, ASOs have a sequence that is completely complementary across its length to the target sequence or a sequence near complementarity (e.g., sufficient complementarity to bind the ncRNA target sequence and interfere with ncRNA binding at the PRPF31 pre-mRNA or mRNA binding site). ASOs are designed so that they bind (hybridize) to a target sequence (i.e., a targeted portion of a transcript) and remain hybridized under physiological conditions. Selection of suitable sequences for ASOs generally avoids, where possible, similar nucleic acid sequences in other (i. e. , off-target) locations in the genome or in cellular RNAs, such that the likelihood the ASO will hybridize at such sites is limited.

[0436] In some examples, ASOs “specifically hybridize” to or are “specific” to a target nucleic acid or a targeted portion of a pre-mRNA, mRNA or ncRNA transcript. At a given ionic strength and pH, the Tmis the temperature at which 50% of a target sequence hybridizes to a complementary oligonucleotide.

[0437] ASO sequences are “complementary” to their target sequences when hybridization occurs in an antiparallel configuration between two single-stranded polynucleotides of complementary sequence. Complementarity is quantifiable in terms of the proportion (e.g., the percentage) of bases in opposing strands that are expected to form hydrogen bonds with each other, according to generally accepted base-pairing rules. The nucleotide sequence of an ASO need not be 100% complementary to that of its target nucleic acid to hybridize. In certain examples, the nucleotide sequences of nucleic acids or ASOs in the compositions disclosed herein can be at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence complementary to the nucleotide sequence of the targeted portion of an RNA transcript over the length of the ASO nucleotide sequence. For example, an ASO in which 18 of 20 nucleotides of ASO sequence are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In such an example, the remaining non-complementary nucleotides of the ASO could be clustered together or interspersed with complementary nucleotides and need not be contiguous. Complementarity of an ASO sequence to a target nucleotide sequence (expressed as “percent complementarity” to its target sequence; or “percent identity” to its reverse complement sequence) can be determined routinely using algorithms known in the art, as exemplified in the BLAST programs (basic local alignment search tools) and PowerBLAST programs (Altschul, et al., 1990, J. Mol. Biol., 215:403-410; Zhang et al., 1997, Genome Res., 7: 649-656).

[0438] In some examples, an ASO does not hybridize to all nucleotides in a target sequence and the nucleotide positions at which it does hybridize may be contiguous or non-contiguous. ASOs may hybridize over one or more segments of a ncRNA or 3 ’UTR region of a mRNA, such that intervening or adjacent segments are not involved in the hybridization event (e.g. , a loop structure or hairpin structure may be formed).

[0439] In one example, the nucleic acid (or ASO) described herein is complementary to a targeted portion of a PRPF31 pre-mRNA or mRNA. In another example, the nucleic acid (or ASO) described herein is complementary to a targeted portion of a PRPF31 mRNA 3 ’UTR. For example, the nucleic acid (or ASO) is complementary to a targeted portion of a PRPF31 mRNA 3 ’UTR corresponding to SEQ ID NO: 1. In another example, the nucleic acid (or ASO) described herein is complementary to a targeted portion of a PRPF31 mRNA 3’UTR corresponding to SEQ ID NO: 41861. In one example, the nucleotide sequence of the nucleic acid is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the nucleotide sequence of the targeted portion of the PRPF31 3' UTR over the length of the nucleic acid (e.g., ASO). In another example, the nucleic acid (or ASO) described herein is complementary to a targeted portion of PRPF31 mRNA 5 ’UTR. For example, the nucleic acid (or ASO) is complementary to a targeted portion of a PRPF31 mRNA 5 ’UTR corresponding to SEQ ID NO: 1. In one example, the nucleic acid (or ASO) is complementary to a targeted portion of a PRPF31 mRNA 5’UTR corresponding to SEQ ID NO: 41862. In one example, the nucleotide sequence of the nucleic acid is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the nucleotide sequence of the targeted portion of the PRPF31 5' UTR over the length of the nucleic acid (e.g., ASO).

[0440] In one example, nucleic acids of the disclosure have about or at least about 60% sequence identity , e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

[0441] In one example, nucleic acids of the disclosure have about or at least about 60% sequence identity , e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193.

[0442] In one example, nucleic acids of the disclosure have about or at least about 60% sequence identity , e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41833 to 41849.

[0443] In one example, nucleic acids of the disclosure have about or at least about 75% sequence identity, e.g., 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ

[0444] ID NOs: 6 to 18193 or 41833 to 41849. For example, nucleic acids of the disclosure have about or at least about 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

[0445] In one example, nucleic acids of the disclosure have about or at least about 75% sequence identity, e.g., 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193. For example, nucleic acids of the disclosure have about or at least about 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193.

[0446] In one example, nucleic acids of the disclosure have about or at least about 75% sequence identity, e.g., 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41833 to 41849. For example, nucleic acids of the disclosure have about or at least about 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41833 to 41849. In one example, nucleic acids of the disclosure have about or at least about 85% sequence identity, e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

[0447] In one example, nucleic acids of the disclosure have about or at least about 85% sequence identity, e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193.

[0448] In one example, nucleic acids of the disclosure have about or at least about 85% sequence identity, e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41833 to 41849.

[0449] In one example, nucleic acids of the disclosure have about or at least about 90% sequence identity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193 or 41833 to 41849. In one example, antisense oligonucleotides of the disclosure have about or at least about 95% sequence identity, e.g., 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

[0450] In one example, nucleic acids of the disclosure have about or at least about 90% sequence identity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193. In one example, antisense oligonucleotides of the disclosure have about or at least about 95% sequence identity, e.g., 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 6 to 18193.

[0451] In one example, nucleic acids of the disclosure have about or at least about 90% sequence identity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41833 to 41849. In one example, antisense oligonucleotides of the disclosure have about or at least about 95% sequence identity, e.g., 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41833 to 41849.

[0452] In one example, a nucleic acid (e.g., ASO) disclosed herein is complementary to a targeted portion of a ncRNA that is complementary to a portion of a PRPF31 pre- mRNA or mRNA. For example, a nucleic acid (e.g., ASO) disclosed herein is complementary to a targeted portion of a ncRNA corresponding to any one of SEQ ID

[0453] NOs: 2 to 5, that is complementary to a portion of a PRPF31 pre-mRNA or mRNA. For example, the nucleic acid (e.g, ASO) is complementary to an antisense ncRNA of

[0454] PRPF31 pre-mRNA. In one example, the nucleic acid (e.g., ASO) is complementary to unspliced and / or spliced antisense ncRNA of PRPF31 pre-mRNA.

[0455] In one example, nucleic acids of the disclosure have about or at least about 60% sequence identity , e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,

[0456] 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,

[0457] 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831 or 41850 to 41860.

[0458] In one example, nucleic acids of the disclosure have about or at least about 60% sequence identity , e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,

[0459] 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,

[0460] 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831.

[0461] In one example, nucleic acids of the disclosure have about or at least about 60% sequence identity , e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,

[0462] 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,

[0463] 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41850 to 41860.

[0464] In one example, nucleic acids of the disclosure have about or at least about 75% sequence identity, e.g., 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ

[0465] ID NOs: 18194 to 41831 or 41850 to 41860. In one example, nucleic acids of the disclosure have about or at least about 75% sequence identity, e.g., 75%, 76%, 77%,

[0466] 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,

[0467] 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831. In one example, nucleic acids of the disclosure have about or at least about 75% sequence identity, e.g., 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%.

[0468] 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41850 to 41860. For example, nucleic acids of the disclosure have about or at least about

[0469] 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831 or 41850 to 41860. For example, nucleic acids of the disclosure have about or at least about 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,

[0470] 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs:

[0471] 18194 to 41831. For example, nucleic acids of the disclosure have about or at least about

[0472] 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,

[0473] 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41850 to 41860.

[0474] In one example, nucleic acids of the disclosure have about or at least about 85% sequence identity, e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%.

[0475] 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831 or 41850 to 41860.

[0476] In one example, nucleic acids of the disclosure have about or at least about 85% sequence identity, e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%.

[0477] 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831. In one example, nucleic acids of the disclosure have about or at least about 85% sequence identity, e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41850 to 41860.

[0478] In one example, nucleic acids of the disclosure have about or at least about 90% sequence identity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831 or 41850 to 41860. In one example, nucleic acids of the disclosure have about or at least about 90% sequence identity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831. In one example, nucleic acids of the disclosure have about or at least about 90% sequence identity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41850 to 41860. In one example, antisense oligonucleotides of the disclosure have about or at least about 95% sequence identity, e.g., 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831 or 41850 to 41860. In one example, antisense oligonucleotides of the disclosure have about or at least about 95% sequence identity, e.g., 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 18194 to 41831. In one example, antisense oligonucleotides of the disclosure have about or at least about 95% sequence identity, e.g., 95%, 96%, 97%, 98%, 99% or 100% sequence identity, over the entire length of any of the sequences provided in any of SEQ ID NOs: 41850 to 41860.

[0479] The nucleic acids for use in the compositions described herein may be of any length suitable for specific hybridization to a target sequence. In some examples, the nucleotide sequence of the nucleic acid (e.g., ASO) consist of 8 to 50 nucleotides. For example, the nucleic acid can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, or 50 nucleotides in length. In one example, the nucleic acid consists of more than 50 nucleotides, but no more than 100 nucleotides in length. In one example, the nucleic acid is from 8 to 50 nucleotides, 8 to 40 nucleotides, 8 to 35 nucleotides, 8 to 30 nucleotides, 8 to 25 nucleotides, 8 to 20 nucleotides, 8 to 15 nucleotides, 9 to 50 nucleotides, 9 to 40 nucleotides, 9 to 35 nucleotides, 9 to 30 nucleotides, 9 to 25 nucleotides, 9 to 20 nucleotides, 9 to 15 nucleotides, 10 to 50 nucleotides, 10 to 40 nucleotides, 10 to 35 nucleotides, 10 to 30 nucleotides, 10 to 25 nucleotides, 10 to 20 nucleotides, 10 to 15 nucleotides, 11 to 50 nucleotides, 11 to 40 nucleotides, 11 to 35 nucleotides, 11 to 30 nucleotides, 11 to 25 nucleotides, 11 to 20 nucleotides, 11 to 15 nucleotides, 12 to 50 nucleotides, 12 to 40 nucleotides, 12 to 35 nucleotides, 12 to 30 nucleotides, 12 to 25 nucleotides, 12 to 20 nucleotides, 12 to 15 nucleotides, 13 to 50 nucleotides, 13 to 40 nucleotides, 13 to 35 nucleotides, 13 to 30 nucleotides, 13 to 25 nucleotides, 13 to 20 nucleotides, 14 to 50 nucleotides, 14 to 40 nucleotides, 14 to 35 nucleotides, 14 to 30 nucleotides, 14 to 25 nucleotides, 14 to 20 nucleotides, 15 to 50 nucleotides, 15 to 40 nucleotides, 15 to 35 nucleotides, 15 to 30 nucleotides, 15 to 25 nucleotides, 15 to 20 nucleotides, 20 to 50 nucleotides, 20 to 40 nucleotides, 20 to 35 nucleotides, 20 to 30 nucleotides, 20 to 25 nucleotides, 25 to 50 nucleotides, 25 to 40 nucleotides, 25 to 35 nucleotides, or 25 to 30 nucleotides in length. In one example, the nucleic acid is 20 nucleotides in length. In another example, the nucleotide sequence of the nucleic acid is 25 nucleotides in length.

[0480] In one example, for each occurrence of “G” in a nucleic acid or ASO sequence disclosed herein, the “G” is guanosine or inosine. In one example, for each occurrence of “T” in a nucleic acid or ASO sequence disclosed herein, the “T” is any one of: thymidine, inosine, uracil, or an isomeric or modified form of uracil (e.g., pseudouridine or Nl-methyl-pseudouridine).

[0481] In one example, for each occurrence of “C” in a nucleic acid or ASO sequence disclosed herein, the C is cytosine or a modified form of cytosine (e.g., 5 ’-methyl cytosine).

[0482] In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 6 to 41831 or 41833 to 41860. In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 6 to 41831. For example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 6 to 18193 or 41833 to 41849. For example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 6 to 18193. In another example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 6 to 9098. In a further example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 9099 to 18193. In another example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 41833 to 41849. For example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 41833 to 41843. In another example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 41844 to 41849. In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 18194 to 41831. In another example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 18194 to 27282. In a further example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 27283 to 36362. In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 36363 to 37743. In a further example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 37744 to 39121. In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 39122 to 39876. In a further example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 39877 to 40628. In another example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 40629 to 41231. In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 41232 to 41831. In one example, the nucleotide sequence of the nucleic acid or ASO comprises the sequence of any one of SEQ ID NOs: 41850 to 41860.

[0483] In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 6 to 41831 or 41833 to 41860. In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 6 to 41831. For example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 6 to 18193 or 41833 to 41849. For example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 6 to 18193. In another example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 6 to 9098. In a further example, the nucleotide sequence of the nucleic acid or ASO consists ofthe sequence of any one of SEQ ID NOs: 9099 to 18193. In a further example, the nucleotide sequence of the nucleic acid or ASO consists of a sequence of any one of SEQ ID NOs: 41833 to 41849. For example, the nucleotide sequence ofthe nucleic acid or ASO consists of a sequence of any one of SEQ ID NOs: 41833 to 41843. In a further example, the nucleotide sequence of the nucleic acid or ASO consists of a sequence of any one of SEQ ID NOs: 41844 to 41849. In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 18194 to 41831. In another example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 18194 to 27282. In a further example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 27283 to 36362. In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 36363 to 37743. In a further example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 37744 to 39121. In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 39122 to 39876. In a further example, the nucleotide sequence of the nucleic acid or ASO consists ofthe sequence of any one of SEQ ID NOs: 39877 to 40628. In another example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 40629 to 41231. In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 41232 to 41831. In one example, the nucleotide sequence of the nucleic acid or ASO consists of the sequence of any one of SEQ ID NOs: 41850 to 41860.

[0484] Gapmer In one example, the antisense oligonucleotide is a gapmer. For example, the antisense oligonucleotide is a modified oligonucleotide comprising a gapmer motif.

[0485] As used herein, a “gapmer motif’ refers to a region that is defined by two external regions or "wings" and a central or internal region or "gap." The three regions of a gapmer motif (i.e., the 5'-wing, the gap, and the 3'-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3 '-most nucleoside of the 5' -wing and the 5' -most nucleoside of the 3 '- wing) differ from the sugar moiety of the neighbouring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing / gap junction). In one example, the sugar moieties within the gap are the same as one another. In one example, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the ap. In one example, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In one example, the sugar motif of the 5 '-wing differs from the sugar motif of the 3 '-wing (asymmetric gapmer).

[0486] In one example, the wings of a gapmer comprise 1-6 nucleosides. In one example, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In one example, at least one, at least two, at least three, at least four, at least five, or at least six nucleosides of each wing of a gapmer comprises a modified sugar moiety.

[0487] In one example, the gap of a gapmer comprises 7-12 nucleosides. In one example, each nucleoside of the gap of a gapmer comprises a 2' -deoxyribosyl sugar moiety. In one example, at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety and each remaining nucleoside comprises a 2' -deoxyribosyl sugar moiety.

[0488] It will be apparent to the skilled person that the lengths (number of nucleosides) of the three regions of a gapmer may be provided using the notation [# of nucleosides in the 5'-wing] -[# of nucleosides in the gap] -[# of nucleosides in the 3'-wing], Thus, a 5- 10-5 gapmer consists of 5 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprise a 2'-deoxyribosyl sugar moiety. Thus, a 5-10-5 MOE gapmer consists of 5 linked 2'-2'-O-methoxyethyl-RNA (MOE) nucleosides in the 5' -wing, 10 linked 2'-deoxyribonucleosides in the gap, and 5 linked 2'-O-methoxyethyl-RNA (MOE) nucleosides in the 3 '-wing.

[0489] In one example, each nucleoside of a modified oligonucleotide, or portion thereof, comprises a 2' -substituted sugar moiety, a bicyclic sugar moiety, a sugar surrogate, or a 2'-deoxyribosyl sugar moiety. In certain embodiments, the 2'-substituted sugar moiety is selected from a 2'-MOE sugar moiety, a 2'-OMe sugar moiety, and a 2' -F sugar moiety. In certain embodiments, the bicyclic sugar moiety is selected from a cEt sugar moiety and a locked nucleic acid nucleoside (LNA) sugar moiety. In certain embodiments, the sugar surrogate is selected from morpholino, modified morpholino, PNA, and F-ANA.

[0490] The term mixed wing gapmer refers to a LNA gapmer wherein the flank regions comprise at least one LNA nucleoside and at least one non-LNA modified nucleoside, such as at least one 2' substituted modified nucleoside, for example, 2'-O-alkyl-RNA, 2'- O-methyl-RNA, 2'-alkyoxy-RNA, 2'-MOE, 2'-amino-DNA, 2'-fluoro-RNA, and 2'-F- ANA nucleoside(s). In one example, the mixed wing gapmer has one flank which comprises LNA nucleosides (e.g. 5' or 3') and the other flank (3' or 5' respectfully) comprises 2' substituted modified nucleoside(s).

[0491] ASO Chemistry and Modifications

[0492] The ASOs used in the compositions described herein may comprise naturally- occurring nucleotides, nucleotide analogues, modified nucleotides, or any combination thereof. The term “naturally occurring nucleotides” includes deoxyribonucleotides and ribonucleotides. The term “modified nucleotides” includes nucleotides with modified or substituted sugar groups and / or having a modified backbone. In some examples, all the nucleotides of an ASO are modified nucleotides. Chemical modifications of ASOs or components of ASOs that are compatible with the compositions and methods described herein are known in the art as disclosed in, e.g., in U.S. Patent No. 8,258,109, U.S. Patent No. 5,656,612, U.S. Patent Publication No. 2012 / 0190728, and Roberts et al., 2020, Nature Rev. Drug Disc., 19:673-694.

[0493] One or more nucleotides of an ASO may be any naturally occurring, unmodified nucleobase such as adenine, guanine, cytosine, thymine, uracil and inosine, or any synthetic or modified nucleobase that is sufficiently similar to an unmodified nucleobase such that it is capable of hydrogen bonding with a nucleobase present on a target RNA transcript. Examples of suitable modified nucleobases include, but are not limited to, hypoxanthine, xanthine, 7-methylguanine, 5, 6-dihydrouracil, 5 -methylcytosine, and 5 hydroxymethoylcyto sine .

[0494] ASOs include a “backbone” structure that refers to the connection between nucleotides / monomers of the ASO . In naturally occurring oligonucleotides, the backbone comprises a 3'-5' phosphodiester linkage connecting sugar moieties of adjacent nucleotides. Suitable types of backbone linkages for the ASOs described herein include, but are not limited to, phosphodiester, phosphorothioate, phosphorodithioate, phosphorodiamidate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoraniladate, phosphoramidate, phosphoramidite, phosphoryl guanidine, and the like. In some examples, the backbone modification is a phosphorothioate linkage. In one example, the backbone modification is a phosphoramidite linkage. In one example, the phosphoramidite is a vinyl phosphonate linkage. For example, a 5'-deoxy-5'-vinylphosphonate. In other examples, the backbone modification is a phosphorodiamidate linkage. See, e.g., Roberts et al. supra; and Agrawal (2021), Biomedicines, 9:503. In some examples, the backbone structure of the ASO does not contain phosphorous-based linkages, but rather contains peptide bonds, for example in a peptide nucleic acid (PNA), or linking groups including carbamate, amides, and linear and cyclic hydrocarbon groups.

[0495] Additional backbone modifications suitable for use in the ASOs and / or other nucleic acids of the present disclosure will be apparent to the skilled person and described, for example, in Prakash et al., Nucleic Acids Research, 43(6), 2015, pp 2993- 3011 and Kandasamy et al., Nucleic Acids Research, 50(10), 2022, pp 5401-5423.

[0496] In some examples, the stereochemistry at each of the phosphorus inter-nucleotide linkages of the ASO backbone is random. In other examples, the stereochemistry at each of the phosphorus inter-nucleotide linkages of the ASO backbone is controlled and is not random. For example, U.S. Pat. No. 9,605,019 describes methods for independently selecting the handedness of chirality at each phosphorous atom in an oligonucleotide. In some examples, a composition or composition used in the methods disclosed herein comprises a pure diastereomeric ASO. In other examples, the composition comprises an ASO that has diastereomeric purity of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, about 100%, about 90% to about 100%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, or about 99% to about 100%.

[0497] In some examples, the ASO has a non-random mixture of Rp and Sp configurations at its phosphorus intemucleotide linkages. In some examples, an ASO used in the compositions and methods disclosed herein, comprises about 5-100% Rp, at least about 5% Rp, at least about 10% Rp, at least about 15% Rp, at least about 20% Rp, at least about 25% Rp, at least about 30% Rp, at least about 35% Rp, at least about 40% Rp, at least about 45% Rp, at least about 50% Rp, at least about 55% Rp, at least about 60% Rp, at least about 65% Rp, at least about 70% Rp, at least about 75% Rp, at least about 80% Rp, at least about 85% Rp, at least about 90% Rp, or at least about 95% Rp, with the remainder Sp, or about 100% Rp.

[0498] In some examples, the ASOs described herein contain a sugar moiety that comprises ribose or deoxyribose, or a modified sugar moiety or sugar analogue, including a morpholine ring. Suitable examples of modified sugar moieties include, but are not limited to, 2' substitutions such as 2'-O-modifications, 2'-O-methyl (2'-O-Me), T-O- methoxyethyl (2'MOE), 2'-O-aminoethyl, 2'F, N3'->P5' phosphoramidate,

[0499] 2'dimethylaminooxyethoxy, 2'dimethylaminoethoxyethoxy, 2'-guanidinidium, T-O- guanidinium ethyl, 2'-O-alkyl, carbamate modified sugars, and bicyclic modified sugars. In some examples, the sugar moiety modification is selected from among 2'-O-Me, 2'F, and 2'MOE. In one example, the sugar moiety modification is an unlocked nucleic acid (UNA). In another example, the sugar moiety modification is a glycol nucleic acid (GNA). In other examples, the sugar moiety modification is an extra bridge bond, such as in a locked nucleic acid (LNA). In some examples, the sugar analogue contains a morpholine ring, such as phosphorodiamidate morpholino (PMO). In some examples, the sugar moiety comprises a ribofuransyl or 2'deoxyribofiiransyl modification. In some examples, the sugar moiety comprises 2'4'-constrained 2'-O-methyloxyethyl (cMOE) modifications. In some examples, the sugar moiety comprises cEt 2', 4' constrained -0 ethyl BNA modifications. In other examples, the sugar moiety comprises tricycloDNA (tcDNA) modifications. In some examples, the sugar moiety comprises ethylene nucleic acid (ENA) modifications. In some examples, the sugar moiety comprises 2'-O-(2-N- methylcarbamoylethyl) (MCE). Modifications are known in the art as exemplified in Jarver, et al., 2014, Nucleic Acid Therapeutics, 24(1): 37 47, Bramsen et al., 2010, Nucleic Acid Research, 38(17): 5761-73 and Schlegel et al., 2017, Journal of the American Chemical Society, 139(25): 8537-46.

[0500] In some examples, each constituent nucleotide of the ASO is modified in the same way, e.g., every linkage of the backbone of the ASO comprises a phosphorothioate linkage, or each ribose sugar moiety comprises a 2'-O-methyl modification. In other examples, a combination of different modifications is used, e.g., an ASO comprising a combination of phosphorodiamidate linkages and sugar moieties comprising morpholine rings (morpholines).

[0501] In some examples, the ASO comprises one or more backbone modifications. In some examples, the ASO comprises one or more sugar moiety modification. In some examples, the ASO comprises one or more backbone modifications and one or more sugar moiety modifications. In some examples, the ASO comprises a 2'MOE modification and a phosphorothioate backbone. In some examples, the ASO comprises a peptide nucleic acid (PNA).

[0502] In some preferred examples, the ASO comprises a phosphorodiamidate morpholino (PMO).

[0503] The skilled person in the art will appreciate that ASOs may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO. In some examples, an ASO is modified to alter one or more properties. For example, such modifications can: enhance binding affinity to a target sequence on a pre-mRNA transcript; reduce binding to any non-target sequence; reduce degradation by cellular nucleases (e.g., RNase H); improve uptake of an ASO into a cell and / or particular subcellular compartments; alter the pharmacokinetics or pharmacodynamics of the ASO; and / or modulate the half-life of the ASO in vivo.

[0504] In some examples, the ASOs comprise one or more 2'-O-(methoxyethyl) (MOE) phosphorothioate-modified nucleotides that have been shown to confer significantly enhanced resistance of ASOs to nuclease degradation and increased bioavailability.

[0505] Methods for synthesis and chemical modification of ASOs, as well as synthesis of ASO conjugates is well known in the art, and such ASOs are available commercially.

[0506] In some examples, a composition (e.g., a pharmaceutical composition) provided here includes two or more ASOs with different chemistries but complementary to the same targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA. In other examples, two or more ASOs that are complementary to different targeted portions of the PRPF31 pre-mRNA, mRNA and / or ncRNA.

[0507] In some examples, the compositions disclosed herein include ASOs that are linked to a functional moiety. In some examples, the functional moiety is a delivery moiety, a targeting moiety, a detection moiety, a stabilizing moiety, or a therapeutic moiety. In some examples, the functional moiety includes a delivery moiety or a targeting moiety. In some examples, the functional moiety includes a stabilizing moiety. In some preferred examples the functional moiety is a delivery moiety.

[0508] In one example, the targeting moiety is a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody that binds to a specified cell type. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl- galactosamine, N-acetyl-glucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B 12, biotin, or an RGD peptide, RGD peptide mimetic, peptide or receptor-binding peptide. In certain embodiments, the ligand is a multivalent galactose, e.g., an N-acetyl- galactosamine.

[0509] Suitable delivery moieties include, but are not limited to, lipids, peptides, carbohydrates, polyethers, and antibodies.

[0510] In some examples, the delivery moiety includes a cell-penetrating peptide (CPP).

[0511] In other examples, the delivery moiety includes a carbohydrate or glycan. In some examples, a carbohydrate delivery moiety is selected from among N-acetylgalactosamine (GalNAc), N-Ac-Glucosamine (GluNAc), and a mannose. In one example, the carbohydrate delivery moiety is GalNAc.

[0512] In one example, the delivery moiety is a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), or globulin); carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid); or a lipid. The moiety may also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an a helical peptide.

[0513] In another example, the delivery moiety includes dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipophilic molecules, e.g., cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis- O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,O3-(oleoyl)lithocholic acid, 03-( oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine )and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG]z, polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport / absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, bisimidazole, histamine, imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles), dinitrophenyl, HR P, or AP. For example, the delivery moiety is palmitic acid.

[0514] In other examples, the delivery moiety includes a lipid. Examples of suitable lipids as delivery moieties include, but are not limited to, cholesterol moiety, a cholesteryl moiety, and aliphatic lipids. In some examples, the delivery moiety includes a fatty acid or lipid moiety. In some embodiments the fatty acid chain length is about C8 to C20. Examples of suitable fatty acid moieties and their conjugation to oligonucleotides are found in, e.g., International Patent Publication WO 2019232255 and in Prakash et al., (2019). In one example, the lipid moiety includes a cholesterol moiety, cholic acid, a thioether, e.g., beryl-S-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium l,2-di-O-hexadecyl-rac-glycero-3 -phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmitoyl moiety, or an octadecylamine or hexylamino-carbonyloxycholesterol moiety or a docosahexaenoic acid delivery. In one example, the delivery moiety is a docosahexaenoic acid delivery moiety.

[0515] In further examples, the delivery moiety includes an antibody, as described in, e.g., Dugal-Tessier et al., (2021), J Clin Med., 10(4) : 838.

[0516] Suitable examples of stabilizing moieties include, but are not limited to, polyethylene glycol (PEG), poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), and Poly(2-oxazoline)s (POx).

[0517] In some examples, where an ASO is linked to a functional moiety, the functional moiety is covalently linked to the ASO. In other examples, the functional moiety is non- covalently linked to the ASO.

[0518] Functional moieties can be linked to one or more of any nucleotides in an ASO at any of several positions on the sugar, base or phosphate group, as understood in the art and described in the literature, e.g., using a linker. Linkers can include a bivalent or trivalent or multivalent branched linkers. In one example, the linker is a multivalent branched linker, wherein the multivalency is about 2 to about 10 linked moieties. For example, the multivalency is 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10 linked moieties. In some examples, the functional moiety is linked to the 5' end of the ASO. In other examples, the functional moiety is linked to the 3' end of the ASO.

[0519] In some examples, compositions comprising any of the ASOs disclosed herein also include a delivery nanocarrier complexed with ASO. In some examples, a delivery nanocarrier is selected from among lipoplexes, liposomes, exosomes, inorganic nanoparticles, and DNA nanostructures. In other examples the delivery nanocarrier includes a lipid nanoparticle encapsulating the ASO. Various delivery ASO-nanocarrier complex formats are known in the art, as reviewed in, e.g., Roberts et al., supra.

[0520] RNA interference

[0521] RNA interference (RNAi) is useful for specifically inhibiting the production of a particular protein, i.e., PRPF31. Without being bound by theory, this technology relies on the presence of double stranded RNA (dsRNA) molecules that contain a sequence that is essentially identical to the mRNA of the gene of interest or part thereof, in this case a PRPF31 pre-mRNA or mRNA.

[0522] The length of the sense and antisense sequences that hybridize should each be at least 4 contiguous nucleotides, or at least 5 contiguous nucleotides, or at least 19 contiguous nucleotides, such as at least 30 or 50 nucleotides, for example at least 100, 200, 500 or 1000 nucleotides. In one example, the length of the sense and antisense sequences that hybridize should each be at least 4 contiguous nucleotides. In another example, the length of the sense and antisense sequences that hybridize should each be at least 5 contiguous nucleotides. The full-length sequence corresponding to the entire gene transcript may be used. The lengths can be 100-2000 nucleotides. The degree of identity of the sense and antisense sequences to the targeted transcript should be at least 85%, for example, at least 90% such as, 95-100%.

[0523] Exemplary small interfering RNA (“siRNA”) molecules comprise a nucleotide sequence that is identical to about 19-21 contiguous nucleotides of the target PRPF31 pre-mRNA or mRNA. For example, the siRNA sequence commences with the dinucleotide AA, comprises a GC-content of about 30-70% (for example, 30-60%, such as 40-60% for example about 45%-55%), and does not have a high percentage identity to any nucleotide sequence other than the target in the genome of the mammal in which it is to be introduced, for example as determined by standard BLAST search.

[0524] The design and production of suitable siRNA molecules for the present disclosure is well within the capacity of a person skilled in the art, particularly considering U.S. Patent No. 8,101,348 and in Lima et al., (2012) Cell 150:883-894.

[0525] It will be apparent to the skilled person that the backbone modifications described herein in relation to ASOs may also be applied to other nucleic acids, such as siRNAs, of the disclosure.

[0526] Exemplary short hairpin RNA (“shRNA”) molecules comprise a nucleotide sequence that is identical to about 19-21 contiguous nucleotides of the target PRPF31 pre-mRNA or mRNA and a hairpin loop structure. In some examples, the hairpin loop comprises at least one unpaired nucleotide. In some examples, the hairpin loop can comprise at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides or nucleotides not directed to the target PRPF31 pre-mRNA or mRNA. In some examples, the hairpin loop comprises 10 or fewer nucleotides. In some examples, the hairpin loop comprises 8 or fewer unpaired nucleotides. In some examples, the hairpin loop comprises 4-10 unpaired nucleotides. In some examples, the hairpin loop comprises 4-8 nucleotides.

[0527] Vectors for Expression of Nucleic Acids Targeting PRPF31 Transcripts and PRPF31 ncRNA Transcripts

[0528] In one example, provided herein is a vector for expression, in a mammalian cell, of a nucleic acid that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre- mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre- mRNA, mRNA or ncRNA in a cell increases the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

[0529] In one example, the vector comprises a cell type-selective or tissue-selective promoter for driving expression of the nucleic acid in the mammalian cell.

[0530] In one example the promoter is an inducible promoter, e.g., inducible by a ligand- regulated transactivator such as the Tet-inducible rtTA that allows titration of the nucleic acid transcription in a target mammalian cell. In one example, the promoter driving expression is a U6 or other Pol III promoter, which is particularly suitable for transcription of short RNA sequences such nucleic acid sequences disclosed herein. In one example, an expression vector utilizes hybrid promoter systems, e.g., a Tet-O- regulated U6 promoter system as described in Lin et al. (2004), FEBS Letters, 577 (2004) 376-380. In one example, where both cell type -specificity and inducibility of a nucleic acid expression vector are desired, a two-part expression system is used in which expression of a ligand-regulated transactivator is driven by a cell type-selective promoter and expression of a nucleic acid disclosed herein is driven by a promoter regulated by the ligand-regulated transactivator.

[0531] In one example, the expression vector used in the compositions disclosed herein are non-viral expression vectors, e.g., plasmid vectors, minicircle DNA vectors, linear amplicon expression cassettes, and the like.

[0532] In one example, a composition containing a non-viral expression virus further comprises a transfection agent. Exemplary transfection agents for transfection include, but are not limited to, jet-PEI® (available from Polyplus-transfection® SA, Strasbourg, France); TurboFect in vivo Transfection Reagent (ThermoFisher), and cationic derivatives of polyisoprenoid alcohols (PTAI) as described in, e.g., Rak et al. (2016), J Gene Med, 18(11-12):331-342.

[0533] In one example, the expression vectors to be used are viral vectors, i.e., non- replicative recombinant viruses suitable for expression of a nucleic acid disclosed herein.

[0534] In one example, the recombinant virus for expression of the PRPF31 nucleic acid sequence or PRPF31 ncRNA nucleic acid sequence is a DNA virus. Suitable types of DNA viruses include adeno-associated virus (AAV), adenovirus, lentivirus, herpes simplex virus (HSV), and anelloviruses. Methods for design, production, and use of such types of recombinant DNA viruses are established in the art, as exemplified in Fukazawa et al., (2010), International J of Mol. Med, 25(1), 3-10, and in "Gene Therapy Protocols" for adenovirus; "Adeno- Associated Virus: Methods and Protocols" for AAV; Cody et al (2013), Journal of Genetic Syndromes & Gene Therapy, 4(1), 126, and "Herpes Simplex Virus: Methods and Protocols" for HSV; "Gene Therapy Protocols Vol. 1: Production and In Vivo Applications of Gene Transfer Vectors"; and Merten et al. (2016), Molecular Therapy - Methods & Clinical Development, 3, 16017, and Emeagi et al. (2013), Current Molecular Medicine 13(4), 602-625 for lentivirus. In one example, the viral vector is a recombinant AAV.

[0535] Genetically Modified Cells

[0536] Also provided herein are genetically modified cells. In one example, the genetically modified cells are genetically modified mammalian cells that have been transfected with any of the nucleic acids or non-viral expression vectors; or transduced with any of the viral expression vectors disclosed herein. In one example, the genetically modified mammalian cells are ex vivo, e.g., as a cultured cell population. In another example, the genetically modified mammalian cells are in vivo, e.g., in a mouse. In one example, the genetically modified mammalian cells are human cells.

[0537] In one example, the genetically modified mammalian cells are of primary cell types. Suitable examples of primary cell types include, but are not limited to, retinal pigment epithelium (RPE) cells, Muller glial cells, endothelial cells, glial cells, astrocytes, photoreceptors, bipolar cells, horizontal cells, ganglion cells, amacrine cells and combinations thereof.

[0538] In one example, such primary cell types can be obtained by differentiation of a human pluripotent stem cell line, e.g., a human induced pluripotent stem cell (hiPSC) line or a human embryonic stem cell (hESC) line or a retinal progenitor cell. In another example, the genetically modified mammalian cells are derived from a cell line. In some examples, the cell line is pluripotent stem cell line (e.g., hiPSCs or hESCs) or a human retinal pigment epithelium cell line. In one example, the genetically modified mammalian cells express PRPF31 endogenously.

[0539] The genetically modified cells disclosed herein can be genetically modified by any of a number of methods and strategies known in the art, e.g., transient transfection, stable transfection, and viral transduction.

[0540] In one example, the genetic modification is a stable genetic modification. As used herein, a “stable genetic modification” is a targeted modification of the host cell genome.

[0541] In one example, the genetic modification occurs by introducing an expression cassette and / or an expression vector into one or more mammalian cells. Any suitable expression vector can be used, examples of which include, but are not limited to, a plasmid or viral vector. In some embodiments, the viral vector is a retrovirus, a lentivirus, an adenovirus, or an adeno-associated viral vector.

[0542] In one example, the stable genetic modification includes modification of a host cell genome including one or more of: insertion of an exogenous sequence (e.g., a microRNA binding site), deletion of an endogenous sequence (i.e., one or more base pairs), and substitution of an endogenous sequence.

[0543] In one example, the genetic modification includes use of site-specific nucleases or programmable nuclease-based targeting. As used herein, the term “site-specific nuclease” or “programmable nuclease” relates to nucleases that are “targeted” to recognize and edit a pre-determined genomic location. For example, such nucleases introduce single-strand or double-strand DNA breaks at particular locations within the genome.

[0544] It will be apparent to the skilled person that such DNA breaks can be repaired by endogenous cellular processes, such as homology-directed repair (HDR) and non- homologous end joining (NHEJ). HDR is essentially an error-free mechanism that repairs double-strand DNA breaks in the presence of a homologous DNA sequence. The most common form of HDR is homologous recombination. It utilizes a homologous sequence as a template for inserting or replacing a specific DNA sequence at the break point. The template for the homologous DNA sequence can be an endogenous sequence (e.g., a sister chromatid), or an exogenous or supplied sequence (e.g., plasmid or an oligonucleotide). As such, HDR may be utilized to introduce precise alterations such as replacement or insertion at desired regions. In contrast, NHEJ is an error— prone repair mechanism that directly joins the DNA ends resulting from a double— strand break with the possibility of losing, adding or mutating a few nucleotides at the cleavage site. The resulting small deletions or insertions (termed '"indels") or mutations may disrupt or enhance gene expression. Additionally, if there are two breaks on the same DNA, NHEJ can lead to the deletion or inversion of the intervening segment. Therefore, NHEJ may be utilized to introduce insertions, deletions or mutations at the cleavage site.

[0545] Programmable nucleases that can be used in accordance with the present disclosure include, but are not limited to, RNA-guided engineered nuclease (RGEN) derived from the bacterial clustered regularly interspaced short palindromic repeat (CRISPR)-cas, (CRISPR-associated) system, zinc -finger nuclease (ZFN), transcription activator-like nuclease (TALEN), meganucleases and argonautes.

[0546] RNA-guided engineered nuclease

[0547] In one example, the nuclease is a RNA-guided engineered nuclease (RGEN). In one example, the RGEN is from an archaeal genome or is a recombinant version thereof. In one example, the RGEN is from a bacterial genome or is a recombinant version thereof. In one example, the RGEN is from a Type I (CRISPR)-cas (CRISPR-associated) system. In one example, the RGEN is from a Type II (CRISPR)-cas (CRISPR- associated) system. In one example, the RGEN is from a Type III (CRISPR)-cas (CRISPR-associated) system. In one example, the nuclease is a class I RGEN. In some embodiments the nuclease is a class II RGEN. In one example, the RGEN is a multicomponent enzyme. In one example, the RGEN is a single component enzyme. In some embodiments the RGEN is CAS3. In one example, the RGEN is CASIO. In some embodiments the RGEN is CAS9. In one example, the RGEN is Cpfl (Zetsche et al., 2015). In one example, the RGEN is targeted by a single RNA or DNA. In one example, the RGEN is targeted by more than one RNA and / or DNA. In one example, the programmable nuclease may be a DNA programmed argonaute (WO 14 / 189628).

[0548] In one example, the nuclease is a CRISPR-cas9 nuclease system.

[0549] Zinc-finger nuclease

[0550] In one example, the nuclease is a zinc finger nuclease (ZFN).

[0551] The skilled person will understand that ZFNs are modular proteins comprised of an engineered zinc finger DNA binding domain linked to a DNA-cleavage domain. A typical DNA-cleavage domain is the catalytic domain of the type II endonuclease Fold. Because FokI functions only as a dimer, a pair of ZFNs are required to be engineered to bind to cognate target '"half-site" sequences on opposite DNA strands and with precise spacing between them to allow the two enable the catalytically active Fokl domains to dimerize. Upon dimerization of the Fokl domain, which itself has no sequence specificity per se, a DNA double-strand break is generated between the ZFN half-sites as the initiating step in genome editing.

[0552] Transcription activator-like nuclease

[0553] In one example, the nuclease may be programmed to recognize a genomic location by transcription activator-like effector nucleases (TALENs) DNA binding domains.

[0554] The skilled person will be aware that TALENs are generated by fusing an engineered DNA binding domain (derived from a transcription activator— like effector (TALE) protein) to a nuclease domain, which operate in tandem to achieve targeted DNA cleavage.

[0555] TALEs are comprised of tandem arrays of 33-35 amino acid repeats, with each repeat recognizing a single base pair in the target DNA sequence that is typically up to 20 bp in length, giving a total target sequence length of up to 40 bp. Nucleotide specificity of each repeat is determined by the repeat variable diresidue (RVD), which includes just two amino acids at positions 12 and 13. The bases guanine, adenine, cytosine and thymine are predominantly recognized by the four RVDs: Asn- Asn, Asn-Ile, His-Asp and Asn-Gly, respectively.

[0556] Methods of Treating or Preventing an Ocular Condition

[0557] The present disclosure provides, for example, a method of treating, preventing and / or delaying progression of Pre-mRNA Processing Factor 31 (PRPF3T) gene mediated disease or condition in a subject. The methods described herein include a method for treating, preventing and / or delaying progression of Pre-mRNA Processing Factor 31 (PRPF3 ) gene mediated disease or condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising any of the nucleic acids disclosed herein. Likewise, in some examples, any of the nucleic acids herein are used in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF3 ) gene mediated disease or condition in a subject.

[0558] In one example, the PRPF31 -mediated disease or condition is an ocular condition. For example, the ocular condition is retinitis pigmentosa.

[0559] Retinitis pigmentosa is a phenotypically linked group of related degenerative eye diseases that causes severe vision impairment. Retinitis pigmentosa can be classified as non-syndromic, syndromic, or secondary to other systemic genetic diseases. Several types of non-syndromic retinitis pigmentosa have been identified, which are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked.

[0560] In one example, the retinitis pigmentosa is non-syndromic retinitis pigmentosa. For example, the non-syndromic retinitis pigmentosa is autosomal dominant, autosomal recessive, or X-linked non-syndromic retinitis pigmentosa.

[0561] In one example, the retinitis pigmentosa is syndromic retinitis pigmentosa.

[0562] In one example, the retinitis pigmentosa is retinitis pigmentosa secondary to other systemic genetic diseases. For example, the retinitis pigmentosa is secondary to Ushers syndrome.

[0563] In one example, the subject to be treated is suffering from retinitis pigmentosa. For example, the subject has been diagnosed as having or suffering from retinitis pigmentosa. In one example, the subject suffers from retinitis pigmentosa. For example, the subject is in need of treatment. Such subjects can be administered the ASOs as described here to treat or prevent or delay the progression of retinitis pigmentosa.

[0564] In one example, administration of a nucleic acid as described herein slows progression of retinitis pigmentosa.

[0565] Methods of monitoring the progression of retinitis pigmentosa will be apparent to the skilled person and / or described herein. For example, methods of monitoring retinal changes in the retinal pigment epithelium / photoreceptor complex include fundus autofluorescence (FAF) and spectral -domain optical coherence tomography (OCT).

[0566] In one example, the subject is at risk of developing retinitis pigmentosa. Such subjects can be administered the nucleic acid as described here to prevent onset of retinitis pigmentosa.

[0567] As used herein, the term “at risk” means that the subject has an increased chance of developing retinitis pigmentosa compared to a normal individual. Subjects can be identified as at risk of developing glaucoma using any method known in the art and / or those described herein. For example, the subject may be identified at risk of developing retinitis pigmentosa if that subject has one or more common risk factors including family history, genotype, gender, age, smoking status, physical activity, and other demographic and environmental factors.

[0568] Also provided herein is a method for increasing the PRPF31 protein in a cell, the method comprising contacting the cell with a composition or pharmaceutical composition, as disclosed herein, whereby the amount of PRPF31 protein in the cell is increased. Also provided herein is a method for increasing the level of PRPF31 protein in a cell, ex vivo or in a tissue in vivo, the method comprising contacting the cell with an nucleic acid or pharmaceutical composition, as disclosed herein, whereby the amount of PRPF31 protein in the cell is increased. In some examples, the cell is a retinal cell. In some examples, the tissue is a retinal tissue, e.g., retina and / or retinal pigment epithelium.

[0569] In some examples, administration to a subject or contact with cells with any of the nucleic acids or pharmaceutical compositions disclosed herein increases the level of PRPF31 protein about 1.1 to about 10-fold, e.g., 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8 -fold, about 1.1 to about 9-fold, about 2 to about 5 -fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5 -fold, or at least about 10-fold compared to the level in the tissue prior to the administration or contact.

[0570] Suitable routes of administration for treatment with the compositions, pharmaceutical compositions, or medicaments disclosed herein include, but are not limited to, intravitreal, suprachoroidal, subretinal, ciliary intramuscular, intravenous, intra-arterial, subcutaneous, and topical.

[0571] In some examples administration is into the eye by an intravitreal, suprachoroidal, or sub-retinal route. For example, administration to the eye is by intravitreal administration. In another example, administration to the eye is by suprachoroidal administration. In a further example, administration to the eye is by sub-retinal administration. In one example, administration to the eye is by atopical administration.

[0572] Gene Therapy

[0573] The present disclosure also provides methods of gene therapy for treating, preventing and / or delaying progression of a PRPF31- mediated disease or condition in a subject.

[0574] In one example, the gene therapy comprises use of genetically modified cells to increase the level of PRPF31 protein in the cell.

[0575] In one example, the genetically modified cell is an autologous genetically modified cell. For example, the cell is derived from the subject prior to the cell undergoing genetic modification. In one example, the subject is receiving or will receive gene therapy with an autologous genetically modified cell. The term “autologous” refers to gene therapy with cells collected or obtained from the subject to be or receiving treatment (i.e., the same individual). In one example, the gene therapy comprises obtaining autologous cells from the subject, genetically modifying the cells from the subject and administering the autologous genetically modified cells to the subject.

[0576] In one example, the genetically modified cell is an allogeneic genetically modified cell. For example, the cell is derived from another person to the subject prior to the cell undergoing genetic modification. In one example, the subject is receiving or will receive gene therapy with an allogeneic genetically modified cell. The term “allogeneic” refers to gene therapy with cells collected or obtained from another person to the subject to be or receiving treatment (i.e., a different individual). In one example, the gene therapy comprises obtaining allogeneic cells from another person, genetically modifying the cells and administering the allogeneic genetically modified cells to the subject.

[0577] Pharmaceutical Compositions

[0578] Also provided herein are pharmaceutical compositions comprising any of the foregoing nucleic acids, non-viral expression vectors and or viral expression vectors disclosed herein, and formulated with at least a pharmaceutically acceptable excipient, including a carrier, filler, preservative, adjuvant, solubilizer and / or diluent.

[0579] Pharmaceutical compositions containing any of the nucleic acid or expression vector compositions described herein, for use in the methods disclosed herein, can be prepared according to conventional techniques well known in the pharmaceutical industry and described in the published literature. In some examples, a pharmaceutical composition for treating a subject comprises a therapeutically effective amount of any nucleic acid or expression vector disclosed herein.

[0580] Pharmaceutically acceptable salts are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0581] Exemplary salts useful in a composition of the present disclosure include calcium chloride, magnesium chloride or sodium chloride.

[0582] In one example, a composition comprises a buffer. Exemplary buffers useful in a composition of the present disclosure include sodium phosphate.

[0583] In some examples, pharmaceutical compositions are formulated into any of a number of possible dosage forms including, but not limited to, intravenous administration, subcutaneous injection, intrathecal administration, intra cistema magna administration, tablets, capsules, gel capsules, liquid syrups, and soft gels. In some examples, the compositions are formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension may also contain stabilizers. In some examples, a pharmaceutical formulation disclosed herein is provided in a form including, but not limited to, a solution, emulsion, microemulsion, foam or liposome-containing formulation (e.g., cationic or noncationic liposomes).

[0584] In some examples, pharmaceutical formulations comprising any of the nucleic acids or expression vectors described herein may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients as appropriate and known to the skilled person. In some examples, where a pharmaceutical composition includes liposomes, such liposomes can also include sterically stabilized liposomes, e.g., liposomes comprising one or more specialized lipids. These specialized lipids result in liposomes with enhanced circulation lifetimes. In some examples, a sterically stabilized liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic polymers, such as PEG moiety. In some examples, a surfactant is included in the pharmaceutical formulation.

[0585] In some examples, a pharmaceutical composition also includes a penetration enhancer to enhance the delivery of the nucleic acid ornon-viral expression vectors, e.g., to aid diffusion across cell membranes and / or enhance the permeability of a lipophilic drug. In some examples, the penetration enhancers include a surfactant, a fatty acid, a bile salt, or a chelating agent.

[0586] The optimum concentration of the nucleic acid or vector in the chosen medium can be determined empirically, according to procedures known to the skilled artisan, and will depend on the ultimate pharmaceutical formulation desired. In some examples, a pharmaceutical composition comprises a dose of nucleic acid or non-viral vectors ranging from about 0.01 mg / kg to about 80 mg / kg, e.g., 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.5 mg / kg, 1 mg / kg, 3 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 77 mg / kg, or another dose ranging from about 0.01 mg / kg to about 80 mg / kg.

[0587] The dosage ranges for the administration of the nucleic acid or vector of the disclosure are those large enough to produce the desired effect. For example, the composition comprises a therapeutically or prophylactically effective amount of the nucleic acid or vector.

[0588] As the skilled person will understand, the treatment methods disclosed herein include administration of the compositions and pharmaceutical compositions disclosed herein in a therapeutically effective amount to a subject (e.g., a human subject). The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of a disclosed nucleic acid, non-viral or viral expression vector being administered to relieve to some extent one or more of the symptoms and / or clinical indicia associated with the disease or condition described herein. In some examples, an "effective amount" for therapeutic uses is the amount of one of the foregoing agents required to provide a clinically significant decrease in disease symptoms and / or inflammatory markers or to prevent disease symptoms without undue adverse side effects. An appropriate "effective amount" in any individual case may be determined using techniques, such as a dose escalation study. It is understood that "an effective amount" or "a therapeutically effective amount" can vary from subject to subject, due to variation in metabolism of the compound of any age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial. Where more than one therapeutic agent is used in combination, a “therapeutically effective amount” of each therapeutic agent can refer to an amount of the therapeutic agent that would be therapeutically effective when used on its own, or may refer to a reduced amount that is therapeutically effective by virtue of its combination with one or more additional therapeutic agents. As used herein, the term “prophylactically effective amount” shall be taken to mean a sufficient quantity of a disclosed nucleic acid, non-viral or viral expression vector to prevent or inhibit or delay the onset of one or more detectable symptoms of a disease or condition described herein.

[0589] In some examples, a pharmaceutical composition comprises multiple nucleic acids or expression vectors.

[0590] Combination Therapies

[0591] In some examples described herein, a nucleic acid of the disclosure is administered in combination with one or more additional nucleic acids useful for treating a condition described herein, either as a combined or additional treatment step or as additional components of a therapeutic pharmaceutical composition.

[0592] In one example, one or more nucleic acids of the disclosure is administered in combination with one or more additional nucleic acid(s) that has different chemistries but complementary to the same targeted portion of the target PRPF31 transcript or PRPF31 ncRNA transcript. For example, each of the nucleic acids administered have different chemistries but complementary to the same targeted portion of the target PRPF31 transcript or PRPF31 ncRNA transcript. In other examples, each of the nucleic acids administered are complementary to different targeted portions of the target PRPF31 transcript or PRPF31 ncRNA transcript.

[0593] In some examples, one or more nucleic acids of the disclosure are administered in combination with one or more additional nucleic acid(s), wherein the one or more additional nucleic acids bind to a sequence that is complementary to the same or a different gene transcript as the nucleic acid described herein. For example, the one or more additional nucleic acids target a different gene transcript as the nucleic acid described herein. In one example, the one or more additional nucleic acids target the PRPF31 gene transcript. In one example, the one or more additional nucleic acids are described in W02020 / 0237294.

[0594] In one example, the one or more nucleic acids and the additional one or more nucleic acids may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially. For example, the one or more nucleic acids is administered simultaneously with the additional one or more nucleic acids. In another example, the one or more nucleic acids is administered before the additional one or more nucleic acids. In a further example, the one or more nucleic acids is administered after the additional one or more nucleic acids. It will be apparent to the skilled person that the nucleic acids need not be administered at the same time, only in such a manner that they have an overlapping effect on the subj ect (e .g . , are both active within the subject at the same time).

[0595] In some examples, the one or more nucleic acids is administered in the same composition as the one or more additional nucleic acids, or in a separate composition to the one or more additional nucleic acids.

[0596] The pharmaceutical compositions comprising any of the nucleic acids or expression vectors disclosed herein, can also be used in combination with other agents of therapeutic value in the treatment of a condition described herein. In general, other agents do not necessarily have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, be administered by different routes. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0597] Compositions and pharmaceutical compositions comprising a nucleic acid described herein and an additional therapeutic agent may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the stage and progression of the disease to be treated, the condition of the patient, and the choice of specific therapeutic agents used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

[0598] It is known to those of skill in the art that therapeutically-effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0599] For combination therapies, dosages of co-administered therapeutic agents will of course vary depending on the type of co-agents employed, the nucleic acid, and the disease stage of the patient to be treated. Pharmaceutical compositions comprising nucleic acids described herein and an additional therapeutic agent which make up a combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical compositions that make up the combination therapy may also be administered sequentially, with either therapeutic agent being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of various physiological parameters may also be evaluated to determine the optimal dose interval. The present disclosure is not to be limited by the following non-limiting examples.

[0600] EXAMPLES

[0601] Example 1: Identification of ASO Sequences targeting miRNAs binding sites on PRPF31 pre-mRNA and mRNA

[0602] Mir-129-3p microRNA family (including the hsa-mir-129-2-3p and hsa-mir-129- 1 -3p miRNAs) were predicted to target the 3 ’UTR of PRPF31 mRNA using TargetScan. Additionally, hsa-mir-129-2-3p expression was confirmed in the retinal pigmented epithelium cells (disease relevant tissue) using publicly available data from Fantom 5 miRNA Atlas.

[0603] ASO microwalks of 16-mers and 25-mers in 3 bp increments of distance were performed across SEQ ID NO 1, which comprises the PRPF31 pre-mRNA sequence encoded by the PRPF31 gene (ENSG00000105618), which splicing generates all PRPF31 isoforms including the canonical one (Transcript ID: ENST00000321030.9, PRPF31-201, 1833 bp), with extension of 5 kb upstream and 6 kb downstream (due to the potential presence of ncRNAs in these regions), for total sequence length of 27,310 bp.

[0604] SEQ ID NOs: 6 to 9098 correspond to 16mer ASOs having sequences complementary to SEQ ID NO: 1.

[0605] SEQ ID NOs: 9099 to 18193 correspond to 25mer ASOs having sequences complementary to SEQ ID NO: 1.

[0606] Example 2: Identification of ASO Sequences targeting ncRNAs (spliced and unspliced) complementary to PRPF31

[0607] Natural antisense transcripts of the PRPF31 gene were identified by sequence alignment of both GenCode (transcript ENST00000452097.1; PRPF31 -AS 1-201; SEQ ID NO: 3) and RefSeq (XR_007067340.1; SEQ ID NO: 4) annotations. An additional unannotated natural antisense transcript was identified as a ‘hybrid’ of SEQ ID NO: 3 and SEQ ID NO: 4, (transcript PB.3676.1; SEQ ID NO: 5) using RNA sequencing data from disease relevant tissue.

[0608] ASO microwalks of 16-mers and 25-mers in 3 bp increments of distance were performed across the SEQ ID NO 2, the complementary (antisense) sequence of SEQ ID NO 1. Like SEQ ID NO 1, SEQ ID NO 2 also includes flanking regions from which ncRNAs may originate.

[0609] SEQ ID NOs: 18194 to 27282 correspond to 16mer ASOs having sequences complementary to SEQ ID NO: 2.

[0610] SEQ ID NOs: 27283 to 36362 correspond to 25mer ASOs having sequences complementary to SEQ ID NO: 2. Another ASO microwalk specific to each annotated and unnanotated natural antisense transcript was performed of 16-mers and 25-mers in 3 bp increments across the spliced ncRNA sequences detailed in SEQ ID NO 3-5 (Figure 1).

[0611] SEQ ID NOs: 36363 to 37743 correspond to 16mer ASOs having sequences complementary to SEQ ID NO: 3.

[0612] SEQ ID NOs: 37744 to 39121 correspond to 25mer ASOs having sequences complementary to SEQ ID NO: 3.

[0613] SEQ ID NOs: 39122 to 39876 correspond to 16mer ASOs having sequences complementary to SEQ ID NO: 4.

[0614] SEQ ID NOs: 39877 to 40628 correspond to 25mer ASOs having sequences complementary to SEQ ID NO: 4.

[0615] SEQ ID NOs: 40629 to 41231 correspond to 16mer ASOs having sequences complementary to SEQ ID NO: 5.

[0616] SEQ ID NOs: 41232 to 41831 correspond to 25mer ASOs having sequences complementary to SEQ ID NO: 5.

[0617] Example 3: Prediction of the binding sites for hsa-mir-129-3p and hsa-mir-1251-5p and validation of their role in modulating PRPF31 transcript expression.

[0618] The 3' UTR of PRPF31 canonical transcript (SEQ ID NO: 41861) was analysed by TargetScan (release version 8.0) to predict miR binding sites. The analysis showed that there were two miR binding sites, one for hsa-mir-129-3p and one for hsa-mir- 1251- 5p. To confirm the direct regulatory effect of those miRs, pre-miR-129-3p and pre- miR1251 -5p were transfected in ARPE-19 cells (a spontaneously arising retinal pigment epithelia cell line) using lipofectamine (ThermoFisher, Batch #2404270) at two concentrations: 30 nM and 60 nM (Figure 2). ARPE-19 cells were harvested 48 hours after transfection and RNA was extracted using MagMax-96 total RNA isolation kit. PRPF31 transcripts were quantify using ddPCR (TaqMan Hs00210306_ml). The expression of PRPF31 transcripts was normalised to the housekeeping genes SENP5 and HPRT1 (TaqMan Hs00381410_ml and TaqmanHs02800695_ml, respectively). Results in Figure 2 indicated that hsa-mir- 129-3p regulates negatively PRPF31 at RNA level, showing a significant decrease of PRPF31 RNA. In contrast hsa-mir- 125 l-5p did not show any PRPF31 downregulation effect. Example 4: Design of ASO targeting the 3' UTR of PRPF31 to mediate upregulation of PRPF31.

[0619] ASO targeting the PRPF31 3' UTR was microwalked by 16-mers (SEQ ID NO 7013-7103) and 25-mers (SEQ ID NO: 16106-16193) in 3 bp increments of distance. Matured ASOs were designed targeting the miR-129-3p (SEQ ID NO: 41846) binding site, together with additional microwalks of 3' UTR (SEQ ID NOs: 41844, 41845 and 41847-41849). The proposed mechanism of action (Figure 3) for these ASOs involves a steric block that prevent the binding of the mir-129-3p, thereby inhibiting their negative regulatory effect on PRPF31 and enabling an increase of PRPF31 protein levels.

[0620] Example 5 Screening of peptide-conjugated phosphorodiamidate morpholinos (PPMOs) targeting the 3' UTR of PRPF31 in RP11 patient derived iPSC-RPE cells

[0621] Peptide-conjugated phosphorodiamidate morpholinos (PMOs) corresponding to SEQ ID NOs: 16125, 16126 and 41846 were incubated with RP11 patient-derived iPSC-RPE cells and evaluated for their ability to increase PRPF31 transcript and protein expression levels. PPMO were applied to patient derived iPSC-RPE cells harbouring PRPF31 C.1205OA cultures at concentrations of 1 pM and 3 pM and incubated for 2 days. To assess PRPF31 expression, cells were harvested 2 days post-treatment and total RNA was extracted using MagMax-96 total RNA isolation kit. PRPF31 mRNA (TaqMan Hs00210306_ml). PRPF31 transcript expression was normalised to the housekeeping genes SENP5 and HPRT1 (TaqMan Hs00381410_ml and Taqman Hs02800695_ml respectively). GeneTools control (GTC) PPMO was used as a negative control. Results are presented as fold changes relative to untreated cells, demonstrating that PPMOs increase PRPF31 expression by at least 1.2-fold. (Figure 4).

[0622] Example 6: Confirmation of PRPF31 downregulation in screening cell line

[0623] The hTERT-RPEl cell line with a heterozygous PRPF31 knockout was utilized for screening PPMO and ASO targeting the 5 ' and 3 ' UTRs of PRPF31 transcript. Briefly, the hTERT-RPEl cell line (ATCC CRL-4000) was cultured under supplier specified standard conditions. To generate PRPF31 monoallelic knockouts, Streptococcus pyogenes Cas9 (spCas9) was complexed with one of four modified single-guide RNAs (sgRNAs) designed to target specific regions of PRPF31. These ribonucleoprotein complexes (RNPs) were prepared and introduced into the cells using a nucleofection technique. Following editing, the cells were subjected to single-cell cloning to isolate biallelic and monoallelic knockouts, as well as unedited cells, for further analysis. PCR and Sanger sequencing confirmed the successful generation of the desired knockouts (as previously described in Nazlamova et al., 2021).

[0624] Confirmatory studies were conducted to assess the expression of PRPF31 RNA and protein levels. Total RNA was extracted from wildtype (WT) RPE1 and PRPF31+ / " hTERT-RPEl cells using MagMax-96 Total RNA Isolation Kit. PRPF31 mRNA TaqMan Hs00210306_ml) expression was measured using one-step RT-digital droplet (dd)PCR. PRPF31 mRNA expression levels were normalised to the housekeeping genes SENP5 and HPRT1 (TaqMan Hs00381410_ml and Taqman Hs02800695_ml, respectively) and changes were calculated as fold-change relative to WT cells. Results in Figure 5 show that WT cells express 1.7-fold higher levels of PRPF31 mRNA and 1.5 -fold higher levels of PRPF31 protein compared to PRPF31+ / " hTERT-RPEl, suggesting that approximately 1.5 fold of PRPF31 protein upregulation is required in the PRPF31+ / " hTERT-RPEl to achieve the wild-type levels.

[0625] Example 7: Screening of ASO targeting the 3' UTR of PRPF31 transcript.

[0626] 2'-O-methoxyethyl (2'MOE) ASOs corresponding to (SEQ ID NOs: 16106, 16116, 16126, 16176, 41844, 41845, 41847-41849) were nucleofected at concentrations of2.5 pM and 5 pM to PRPF31+ / RPE1 cell line using Neon™ Transfection System and incubated for 72 hours. Subsequently, total RNA was extracted and the expression levels of PRPF31 mRNA were assessed follwoing to the protocols described in Example 5. PRPF31 mRNA expression levels were normalised to the housekeeping gene HPRT1 and relative to that expressed in mock untreated cells (Utz). The data presented in Figure 6 shows that ASO with SEQ ID NO:41849 increases PRPF31 mRNA levels by 1.27- fold in PRPF31+ / - hTERT-RPEl cell.

[0627] Example 8: Identification of a longer 5' UTR of PRPF31 canonical transcript and ASO design

[0628] Probe-enriched (Twist Bioscience) long read RNA sequencing (PacBio) was performed on HMC3 (ATCC, CRL-3304) and HEK293 (ATCC, CRL-1573) cells at passage 7 and 2, respectively. DNA probes were designed to cover all exons of PRPF31 gene, including non-coding regions, to enable the capturing of all PRPF31 transcript isoforms. Briefly, samples were harvested, and RNA was purified using the RNeasy kit (QIAGEN, cat. no. 74104). RNA samples were DNase treated (QIAGEN, cat. no. 79254) and their RNA integrity (RIN) score was assessed on an RNA screentape using the Tape Station Sytem (Agilent) following manufacture’s protocol. RNA samples with RIN > 8 were used for cDNA library preparation as per PacBio protocol for IsoSeq libraries (PacBio, SMRTbell prep kit). Barcoded cDNA IsoSeq libraries were pooled, and probe captured using the Twist-PacBio vendor protocol (Twist-PacBio). Final probe enriched IsoSeq libraries were quality checked on a TapeStation System (Agilent) and quantified using Quant-iT dsDNA High-Sensitivity Assay Kit (Thermofisher). Libraries were submitted for sequencing on a PacBio SMRT Cell (PacBio).

[0629] Analysis of the probe-enriched IsoSeq libraries was performed following IsoSeq analysis workflow from vendor (PacBio). In HMC3 and HEK293, a 344 bp longer 5' UTR was identified (SEQ ID NO: 41862), extending the total 5' UTR length to 397 bp compared to the 53 bp 5' UTR reported in the GENCODE annotation for the PRPF31 canonical transcript (transcript id ENST00000321030) (Figure 7). This 397 bp 5' UTR has been reported to be used by a protein coding isoform of PRPF31 with an intron retained (transcript id ENST00000419967).

[0630] ASOs were designed to bind complementarily to the newly identified PRPF31 5' UTR (SEQ ID NO: 41862) by microwalking the 5' UTR region with 16-mers (SEQ ID NOs: 1672-1796) and 25-mers (SEQ ID NOs: 10765-10886) in 3 bp increments. Additionally, 20-mers (SEQ ID NOs: 41833-41843) were specifically designed to target secondary structures and / or upstream open reading frames (uORFs) within the 5' UTR. ASOs are expected to augment PRPF31 protein by reducing the complexity of the secondary structures and / or steric blocking uORFs that reduce the translation efficiency of PRPF31 protein (Figure 8).

[0631] Example 9: ASO targeting 5' UTR region increases PRPF31 expression levels in PRPF31+ / RPE cell

[0632] ASOs corresponding to SEQ ID NOs: 41833 to 41843 were nucleofected at concentrations of 2.5 pM and 5 pM to PRPF31+ / " RPE1 cell line using Neon™ Transfection System and incubated for 72 hours. Subsequently, total RNA was extracted and the expression levels of PRPF31 mRNA were assessed according to the protocols described in Example 5. PRPF31 mRNA expression levels were normalised to the housekeeping genes SENP5 and HPRT1 and relative to that expressed in mock untreated cells (Utz). The results showed that the ASOs having an oligonucleotide sequence corresponding to SEQ ID NOs: 41836, 41838, 41839, 41842 and 41843 upregulates > 1.1 -fold PRPF31 mRNA in PRPF3 I1’ hTERT-RPEl cells (Figure 9).

[0633] For protein assessment, total protein was extracted at day 5 post-ASO treatment using iced-cold RIPA buffer supplemented with 3% protease inhibitor cocktail (Sigma, cat no P8340). Protein lysates were cleared by centrifugation, and total protein was quantitated using BCA protein kits (ThermoFisher Scientific, cat no 23225). Expression levels of PRPF31 protein were quantified by Enzyme Linked Immunosorbent Assay (ELISA). Samples were diluted in phosphate buffered saline (PBS), pH 7, and further diluted in 10% RIPA buffer in PBS as necessary, and standard curves were prepared in 10% RIPA buffer in PBS to match. Diluted samples and standards were loaded onto precoated human PRPF31 ELISA plates, and the assays were performed as directed by the manufacturer (Abbexa, Cat no. abx540180). The absorbances at 450 nm were measured using a VICTOR® Nivo™ multimode plate reader, and quantitative analysis was performed using GraphPad Prism Ver 10.2.3 software. A nontargeting control predicted not to hybridize to human transcripts, was included as a negative control. Results were first normalized to total protein concentration and then expressed as fold-change relative to untreated cells (UT). The results showed that the ASOs having an oligonucleotide sequence corresponding to SEQ ID NOs: 41835, 41837, 41839, 41842 and 41843 upregulates >1. 12-fold PRPF31 protein in PRPF31+ / " hTERT-RPEl cells (Figure 10).

[0634] Example 10: PPMO targeting 5' UTR region increases PRPF31 expression levels in PRPF31+ / hTERT RPE cell

[0635] Peptide-conjugated phosphorodiamidate morpholines (PPMOs) corresponding to (SEQ ID NOs: 10870, 10862, 10843 and 10790) were assessed in PRPF31+ / ’ RPE cell cells for their ability to increase PRPF31 expression levels. PPMO were applied to PRPF31+ / " hTERT RPE cells at concentrations indicated in Figure 11. Treated cells were harvest 5 days post-treatment and total protein was extracted using methods described previously in Example 9. A nontargeting control predicted not to hybridize to human transcripts, was included as a negative control. Results were first normalized to total protein concentration and then expressed as fold-change relative to untreated cells (UT). Figure 11 demonstrates the PPMOs having an oligonucleotide sequence corresponding to SEQ ID NOs: 10870, 10862 and 10843 upregulates PRPF31 protein up to 1.7- fold in PRPF31+ / - hTERT RPE cells.

[0636] Example 11: Targeting Natural Antisense Transcript (NAT) of PRPF31 increases PRPF31 expression levels in PRPF31+ / " RPE cell

[0637] Gapmer ASOs sequences correspsonding to SEQ ID NOs: 41856 to 41860 were designed to knockdown PRPF31-AS1 (SEQ ID NO: 3) and antisense transcript PB.3676.1 (SEQ ID NO: 5), respectively. In addition, ASOs (2'MOE) corresponding to SEQ ID NOs: 41850 to 41855 and 31223 were designed for steric inhibition or to mediate exon skipping of PRPF31-AS1 (SEQ ID NO: 3) to mediate upregulation of the PRPF31 levels. ASOs or gapmer ASOs were nucleofected at concentrations of 2.5 pM and 5 pM and 5 pM and 10 pM respectively, to PRPF31+ / " RPE1 cell line using Neon™ Transfection System and incubated for 72 hours. Subsequently, total RNA was extracted and the expression levels of PRPF31 mRNA were assessed according to the protocols described in Example 5. PRPF31 mRNA expression levels were normalised to the housekeeping genes SENP5 and HPRT1 and relative to that expressed in mock untreated cells (Utz). The results demonstrated that gapmer ASOs targeting NAT did not increase the expression of PRPF31 transcript (Figure 12). In contrast, the results in Figure 13 showed that the ASOs having an oligonucleotide sequence corresponding to SEQ ID NOs: 41850 to 41852 and 41854-41855 and 31223 upregulates >1.1-fold PRPF31 mRNA in PRPF31+ / ’ hTERT-RPE 1 cells.

[0638] APPENDIX

[0639] SEQ ID NO: 1: PRPF31 sense strand

[0640] AGAGCCTGAACCTCCCATTAAGTCGAAACACACCAGGCCAGGTGCGGTGGCTCACGCCTGT

[0641] AATCCCAGCACTTTGGGAGGCCGAGGCGAGTAGATCCCCTGAGGTCAGGAGTTCGAGACCA

[0642] GCCTGGCCAACATGATGAAACCCCATCTCTACTAAAAATACAAAAAATTAGCTGGGCGTGG

[0643] TGGCAGGTGCCTGCAGGATAGTCGCACGAACCTGGGAGGTGGAGGGGTGAAGTGAGTTGA

[0644] GATCACCCCACTGCACTCCAGCCTGGGCAACAGAGCGAGGTTCTGTTTCAAAAAAAAAAAT

[0645] TGCAACACACCCGACCCCCCTTCCCATGCCAGAACCCCACCCGGCCATTCACTCCTGGCTTT

[0646] ATTTCCTCCTAGTGCTCATCTGAGGAGGCAGGACGCAGCCTCTCCGCCTCTTTGCTTATTCTG

[0647] CTGACTGACCGCCTCTCCAGCCAGAGCATGAGCTGAAAAACGACAGCAACTTGTTTCTACA

[0648] TCCCGTGCCTTAACCAGAGCCTGGCACGTAGTACATCCTCGATGAACATTTGCAGAATCAAT

[0649] GACTTTGCAAAGTGAGAAGTGCTTGGTGAATACCAAAGAGTCAGACATGCTGGAGGTTAGG

[0650] GCAGGAGGTGCGACTTTAGTTACGACCTGCAGAGAAGGCCCGTGGGCCCAGACTTGAATAA

[0651] GGAGGAGACAAAGGGGTGACAGGAGGAAAGTATGCCAGGCTGAGGGGACAGCCCTGCACG

[0652] CAGCTTCTGAGGACTCCAGCCTAGACATGGAGGGAGAGATGTGACTCAGCCAAACAGGGAC

[0653] CCAAAGACAGTGGCTGAAGCAGGTGCTGCTCCTGGGTCAGAAAGACCTGAGTTCCGGGCGG

[0654] GGCACAGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGGGGCGGGCAGATCACTT

[0655] GAGGTCAGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAGATA

[0656] CAAAAATTGGCCGGATGTTGTGGCACATGCCTGTAATCTCAGCTACTCAAGAGTTTGAGGTC

[0657] GGGAGTTGCAGACCAGCCCGGCCAACATGATGAGACCTCATCTCTACTAAAAAAAAAAAAA

[0658] AAAAAAGAAAAATACAAAAATTAGCTGGGTATGGTGGCGCATGCCTGTAATCCCAGTTTCT

[0659] CAGGAGGCTGAGGCAGGAGAATCGCTTGAACCCAGGAGCTGGAGGTTGCAGTGAGCCGAG

[0660] ATCACACCACTGCCCTCCAGCCTGGGTGACAGAGTAAGACTCTGTCTCAAAAGAAAAAAAA

[0661] AAAAAAAAAGTGCCAGGCACGGTGGCTCACGCTTGTAATCCCAGCACTTTCAGAGGCCAAG

[0662] GCGAGCGGATCACCTGAGGTCAGGAGTTTGAGACCAGCCTAACGTGGTGAAACCCTGTCTC

[0663] TACTAAAAATACAAAATTAGCCAGGTGTAGTGGCGCATGCCTGTAATCCCAGCTACTCGGG

[0664] AGGCTGAGGCAGGAGAATCGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCTGAGATTG

[0665] CAGCATTGCACTCCAGCCTGGACAACAAGAGCGAAAATCCATCTAAAAAAAAAGAGTTCAA

[0666] GTTTTGGCTCTGGCTTGGCACAGTGGCTCATGCCTATAATCCCAGCACTTTGAGAGGCCAGG

[0667] AGTTCGACACCAGCCTGGGCAACAGAGTGAGACCCCAACACTCAAAAACTAACCAAAAAA

[0668] ATTAGCTGGGCTTGGTGGCTGTAGTCCCAGCTCCTTCGGAGGCTGAGATTGCTAGAGTCCAG

[0669] GATGTTGGGGCTGCAGTGAGCCACAGTCATGCCACTGCACTCCAGCCTGGGCAACAGAGAA

[0670] AGACCCTGTCTCAAAAAAAAAAAAAAAATCTCAGATCTGCCACTGCTGAGCTCTGAGCTTG

[0671] GGTGCATTACTTAACCTCTCTGAGCCTTGATTTTCTATACTTGTAAAATAGTAGTAATCTATT

[0672] CCTGGGGGTGGATTAATGGCAGAGGCTCCAGTTGAGTCCGTTTGGGCCTTGGTGTCTGTCTG

[0673] TTAAACAGGGTTTGGAATATGCCCCTGGCCTCTAGCCTTCCTCCTTACAGAACTCCCCAATA

[0674] CTGTCATTAAGAATTGAGGCCAGATGTGGTGGCTCATGCCTGTAATCCTAGCATTTTGGGAG

[0675] GTCAAGGCGAGTGGATCACTTGAGGTCAGGAGTTCAAGACCAGCCTGGGCAACATGGCAAA

[0676] ACCCCATCTCTACAAAAAGTACAAAAATTAGCCAGGTGTGGTGGTGTGTGCCTGTAGTCCC

[0677] AGCTATTTTGGGGGCTGAGGCAGGAGGACTGCTTGAACCTGGGAGACTGAGGCTGCAATGA

[0678] GCTGAGATTGCGCCACTGCACTCCAGCTTTGGTGACAAAGTGAGAACCTGTCTCAAGAAAG

[0679] AGAAAAAGAGTTGAAGGCCAGGCGTGGTGGCTCAAGCCTGTAATCCCAGCACCTTGGGAGG

[0680] CTGAGGTGGGCAGATCACCTGAGGTCAGGAGTTTGAGACCAGCCTGACCAACATGGTGAAA

[0681] CCCTGTCTCTACTAAAAATAGAAAAATTAGCTGGGTGTGGTGGCGGGCGCCTGTAATCCCA

[0682] GCTACTAGGGAGGCTGAGTCAGGAGAATCACTTGAACCCAGGAGGTGGAGGTTACAGTGA

[0683] GCTGAGATGGTGCCATTGCACTCCAGCCTGGGAGACAAGAGCGAGACTCCACCTCAAAAAA

[0684] AAAAAAAAAAAAAAAAAAAAAAGTTGAATTATTTCCCCCAAAAGAGGGTGTTGAGGCTTT

[0685] AACCCCCAGTACCTCAGGATCACCTTATATGGAGACAGTGTCGTTACAAAAGTAATCAAGT

[0686] TCAAATGAAGCCAGTGGGTGGGCCCTAATCCAGTATGACTGGAGTCCTTATAAAAAGGGTA

[0687] AATTGGGACACAGACACACACACAGGGAGCAGCAATGTGAAGATGAAGGCGGAGATCAGG

[0688] GTGATGTTTGTACGTGCCAATGACTGCCAGAAACCTCCAGAAGCCAGGGGAGAGGCCTGGA

[0689] AGATTCTCACAACCCTGTCGACACCTTGCCTTGGATGTCTAGCCTCCAGAACTGTCAGACAG

[0690] GAATTTCTGTGCTTGAGGGACCCTATTTGTGATAAGTTCTGGGAGTCCAAGCAGACTAATAC

[0691] AACTGTCTTCAGAGTTTCAGGCATCCAGACCTGATGCTGTTCCTCCCCCATTTGAAACCCTTC

[0692] AGTGGCTCCTTCACTCTCAAGGAAAAAAAAATATCCAGACTTCTTGTCCTGGTGTTCCTGGC CTGCCAAGATCTGAGCCCTGCCTGCTGTTTAATCCTCATTGATTGATTGATTGATTTTGAGAC

[0693] GGAGTCTCACTCTGTCACCCAGGCTGGAGTACAGCAGCATGATCTTGGCTCACTGCAACCTC

[0694] CGCCTTCCGGGTTCAAGCAATTCTCATGCCTCAGCCTCCCTAGTAGCTGCGACTACAGGTGC

[0695] GCACCACCACACCTGGCTAATTTTTTTGTATTTTAGTAGAGATGGGGTTTCACCATGTTGGC

[0696] CAGGCTGGTCTCGAACTCCTAACCTCAGGTGATCCGCCTGCCTCAGCCTCCCAGTGCTAGGA

[0697] TTACAAGCGTGAGCCACCATGCCCAGCCCATCCTTATTCTCAGCAAGGAGGCTATTGCAGTC

[0698] ATTCAGCCCAGACAGCTGGAGTTTGCAATGGCAGCCATAGGGATGGAGGAGAGGAGAAGG

[0699] GTCCAGAGACACTCAAGAGGCGGAATGAATGAGTCGAGAGGAGTGAATCCTGGCAGGGGT

[0700] ATGGGAGATGTGAAGAGCTTGGGCTTTCACCTGTGAGCGGTGCCACGCATTGAGAGGCCCC

[0701] CGGGAGACATCAGAGAACCCATCTGCGTTGTCAGGGAAGCTCCACGGGAGATGGCCCTTCC

[0702] AGGGGCCCGGCACAGGGCCAGACACATAATGCATGCTAAATGACTGAATATATAAGCTAAA

[0703] TGACTGAATATATCAGCAAGCCAAGAAAGGCTGGGCATGTGGAAAGGCAGAGATTGCGGG

[0704] GGGCGGTAGTTTAGGCCAGGGGACCCCAAAACCGGGGGATCCGCACTCACCTACCTGCTCG

[0705] ATCTCCCGGCAGCGCCGACCTAGTGCCTGGTACTTTCTGCGATTTAATTCCCGCTGGCGCCG

[0706] CCGCCGACCCCGGGCTGCCTCTTCCTCTTCATCTCGCTCCCGGAGCCCTGAGCCGCCCAGAC

[0707] CACCTGACACAAACTCCACTTCCGTCTCCAGCTCGCTCTCCAGGATGTGGCCACCAAATAGG

[0708] GGAGGCAACGCCAACTCTGAGCCTGGCGGCGCTGAGAACTCCTCAAAGCCCACGGCTGCCA

[0709] TGGTCCTGAGAGGCAGGGAAAGGCTCAGGGGCCCTGGATCCTGGACCCCCAGCCCCTTCTC

[0710] CCACTGAACCAGGAGCCCAGACCCCAACCCCTCCTCCCTGAGATCCTAGAATCCAGGCCCC

[0711] CAGCCCCTCCTCCCTCAGACCGTAGAATCCAGCTCCCAGCCCTCCTCCCTCAGACCCAGAAG

[0712] TCCAAGTCCGCAACCCACCCTTCGCAGCACCCACAGGGTTCAAGCCCTGACCCCCTCCTCCC

[0713] AGGATGCAAGAGTCCAGACCTCCAGACTTTTTCTCTCCAAGGACCCAGGGAGTCCAAGCCC

[0714] CAACCCTCAACCAGACGCAAGAGTCCTGGCTTCCAACCTCCTAGTCTGTCAGATCCAGCAGT

[0715] CCAAACCCCTAACCTTCTCCTCCCTCAGGATGACCCCAGTCCATAAAAGGGTTCTAAGGTAA

[0716] AGCAGTTGCATGAACTACAACCCCCATCAGACCTCAGCGTAAAAGCTCATATGGTTGCACA

[0717] CAATGCAGCTGCACTGTTTTCTGGGATTCGCACTTTTTCACAAGGGCTCAGCCACATACCCT

[0718] TCTCTCTGCTCCAATTCCATCTCCGCGACCTCCGGAAGCCCCGGGCCTCAGAGCTTCCGACC

[0719] TCTTCAATCTGTAGGTTAAGCCGTTCGCAAAACTACTTGTCCCATCAGGCTCAGCAGCCGAG

[0720] GACGGCGGGACGTGGCCCTAGGCCTTGTGGGAGTTGTAGTTTCCTGTTTCCGGCTTCGCTTC

[0721] GGCCCACCCCCACGTCCACCCCGAATCCCTGCTTAAAGGCCTTGCTTTCTTGTCTAACGCCG

[0722] CAACCAGTCCTCTGAGTTGCCAACGTCTTTCTTCTTGTCTCGACGCCCCGTCGTCCGGCCACA

[0723] GCGATTCTCTGCTTAGCAGGATCGGTCCACAGCGGGACGTGAGTCCCTTTCCTCCTCGCGGC

[0724] TTACCGCCTCTCTCCGCCTAGTGCCAGGTGCTAATAAAGTTGTTGTTTCAAATGCGGCCAGG

[0725] AACATCGCGAGCGGGGACCAATCAGAGAGTAGCTTTGCCTCTATAACGGCGCGAGAGTGAG

[0726] ACGTCATCGGTGAGCGACTAACGCTAGAAACAGTGGTGCGCGGAGAGGAGAGGTGAGTGT

[0727] GATGGGGACCACGGGGAGCGGGAGGCTGGGCTCCTGGGTCTGGGAGAAGAAGTGTGTGAG

[0728] GAAAAAGGCGGGTCTTTACAGCTTGGTTTTTGTTTTTTTGTTGTTTGTTTGTTTTGAGACGGA

[0729] GTCTCGTTCTGTTGCCCAGGTTGGAGAGCAGTGGCGCGATCTCGGCTCATTGCAACCTCCGT

[0730] CTCCCGGGTTCAAACGATTCTTCTGCCTCAGCCTCCAGAGTAGCTGGGATTACAGGCGCCCG

[0731] CCACCACCCCTGACTAATTTTTGTATTTTTAGTAGAGACGGGGTTTCCCCATGTTGGTCAGG

[0732] CTGGTCTCGAACTCCTGATCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGTGATTAC

[0733] AGGCATGATCCACCGCGCCTGGCCAGTTGTTTGTTTGTTTTGTCTGAGACGGAGTTTCGCTCT

[0734] TGTTGCCCAGGCTGGAGTGCAGTGGCGCGATCTCGGTTCACTGCAACCTCCGCCTCCCGGAT

[0735] TCAAGCGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCGCGCACCACCACGC

[0736] CCGGCTAGTTTTTTGTATTTTTAGTAGAGACGGGGTTTCACTATGTTGGCCAGGCTGGTCTCC

[0737] AACTCCTGACCTCAGATGATCCACCCGCCTGGGCCTCCCAAAGTGCTGGGATTACAGGCAT

[0738] GAGCCACCGCTCCCGGCCTTTTACAGCCTGTTTACCCAAAAGTCTTAATATGCGCCTACCAT

[0739] GGTGTGGCCCTGGGGATGTGGAAGGAGCAAAAATTGTTCGCTACCCTCTTAGAGCTTTGGTT

[0740] GATGCCTGGCAGACAGGCTTTATCAAATAATTACTTCATTAATCACAAATGTGTGAAGTGCC

[0741] TTACTGTAGACACGCAGAGCGTGCGGGACACGTTATCACAAAGCAACCTCCTGTAGTCTAG

[0742] AGTGGGGCGTGTGGGTCAGGGAGGTGGAACGTGAGAGCTGAAGGCTGAGGAGATGCTGGG

[0743] CTACTAAGAAGTGAGGAGAGCCAGACGCCATGGCTCACTCCTGTAATCCCAGCACTTTGGG

[0744] TGGCCCAGGCGAAAGGATCGCTTGAGCCCAGGAGTTTGAGACCAGCCTGAGCAACACAGTG

[0745] AGACCCTGTCTCTACAGAAAAATTTAAAAATTAGCCGGGCGTGCTGGTGCGTGCCTGTCATC

[0746] TCAGCTATCGGGAGGCTGAGGCGGGAGAATCGCTTGAGCCCAGGTGATCGAGGCTGCCGTG

[0747] AGCTATGATGGCGCCACTGCACTGCAGCCTAGGTGACAGAGCAAGACATGGTCTCAAAAAA AAGAAAAGAAAAGAAAAAACAAAGTGAAGGAAAGGGCCACTTTAGTTACAAGGGACTCCT

[0748] GTACAAAGACCTGGAGGCGGGAAGAGACCGATAATGTAACCAACTCAAGTTTCTGCTACTC

[0749] AGAGGCAGAGGAAGTGGGGGGTGGTGAAAGTAAAGCAGCTTTACTGATCAAATGCTCGCA

[0750] GATGAGAAATGGCCAAGCTAATGTCTTTAGAAGACCATTTCAAGCTTTAGGCTGGGGAGAG

[0751] GGGCTTAAAAAGGGGAACTTTGAATGGGAGGCATACAGGAGTGGTGCTGGGTACAAGGTA

[0752] TGTGTGTCTTGCTCCGAAGGCTGTCTTGAGTCACGGGCCACCTGGAGCATGGGCTGGTGTCA

[0753] AGTCAACAATGGCCACGTTGTAGATTGATCGCCTTGAGGTGATCTCTGGAGTTTTGCAGCTG

[0754] GGTTTCCATACCTAGTTTGTTTCAAGATTAGCCCCTGCGGCGAGGCGCGGTGGCTTACGCCT

[0755] GTAATCCCAACAGTTTGGGAGGCCAAGGTGGGTCGCTCACTTGAGGTCAAGAGTTCAAGAC

[0756] CAGCCTGGCTTACATAGTGAAACCTTGACTCTACAAAAAAAAAAAAAAAAAATTAGCTGGG

[0757] CATGGTGGCAGGTGCCTGTAGTCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATCGCTTGA

[0758] ACCCAGGAGGTGGAGGTTGCAAGTGAGCCAAGACTGCGCCACTGCACTCCAACCTGGGTGT

[0759] CAGAGCCAGACTCCATCTTTAAAAAATAAATAAATAAAGATTAGCCCCTGGAACTTCTAAG

[0760] TAAGCACATAGATAAGCCAGCAGTGCAAGACAGTATCTAGTGGGAAAGGAGGGAAACAAA

[0761] GAATTTCAAAGTATGTTTTCAAGGCTAAAGGCAAGAAAGGAATAAGAAAGTTTGCAAATGC

[0762] ATTTGGAATCTACACCACTTGGTTCCAGTAAGTCTTAGCAAGGTGGCGGTCATAGGGGTGTG

[0763] CTGCGTCTTGCACAGGTCGGAGCTGGAGACTCGCCAGTGAACAAAACAAACTAAAGCACCT

[0764] GTTGTCGTGGAGCCTGCATGCTAGTGGGGTTGATAAAGAAGGACCAGGGTCTTCTGGGGGA

[0765] GAATCATCGCTCAGTAATAAGGAGGGACTTTGTCGGGGCAAGTTTTTAGGGAACGCTGCTG

[0766] TCCCTCCCCAGGCCTCGGGATGTCTCTGGCAGATGAGCTCTTAGCTGATCTCGAAGAGGCAG

[0767] CAGAAGAGGAGGAAGGAGGAAGCTATGGGGAGGAAGAAGAGGAGCCAGCGATCGAGGAT

[0768] GTGCAGGAGGAGACACAGCTGGATCTTTCCGGGGATTCAGTCAAGACCATCGCCAAGCTAT

[0769] GGGATAGTAAGATGGTAAGAGGACAAGAGGTGTTCCTAGCAGGGGGCTCTAGACAGAATC

[0770] TCCCAGAAGGGGGTGATACAGGCTTCTTTTTGAAGAGTGCTGGATTCTGACTGTCTTCTCCT

[0771] TTCCTACAGTTTGCTGAGATTATGATGAAGATTGAGGAGTATATCAGCAAGCAAGCCAAAG

[0772] CTTCAGAAGGTGCTTCCTCCCACTCTGTGCCCCTCCCCATCTCCTGTCTCTCCTGCCAGGCCC

[0773] TCTCTTTGTGTCTTTCGCTCTTTGCGACCTCGCCCTATAGCTCGCGGCTTTGCGCGCTTATTTArcTCCATCCTCATTACATTCAATGACTCATTTTTGTCCACTATGGATGACACATGTCCTTCT

[0774] ATGCTTCTTAAGTCCTTCCTGTGTGCTGAGCTTACTGATCATGATAGGACTCAGCTTGAGGTT

[0775] TCCCAGACTTCACTGATTCACATGACCGGTTACAGGGTTTTTGCCACATCTATAAGCCGCTT

[0776] ATCCTATTATTTGCTTAACATATTCTTTGAGTCTAGGACTTTTTTTCTTAAATTTATCTGAGA

[0777] AGGAAGCAAATTGCTACCATGAATGGAAAACTGGTATCATTTGGCAAAGACAAAGTCACTG

[0778] TATAAAAATAGATATATAATTATTTAGGAACCACCTAAGGCCGGGCGCCGTGGCTCACGCC

[0779] TGTAATCCCAGCACTTTGGGAGGCGGAGGCAGGTGGATCATGAGTTCAGGAGATCGAGACC

[0780] ATCCTGGCTAACACGGTGACACCCCGTCTCTACTAAAAATACAAAAAATTAGCCAGGCGTG

[0781] GTGGCGGGTGCCTGTAGTCCCAGCTACTCAGGAGGCTGAGGCGGGAGAATGGCGTGAACCT

[0782] GGGAGGCGGAGCTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGGCGACAGAG

[0783] CAAGACTCCGTCTCAAAAAAAAAAAAAATAACCTAAAACCTTTTCTCATGCCCAAATTGAG

[0784] AGAACACTAGCTTATCTCATGAGTGCTCAGACTCACTCTTAAGAGGGCAGTCCTGTTACCAT

[0785] TCCTATTCTTTTTTTTTTTTCCTTGAGATAGAGTCTCCCTCTGTCGCCCAGGCTGGAGTGCAG

[0786] TGATGTGTTCTTGGCTCATTGCAACCTCCACCTCCCGGGTTCAAGCGATTCTCCTCCCTCAGC

[0787] CTTATGTATAGCTGGGATTACAGGTATGCAACACCATGCCTGGCTATTTTGTATTTTTTAGTA

[0788] GAGATGGGGTTTCACCATGTTGACCAGGCTAGTCTCGAACTCCTGACCTCAAGTAATCCGCC

[0789] CACCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTACGCCCAGCCTTCCCATT

[0790] CTTCTTGAATGGAATTTGTTGATGACAGGAAGCCATAGGAGGTTTCTGGGGAAAGAAGTGT

[0791] AGTGAGAGGGCAGAGTTTCGGGAGACTCACTGCTTGCTTTCTTTAACGTTTACCTGGGCACC

[0792] CAGTTGAATCGCCCAGGTCTTTGCTCTCAAAGTACTCAAGGTCTAGTGGAAGAGGCAGGCC

[0793] AGGTTCCAGACAGCTATCAGTGGTGGTACCAAGCTGGGGACACCGGAGCCACAGGAGGGA

[0794] CTGGCTGACCCTGCCCCAGGTGTCAGGAAGAATCGATAGCTGAATTGGACTGTAGAGCATG

[0795] AATGCATGTGCCAGGCAAAGAAAGGGAGAAGGGGGCCCAGGGAAAGACAGCGGCAGGCC

[0796] CGGGGCCTCAGATATCCGGAGAGAGAATCCTGCAGAGTTCCAGATGCCAGGCCAAGGAATT

[0797] TCTCCCTCCAGAGGGTTATGGGACACAGAAAGTGACATTTCCTGATGTCAGGCCAGGCTCA

[0798] GGGATGGAGTCAGACCCCGTCACACCCGGTGTCTGGTTGAGGAGGCAGAGGTGAAACATCT

[0799] CACAAGCTGTGGCAGTCCCTGTTTACTGGAGGTGCACAAGTGCTGCGGGTACACAGAGGAG

[0800] GCGTCTGATCCTTCCAGAAAGGGAGGGAAGGATTCTGAGTCGCTGCCTGAGTCTTAAGGAC

[0801] TTAAAGAGCCATTTGAGCATCAGGGTTAGGAGTGCAGACTCTGACGCCGCCCTGCCTGGTG TCAGATCTGAGCTCTGCCTTCTACTGGCTGTGACATCAGGCAGTTAGTATTTGCATGACTTTT

[0802] AAACACAACATCTTTTTGTTTGTTTGTTTTTTGAGACAGGGTCTCACTCTGTCACCCAGGCCA

[0803] GAATGCAGTGGCACGATCCCAGCTCACTGCAGCCTTGACCTTGTGGGCTCAGGCGTTCCTGC

[0804] CTCAGCCTCCCAGGCAGCTGGGACCACAGGTGTACACCACCATGCCTGGCTAATTTTTTTTC

[0805] TTTAATTATGTGTAGAGATGGGGTCTCCCTATGTCGCCCAGGTTGCTCTCCAACTCCTGGGC

[0806] TCAAGCAGTTCTCCTGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGTATGAGCCACTGTGC

[0807] CTGACCTCTTATTACTAAAGCACAAAGAAGCGTTTTCCAGAAACAGACGTGGGGTAAGGGA

[0808] TGCTCTGGGGAGAGGGAGCAGCACATGCAGAGGCCAGGAGGGGTCTGGCGCGGTGGCTCA

[0809] CGCCTGTCATCCCAGCACTTTGGGTGGTCAAGGCAGATGGATCACCTGAGGTCGGGAGTTC

[0810] GAGACCAGCCTGCCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAACAAACAAAAA

[0811] AAATTAGCCGGGCATGGTGGCACATGCCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGG

[0812] AGAATCGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCTGAGATCATGCCACTATACTCT

[0813] AGCCTGGGCAACCAGAGCGAAATTATGTCTCAAAAAAAAAAAAAAAAGGCTAGGAGGAGT

[0814] GGGTGTCTGGGGCACTGTGATCACTCCTTTATGGCTGGAGTGGAATAAAATGAGGTGTGGT

[0815] GAGAGGATGGGGCGGGAAGGGCGGGAGGCCAGACTGCAGAGCTGCTGAGTCAGCAAACAG

[0816] GAACGGGGGAACTCCCTGTGTGCCAGGTGCTGTCCTGGGTACTCGGCTGTGGGTACAGCCA

[0817] ACGCAGGCACAGCACTGGTCCCTGCAGAGCTTCCGGAGTTGGGGAGGCCCTGAATGTCAGT

[0818] CTGAGGACTCGGTCATTAGCCTTGGGGCTGTGGGGAGCCGTAGGAGGTTTCACACGGTCAG

[0819] TTCTGGGGTAGATGGGGTCAAGTCTAGACTGGTGTGGAGGGAGAGGGATTGAAGGCAGGA

[0820] ACACAAGTTCAGGGATGTCTGCAGACATCAGCCTGTCCCTGGTTTACTCTTCAGCCCCTCCT

[0821] TCCTGACCCCTCCCAACTTCATCCTCCGCCTCCTCCAGCTGCGGGACCCGAGAGGGGGTAGG

[0822] GATTTAGATACTCACACCCATGCCTCCGTGTCCTCACAGTGATGGGACCAGTGGAGGCCGC

[0823] GCCTGAATACCGCGTCATCGTGGATGCCAACAACCTGACCGTGGAGATCGAAAACGAGCTG

[0824] AGTGAGTGCTGGGGGGCAGGCGGAGACAGCCCCGTGTGACGTCCCTCACGCCCCCTCTCCC

[0825] TTCCCCACTGGCCTTTCCCAGGGTCCTGCCCCTAAGCCCAAGCTCAGATCGAGGTTGACCTG

[0826] CTGTCACAGAGTGGCTGAAATAAGAAGGAAGTGCGTTCTCTCGCGTATGAGTCTGAGGAGC

[0827] ACTCGGGGATGGTGTGGCCGCTTGGCTGCCTGTAGGGCCCCGGCTCTTTCCATCCTGTTGGT

[0828] CGGCCACCTGCCTCACGGTGCGAGGTGACTGCCCCACCTCCAGCCATCACCTCCGCATTCCC

[0829] ACCAGCAAGGCGCTTCTTTTCTTTAAGAACATGTCACTGCAGCTCACGTTTTACAGACCAGA

[0830] ACTAATTCCCCTGGTCACACCTAGCGGTAAGGACGGCTGAGAAAGGCTGTATGCTGGTGCC

[0831] CGTGTGCCAGGCCACAAGCCAGGGCTTCAGTTACTAAAGGAAGAAGGGGACATGGGTGTTA

[0832] GGGCCAACCAGCAGAGTCTACCTTCCATCTCACCCGACAACCTCCTGTCCCGTTTACCCTAG

[0833] ACATCATCCATAAGTTCATCCGGGATAAGTACTCAAAGAGATTCCCTGAACTGGAGTCCTTG

[0834] GTCCCCAATGCACTGGATTACATCCGCACGGTCAAGGTGAGCGCAGAGAAGGTGGGGTGCT

[0835] TCTGCTGGCGTGAAGGGGCAGGCGGGGCTCACTCTCGGACCCCCTCCCAGAGGCCTGAGGG

[0836] TCTGGAGACGATGGAGAGGAGTGGACGAGGGCTCAGTGGTCTGCTCTGCCCAGCGTGGGAG

[0837] GGACGGAGCCTGGACAGGACTTTCTCAGGGCTCCCCTCCAACCCCAGTCTCCCGAGAGGGC

[0838] TTCCCCGCTGGCCTGACCCACGCTGCTCCCGCTGTGGTTGGAGCCGGTGGCATTGGAGTTGA

[0839] CATCCGAAGGTTGACACAGGGCAGGCACACGGAGATTTGGGGGAGAGAGACGTCTAAGTG

[0840] CAGAGAGCTGGAGAGGGAACAAGTGGGGAGGAAGTGAGGCGGGGAAGGAGGGGACGGGG

[0841] AAGAGGTCGGATCACGTCCAGCCTTTGGGTCTTAGGAGAAAGCCAAGGAAGGGTTTCGGAA

[0842] AAGAGGGGCAGGTGTGCGTGAGGGCGGGGAGAGGAGGAGGTCCCCACGCATGTCCAGGAA

[0843] AGGATTAGGATGGCGGTGGGGAAGCCCCTGCAGGGAAGCGAGGCCGCGGATTTGCACTCC

[0844] GACTTGACGCAGGCCAGAGGCTTGTGAGGCCACAGTCTTTCCAGACGCCACTCTGCCCGGG

[0845] CTCCGTTTCCAGGTCAGCGAAAGCAGGGCAGATGGTGTGGATGCTTGACGTGGTGGAGGCA

[0846] GGAATGGTGTGGATGCTTCAGGCGGTGGAGGCAGGAGAGGCCCCCAGTGCAGAGACCCTG

[0847] ACTGTCCCAGTGTCCCTAAGAAGAGACCTGAGGAGGTGCTGAGCAAGAGAGGTTCTCGAGC

[0848] CTTCCTGAGTTCCCGAGCCTCCCCTATCTTCTCTGCTCGCCCCCAGGAGCTGGGCAACAGCC

[0849] TGGACAAGTGCAAGAACAATGAGAACCTGCAGCAGATCCTCACCAATGCCACCATCATGGT

[0850] CGTCAGCGTCACCGCCTCCACCACCCAGGGGTATGTCCGCTTCGAGGGAGGCGCCGGGCCC

[0851] TAATGGGATTGGGGATTAGGCTGGAGCTACACACGCAGGTGTACACACGCACACACACATA

[0852] CACACATGCACACACACACACAGAACCGAGAGGGCTGGGGCTGGGCACACCAGGCAGGCG

[0853] GGAGACCCAGGAGGCTGGGCCCACCCGCCCCTGCAGGCAGCAGCTGTCGGAGGAGGAGCT

[0854] GGAGCGGCTGGAGGAGGCCTGCGACATGGCGCTGGAGCTGAACGCCTCCAAGCACCGCATC

[0855] TACGAGTATGTGGAGTCCCGGATGTCCTTCATCGCACCCAACCTGTCCATCATTATCGGGGC

[0856] ATCCACGGCCGCCAAGATCATGGGTGAGTCCCCGGGCTGGGTCCCATGGAGCGGGGGTCTG CTGACACTGTGACCTTGGGAAAGCTACATCCTTTTCTGTAGAATGGGGGCTTTGGCACCTGG ACCTCAGCACCCCGTCTCCCTGGACATCACAGAGGTCAGCCAGCCTGGCACACAGCAAAGC CTCATCTGTGGGAAAAACACTCACCCACAGCTCCTTCTCCCTCCCCTGTGCCGGAAACCCAG AGATGACCACACCCAGGCCCTGTTGTCAGGGAGCTCCTGGTTTGGTGAAAATGGTTCCAAA ACACAGCCATCCCTGGAACGGCGTTAGTGTGGCTTAGCACAAACGTGGTGGTCAGCTTCCT GTTGGGGGCCTCCTCCCTGCACCCCCAGGCCAGCTGCCCTCCCTCTCTGAGCCTCCTTTGCAT CTGCCCCTTGCGGAATGGGCCAGGTCGCCCGCCTGGCAGGGCCATCGAGGAATCCAACCAG AACTTCATGTAAAGGTGCCCAGCACACGTCGAGCCCCCAGGCAGATTTACTCACCCCCACCT CTCTGCTTTCTTCTGACCGCCCCCCCTTCCTCCCTCCCTCCCACCGCAGGTGTGGCCGGCGGC CTGACCAACCTCTCCAAGATGCCCGCCTGCAACATCATGCTGCTCGGGGCCCAGCGCAAGA CGCTGTCGGGCTTCTCGTCTACCTCAGTGCTGCCCCACACCGGCTACATCTACCACAGTGAC ATCGTGCAGTCCCTGCCACCGGTGAGCCCACTGCGTCATGGCCCCTCCCCCGGCCCCCCTGG AGCCTTCCGCTGTGCCCAGACAGCCTGAGCAGCCACCCACCATCTGGCCCAGCTGACGGTA GCACTCAGGAGCTGGGAACAGGGTGGCATGGGACGTGAGAGCCAGGGCTCTGCAGCAGAC CAGCTCCAGCACCCACCAGTCAGGTGACTGTGGGCAAGAGGCATGAGCGCCCTGTGCCTCA

[0857] GTCTCCTCCCCTATCAAATGGGAGCACAGCGCCTGCTTCATGAGTTGGGACGAGGGCTCAGT GCACATGAAGCACTTACAGTTCAGGCCTAGCTCACGACAAGCAGCGTCGGGTTAGCGTGCA ACTGCTCCGAAGACCACCCTCAGGTTTGACCATTCACTAGAAAGACTCACAGAATCCACTG AGGGCTGCACATCAGCCATGGGGAGAGACACACAGGAGGGGCAGGAGAGGTCACCAACCT CGGAGCTTCCCGGGTCCTCTCCCTGCAGTCGGGACACATCACCATCCCAGCATCGACGCCTG ACAGCACACACACAGGCCCGCTAGCCTGGCGGGGCGCAGTGGCTCGTGCCTGTCATCCCAG CACTTTGGGAGGCCGAGGCGGGCAGATCACCTGAGGTCAGGTGTTCGAGACCAGCCTGGCC AACATGGTGAAACCCCATCTCTACCAAAAATACAAAAAACTAGCTGGGTATAGTGGCACAC ACTTATAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCAGGAGGTGG AGGTTGCAGTGAGCTAAGATCATACCACTGCCCTCCAGCCTGGGTGACAGAGTGAGACTCT GTCTCAAAAAAAAAAAAAAACAAGCAAGACAGGTTCTGGGACAGACAGGCCTGGGTCCAG ACCCTGCTCTGTCCAACTGTGGCGAGTTACCTCAGGCTCACGGCCCTGTGCCCTGCCTGGCC TCCCCCAGGGATGGGGAGAACAATAGCACTGATGGCCAAGGCTGGGCAGGCACTTCCTGGC CCCACCCCCCAGCCCTGTGTGGGGTTTTTTTTGTGGTCTTTTCTGCGACCCTTTAGGTCAGGC

[0858] ACTGCTACTGGAACACACCCAGGGAGGCTGGCAGGTCACCCCATCCTGGGAGGAGAGAGA GTGGGCGATAGAACCCAGGACGGGTGGGCCTGGGGCTCGGGGCTCCAGCTGCCTCACTGCA CCCCTGCCATCGCCACCGCCTCACAGCCCTGGGCATATGGGTTAAACCTGCCCCAGGGAGC CTGATGTCTTGTCACCCAGGCCTCTGCCTCTTCATTTGGCCATCTCACATCGGTCCAGGCACA GGCCGTAGACACCACAGGCCTGTAAGGGAGGCCAGGGCTGGCCATCGCTTCACTGTGGCTG ACAGCTGGGCTCTGTTTGCAGTTTGGATTGGAACCCTGGCTCCATCACCTGCTGGCTGTCTC CCTGGCCACATGACTTGAAGCCTTGGTTTCCACATCTGAAAAGGGGGTGCAATGATCACAC CAGCCCGATATTTGAATATTTGATGAGATGATCCGAGGGGCGTGCTTAGCATGGGGCTGGC ATCCAGGCCGAGTGCACTCCCCCCGGCGTCTCCACAGTCACCACCGTCCTCGTTGTCAGCGT GCCTTACTGTCATCCTTACCTGATGGCCACTTATCAGCTGGGACATGGCTCTGTGCCCTGCC CTCATCCCCTCTTCCTGTGAAGTAGGAGCTGAGAGCACACACCTCTAGAGCCCAAGGGTGG AAAGCCCCCTTCCAGGACCCCAGGTAGAGCCAGAGGAGGAGCGCGCGCGGTTGCTTTGCTG TTACCTCTGTCTGTCTGTCTCACACAGATTCCACCCCCGTTTTCCGTTGCTCCAGGATCTGCG GCGGAAAGCGGCCCGGCTGGTGGCCGCCAAGTGCACACTGGCAGCCCGTGTGGACAGTTTC

[0859] CACGAGAGCACAGAAGGGAAGGTGAGGAGGGAAAGGTGAGGGGCGGCCGGGCGTCTTTTC CTCTGGGCCTGGGGTGTCTCTGCAGGGAGACCCTCAGCAGGGAGCCCACCCCAGCGAGCAC TGTCCTACCAAGGCGGAGGCAGTGCTTCTGCCCACCCTCCCTGGGGTCAGGCACCCCCTTCC CCAGTGGGGTTTCCTAGGTCTGCTGTTGGAAGGTAGCATGAACCTACTGGCTTAAAACAGTG CAGGTGTGGCCGGGTGCAGTAGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAGGGTG GGCGGGTCACAAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGGTGAAACCCCATCTCT ACCAAAATTAGCCGGGTGTGGTGGCACGCACCTGTAATCCCAGTTACTCAGGAGGCTGAGG CAGGAGAATTGCTTGAACCTGGGAGACGGAGGTTGCAGTGAACTGAGATTGCATCATTGCA CTCCAGCTTGGGTGACATAGCGAGACTCCATCTAAAAACAAAAACAAAAAACAGTACAGGT TTATTATCTGTGGTCCTGTAGGTCAGAAGTCCAAAATGAGTTTCACTGGGCTGAAGTCAGGG TGTCATCCTGGAGCGTTCCTTCTGGGGGATTCAAGGGATAATCCATTCCCTGGTCTTTTCCA GCTTCTAGGGGTCACTGGCACCCCTTAGCTCGTGGCCCTCCCTCTGTCTGCGGAGCCAGCCA CATAGCACCCTCAGACCTCTCTCTGACTCTGCTTCTGTCTTCATATCTCCGCCTCTGTTTTTGT TCCCCTCTTCTATTTTAAGGGCCCCTGTGGCTATACTGAGCCTACTCAGATGGTCCAGGATA

[0860] GTCTTCCCAGCTCACAATCCTTAAAATCCTTCTTAACCTCTTCACGTCCCTTTTGCCCTGTGA

[0861] TTCTGGGAATTAGAACATGGGCCTCTTTGGGCATGTGTGTGTTGGTGGGGGCGTAATTTGCC

[0862] TTCCACACCAGGATCTGTCCCCGCTGCAACAGGGGATGTTATTCAAGTAATTATTCAGTTAC

[0863] CTTCTGTCTTCCTTGGTAGATGTACTCGGGAGAGGAGACGTTTTCTGTCTTGTGAACTGTCGT

[0864] TTGCCAAGCACCCGGCCTGGCACAGCGTTCAGGTGTTCCGTGTCCCCTTCTCCTTTCCCTCTC

[0865] CCCATCTCACCCCTGGTCTGGGTGTGGGGGTGCAGCTGTGAGTAGCACAGACAGGACCCCT

[0866] GCCCCGTGGCGTGGACATTCTTGTTGGGGCCGGGTCAAAGAGACAGTCAACAGGTGAACTC

[0867] TGTCCTGCGTCTAGCGGTGCTAAGTCAACACCAAGAAGAAAAAGAAAGGGGGTGGCGGTG

[0868] AGGCAGCATTAGGTGCTGATTTAACTAAGGCACGTGGATACTCGGGGGGCCCGCTCAGAGG

[0869] AGGCCTGGGTGGGCAGCCCACGCGAGCAGCTGCAGGACCTCCCCCTCGCCCTCCCCAGGTG

[0870] GGCTACGAACTGAAGGATGAGATCGAGCGCAAATTCGACAAGTGGCAGGAGCCGCCGCCT

[0871] GTGAAGCAGGTGAAGCCGCTGCCTGCGCCCCTGGATGGACAGCGGAAGAAGCGAGGCGGC

[0872] CGCAGGTGAGGGGCCCTGGGGGTCCGGTAGGCATGGGGGTCATGGAGGGGAGAAGCCGGC

[0873] GTCCTCCTCCCAGCCGACTCCCTGGCGCCGCCCACCCACCCGTCCCCAGGTACCGCAAGATG

[0874] AAGGAGCGGCTGGGGCTGACGGAGATCCGGAAGCAGGCCAACCGTATGAGCTTCGGAGAG

[0875] GTCAGACTCCCAGAGCGCCCTCCTCAACCCCACAGCCAGCCAGCCGCCACCGCCCTCTGCCT

[0876] CCTGCCACCGCCCCTCCTCTCGTCCTGTGGCCCTGGCTCATGTCTAGGGCGCTGCCCCAGCC

[0877] TCCCCCCCCCCGGCCTCTATTCTCGTTTCCATCCGTTCAGCCCCAAAGCGACCCTCGCGACCC

[0878] TTGGAGCCTGTGTCTCCGCTGCTTAGAGCCCCCGCGGCTTCCCATCGCCCCGGGCTCCTTGG

[0879] CCGGTTCCTCCCTGCCCAGAGGCTCCTTAGTGCCCTGCTGCACGGCCGCCCCGTCCCTGGGC

[0880] CCCGCCAGTCTCCTCTGTTATCCCAGCGTCATCCCCTTGGTCCTGCAGGACCGAACTCAGAG

[0881] GCCACCTCATCCTATTAAACCTGTTCTGGTTCCTGACATCCCCCGACCCACACGAGTAAGGA

[0882] AGGAATGGCCTCCCAACTCTGAGCTCACAGAGCAGTGCTGGGACCGGGCCCCTCTCAGGCT

[0883] CCCCAGCATCCCCCGCGTGTGTGGGCCCCCAGGCCTCAGCCGGGCCGAGTGGGTACCGGAG

[0884] CAGGTGCCCGTGGGACCGGCCGGCTGGTGACCGCTGGGCTTCGGGCTGGTGGAGGGGGTGC

[0885] CTCGGTGGCTGGAGGGCAGGGCCTGGTCGCTGAACTGCAGGGCGCCTCCTCTCCCCCCTAG

[0886] ATCGAGGAGGACGCCTACCAGGAGGACCTGGGATTCAGCCTGGGCCACCTGGGCAAGTCGG

[0887] GCAGTGGGCGTGTGCGGCAGACACAGGTAAACGAGGCCACCAAGGCCAGGATCTCCAAGA

[0888] CGCTGCAGGTATGGGCCAGACCCAGGTGGGGCTGGGGACCGAGGGACACAAGGTGGGGGG

[0889] AGCCCAGATCGCAGCCTCCCTGTCCTCCCCACAGCGGACCCTGCAGAAGCAGAGCGTCGTA

[0890] TATGGCGGGAAGTCCACCATCCGCGACCGCTCCTCGGGCACGGCCTCCAGCGTGGCCTTCA

[0891] CCCCACTCCAGGTACCTCCCCTGGGCCGGCTCTGTCCCCAGCCCTGAGACCTTGGCAAGGCC

[0892] CCTTGCCCTCTGCCCCTGTGAAGAAGGCCAGGATGAGTCTCCTCATGGGGCTGTTGTGGAGG

[0893] GTGTGGTGACGAGGTATGCAGAGGACGTAGACAGCTCCTGGCACACAGGAAGAGGTTAGC

[0894] AGAGACGAGAGCCCAGCGCTGAGCAGTCCTCGTGAGCACGCACTGCTTTAGAACCAGGCCC

[0895] ACAGCTGTGTTCAGGGCACCCAGTTCCTCTGTCGGGCTGTGAGCGGGTAACACTGCTCAGCC

[0896] TCCAGGCCCTCCAGTTCAAAACGGCCAGGACGGTTAAGGTAACCTCAGGACCCCACTCGAG

[0897] AAAGTTCCCGGCTAGGCGGGCTTGGATGTCAAGTGTGGGTCCAGGCCCCAGCCAGTCAGCA

[0898] GTGAGCAGCGTGGAGCATGGCAGTCACCGCATCGTCGGAGCCTCGGTTTACCATCCACAGA

[0899] GCAGGGCGAGCCTGCACCACGGAGGCGAGACAGCAGCGAGCTCATCTGCCCAGTCAGCGG

[0900] GTGTCTACGCAGCACCTGCTGAGTTCTGTCAGTGTTCCCGGCTCTGGGGATGAAGCAACGAA

[0901] TGAGAGACAAGTCTTACCTTCTTGGAGCCAGTGGGTGGCCGGGCGCAGACAGCTCAGTAAG

[0902] ATGTCCAGTGTAGGAGAAGGCAGAAATGCCAGGCCGGGCGCAGACAGCTCAGTAAGATGT

[0903] CCAGTGTAGGAGAAGGCAGAAATGCCAGGCCGGGCGCAGACAGCTCAGTAAGATGTCCAG

[0904] TGTAGGAGAAGGCAGAAATGCCAGGCCGGGCGCAGACAGCTCAGTAAGATGTCCAGTGTA

[0905] GGAGAAGGCAGAAATGCCAGGCTGGGCGCAGACAGCTCAGTAAGATGTCCAGTGTAGGAG

[0906] AAGGCAGAAATGCCAGGCCGGGCGCAGACAGCTCAGTAAGATGCCCAGTGTAGTAGAAGG

[0907] CAGAAATGCCAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGA

[0908] GGCAGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACACGGTGAAACCCCGT

[0909] CTCTACTAAAAATACAAAAACTTAGCCGGGCGTGGTGGCGGGCGCCTGTAGTCCCAGCTAC

[0910] TTGGGAGGCTGAGGCAGGAGAATGGCGTGAACCCGGGAGGCGGAGCTTGCAGTGAGCCGA

[0911] GATCGCGCCACTGCACTTCAGCCTGGGCGACAGAGCCAGACTCTGTCTCAAAAAAAAAAAA

[0912] AAGAAGGCAGAAATGCCAGGGAGGGGAGGAGGTGGAAGGTAGGAGGTGGGACAGGGGAG

[0913] GCTCTCGTTTCGGAGCAGCCAGGGAGGGCCTCTTTGAGAAGATGAGGCCAGTGGCTGTGCC

[0914] TTTCCAAGCCTCCCCTCCTCCATCATGAGGTGCTCAGGACTGAAAAGAACGCACAGGAAGC ACTTGGCACTGGGCTCACCATTAGAGCCCAATGACTGGGTCCTGTTATTATTTTTAGAGACG

[0915] GGGGCTCGCTCTGTTGCCTTGAAAATATTTAGGAAGTGCCAGCCAGGTGTTGGCTCCCATTG

[0916] CTGCCACTATGATCGTCAGTGGTGTTGGTGTGATTTGTGCTAGGACCTCGGGCCAGCCATGT

[0917] CCCCCAGGGACTCAGTTTCCTTATGCAGAAACTGGGCAGGATTGGCTGTCCTCAAGCATTGG

[0918] TTGTTTTTAGCACCCCTGAGGAACTTCGTACAAATCCAGGCGCCCTGGTTCCTCCCCACCCT

[0919] CTCCCTCTAGACCCACTGAGTCAGAATCTCCCAAGACAGGGCAACTCCAGGGACAGGCAAA

[0920] CTGTCTCATGCCCACCAAGGCCTGAGTGCCATGGGGAAGGGCCTGGGGGGCTCTGATGGGT

[0921] CACAGTTGGGGCCTTCTCCTCACCTAACCCATCATCCTCTCTCCCTCACCTGCCCAGGGCCTG

[0922] GAGATTGTGAACCCACAGGCGGCAGAGAAGAAGGTGGCTGAGGCCAACCAGAAGTATTTC

[0923] TCCAGCATGGCTGAGTTCCTCAAGGTCAAGGGCGAGAAGAGTGGCCTTATGTCCACCTGAA

[0924] TGACTGCGTGTGTCCAAGGTGGCTTCCCACTGAAGGGACACAGAGGTCCAGTCCTTCTGAA

[0925] GGGCTAGGATCGGGTTCTGGCAGGGAGAACCTGCCCTGCCACTGGCCCCATTGCTGGGACT

[0926] GCCCAGGGAGGAGGCCTTGGAAGAGTCCGGCCTGGCCTCCCCCAGGACCGAGATCACCGCC

[0927] CAGTATGGGCTAGAGCAGGTCTTCATCATGCCTTGTCTTTTTTAACTGAGAAAGGAGATTTT

[0928] TTGAAAAGAGTACAATTAAAAGGACATTGTCAAGATCTGTCCTTGGGGAGTGATCATTTTTC

[0929] AAACAGCCGGGGCAACTAGAAGAATCAGAGCTGTGGAGCTTTGAGAAAAGAGCTTGGCCC

[0930] TCGGGTCCAAGCGGTGTCTAGGCCCACTCCCTTCCCCGTTACTTTCTCGTCATGGGATCCCA

[0931] GAAGGAAAAAGCCCTCTCCAACCCCCTGGAGAGCCGCAGTCACTTTGATAGCAAATGATGT

[0932] GGCTGCCAACAGCCGCAGATCTCAGCGCAGGCCGACCGGGATTGCTGTCCACCTCAGGCCA

[0933] GCCTCCTCACCTTTCCAAGCCTCCACACCTACGCCCAGGTGCCCAGGACTGGAAAGAATGC

[0934] ACAGAAAGCACTTAGCATGGGACTTGCCATCAGCGCCCTATAACCAGGTCCTGTTATGATTG

[0935] GGTTTTTTAGAGACGGGGTCTCTGTTGCCCAGGTTGGAGTACAGTGATGCGATGAAGCTCAC

[0936] TAAAGCCTCAAACTCCTGGGCTGGGATTACAGGCATGAACCAGCACAGCTGGCCTCCTGGT

[0937] TAATTTAAATTTTTTTTTTTTTTCTGAGGTGGAGTCTCGCTCTGTTGCCCAGGCTAGAGTACA

[0938] GTGGTGCAATCTTGGCTCACTGCAACCTCTACCTCCCGGGTTCAAGCAATTCTCCTGCCTCA

[0939] GCCTCCTGAGTAGCTGGGATTACAGGCATGTGCCACCATGTCCCGCTAATTTTTATAGTTTTT

[0940] AGTAGAGACAGGGTTTCGCCATGTTGGTCAGGCTGTTCTCGAACTCCTGACCTCATGATATG

[0941] CCCACCTCAGCCTCCCAAAGTGCCAGGATTACAGGTGTGAGCCACCACCCCAGCCCCATTTT

[0942] TAAATTGTTTATAGACAGGGTCGTGCTCTATTACCCAGGCTGGGCTTGAACTCCTGTGCTCA

[0943] AGTGAGCTTTCCACCTCAGCCTCCCTAAGTGTTGAGATTACAGGCTTGAGCCGCTGTGTCTG

[0944] GCCTCTTATTATTATTATTATTTTTTTTTTTGAGACAGAATCTCACTCTGTTGCCCAGGCTGG

[0945] AGTGCAGTGGGATGATCCTGGCTCATGGCAACCTCCACCTCCCGGGTCCAGGTGATTCTCCT

[0946] GCCTCAGTCTCCTGAGTAGCTGGGATTACAGGCGCCCATGGGTTTTGTTTGTTTGTTTGTTTG

[0947] TTTGTTTGTTTGTTTTTCAGACGGAGTCTTGCTCTGTCACCCAGGCTGGAGTGCAATGACATG

[0948] GTCTTGGCTCACTGCAAACTCCGCCTCCCAGGTTGAAGTGATTCTCCTGCCTCAGCCTCCCG

[0949] AATAGCTGGGATTACAGGCGCCCGCCACCACGCCTGGCTAATTTTGTATTTTTAGCAGAGAC

[0950] GGGGTTTCACCATTTGGGCCAGGCTGGTCTTGAATTGCTGACCTTGTGATCTGCCCGCCTCG

[0951] GCCTCCCAAAGTGCTGGGATTACGGGTGTGACCCACCGCGCCCGGCCGAGATGGGGTTTTA

[0952] CCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAACTAATCCGCCTGCCTCGTCTCCCA

[0953] AAGTGCTGGGATTACCCTGTGCCTGGCCCAGCCTCTTATTTATAACCAGTGTTGAGGGACTG

[0954] TGTGGAGCCGGGCACAGGCGAAGCAGGCAGGCTTCCTGCCCTGGTAGGACCTGGTTGCTAT

[0955] AAAAGTCCTGCCAGGTGAGCAGAAGGAGCACACTTCCCCTCCCCTGACCTCCAGTCACTGA

[0956] GTCTCGGGAACCGGGGCTCGGCCAGGAGCGCCTTTACTTGGACTGAGGGGAATGTGGCCTG

[0957] CAGACAGTCAGGAGAGTTTCCAGGGGACAGCAGGGGCTGTCCTAGCGGGTGGCATGAAAC

[0958] CGTCTCCCTGGAGAGGTTAAGGAAGAGCAACTCCAGGGGTTCCATTTACTATGTGCTCCGG

[0959] AGCTGGGCTACACGGTGGTACTAAGGAGGCAGCGCTAGTCACCTGACCTACAAGGTCGGGC

[0960] TTCTGTTAGTTACCTAAGAGATGTTACCAGGACAAGCAGCAGCCTGGTGGGAAGATGATGC

[0961] CTCCAGGTCTCTACCTCCTCTCTCTCTCCCTCCTTCTCTCCACCTCCCCTCTCTCTCCCTCCCT

[0962] CTCTCCACCTCCCCTCTCTCTCTTCCTCCCTCTCCACCTCCCCTCTCTCTCTCCCTCCCTCTCTC

[0963] CACCTCCCCTCTCTCTCTCCCTCCCTCTCCACCTCCCCTCTCTCCACCTCCCCTCACTCCACCT

[0964] TCCCTCTCTCCACCTCCCCTCCCTCTCTCCACCTTCCCCTCTCTCCCTCCCTCCCTCTCTCCAC

[0965] CTTCCCTCTCTCCTCCCCTCTCCCCCTCCCTCCCTCTCTCCACCTTCCCTCTCTCCACCTCCCC

[0966] TCTCCCCCTCCCTCCCTCTCTCCACCTCCCCTCTCCCTCCCTCTCTCTCCTCCCCTCTCCCTCC

[0967] CTCCACCTCCCCTCCCTCTCTCCACCTCCCCTCCCTCTCTCCCTCCCTCCCTCCCTCTCTCCAC

[0968] CTTCCCTCTCCCTCCCTCCACCTTCCCTCTCCCTCCCTCCACCTTCCCTCTCCCTCCCTCTCCA

[0969] CCTTCCCTCTCTCCTCCCCTCTCCCTCCCTCTCTCCACCTCCCCTCTCTCCCTCCCTCCCTCCC TCTCTCCACCTTCCCTCTCTCCCTCCCTCTCTCCACCTTCCCTCTCTCTCTCTCCCTCCCTCTCT

[0970] CCAGCTCATGCTATCTGGGTCTCCCTCTGACTTTCTAGGTCCTGTCTGAGATTTTGCTCTTTC

[0971] TGTTCCCCTCTCTGGGCCTCCCCGTCACCACTCTGTGTATCTCTGGATCCCTGTCCTTCAACC

[0972] CAGAGCTCTGTCTCTGGACCTCAGTGGCAATCTCTAAATCTCTCTCCTTCCTCAAGTCAAAA

[0973] AGTCGACACACTCAGGAGGTTCCCTTGAGTGGCTGAACTACCCCAGGTTGTATAACTCAAGT

[0974] CTGTTTTCTCAATGTTATCCCTGACCCTCTGGGTCAACCCTGTTTGAAAATGACAACCTTTGC

[0975] TGATCTCTACATACTGGTCTGCCAGGGAAGGACCCGTGGTCCACAACCCTGTTCAGAATCCC

[0976] CCATCTCCCTTGGCCAAAATATCCGGCATCTACCAATGGGGCTGTGGCATGAGGGTGTCAAT

[0977] CTCAGGAAAGGAATCTTGAGTCGCCTGGGCCTGCAGCCCTCGTACTTTCAGAACAGAGGTT

[0978] CTCAGAATTTAATGCGCTTCAGAATTACACTGAGGACTTGTTAAAACATAGTTGCTGGGCCC

[0979] AGAGTTTCTGATTCAGTCTAGGGTGGGGCTCAAAAATGTGCCTTTCAAACAAGTTCCCAGGT

[0980] GATGGGTACGTGCCTGACCCAAGGCCACATTTCAGAAGCACTGCTCTAGAAAAGAAGACTC

[0981] TGTAAGCGGCTCTTACGCTGGGCGCGGTGGCTCACGCCTGTAATCCCAGCTACTTGGGAGGC

[0982] TGAGGTGGGAGAATGGCTTGAACCTGGGAGGCAGAGGTTGCAGTGAGCCGAGATGGCGCC

[0983] CCTGCACTCCAGCCTGGGTGAGAGAGACACTGGCTCCCACCTCAAGATCGTTTTAGTTGGTC

[0984] CAGTGTAAGCCTGGGTATCTGGACTTTTTTATTTTTTATTTTTATTTTTTGAGACGGCGTCTTG

[0985] CTCTGTCACCCAGGCTGGAGTGCAATGGCGCAATCTCGGGTCACTGCAACCTCTGCCTCCCA

[0986] GGTTCAAGTGATTCTCCCGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCACATGCCACCA

[0987] TGCCCAGCTAATTTTTGTATTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTTT

[0988] TGAACTCCCTACCTCAGGTGATCCGCCCACCTCGGCCTCTGAGAGTGCTGGGATTACAGGTG

[0989] CAATGGCGCAATCTAGGCTCACTGCAGCCTCTGCCTCCCGGGTTCAAGTGATTCTCCCGGCC

[0990] CGGCCTGGCCTCTAATTTAAAAAAAATTTTTTTTTTTTAAAGTTCCTCAGGTAGGCCAGGCG

[0991] CAGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGACTGAGGCGAGCGGATCACCTGAGG

[0992] TCAGGAGTTCGACACCAGCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAA

[0993] AATTAGTCGGGCGTGGTGGCGGGCGCCTGTAATCCCAGCTACTCGGGAGGCTGAGGCGGGA

[0994] GAATCACTTGAACCCCGGGAGGCAGAGGCTGCAGTGAGCCTAGATTGTGCCACTGCTCTCC

[0995] AGCCTGGGGGACAAGAGCAAGTCTTCGTCTCAACAACAACAACAATAACAACAAGTTCCTC

[0996] AGGTGACTCTGATGTGCAGCCAAGTTGGAAAGTCATCGCTAGATCCGCGGTGTGCAAAGTG

[0997] AACTGCGGACCGTGGACTGCGGCACTTGTTAGAAAAGCAGAATTTGCATTTTAACACATTCC

[0998] TAGGTGATTCCGGAGATGTCTGAGAAGCGATACTTTGTCCAGGGGCCACAGTTTGAATAGC

[0999] AAAGCTCTAGAACAATAACTCTAGGCTTCATTCCCGTTGTCTGTGTGTGGGCCTACGAATAT

[1000] GCATTTTCGCAAGCATTCCTCCTCCCCCTTGCCTCAGACCATTCTGATGCGGGTGGTGCTGA

[1001] ACGGCTCCATCCTCCTTCACGTTCACCTCTCCCTGGGATTTATCTTACTTTCCACCACCTAGA

[1002] CAGGAAGGGGCGAATCTGGCTTCCCATCTCGGTTGTGTGACCCTGGGCAAATGCCTCCCAGT

[1003] TCGTGGAAGTCTCAGTGTCTAGTTAAGTTTTCAATCACAAGTCATTCCTCACATTCATTCATC

[1004] TATTCCTTTGACAAATGGTTACTGACTACTTCCTGCGTGCTAAGTGCTGGAGATGCAAAATC

[1005] CAGACAGGGAAACCGAATAATTACGAAAATGACGGTAGACGTACAAAAATAAATCCTAAC

[1006] GAACAAGGCGCGCAGGAGCGCTCCGCCCGGGAGGGAGGTCAGGGAAGTTTTCTCTCCAAG

[1007] AAGACAACAGAGCTGAGACCTGAAACGAGCAGGCATTAGGGAGCCACCCGTCTCCTCTGTA

[1008] CCTTCTGCAGCGTCCTCAACACACTAAGGAAGCGGAGACGCAGAGGAGAATGACTGTCCCA

[1009] CCATCTGGTCGCCTAACCAGGCAGGGGCAGGACAAAAACTCCATGCCTCACGCTTCCCAAC

[1010] CAATTCTGCTATGCACGGTGCCAGAGACTTAAAGCAGTGTCTCTGGTCCCTTTCTTCTTTCAC

[1011] TCAGCAAATAATGAATTTCAGAGATGTGCCAACATAGAGGCACTTGGAGAAAGACGAGGC

[1012] AGCTGAGAGGGAAGCTGCTTACCTGGCCGGGACGCAACGGTTGCGACCAAGTCCCACTTCT

[1013] GCCAGCTACATACACCCTCTTTCACACGCTCTACGAGCAGCTACCGCCCACTCGCCACGCTA

[1014] TTGGTCCAACTAGCATGAATGATAACTTTTAGGGCCAACGAAGAAAAAGGGGTGGACTTTC

[1015] TTGCCCAGCTCCTCCCACTTGGCCCTGTGGCTGTTTTGATTGGCAGATGACTTCGGCTCGGCC

[1016] CCCGCTTTAAAGGCACCTGTCTGTCTCCCATTAGGTACGCGGCCCCTAACGCCCACACTCCA

[1017] TGCCTTCCTCCGCTTTCCCCACCCACTTCCAGGACCAACCAATGACTTCAAGGCAGAATATG

[1018] CCCCCGCAACCAATTAAAAAGAGCTCTAAACTTGACGGACGACTTCCCGCCCCTGGACTGT

[1019] CGTAGCTCCTCCCCCAGACCAATTGTTTTAAGAGAGGGGGGCGGATACATCCAATCAGCAC

[1020] GACACAGGTCTCTTGATTGACGTTCGGGTCCTCGCGCTGGCGTGTTGTGCCCTGAGGCGGGA

[1021] GGAGGAGGAGGAGCGGGGAGGAAAACCTGAGCCAATCCTAGCAGCCTGCGCGGGAGGCCA

[1022] ATCGAACGCCGCGCCTTGGAGCGATCACCCAATCCGCGAAAGGGGGCAGGGCGCATCCCTG

[1023] CCAGGAACCAATAGAAAGCCTCCAAGGGTCAGGAGCGACGTTCAGCGGGAGCAATGACTG

[1024] GCCTATATTCGGGACTCGGGGGCGGGTCGGCGCC SEQ ID NO: 2 PRPF31 antisense strand

[1025] GGCGCCGACCCGCCCCCGAGTCCCGAATATAGGCCAGTCATTGCTCCCGCTGAACGTCGCTC

[1026] CTGACCCTTGGAGGCTTTCTATTGGTTCCTGGCAGGGATGCGCCCTGCCCCCTTTCGCGGAT

[1027] TGGGTGATCGCTCCAAGGCGCGGCGTTCGATTGGCCTCCCGCGCAGGCTGCTAGGATTGGCT

[1028] CAGGTTTTCCTCCCCGCTCCTCCTCCTCCTCCCGCCTCAGGGCACAACACGCCAGCGCGAGG

[1029] ACCCGAACGTCAATCAAGAGACCTGTGTCGTGCTGATTGGATGTATCCGCCCCCCTCTCTTA

[1030] AAACAATTGGTCTGGGGGAGGAGCTACGACAGTCCAGGGGCGGGAAGTCGTCCGTCAAGTT

[1031] TAGAGCTCTTTTTAATTGGTTGCGGGGGCATATTCTGCCTTGAAGTCATTGGTTGGTCCTGG

[1032] AAGTGGGTGGGGAAAGCGGAGGAAGGCATGGAGTGTGGGCGTTAGGGGCCGCGTACCTAA

[1033] TGGGAGACAGACAGGTGCCTTTAAAGCGGGGGCCGAGCCGAAGTCATCTGCCAATCAAAAC

[1034] AGCCACAGGGCCAAGTGGGAGGAGCTGGGCAAGAAAGTCCACCCCTTTTTCTTCGTTGGCC

[1035] CTAAAAGTTATCATTCATGCTAGTTGGACCAATAGCGTGGCGAGTGGGCGGTAGCTGCTCGT

[1036] AGAGCGTGTGAAAGAGGGTGTATGTAGCTGGCAGAAGTGGGACTTGGTCGCAACCGTTGCG

[1037] TCCCGGCCAGGTAAGCAGCTTCCCTCTCAGCTGCCTCGTCTTTCTCCAAGTGCCTCTATGTTG

[1038] GCACATCTCTGAAATTCATTATTTGCTGAGTGAAAGAAGAAAGGGACCAGAGACACTGCTT

[1039] TAAGTCTCTGGCACCGTGCATAGCAGAATTGGTTGGGAAGCGTGAGGCATGGAGTTTTTGTC

[1040] CTGCCCCTGCCTGGTTAGGCGACCAGATGGTGGGACAGTCATTCTCCTCTGCGTCTCCGCTT

[1041] CCTTAGTGTGTTGAGGACGCTGCAGAAGGTACAGAGGAGACGGGTGGCTCCCTAATGCCTG

[1042] CTCGTTTCAGGTCTCAGCTCTGTTGTCTTCTTGGAGAGAAAACTTCCCTGACCTCCCTCCCGG

[1043] GCGGAGCGCTCCTGCGCGCCTTGTTCGTTAGGATTTATTTTTGTACGTCTACCGTCATTTTCG

[1044] TAATTATTCGGTTTCCCTGTCTGGATTTTGCATCTCCAGCACTTAGCACGCAGGAAGTAGTC

[1045] AGTAACCATTTGTCAAAGGAATAGATGAATGAATGTGAGGAATGACTTGTGATTGAAAACT

[1046] TAACTAGACACTGAGACTTCCACGAACTGGGAGGCATTTGCCCAGGGTCACACAACCGAGA

[1047] TGGGAAGCCAGATTCGCCCCTTCCTGTCTAGGTGGTGGAAAGTAAGATAAATCCCAGGGAG

[1048] AGGTGAACGTGAAGGAGGATGGAGCCGTTCAGCACCACCCGCATCAGAATGGTCTGAGGC

[1049] AAGGGGGAGGAGGAATGCTTGCGAAAATGCATATTCGTAGGCCCACACACAGACAACGGG

[1050] AATGAAGCCTAGAGTTATTGTTCTAGAGCTTTGCTATTCAAACTGTGGCCCCTGGACAAAGT

[1051] ATCGCTTCTCAGACATCTCCGGAATCACCTAGGAATGTGTTAAAATGCAAATTCTGCTTTTC

[1052] TAACAAGTGCCGCAGTCCACGGTCCGCAGTTCACTTTGCACACCGCGGATCTAGCGATGACT

[1053] TTCCAACTTGGCTGCACATCAGAGTCACCTGAGGAACTTGTTGTTATTGTTGTTGTTGTTGAG

[1054] ACGAAGACTTGCTCTTGTCCCCCAGGCTGGAGAGCAGTGGCACAATCTAGGCTCACTGCAG

[1055] CCTCTGCCTCCCGGGGTTCAAGTGATTCTCCCGCCTCAGCCTCCCGAGTAGCTGGGATTACA

[1056] GGCGCCCGCCACCACGCCCGACTAATTTTTGTATTTTTAGTAGAGACGGGGTTTCACCATGT

[1057] TGGCCAGGCTGGTGTCGAACTCCTGACCTCAGGTGATCCGCTCGCCTCAGTCTCCCAAAGTG

[1058] TCTTTGTGTGTATTTTAAACAATGTGACGGATGGGACGCCACGAGCCTCGGCGGGCCCCTGGGGGCACGTAAACCTTCGAACTGTGGAAAACCTCTCTAGGAAGAAAGGAACAAGAAAGAGA

[1059] CTGCAGTGAGCCTAGATTGCGCCATTGCACCTGTAATCCCAGCACTCTCAGAGGCCGAGGT

[1060] GGGCGGATCACCTGAGGTAGGGAGTTCAAAACCAGCCTGGCCAACATGGTGAAACCCCGTC

[1061] TCTACTAAAAATACAAAAATTAGCTGGGCATGGTGGCATGTGCCTGTAATCCCAGCTACTCG

[1062] GGAGGCTGAGGCGGGAGAATCACTTGAACCTGGGAGGCAGAGGTTGCAGTGACCCGAGAT

[1063] TGCGCCATTGCACTCCAGCCTGGGTGACAGAGCAAGACGCCGTCTCAAAAAATAAAAATAA

[1064] AAAATAAAAAAGTCCAGATACCCAGGCTTACACTGGACCAACTAAAACGATCTTGAGGTGG

[1065] GAGCCAGTGTCTCTCTCACCCAGGCTGGAGTGCAGGGGCGCCATCTCGGCTCACTGCAACCT

[1066] CTGCCTCCCAGGTTCAAGCCATTCTCCCACCTCAGCCTCCCAAGTAGCTGGGATTACAGGCG

[1067] TGAGCCACCGCGCCCAGCGTAAGAGCCGCTTACAGAGTCTTCTTTTCTAGAGCAGTGCTTCT

[1068] GAAATGTGGCCTTGGGTCAGGCACGTACCCATCACCTGGGAACTTGTTTGAAAGGCACATTT

[1069] TTGAGCCCCACCCTAGACTGAATCAGAAACTCTGGGCCCAGCAACTATGTTTTAACAAGTCC

[1070] TCAGTGTAATTCTGAAGCGCATTAAATTCTGAGAACCTCTGTTCTGAAAGTACGAGGGCTGC

[1071] AGGCCCAGGCGACTCAAGATTCCTTTCCTGAGATTGACACCCTCATGCCACAGCCCCATTGG

[1072] TAGATGCCGGATATTTTGGCCAAGGGAGATGGGGGATTCTGAACAGGGTTGTGGACCACGG

[1073] GTCCTTCCCTGGCAGACCAGTATGTAGAGATCAGCAAAGGTTGTCATTTTCAAACAGGGTTG

[1074] ACCCAGAGGGTCAGGGATAACATTGAGAAAACAGACTTGAGTTATACAACCTGGGGTAGTT

[1075] CAGCCACTCAAGGGAACCTCCTGAGTGTGTCGACTTTTTGACTTGAGGAAGGAGAGAGATT

[1076] TAGAGATTGCCACTGAGGTCCAGAGACAGAGCTCTGGGTTGAAGGACAGGGATCCAGAGAT

[1077] ACACAGAGTGGTGACGGGGAGGCCCAGAGAGGGGAACAGAAAGAGCAAAATCTCAGACA GGACCTAGAAAGTCAGAGGGAGACCCAGATAGCATGAGCTGGAGAGAGGGAGGGAGAGA

[1078] GAGAGAGGGAAGGTGGAGAGAGGGAGGGAGAGAGGGAAGGTGGAGAGAGGGAGGGAGG

[1079] GAGGGAGAGAGGGGAGGTGGAGAGAGGGAGGGAGAGGGGAGGAGAGAGGGAAGGTGGA

[1080] GAGGGAGGGAGAGGGAAGGTGGAGGGAGGGAGAGGGAAGGTGGAGGGAGGGAGAGGGA

[1081] AGGTGGAGAGAGGGAGGGAGGGAGGGAGAGAGGGAGGGGAGGTGGAGAGAGGGAGGGG

[1082] AGGTGGAGGGAGGGAGAGGGGAGGAGAGAGAGGGAGGGAGAGGGGAGGTGGAGAGAGG

[1083] GAGGGAGGGGGAGAGGGGAGGTGGAGAGAGGGAAGGTGGAGAGAGGGAGGGAGGGGGA

[1084] GAGGGGAGGAGAGAGGGAAGGTGGAGAGAGGGAGGGAGGGAGAGAGGGGAAGGTGGAG

[1085] AGAGGGAGGGGAGGTGGAGAGAGGGAAGGTGGAGTGAGGGGAGGTGGAGAGAGGGGAGG

[1086] TGGAGAGGGAGGGAGAGAGAGAGGGGAGGTGGAGAGAGGGAGGGAGAGAGAGAGGGGA

[1087] GGTGGAGAGGGAGGAAGAGAGAGAGGGGAGGTGGAGAGAGGGAGGGAGAGAGAGGGGA

[1088] GGTGGAGAGAAGGAGGGAGAGAGAGAGGAGGTAGAGACCTGGAGGCATCATCTTCCCACC

[1089] AGGCTGCTGCTTGTCCTGGTAACATCTCTTAGGTAACTAACAGAAGCCCGACCTTGTAGGTC

[1090] AGGTGACTAGCGCTGCCTCCTTAGTACCACCGTGTAGCCCAGCTCCGGAGCACATAGTAAA

[1091] TGGAACCCCTGGAGTTGCTCTTCCTTAACCTCTCCAGGGAGACGGTTTCATGCCACCCGCTA

[1092] GGACAGCCCCTGCTGTCCCCTGGAAACTCTCCTGACTGTCTGCAGGCCACATTCCCCTCAGT

[1093] CCAAGTAAAGGCGCTCCTGGCCGAGCCCCGGTTCCCGAGACTCAGTGACTGGAGGTCAGGG

[1094] GAGGGGAAGTGTGCTCCTTCTGCTCACCTGGCAGGACTTTTATAGCAACCAGGTCCTACCAG

[1095] GGCAGGAAGCCTGCCTGCTTCGCCTGTGCCCGGCTCCACACAGTCCCTCAACACTGGTTATA

[1096] AATAAGAGGCTGGGCCAGGCACAGGGTAATCCCAGCACTTTGGGAGACGAGGCAGGCGGA

[1097] TTAGTTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACATGGTAAAACCCCATCTCGGCCG

[1098] GGCGCGGTGGGTCACACCCGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCAGATCACAA

[1099] GGTCAGCAATTCAAGACCAGCCTGGCCCAAATGGTGAAACCCCGTCTCTGCTAAAAATACA

[1100] AAATTAGCCAGGCGTGGTGGCGGGCGCCTGTAATCCCAGCTATTCGGGAGGCTGAGGCAGG

[1101] AGAATCACTTCAACCTGGGAGGCGGAGTTTGCAGTGAGCCAAGACCATGTCATTGCACTCC

[1102] AGCCTGGGTGACAGAGCAAGACTCCGTCTGAAAAACAAACAAACAAACAAACAAACAAAC

[1103] AAACAAAACCCATGGGCGCCTGTAATCCCAGCTACTCAGGAGACTGAGGCAGGAGAATCAC

[1104] CTGGACCCGGGAGGTGGAGGTTGCCATGAGCCAGGATCATCCCACTGCACTCCAGCCTGGG

[1105] CAACAGAGTGAGATTCTGTCTCAAAAAAAAAAATAATAATAATAATAAGAGGCCAGACAC

[1106] AGCGGCTCAAGCCTGTAATCTCAACACTTAGGGAGGCTGAGGTGGAAAGCTCACTTGAGCA

[1107] CAGGAGTTCAAGCCCAGCCTGGGTAATAGAGCACGACCCTGTCTATAAACAATTTAAAAAT

[1108] GGGGCTGGGGTGGTGGCTCACACCTGTAATCCTGGCACTTTGGGAGGCTGAGGTGGGCATA

[1109] TCATGAGGTCAGGAGTTCGAGAACAGCCTGACCAACATGGCGAAACCCTGTCTCTACTAAA

[1110] AACTATAAAAATTAGCGGGACATGGTGGCACATGCCTGTAATCCCAGCTACTCAGGAGGCT

[1111] GAGGCAGGAGAATTGCTTGAACCCGGGAGGTAGAGGTTGCAGTGAGCCAAGATTGCACCA

[1112] CTGTACTCTAGCCTGGGCAACAGAGCGAGACTCCACCTCAGAAAAAAAAAAAAAATTTAAA

[1113] TTAACCAGGAGGCCAGCTGTGCTGGTTCATGCCTGTAATCCCAGCCCAGGAGTTTGAGGCTT

[1114] TAGTGAGCTTCATCGCATCACTGTACTCCAACCTGGGCAACAGAGACCCCGTCTCTAAAAA

[1115] ACCCAATCATAACAGGACCTGGTTATAGGGCGCTGATGGCAAGTCCCATGCTAAGTGCTTTC

[1116] TGTGCATTCTTTCCAGTCCTGGGCACCTGGGCGTAGGTGTGGAGGCTTGGAAAGGTGAGGA

[1117] GGCTGGCCTGAGGTGGACAGCAATCCCGGTCGGCCTGCGCTGAGATCTGCGGCTGTTGGCA

[1118] GCCACATCATTTGCTATCAAAGTGACTGCGGCTCTCCAGGGGGTTGGAGAGGGCTTTTTCCT

[1119] TCTGGGATCCCATGACGAGAAAGTAACGGGGAAGGGAGTGGGCCTAGACACCGCTTGGAC

[1120] CCGAGGGCCAAGCTCTTTTCTCAAAGCTCCACAGCTCTGATTCTTCTAGTTGCCCCGGCTGTT

[1121] TGAAAAATGATCACTCCCCAAGGACAGATCTTGACAATGTCCTTTTAATTGTACTCTTTTCA

[1122] AAAAATCTCCTTTCTCAGTTAAAAAAGACAAGGCATGATGAAGACCTGCTCTAGCCCATAC

[1123] TGGGCGGTGATCTCGGTCCTGGGGGAGGCCAGGCCGGACTCTTCCAAGGCCTCCTCCCTGG

[1124] GCAGTCCCAGCAATGGGGCCAGTGGCAGGGCAGGTTCTCCCTGCCAGAACCCGATCCTAGC

[1125] CCTTCAGAAGGACTGGACCTCTGTGTCCCTTCAGTGGGAAGCCACCTTGGACACACGCAGTC

[1126] ATTCAGGTGGACATAAGGCCACTCTTCTCGCCCTTGACCTTGAGGAACTCAGCCATGCTGGA

[1127] GAAATACTTCTGGTTGGCCTCAGCCACCTTCTTCTCTGCCGCCTGTGGGTTCACAATCTCCAG

[1128] GCCCTGGGCAGGTGAGGGAGAGAGGATGATGGGTTAGGTGAGGAGAAGGCCCCAACTGTG

[1129] ACCCATCAGAGCCCCCCAGGCCCTTCCCCATGGCACTCAGGCCTTGGTGGGCATGAGACAG

[1130] TTTGCCTGTCCCTGGAGTTGCCCTGTCTTGGGAGATTCTGACTCAGTGGGTCTAGAGGGAGA

[1131] GGGTGGGGAGGAACCAGGGCGCCTGGATTTGTACGAAGTTCCTCAGGGGTGCTAAAAACAA

[1132] CCAATGCTTGAGGACAGCCAATCCTGCCCAGTTTCTGCATAAGGAAACTGAGTCCCTGGGG GACATGGCTGGCCCGAGGTCCTAGCACAAATCACACCAACACCACTGACGATCATAGTGGC

[1133] AGCAATGGGAGCCAACACCTGGCTGGCACTTCCTAAATATTTTCAAGGCAACAGAGCGAGC

[1134] CCCCGTCTCTAAAAATAATAACAGGACCCAGTCATTGGGCTCTAATGGTGAGCCCAGTGCC

[1135] AAGTGCTTCCTGTGCGTTCTTTTCAGTCCTGAGCACCTCATGATGGAGGAGGGGAGGCTTGG

[1136] AAAGGCACAGCCACTGGCCTCATCTTCTCAAAGAGGCCCTCCCTGGCTGCTCCGAAACGAG

[1137] ATTGTCTCTTTCTCTCTCTTGGATGCACCCAAGCACGTTCCCTTGAGCCCTTCTTCGCTACCGCCTCCCCATCGCGCCCTTGCACACGTTGGGCCAAGTTTGTGCCTGGCCCGTATTCCTTTCTGT

[1138] GCTCACTGCAAGCTCCGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCAAGTAGC

[1139] TGGGACTACAGGCGCCCGCCACCACGCCCGGCTAAGTTTTTGTATTTTTAGTAGAGACGGGG

[1140] TTTCACCGTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCATGATCCACCTGCCTCGGCCTC

[1141] CCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCTGGCATTTCTGCCTTCTACT

[1142] ACACTGGGCATCTTACTGAGCTGTCTGCGCCCGGCCTGGCATTTCTGCCTTCTCCTACACTG

[1143] GACATCTTACTGAGCTGTCTGCGCCCAGCCTGGCATTTCTGCCTTCTCCTACACTGGACATCT

[1144] TACTGAGCTGTCTGCGCCCGGCCTGGCATTTCTGCCTTCTCCTACACTGGACATCTTACTGAG

[1145] CTGTCTGCGCCCGGCCTGGCATTTCTGCCTTCTCCTACACTGGACATCTTACTGAGCTGTCTG

[1146] CGCCCGGCCTGGCATTTCTGCCTTCTCCTACACTGGACATCTTACTGAGCTGTCTGCGCCCG

[1147] GCCACCCACTGGCTCCAAGAAGGTAAGACTTGTCTCTCATTCGTTGCTTCATCCCCAGAGCC

[1148] GGGAACACTGACAGAACTCAGCAGGTGCTGCGTAGACACCCGCTGACTGGGCAGATGAGCT

[1149] CGCTGCTGTCTCGCCTCCGTGGTGCAGGCTCGCCCTGCTCTGTGGATGGTAAACCGAGGCTC

[1150] CGACGATGCGGTGACTGCCATGCTCCACGCTGCTCACTGCTGACTGGCTGGGGCCTGGACCC

[1151] ACACTTGACATCCAAGCCCGCCTAGCCGGGAACTTTCTCGAGTGGGGTCCTGAGGTTACCTT

[1152] AACCGTCCTGGCCGTTTTGAACTGGAGGGCCTGGAGGCTGAGCAGTGTTACCCGCTCACAG

[1153] CCCGACAGAGGAACTGGGTGCCCTGAACACAGCTGTGGGCCTGGTTCTAAAGCAGTGCGTG

[1154] CTCACGAGGACTGCTCAGCGCTGGGCTCTCGTCTCTGCTAACCTCTTCCTGTGTGCCAGGAG

[1155] CTGTCTACGTCCTCTGCATACCTCGTCACCACACCCTCCACAACAGCCCCATGAGGAGACTC

[1156] ATCCTGGCCTTCTTCACAGGGGCAGAGGGCAAGGGGCCTTGCCAAGGTCTCAGGGCTGGGG

[1157] ACAGAGCCGGCCCAGGGGAGGTACCTGGAGTGGGGTGAAGGCCACGCTGGAGGCCGTGCC

[1158] CGAGGAGCGGTCGCGGATGGTGGACTTCCCGCCATATACGACGCTCTGCTTCTGCAGGGTC

[1159] CGCTGTGGGGAGGACAGGGAGGCTGCGATCTGGGCTCCCCCCACCTTGTGTCCCTCGGTCCC

[1160] CAGCCCCACCTGGGTCTGGCCCATACCTGCAGCGTCTTGGAGATCCTGGCCTTGGTGGCCTC

[1161] GTTTACCTGTGTCTGCCGCACACGCCCACTGCCCGACTTGCCCAGGTGGCCCAGGCTGAATC

[1162] CCAGGTCCTCCTGGTAGGCGTCCTCCTCGATCTAGGGGGGAGAGGAGGCGCCCTGCAGTTC

[1163] AGCGACCAGGCCCTGCCCTCCAGCCACCGAGGCACCCCCTCCACCAGCCCGAAGCCCAGCG

[1164] GTCACCAGCCGGCCGGTCCCACGGGCACCTGCTCCGGTACCCACTCGGCCCGGCTGAGGCC

[1165] TGGGGGCCCACACACGCGGGGGATGCTGGGGAGCCTGAGAGGGGCCCGGTCCCAGCACTG

[1166] CTCTGTGAGCTCAGAGTTGGGAGGCCATTCCTTCCTTACTCGTGTGGGTCGGGGGATGTCAG

[1167] GAACCAGAACAGGTTTAATAGGATGAGGTGGCCTCTGAGTTCGGTCCTGCAGGACCAAGGG

[1168] GATGACGCTGGGATAACAGAGGAGACTGGCGGGGCCCAGGGACGGGGCGGCCGTGCAGCA

[1169] GGGCACTAAGGAGCCTCTGGGCAGGGAGGAACCGGCCAAGGAGCCCGGGGCGATGGGAAG

[1170] CCGCGGGGGCTCTAAGCAGCGGAGACACAGGCTCCAAGGGTCGCGAGGGTCGCTTTGGGGC

[1171] TGAACGGATGGAAACGAGAATAGAGGCCGGGGGGGGGGAGGCTGGGGCAGCGCCCTAGAC

[1172] ATGAGCCAGGGCCACAGGACGAGAGGAGGGGCGGTGGCAGGAGGCAGAGGGCGGTGGCG

[1173] GCTGGCTGGCTGTGGGGTTGAGGAGGGCGCTCTGGGAGTCTGACCTCTCCGAAGCTCATAC

[1174] GGTTGGCCTGCTTCCGGATCTCCGTCAGCCCCAGCCGCTCCTTCATCTTGCGGTACCTGGGG

[1175] ACGGGTGGGTGGGCGGCGCCAGGGAGTCGGCTGGGAGGAGGACGCCGGCTTCTCCCCTCCA

[1176] TGACCCCCATGCCTACCGGACCCCCAGGGCCCCTCACCTGCGGCCGCCTCGCTTCTTCCGCT

[1177] GTCCATCCAGGGGCGCAGGCAGCGGCTTCACCTGCTTCACAGGCGGCGGCTCCTGCCACTT

[1178] GTCGAATTTGCGCTCGATCTCATCCTTCAGTTCGTAGCCCACCTGGGGAGGGCGAGGGGGA

[1179] GGTCCTGCAGCTGCTCGCGTGGGCTGCCCACCCAGGCCTCCTCTGAGCGGGCCCCCCGAGTA

[1180] TCCACGTGCCTTAGTTAAATCAGCACCTAATGCTGCCTCACCGCCACCCCCTTTCTTTTTCTT

[1181] CTTGGTGTTGACTTAGCACCGCTAGACGCAGGACAGAGTTCACCTGTTGACTGTCTCTTTGA

[1182] CCCGGCCCCAACAAGAATGTCCACGCCACGGGGCAGGGGTCCTGTCTGTGCTACTCACAGC

[1183] TGCACCCCCACACCCAGACCAGGGGTGAGATGGGGAGAGGGAAAGGAGAAGGGGACACGG

[1184] AACACCTGAACGCTGTGCCAGGCCGGGTGCTTGGCAAACGACAGTTCACAAGACAGAAAAC

[1185] GTCTCCTCTCCCGAGTACATCTACCAAGGAAGACAGAAGGTAACTGAATAATTACTTGAAT

[1186] AACATCCCCTGTTGCAGCGGGGACAGATCCTGGTGTGGAAGGCAAATTACGCCCCCACCAA CACACACATGCCCAAAGAGGCCCATGTTCTAATTCCCAGAATCACAGGGCAAAAGGGACGT

[1187] GAAGAGGTTAAGAAGGATTTTAAGGATTGTGAGCTGGGAAGACTATCCTGGACCATCTGAG

[1188] TAGGCTCAGTATAGCCACAGGGGCCCTTAAAATAGAAGAGGGGAACAAAAACAGAGGCGG

[1189] AGATATGAAGACAGAAGCAGAGTCAGAGAGAGGTCTGAGGGTGCTATGTGGCTGGCTCCG

[1190] CAGACAGAGGGAGGGCCACGAGCTAAGGGGTGCCAGTGACCCCTAGAAGCTGGAAAAGAC

[1191] CAGGGAATGGATTATCCCTTGAATCCCCCAGAAGGAACGCTCCAGGATGACACCCTGACTT

[1192] CGATTGTCTCTCTAGGTTTGTATTAGATCTTTCTATTATGTATTGGGGAACGTTTCCTTGCGACCTCATATGCTACGAGCACCCCAAACGACGTAGTGAAAGTTAGACAACACTTGGATTAGCCT

[1193] AATCTCAGTTCACTGCAACCTCCGTCTCCCAGGTTCAAGCAATTCTCCTGCCTCAGCCTCCTG

[1194] AGTAACTGGGATTACAGGTGCGTGCCACCACACCCGGCTAATTTTGGTAGAGATGGGGTTT

[1195] CACCATGTTGGCCAGGCTGGTCTCAAACTCCTGACCTTGTGACCCGCCCACCCTGGCCTCCC

[1196] AAAGTGCTGGGATTACAGGCGTGAGCTACTGCACCCGGCCACACCTGCACTGTTTTAAGCC

[1197] AGTAGGTTCATGCTACCTTCCAACAGCAGACCTAGGAAACCCCACTGGGGAAGGGGGTGCC

[1198] TGACCCCAGGGAGGGTGGGCAGAAGCACTGCCTCCGCCTTGGTAGGACAGTGCTCGCTGGG

[1199] GTGGGCTCCCTGCTGAGGGTCTCCCTGCAGAGACACCCCAGGCCCAGAGGAAAAGACGCCC

[1200] GGCCGCCCCTCACCTTTCCCTCCTCACCTTCCCTTCTGTGCTCTCGTGGAAACTGTCCACACG

[1201] GGCTGCCAGTGTGCACTTGGCGGCCACCAGCCGGGCCGCTTTCCGCCGCAGATCCTGGAGC

[1202] AACGGAAAACGGGGGTGGAATCTGTGTGAGACAGACAGACAGAGGTAACAGCAAAGCAAC

[1203] CGCGCGCGCTCCTCCTCTGGCTCTACCTGGGGTCCTGGAAGGGGGCTTTCCACCCTTGGGCT

[1204] CTAGAGGTGTGTGCTCTCAGCTCCTACTTCACAGGAAGAGGGGATGAGGGCAGGGCACAGA

[1205] GCCATGTCCCAGCTGATAAGTGGCCATCAGGTAAGGATGACAGTAAGGCACGCTGACAACG

[1206] AGGACGGTGGTGACTGTGGAGACGCCGGGGGGAGTGCACTCGGCCTGGATGCCAGCCCCAT

[1207] GCTAAGCACGCCCCTCGGATCATCTCATCAAATATTCAAATATCGGGCTGGTGTGATCATTG

[1208] CACCCCCTTTTCAGATGTGGAAACCAAGGCTTCAAGTCATGTGGCCAGGGAGACAGCCAGC

[1209] AGGTGATGGAGCCAGGGTTCCAATCCAAACTGCAAACAGAGCCCAGCTGTCAGCCACAGTG

[1210] AAGCGATGGCCAGCCCTGGCCTCCCTTACAGGCCTGTGGTGTCTACGGCCTGTGCCTGGACC

[1211] GATGTGAGATGGCCAAATGAAGAGGCAGAGGCCTGGGTGACAAGACATCAGGCTCCCTGG

[1212] GGCAGGTTTAACCCATATGCCCAGGGCTGTGAGGCGGTGGCGATGGCAGGGGTGCAGTGAG

[1213] GCAGCTGGAGCCCCGAGCCCCAGGCCCACCCGTCCTGGGTTCTATCGCCCACTCTCTCTCCT

[1214] CCCAGGATGGGGTGACCTGCCAGCCTCCCTGGGTGTGTTCCAGTAGCAGTGCCTGACCTAA

[1215] AGGGTCGCAGAAAAGACCACAAAAAAAACCCCACACAGGGCTGGGGGGTGGGGCCAGGAA

[1216] GTGCCTGCCCAGCCTTGGCCATCAGTGCTATTGTTCTCCCCATCCCTGGGGGAGGCCAGGCA

[1217] GGGCACAGGGCCGTGAGCCTGAGGTAACTCGCCACAGTTGGACAGAGCAGGGTCTGGACCC

[1218] AGGCCTGTCTGTCCCAGAACCTGTCTTGCTTGTTTTTTTTTTTTTTTGAGACAGAGTCTCACT

[1219] CTGTCACCCAGGCTGGAGGGCAGTGGTATGATCTTAGCTCACTGCAACCTCCACCTCCTGGG

[1220] TTCAAGCGATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGATTATAAGTGTGTGCCACTATA

[1221] CCCAGCTAGTTTTTTGTATTTTTGGTAGAGATGGGGTTTCACCATGTTGGCCAGGCTGGTCTC

[1222] GAACACCTGACCTCAGGTGATCTGCCCGCCTCGGCCTCCCAAAGTGCTGGGATGACAGGCA

[1223] CGAGCCACTGCGCCCCGCCAGGCTAGCGGGCCTGTGTGTGTGCTGTCAGGCGTCGATGCTG

[1224] GGATGGTGATGTGTCCCGACTGCAGGGAGAGGACCCGGGAAGCTCCGAGGTTGGTGACCTC

[1225] TCCTGCCCCTCCTGTGTGTCTCTCCCCATGGCTGATGTGCAGCCCTCAGTGGATTCTGTGAGT

[1226] CTTTCTAGTGAATGGTCAAACCTGAGGGTGGTCTTCGGAGCAGTTGCACGCTAACCCGACGC

[1227] TGCTTGTCGTGAGCTAGGCCTGAACTGTAAGTGCTTCATGTGCACTGAGCCCTCGTCCCAAC

[1228] TCATGAAGCAGGCGCTGTGCTCCCATTTGATAGGGGAGGAGACTGAGGCACAGGGCGCTCA

[1229] TGCCTCTTGCCCACAGTCACCTGACTGGTGGGTGCTGGAGCTGGTCTGCTGCAGAGCCCTGG

[1230] CTCTCACGTCCCATGCCACCCTGTTCCCAGCTCCTGAGTGCTACCGTCAGCTGGGCCAGATG

[1231] GTGGGTGGCTGCTCAGGCTGTCTGGGCACAGCGGAAGGCTCCAGGGGGGCCGGGGGAGGG

[1232] GCCATGACGCAGTGGGCTCACCGGTGGCAGGGACTGCACGATGTCACTGTGGTAGATGTAG

[1233] CCGGTGTGGGGCAGCACTGAGGTAGACGAGAAGCCCGACAGCGTCTTGCGCTGGGCCCCGA

[1234] GCAGCATGATGTTGCAGGCGGGCATCTTGGAGAGGTTGGTCAGGCCGCCGGCCACACCTGC

[1235] GGTGGGAGGGAGGGAGGAAGGGGGGGCGGTCAGAAGAAAGCAGAGAGGTGGGGGTGAGT

[1236] AAATCTGCCTGGGGGCTCGACGTGTGCTGGGCACCTTTACATGAAGTTCTGGTTGGATTCCT

[1237] CGATGGCCCTGCCAGGCGGGCGACCTGGCCCATTCCGCAAGGGGCAGATGCAAAGGAGGCT

[1238] CAGAGAGGGAGGGCAGCTGGCCTGGGGGTGCAGGGAGGAGGCCCCCAACAGGAAGCTGAC

[1239] CACCACGTTTGTGCTAAGCCACACTAACGCCGTTCCAGGGATGGCTGTGTTTTGGAACCATT

[1240] TTCACCAAACCAGGAGCTCCCTGACAACAGGGCCTGGGTGTGGTCATCTCTGGGTTTCCGGC ACAGGGGAGGGAGAAGGAGCTGTGGGTGAGTGTTTTTCCCACAGATGAGGCTTTGCTGTGT

[1241] GCCAGGCTGGCTGACCTCTGTGATGTCCAGGGAGACGGGGTGCTGAGGTCCAGGTGCCAAA

[1242] GCCCCCATTCTACAGAAAAGGATGTAGCTTTCCCAAGGTCACAGTGTCAGCAGACCCCCGC

[1243] TCCATGGGACCCAGCCCGGGGACTCACCCATGATCTTGGCGGCCGTGGATGCCCCGATAAT

[1244] GATGGACAGGTTGGGTGCGATGAAGGACATCCGGGACTCCACATACTCGTAGATGCGGTGC

[1245] TTGGAGGCGTTCAGCTCCAGCGCCATGTCGCAGGCCTCCTCCAGCCGCTCCAGCTCCTCCTC

[1246] CGACAGCTGCTGCCTGCAGGGGCGGGTGGGCCCAGCCTCCTGGGTCTCCCGCCTGCCTGGT

[1247] GTGCCCAGCCCCAGCCCTCTCGGTTCTGTGTGTGTGTGTGCATGTGTGTATGTGTGTGTGCGT

[1248] GTGTACACCTGCGTGTGTAGCTCCAGCCTAATCCCCAATCCCATTAGGGCCCGGCGCCTCCC

[1249] TCGAAGCGGACATACCCCTGGGTGGTGGAGGCGGTGACGCTGACGACCATGATGGTGGCAT

[1250] TGGTGAGGATCTGCTGCAGGTTCTCATTGTTCTTGCACTTGTCCAGGCTGTTGCCCAGCTCCT

[1251] GGGGGCGAGCAGAGAAGATAGGGGAGGCTCGGGAACTCAGGAAGGCTCGAGAACCTCTCT

[1252] TGCTCAGCACCTCCTCAGGTCTCTTCTTAGGGACACTGGGACAGTCAGGGTCTCTGCACTGG

[1253] GGGCCTCTCCTGCCTCCACCGCCTGAAGCATCCACACCATTCCTGCCTCCACCACGTCAAGC

[1254] ATCCACACCATCTGCCCTGCTTTCGCTGACCTGGAAACGGAGCCCGGGCAGAGTGGCGTCT

[1255] GGAAAGACTGTGGCCTCACAAGCCTCTGGCCTGCGTCAAGTCGGAGTGCAAATCCGCGGCC

[1256] TCGCTTCCCTGCAGGGGCTTCCCCACCGCCATCCTAATCCTTTCCTGGACATGCGTGGGGAC

[1257] CTCCTCCTCTCCCCGCCCTCACGCACACCTGCCCCTCTTTTCCGAAACCCTTCCTTGGCTTTC

[1258] TCCTAAGACCCAAAGGCTGGACGTGATCCGACCTCTTCCCCGTCCCCTCCTTCCCCGCCTCA

[1259] CTTCCTCCCCACTTGTTCCCTCTCCAGCTCTCTGCACTTAGACGTCTCTCTCCCCCAAATCTC

[1260] CGTGTGCCTGCCCTGTGTCAACCTTCGGATGTCAACTCCAATGCCACCGGCTCCAACCACAG

[1261] CGGGAGCAGCGTGGGTCAGGCCAGCGGGGAAGCCCTCTCGGGAGACTGGGGTTGGAGGGG

[1262] AGCCCTGAGAAAGTCCTGTCCAGGCTCCGTCCCTCCCACGCTGGGCAGAGCAGACCACTGA

[1263] GCCCTCGTCCACTCCTCTCCATCGTCTCCAGACCCTCAGGCCTCTGGGAGGGGGTCCGAGAG

[1264] TGAGCCCCGCCTGCCCCTTCACGCCAGCAGAAGCACCCCACCTTCTCTGCGCTCACCTTGAC

[1265] CGTGCGGATGTAATCCAGTGCATTGGGGACCAAGGACTCCAGTTCAGGGAATCTCTTTGAG

[1266] TACTTATCCCGGATGAACTTATGGATGATGTCTAGGGTAAACGGGACAGGAGGTTGTCGGG

[1267] TGAGATGGAAGGTAGACTCTGCTGGTTGGCCCTAACACCCATGTCCCCTTCTTCCTTTAGTA

[1268] ACTGAAGCCCTGGCTTGTGGCCTGGCACACGGGCACCAGCATACAGCCTTTCTCAGCCGTCC

[1269] TTACCGCTAGGTGTGACCAGGGGAATTAGTTCTGGTCTGTAAAACGTGAGCTGCAGTGACA

[1270] TGTTCTTAAAGAAAAGAAGCGCCTTGCTGGTGGGAATGCGGAGGTGATGGCTGGAGGTGGG

[1271] GCAGTCACCTCGCACCGTGAGGCAGGTGGCCGACCAACAGGATGGAAAGAGCCGGGGCCC

[1272] TACAGGCAGCCAAGCGGCCACACCATCCCCGAGTGCTCCTCAGACTCATACGCGAGAGAAC

[1273] GCACTTCCTTCTTATTTCAGCCACTCTGTGACAGCAGGTCAACCTCGATCTGAGCTTGGGCTT

[1274] AGGGGCAGGACCCTGGGAAAGGCCAGTGGGGAAGGGAGAGGGGGCGTGAGGGACGTCAC

[1275] ACGGGGCTGTCTCCGCCTGCCCCCCAGCACTCACTCAGCTCGTTTTCGATCTCCACGGTCAG

[1276] GTTGTTGGCATCCACGATGACGCGGTATTCAGGCGCGGCCTCCACTGGTCCCATCACTGTGA

[1277] GGACACGGAGGCATGGGTGTGAGTATCTAAATCCCTACCCCCTCTCGGGTCCCGCAGCTGG

[1278] AGGAGGCGGAGGATGAAGTTGGGAGGGGTCAGGAAGGAGGGGCTGAAGAGTAAACCAGG

[1279] GACAGGCTGATGTCTGCAGACATCCCTGAACTTGTGTTCCTGCCTTCAATCCCTCTCCCTCCA

[1280] CACCAGTCTAGACTTGACCCCATCTACCCCAGAACTGACCGTGTGAAACCTCCTACGGCTCC

[1281] CCACAGCCCCAAGGCTAATGACCGAGTCCTCAGACTGACATTCAGGGCCTCCCCAACTCCG

[1282] GAAGCTCTGCAGGGACCAGTGCTGTGCCTGCGTTGGCTGTACCCACAGCCGAGTACCCAGG

[1283] ACAGCACCTGGCACACAGGGAGTTCCCCCGTTCCTGTTTGCTGACTCAGCAGCTCTGCAGTC

[1284] TGGCCTCCCGCCCTTCCCGCCCCATCCTCTCACCACACCTCATTTTATTCCACTCCAGCCATA

[1285] AAGGAGTGATCACAGTGCCCCAGACACCCACTCCTCCTAGCCTTTTTTTTTTTTTTTTGAGAC

[1286] ATAATTTCGCTCTGGTTGCCCAGGCTAGAGTATAGTGGCATGATCTCAGCTCACTGCAACCT

[1287] CCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGGCA

[1288] TGTGCCACCATGCCCGGCTAATTTTTTTTGTTTGTTTGTATTTTTAGTAGAGACGGGGTTTCA

[1289] CCATGTTGGGCAGGCTGGTCTCGAACTCCCGACCTCAGGTGATCCATCTGCCTTGACCACCC

[1290] AAAGTGCTGGGATGACAGGCGTGAGCCACCGCGCCAGACCCCTCCTGGCCTCTGCATGTGC

[1291] TGCTCCCTCTCCCCAGAGCATCCCTTACCCCACGTCTGTTTCTGGAAAACGCTTCTTTGTGCT

[1292] TTAGTAATAAGAGGTCAGGCACAGTGGCTCATACCTGTAATCCCAGCACTTTGGGAGGCTG

[1293] AGGCAGGAGAACTGCTTGAGCCCAGGAGTTGGAGAGCAACCTGGGCGACATAGGGAGACC

[1294] CCATCTCTACACATAATTAAAGAAAAAAAATTAGCCAGGCATGGTGGTGTACACCTGTGGT

[1295] CCCAGCTGCCTGGGAGGCTGAGGCAGGAACGCCTGAGCCCACAAGGTCAAGGCTGCAGTG AGCTGGGATCGTGCCACTGCATTCTGGCCTGGGTGACAGAGTGAGACCCTGTCTCAAAAAA

[1296] CAAACAAACAAAAAGATGTTGTGTTTAAAAGTCATGCAAATACTAACTGCCTGATGTCACA

[1297] GCCAGTAGAAGGCAGAGCTCAGATCTGACACCAGGCAGGGCGGCGTCAGAGTCTGCACTCC

[1298] TAACCCTGATGCTCAAATGGCTCTTTAAGTCCTTAAGACTCAGGCAGCGACTCAGAATCCTT

[1299] CCCTCCCTTTCTGGAAGGATCAGACGCCTCCTCTGTGTACCCGCAGCACTTGTGCACCTCCA

[1300] GTAAACAGGGACTGCCACAGCTTGTGAGATGTTTCACCTCTGCCTCCTCAACCAGACACCGG

[1301] GTGTGACGGGGTCTGACTCCATCCCTGAGCCTGGCCTGACATCAGGAAATGTCACTTTCTGT

[1302] GTCCCATAACCCTCTGGAGGGAGAAATTCCTTGGCCTGGCATCTGGAACTCTGCAGGATTCT

[1303] CTCTCCGGATATCTGAGGCCCCGGGCCTGCCGCTGTCTTTCCCTGGGCCCCCTTCTCCCTTTC

[1304] TTTGCCTGGCACATGCATTCATGCTCTACAGTCCAATTCAGCTATCGATTCTTCCTGACACCT

[1305] GGGGCAGGGTCAGCCAGTCCCTCCTGTGGCTCCGGTGTCCCCAGCTTGGTACCACCACTGAT

[1306] AGCTGTCTGGAACCTGGCCTGCCTCTTCCACTAGACCTTGAGTACTTTGAGAGCAAAGACCT

[1307] GGGCGATTCAACTGGGTGCCCAGGTAAACGTTAAAGAAAGCAAGCAGTGAGTCTCCCGAAA

[1308] CTCTGCCCTCTCACTACACTTCTTTCCCCAGAAACCTCCTATGGCTTCCTGTCATCAACAAAT

[1309] TCCATTCAAGAAGAATGGGAAGGCTGGGCGTAGTGGCTCATGCCTGTAATCCCAGCACTTT

[1310] GGGAGGCCGAGGTGGGCGGATTACTTGAGGTCAGGAGTTCGAGACTAGCCTGGTCAACATG

[1311] GTGAAACCCCATCTCTACTAAAAAATACAAAATAGCCAGGCATGGTGTTGCATACCTGTAA

[1312] TCCCAGCTATACATAAGGCTGAGGGAGGAGAATCGCTTGAACCCGGGAGGTGGAGGTTGCA

[1313] ATGAGCCAAGAACACATCACTGCACTCCAGCCTGGGCGACAGAGGGAGACTCTATCTCAAG

[1314] GAAAAAAAAAAAAGAATAGGAATGGTAACAGGACTGCCCTCTTAAGAGTGAGTCTGAGCA

[1315] TCTTTCTATTTGTAGGAAGTAACAGGGCATGATGCTTGTTGTCCTTCCTTGCTACAGTCTCTCGAGGGGCCATTGGGAAGGATAGACAAGGGTTGTGTCTAACGGGATTTCATTCTGTTGTCTTT

[1316] CACTGCAAGCTCCGCCTCCCAGGTTCACGCCATTCTCCCGCCTCAGCCTCCTGAGTAGCTGG

[1317] GACTACAGGCACCCGCCACCACGCCTGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTGT

[1318] CACCGTGTTAGCCAGGATGGTCTCGATCTCCTGAACTCATGATCCACCTGCCTCCGCCTCCC

[1319] AAAGTGCTGGGATTACAGGCGTGAGCCACGGCGCCCGGCCTTAGGTGGTTCCTAAATAATT

[1320] ATATATCTATTTTTATACAGTGACTTTGTCTTTGCCAAATGATACCAGTTTTCCATTCATGGT

[1321] AGCAATTTGCTTCCTTCTCAGATAAATTTAAGAAAAAAAGTCCTAGACTCAAAGAATATGTT

[1322] AAGCAAATAATAGGATAAGCGGCTTATAGATGTGGCAAAAACCCTGTAACCGGTCATGTGA

[1323] ATCAGTGAAGTCTGGGAAACCTCAAGCTGAGTCCTATCATGATCAGTAAGCTCAGCACACA

[1324] GGAAGGACTTAAGAAGCATGAGCTTTACAATGCAATATATATTTAGTGGAAAAGGGAACGG

[1325] GTTGGGGTGAAACAAAAAAAAAAGAAGGCTCTGGAAAAGGCTGAGAAGGAGATATACCCA

[1326] GCCACAAGCAGCCAGGGAGCCAGGGGGCCTGGCAGGAGAGACAGGAGATGGGGAGGGGC

[1327] ACAGAGTGGGAGGAAGCACCTTCTGAAGCTTTGGCTTGCTTGCTGATATACTCCTCAATCTT

[1328] CATCATAATCTCAGCAAACTGTAGGAAAGGAGAAGACAGTCAGAATCCAGCACTCTTCAAA

[1329] AAGAAGCCTGTATCACCCCCTTCTGGGAGATTCTGTCTAGAGCCCCCTGCTAGGAACACCTC

[1330] TTGTCCTCTTACCATCTTACTATCCCATAGCTTGGCGATGGTCTTGACTGAATCCCCGGAAA

[1331] GATCCAGCTGTGTCTCCTCCTGCACATCCTCGATCGCTGGCTCCTCTTCTTCCTCCCCATAGC

[1332] TTCCTCCTTCCTCCTCTTCTGCTGCCTCTTCGAGATCAGCTAAGAGCTCATCTGCCAGAGACA

[1333] TCCCGAGGCCTGGGGAGGGACAGCAGCGTTCCCTAAAAACTTGCCCCGACAAAGTCCCTCC

[1334] TTATTACTGAGCGATGATTCTCCCCCAGAAGACCCTGGTCCTTCTTTATCAACCCCACTAGC

[1335] ATGCAGGCTCCACGACAACAGGTGCTTTAGTTTGTTTTGTTCACTGGCGAGTCTCCAGCTCC

[1336] GACCTGTGCAAGACGCAGCACACCCCTATGACCGCCACCTTGCTAAGACTTACTGGAACCA

[1337] AGTGGTGTAGATTCCAAATGCATTTGCAAACTTTCTTATTCCTTTCTTGCCTTTAGCCTTGAA

[1338] AACATACTTTGAAATTCTTTGTTTCCCTCCTTTCCCACTAGATACTGTCTTGCACTGCTGGCT

[1339] TATCTATGTGCTTACTTAGAAGTTCCAGGGGCTAATCTTTATTTATTTATTTTTTAAAGATGG

[1340] AGTCTGGCTCTGACACCCAGGTTGGAGTGCAGTGGCGCAGTCTTGGCTCACTTGCAACCTCC

[1341] ACCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGGCACC

[1342] TGCCACCATGCCCAGCTAATTTTTTTTTTTTTTTTTTGTAGAGTCAAGGTTTCACTATGTAAG

[1343] CCAGGCTGGTCTTGAACTCTTGACCTCAAGTGAGCGACCCACCTTGGCCTCCCAAACTGTTG

[1344] GGATTACAGGCGTAAGCCACCGCGCCTCGCCGCAGGGGCTAATCTTGAAACAAACTAGGTA

[1345] TGGAAACCCAGCTGCAAAACTCCAGAGATCACCTCAAGGCGATCAATCTACAACGTGGCCA

[1346] TTGTTGACTTGACACCAGCCCATGCTCCAGGTGGCCCGTGACTCAAGACAGCCTTCGGAGCA

[1347] AGACACACATACCTTGTACCCAGCACCACTCCTGTATGCCTCCCATTCAAAGTTCCCCTTTTT

[1348] AAGCCCCTCTCCCCAGCCTAAAGCTTGAAATGGTCTTCTAAAGACATTAGCTTGGCCATTTC

[1349] TCATCTGCGAGCATTTGATCAGTAAAGCTGCTTTACTTTCACCACCCCCCACTTCCTCTGCCT CTGAGTAGCAGAAACTTGAGTTGGTTACATTATCGGTCTCTTCCCGCCTCCAGGTCTTTGTA

[1350] CAGGAGTCCCTTGTAACTAAAGTGGCCCTTTCCTTCACTTTGTTTTTTCTTTTCTTTTCTTTTT

[1351] TTTGAGACCATGTCTTGCTCTGTCACCTAGGCTGCAGTGCAGTGGCGCCATCATAGCTCACG

[1352] GCAGCCTCGATCACCTGGGCTCAAGCGATTCTCCCGCCTCAGCCTCCCGATAGCTGAGATGA

[1353] CAGGCACGCACCAGCACGCCCGGCTAATTTTTAAATTTTTCTGTAGAGACAGGGTCTCACTG

[1354] TGTTGCTCAGGCTGGTCTCAAACTCCTGGGCTCAAGCGATCCTTTCGCCTGGGCCACCCAAA

[1355] GTGCTGGGATTACAGGAGTGAGCCATGGCGTCTGGCTCTCCTCACTTCTTAGTAGCCCAGCA

[1356] TCTCCTCAGCCTTCAGCTCTCACGTTCCACCTCCCTGACCCACACGCCCCACTCTAGACTACA

[1357] GGAGGTTGCTTTGTGATAACGTGTCCCGCACGCTCTGCGTGTCTACAGTAAGGCACTTCACA

[1358] CATTTGTGATTAATGAAGTAATTATTTGATAAAGCCTGTCTGCCAGGCATCAACCAAAGCTC

[1359] TAAGAGGGTAGCGAACAATTTTTGCTCCTTCCACATCCCCAGGGCCACACCATGGTAGGCG

[1360] CATATTAAGACTTTTGGGTAAACAGGCTGTAAAAGGCCGGGAGCGGTGGCTCATGCCTGTA

[1361] ATCCCAGCACTTTGGGAGGCCCAGGCGGGTGGATCATCTGAGGTCAGGAGTTGGAGACCAG

[1362] CCTGGCCAACATAGTGAAACCCCGTCTCTACTAAAAATACAAAAAACTAGCCGGGCGTGGT

[1363] GGTGCGCGCCTGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAATCCGG

[1364] GAGGCGGAGGTTGCAGTGAACCGAGATCGCGCCACTGCACTCCAGCCTGGGCAACAAGAG

[1365] CGAAACTCCGTCTCAGACAAAACAAACAAACAACTGGCCAGGCGCGGTGGATCATGCCTGT

[1366] AATCACAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGATCAGGAGTTCGAGACCAG

[1367] CCTGACCAACATGGGGAAACCCCGTCTCTACTAAAAATACAAAAATTAGTCAGGGGTGGTG

[1368] GCGGGCGCCTGTAATCCCAGCTACTCTGGAGGCTGAGGCAGAAGAATCGTTTGAACCCGGG

[1369] AGACGGAGGTTGCAATGAGCCGAGATCGCGCCACTGCTCTCCAACCTGGGCAACAGAACGA

[1370] GACTCCGTCTCAAAACAAACAAACAACAAAAAAACAAAAACCAAGCTGTAAAGACCCGCC

[1371] TTTTTCCTCACACACTTCTTCTCCCAGACCCAGGAGCCCAGCCTCCCGCTCCCCGTGGTCCCC

[1372] ATCACACTCACCTCTCCTCTCCGCGCACCACTGTTTCTAGCGTTAGTCGCTCACCGATGACGT

[1373] CTCACTCTCGCGCCGTTATAGAGGCAAAGCTACTCTCTGATTGGTCCCCGCTCGCGATGTTC

[1374] CTGGCCGCATTTGAAACAACAACTTTATTAGCACCTGGCACTAGGCGGAGAGAGGCGGTAA

[1375] GCCGCGAGGAGGAAAGGGACTCACGTCCCGCTGTGGACCGATCCTGCTAAGCAGAGAATCG

[1376] CTGTGGCCGGACGACGGGGCGTCGAGACAAGAAGAAAGACGTTGGCAACTCAGAGGACTG

[1377] GTTGCGGCGTTAGACAAGAAAGCAAGGCCTTTAAGCAGGGATTCGGGGTGGACGTGGGGGT

[1378] GGGCCGAAGCGAAGCCGGAAACAGGAAACTACAACTCCCACAAGGCCTAGGGCCACGTCC

[1379] CGCCGTCCTCGGCTGCTGAGCCTGATGGGACAAGTAGTTTTGCGAACGGCTTAACCTACAG

[1380] ATTGAAGAGGTCGGAAGCTCTGAGGCCCGGGGCTTCCGGAGGTCGCGGAGATGGAATTGGA

[1381] GCAGAGAGAAGGGTATGTGGCTGAGCCCTTGTGAAAAAGTGCGAATCCCAGAAAACAGTG

[1382] CAGCTGCATTGTGTGCAACCATATGAGCTTTTACGCTGAGGTCTGATGGGGGTTGTAGTTCA

[1383] TGCAACTGCTTTACCTTAGAACCCTTTTATGGACTGGGGTCATCCTGAGGGAGGAGAAGGTT

[1384] AGGGGTTTGGACTGCTGGATCTGACAGACTAGGAGGTTGGAAGCCAGGACTCTTGCGTCTG

[1385] GTTGAGGGTTGGGGCTTGGACTCCCTGGGTCCTTGGAGAGAAAAAGTCTGGAGGTCTGGAC

[1386] TCTTGCATCCTGGGAGGAGGGGGTCAGGGCTTGAACCCTGTGGGTGCTGCGAAGGGTGGGT

[1387] TGCGGACTTGGACTTCTGGGTCTGAGGGAGGAGGGCTGGGAGCTGGATTCTACGGTCTGAG

[1388] GGAGGAGGGGCTGGGGGCCTGGATTCTAGGATCTCAGGGAGGAGGGGTTGGGGTCTGGGC

[1389] TCCTGGTTCAGTGGGAGAAGGGGCTGGGGGTCCAGGATCCAGGGCCCCTGAGCCTTTCCCT

[1390] GCCTCTCAGGACCATGGCAGCCGTGGGCTTTGAGGAGTTCTCAGCGCCGCCAGGCTCAGAG

[1391] TTGGCGTTGCCTCCCCTATTTGGTGGCCACATCCTGGAGAGCGAGCTGGAGACGGAAGTGG

[1392] AGTTTGTGTCAGGTGGTCTGGGCGGCTCAGGGCTCCGGGAGCGAGATGAAGAGGAAGAGG

[1393] CAGCCCGGGGTCGGCGGCGGCGCCAGCGGGAATTAAATCGCAGAAAGTACCAGGCACTAG

[1394] GTCGGCGCTGCCGGGAGATCGAGCAGGTAGGTGAGTGCGGATCCCCCGGTTTTGGGGTCCC

[1395] CTGGCCTAAACTACCGCCCCCCGCAATCTCTGCCTTTCCACATGCCCAGCCTTTCTTGGCTTG

[1396] CTGATATATTCAGTCATTTAGCTTATATATTCAGTCATTTAGCATGCATTATGTGTCTGGCCC

[1397] TGTGCCGGGCCCCTGGAAGGGCCATCTCCCGTGGAGCTTCCCTGACAACGCAGATGGGTTCT

[1398] CTGATGTCTCCCGGGGGCCTCTCAATGCGTGGCACCGCTCACAGGTGAAAGCCCAAGCTCTT

[1399] CACATCTCCCATACCCCTGCCAGGATTCACTCCTCTCGACTCATTCATTCCGCCTCTTGAGTG

[1400] TCTCTGGACCCTTCTCCTCTCCTCCATCCCTATGGCTGCCATTGCAAACTCCAGCTGTCTGGG

[1401] CTGAATGACTGCAATAGCCTCCTTGCTGAGAATAAGGATGGGCTGGGCATGGTGGCTCACG

[1402] CTTGTAATCCTAGCACTGGGAGGCTGAGGCAGGCGGATCACCTGAGGTTAGGAGTTCGAGA

[1403] CCAGCCTGGCCAACATGGTGAAACCCCATCTCTACTAAAATACAAAAAAATTAGCCAGGTG

[1404] TGGTGGTGCGCACCTGTAGTCGCAGCTACTAGGGAGGCTGAGGCATGAGAATTGCTTGAAC CCGGAAGGCGGAGGTTGCAGTGAGCCAAGATCATGCTGCTGTACTCCAGCCTGGGTGACAG

[1405] AGTGAGACTCCGTCTCAAAATCAATCAATCAATCAATGAGGATTAAACAGCAGGCAGGGCT

[1406] CAGATCTTGGCAGGCCAGGAACACCAGGACAAGAAGTCTGGATATTTTTTTTTCCTTGAGAG

[1407] TGAAGGAGCCACTGAAGGGTTTCAAATGGGGGAGGAACAGCATCAGGTCTGGATGCCTGA

[1408] AACTCTGAAGACAGTTGTATTAGTCTGCTTGGACTCCCAGAACTTATCACAAATAGGGTCCC

[1409] TCAAGCACAGAAATTCCTGTCTGACAGTTCTGGAGGCTAGACATCCAAGGCAAGGTGTCGA

[1410] CAGGGTTGTGAGAATCTTCCAGGCCTCTCCCCTGGCTTCTGGAGGTTTCTGGCAGTCATTGG

[1411] CACGTACAAACATCACCCTGATCTCCGCCTTCATCTTCACATTGCTGCTCCCTGTGTGTGTGT

[1412] CTGTGTCCCAATTTACCCTTTTTATAAGGACTCCAGTCATACTGGATTAGGGCCCACCCACT

[1413] GGCTTCATTTGAACTTGATTACTTTTGTAACGACACTGTCTCCATATAAGGTGATCCTGAGG

[1414] TTATTCTTTGTGTGTGTTGTTTTTATAGAAGGCGCTTGCGAAAGCTACCTCCCGTCCTTCTTTTTGGTGCGTGCGCACAAAGTGACATTGTGCAAGATCGTCTATATTTTGTGTCTATCTCTATTT

[1415] CTCAGCTCACTGTAACCTCCACCTCCTGGGTTCAAGTGATTCTCCTGACTCAGCCTCCCTAGT

[1416] AGCTGGGATTACAGGCGCCCGCCACCACACCCAGCTAATTTTTCTATTTTTAGTAGAGACAG

[1417] GGTTTCACCATGTTGGTCAGGCTGGTCTCAAACTCCTGACCTCAGGTGATCTGCCCACCTCA

[1418] GCCTCCCAAGGTGCTGGGATTACAGGCTTGAGCCACCACGCCTGGCCTTCAACTCTTTTTCT

[1419] CTTTCTTGAGACAGGTTCTCACTTTGTCACCAAAGCTGGAGTGCAGTGGCGCAATCTCAGCT

[1420] CATTGCAGCCTCAGTCTCCCAGGTTCAAGCAGTCCTCCTGCCTCAGCCCCCAAAATAGCTGG

[1421] GACTACAGGCACACACCACCACACCTGGCTAATTTTTGTACTTTTTGTAGAGATGGGGTTTT

[1422] GCCATGTTGCCCAGGCTGGTCTTGAACTCCTGACCTCAAGTGATCCACTCGCCTTGACCTCC

[1423] CAAAATGCTAGGATTACAGGCATGAGCCACCACATCTGGCCTCAATTCTTAATGACAGTATT

[1424] GGGGAGTTCTGTAAGGAGGAAGGCTAGAGGCCAGGGGCATATTCCAAACCCTGTTTAACAG

[1425] ACAGACACCAAGGCCCAAACGGACTCAACTGGAGCCTCTGCCATTAATCCACCCCCAGGAA

[1426] TAGATTACTACTATTTTACAAGTATAGAAAATCAAGGCTCAGAGAGGTTAAGTAATGCACC

[1427] CAAGCTCAGAGCTCAGCAGTGGCAGATCTGAGATTTTTTTTTTTTTTTTGAGACAGGGTCTTT

[1428] CTCTGTTGCCCAGGCTGGAGTGCAGTGGCATGACTGTGGCTCACTGCAGCCCCAACATCCTG

[1429] GACTCTAGCAATCTCAGCCTCCGAAGGAGCTGGGACTACAGCCACCAAGCCCAGCTAATTT

[1430] TTTTGGTTAGTTTTTGAGTGTTGGGGTCTCACTCTGTTGCCCAGGCTGGTGTCGAACTCCTGG

[1431] CCTCTCAAAGTGCTGGGATTATAGGCATGAGCCACTGTGCCAAGCCAGAGCCAAAACTTGA

[1432] ACTCTTTTTTTTTAGATGGATTTTCGCTCTTGTTGTCCAGGCTGGAGTGCAATGCTGCAATCT

[1433] CAGCTCACTGCAACCTCCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCGAGTA

[1434] GCTGGGATTACAGGCATGCGCCACTACACCTGGCTAATTTTGTATTTTTAGTAGAGACAGGG

[1435] TTTCACCACGTTAGGCTGGTCTCAAACTCCTGACCTCAGGTGATCCGCTCGCCTTGGCCTCT

[1436] GAAAGTGCTGGGATTACAAGCGTGAGCCACCGTGCCTGGCACTTTTTTTTTTTTTTTTTCTTT

[1437] TGAGACAGAGTCTTACTCTGTCACCCAGGCTGGAGGGCAGTGGTGTGATCTCGGCTCACTGC

[1438] AACCTCCAGCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGAAACTGGGATTAC

[1439] AGGCATGCGCCACCATACCCAGCTAATTTTTGTATTTTTCTTTTTTTTTTTTTTTTTTTAGTAG

[1440] AGATGAGGTCTCATCATGTTGGCCGGGCTGGTCTGCAACTCCCGACCTCAAACTCTTGAGTA

[1441] GCTGAGATTACAGGCATGTGCCACAACATCCGGCCAATTTTTGTATCTTTAGTAGAGACGGG

[1442] GTTTCACCATGTTGGCCAGGCTGGTCTTGAACTCCTGACCTCAAGTGATCTGCCCGCCCCGG

[1443] CCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCCCGCCCGGAACTCAGGTCTTT

[1444] CTGACCCAGGAGCAGCACCTGCTTCAGCCACTGTCTTTGGGTCCCTGTTTGGCTGAGTCACA

[1445] TCTCTCCCTCCATGTCTAGGCTGGAGTCCTCAGAAGCTGCGTGCAGGGCTGTCCCCTCAGCC

[1446] TGGCATACTTTCCTCCTGTCACCCCTTTGTCTCCTCCTTATTCAAGTCTGGGCCCACGGGCCT

[1447] TCTCTGCAGGTCGTAACTAAAGTCGCACCTCCTGCCCTAACCTCCAGCATGTCTGACTCTTT

[1448] GGTATTCACCAAGCACTTCTCACTTTGCAAAGTCATTGATTCTGCAAATGTTCATCGAGGAT

[1449] GTACTACGTGCCAGGCTCTGGTTAAGGCACGGGATGTAGAAACAAGTTGCTGTCGTTTTTCA

[1450] GCTCATGCTCTGGCTGGAGAGGCGGTCAGTCAGCAGAATAAGCAAAGAGGCGGAGAGGCT

[1451] GCGTCCTGCCTCCTCAGATGAGCACTAGGAGGAAATAAAGCCAGGAGTGAATGGCCGGGTG

[1452] GGGTTCTGGCATGGGAAGGGGGGTCGGGTGTGTTGCAATTTTTTTTTTTGAAACAGAACCTC

[1453] GCTCTGTTGCCCAGGCTGGAGTGCAGTGGGGTGATCTCAACTCACTTCACCCCTCCACCTCC

[1454] CAGGTTCGTGCGACTATCCTGCAGGCACCTGCCACCACGCCCAGCTAATTTTTTGTATTTTTA

[1455] GTAGAGATGGGGTTTCATCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGGGATCT

[1456] ACTCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCACCTGGCCTGGT

[1457] GTGTTTCGACTTAATGGGAGGTTCAGGCTCT SEQ ID NO: 3 PRPF31 antisense strand - spliced

[1458] TTTGTATTTTTGGTAGAGATGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACACCTGAC

[1459] CTCAGGTGATCTGCCCGCCTCGGCCTCCCAAAGTGCTGGGATGACAGGCACGAGCCACTGC

[1460] GCCCCGCCAGGCTAGCGGGCCTGTGTGTGTGCTGTCAGGCGTCGATGCTGGGATGGTGATG

[1461] TGTCCCGACTGCAGGGAGAGGACCCGGGAAGCTCCGAGGTTGGTGACCTCTCCTGCCCCTC CTGTGTGTCTCTCCCCATGGCTGATGTGCAGCCCTCAGTGGATTCTGTGAGTCTTTCTAGTGA

[1462] ATGGTCAAACCTGAGGGTGGTCTTCGGAGCAGTTGCACGCTAACCCGACGCTGCTTGTCGTG

[1463] AGCTAGGCCTGAACTGTAAGTGCTTCATGTGCACTGAGCCCTCGTCCCAACTCATGAAGCAG

[1464] GCGCTGTGCTCCCATTTGATAGGGGAGGAGACTGAGGCACAGGGCGCTCATGCCTCTTGCC

[1465] CACAGTCACCTGACTGGTGGGTGCTGGAGCTGGTCTGCTGCAGAGCCCTGGCTCTCACGTCC

[1466] CATGCCACCCTGTTCCCAGCTCCTGAGTGCTACCGTCAGCTGGGCCAGATGGTGGGTGGCTG

[1467] CTCAGGCTGTCTGGGCACAGCGGAAGGCTCCAGGGGGGCCGGGGGAGGGGCCATGACGCA

[1468] GTGGGCTCACCGGTGGCAGGGACTGCACGATGTCACTGTGGTAGATGTAGCCGGTGTGGGG

[1469] CAGCACTGAGGTAGACGAGAAGCCCGACAGCGTCTTGCGCTGGGCCCCGAGCAGCATGATG

[1470] TTGCAGGCGGGCATCTTGGAGAGGTTGGTCAGGCCGCCGGCCACACCTGCGGTGGGAGGGA

[1471] GGGAGGAAGGGGGGGCGGTCAGAAGAAAGCAGAGAGGTGGGGGTGAGTAAATCTGCCTGG GGGCTCGACGTGTGCTGGGCACCTTTACATGAAGTTCTGGTTGGATTCCTCGATGGCCCTGC

[1472] CAGGCGGGCGACCTGGCCCATTCCGCAAGGGGCAGATGCAAAGGAGGCTCAGAGAGGGAG

[1473] GGCAGCTGGCCTGGGGGTGCAGGGAGGAGGCCCCCAACAGGAAGCTGACCACCACGT...

Claims

CLAIMS1. A nucleic acid that binds to :(i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or(ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

2. A vector for expression, in a mammalian cell, of a nucleic acid that binds to:(i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or(ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

3. The vector of claim 2, wherein the vector comprises a retinal cell type-selective or tissue-selective promoter for driving expression of the nucleic acid in the mammalian cell.

4. The vector of claim 3, wherein the retinal cell type-selective or tissue-selective promoter is selective for expression in a retinal cell and / or tissue selected from the group consisting of retina, retinal pigment epithelium, Muller glial cells, endothelial cells, glial cells, astrocytes, photoreceptors, bipolar cells, horizontal cells, ganglion cells, amacrine cells and combinations thereof.

5. The vector of claim 3 or 4, wherein the vector comprises an inducible promoter.

6. The vector of any one of claims 2 to 5, wherein the vector is a non-viral vector.

7. The vector of any one of claims 2 to 6, wherein the vector is a viral vector.

8. The vector according to claim 7, wherein the viral vector is a recombinant virus selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus and anellovirus.

9. A composition comprising the non-viral vector according to claim 6 and a transfection agent.

10. A method of treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, the method comprising administering to the subject a nucleic acid that binds to:(i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or(ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

11. The method of claim 2, wherein the disease or condition is an ocular condition.

12. The method of claim 3, wherein the ocular condition is retinitis pigmentosa.

13. The nucleic acid of claim 1, or the vector of any one of claims 2 to 8, or the composition of claim 9, or the method of any one of claims 10 to 12, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein is increased by about 1. 1 to about 10-fold in the cell.

14. The nucleic acid according to claims 1 or 13, or the vector according to any one of claims 2 to 8 or 13, or the composition of claims 9 or 13, or the method according to any one of claims 10 to 13, wherein the nucleic acid binds near or within a targeted portion of:(i) aPRPF31 gene pre-mRNA intron;(ii) a.PRPF31 gene pre-mRNA exon;(iii) PRPF31 gene mRNA exon-exon junction(iv) aPRPF31 gene 3’ untranslated region (UTR); and / or(v) aPRPF31 gene 5 ’UTR.

15. The nucleic acid according to claims 1, 13 or 14, or the vector according to any one of claims 2 to 8, 13 or 14, or the composition of claims 9, 13 or 14, or the method according to any one of claims 10 to 14, wherein binding of the nucleic acid to the targeted portion of the PRPF31 pre-mRNA or mRNA reduces specific binding of a microRNA (miRNA) to the PRPF31 mRNA.

16. The nucleic acid, or the vector, or the composition or the method of claim 15, wherein the miRNA is a miR-129-3p and / or miR-1251 -5p microRNA family member.

17. The nucleic acid according to claims 1, 13 to 16, or the vector according to any one of claims 2 to 8, 13 to 16, or the composition of claims 9, 13 to 16, or the method according to any one of claims 10 to 16, wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA and increases translation of PRPF31 mRNA.

18. The nucleic acid according to claims 1, 13 to 17, or the vector according to any one of claims 2 to 8, 13 to 17, or the composition of claims 9, 13 to 17, or the method according to any one of claims 10 to 17, wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862.

19. The nucleic acid according to claims 1, 13 to 18, or the vector according to any one of claims 2 to 8, 13 to 18, or the composition of claims 9, 13 to 18, or the method according to any one of claims 10 to 18, wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

20. The nucleic acid according to claims 1, 13 to 19, or the vector according to any one of claims 2 to 8, 13 to 19, or the composition of claims 9, 13 to 19, or the method according to any one of claims 10 to 19, wherein the nucleic acid binds within a targeted portion of the PRPF31 gene 3’ UTR and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 7008 to 7103, 16098 to 16201, or 41844 to 41849.

21. The nucleic acid according to claims 1, 13 to 20, or the vector according to any one of claims 2 to 8, 13 to 20, or the composition of claims 9, 13 to 20, or the method according to any one of claims 10 to 20, wherein the nucleic acid binds within a targeted portion of the PRPF31 gene 3’ UTR and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 16125, 41848 or 41849.

22. The nucleic acid according to claims 1, 13 to 19, or the vector according to any one of claims 2 to 8, 13 to 19, or the composition of claims 9, 13 to 19, or the method according to any one of claims 10 to 19, wherein the nucleic acid binds within a targeted portion of the PRPF31 gene 5’ UTR and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 1672 to 1796, 10765 to 10886 or 41833 to 41843.

23. The nucleic acid according to claims 1, 13 to 19 or 22, or the vector according to any one of claims 2 to 8, 13 to 19, or the composition of claims 9, 13 to 19 or 22, or the method according to any one of claims 10 to 19 or 22, wherein the nucleic acid binds within a targeted portion of the PRPF31 gene 5’ UTR and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 41833, 41836, 41838, 41839, 41842, 41843, 10870, 10862 or 10843.

24. The nucleic acid according to claims 1, 13 or 14, or the vector according to any one of claims 2 to 8, 13 or 14, or the composition of claims 9, 13 or 14, or the method according to any one of claims 10 to 14, wherein binding of the nucleic acid to the targeted portion of the ncRNA that is complementary to a portion of a PRPF31 pre- mRNA or mRNA:(i) reduces function of the ncRNA; and / or(ii) modulates splicing of the ncRNA.

25. The nucleic acid according to claims 1, 13, 14, or 24, or the vector according to any one of claims 2 to 8, 13, 14 or 24, or the composition of claims 9, 13, 14 or 24, or the method according to any one of claims 10 to 12 to 14 or 24, wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

26. The nucleic acid according to claims 1, 13, 14, 24 or 25, or the vector according to any one of claims 2 to 8, 13, 14, 24 or 25, or the composition of claims 9, 13, 14, 24 or 25, or the method according to any one of claims 10 to 14, 24 or 25, wherein thenucleic acid binds within a targeted portion of ncRNA and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 18194 to 41831 or 41850 to 41860.

27. The nucleic acid according to claims 1, 13, 14, or 23 to 26, or the vector according to any one of claims 2 to 8, 13, 14, 23, 24 or 25, or the composition of claims 9, 13, 14, or 23 to 26, or the method according to any one of claims 10 to 14, or 23 to 26, wherein the nucleic acid binds within a targeted portion of ncRNA and the nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 31223, 41850, 41852, 41854, or 41855.

28. The nucleic acid according to claims 1, 13 to 27, or the vector according to any one of claims 2 to 8, 13 to 22, or the composition of claims 9, 13 to 27, or the method according to any one of claims 10 to 27, wherein the nucleic acid is:(i) an antisense oligonucleotide;(ii) a small interfering RNA (siRNA);(iii)a short hairpin RNA (shRNA);(iv)a guide RNA (gRNA); and / or(v) a nucleic acid encoding a DNA endonuclease or an endonuclease system.

29. The nucleic acid, or the method, or the composition of claim 28, wherein the antisense oligonucleotide is a gapmer antisense oligonucleotide.

30. The nucleic acid, or the method, or the vector, or the composition of claim 28, wherein the antisense oligonucleotide comprises a phosphorodiamidate morpholino moiety.

31. The nucleic acid or the method, or the vector, or the composition of claim 28, wherein the endonuclease and / or the endonuclease system is a meganuclease, a zinc finger nuclease (ZFN), a transcription-activator like effector nuclease (TALEN) and / or a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas nuclease.

32. The nucleic acid, or the method, or the vector, or the composition of claim 28 or 29, wherein the antisense oligonucleotide or siRNA comprises a backbone modification.

33. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30 or 32, wherein the antisense oligonucleotide or siRNA comprises a backbone modification comprising a phosphorothioate linkage, a phosphorodiamidatelinkage a mesyl phosphoramidate, a phosphodiester, a peptide nucleic acid, a boranophosphonate or a stereorandom.

34. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30, 32 or 33, wherein the antisense oligonucleotide or siRNA comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a T-O- methyl, a 2' -Fluoro, or a 2'-O-methoxyethyl moiety.

35. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30 or 32 to 34, wherein the antisense oligonucleotide or siRNA comprises at least one modified sugar moiety.

36. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30 or 32 to 35, wherein each sugar moiety in the antisense oligonucleotide or siRNA is a modified sugar moiety.

37. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30 or 32 to 36, wherein the antisense oligonucleotide or siRNA comprises a 2'-O-methoxyethyl moiety.

38. The nucleic acid, or the method, or the vector, or the composition of claim 37, wherein each nucleotide of the antisense oligonucleotide or siRNA comprises a T-O- methoxy ethyl moiety.

39. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30 or 32 to 38, wherein the nucleotide sequence of the antisense oligonucleotide or siRNA consists of 10 to 50 nucleotides, 15 to 40 nucleotides, 18 to 40 nucleotides, 16 to 20 nucleotides, 17 to 25 nucleotides, 19 to 23 nucleotides, 20 to 35 nucleotides, 20 to 30 nucleotides, 22 to 30 nucleotides, 22 to 28 nucleotides, 24 to 30 nucleotides, 25 to 30 nucleotides, or 26 to 30 nucleotides.

40. The nucleic acid, or the method, or the vector, or the composition of claim 39, wherein the nucleotide sequence of the antisense oligonucleotide or siRNA consists of 10 to 50 nucleotides.

41. The nucleic acid, or the method, or the vector, or the composition of claim 40, wherein the antisense oligonucleotide or siRNA comprises one or more phosphorodiamidate morpholino moieties.

42. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 30 or 32 to 41, wherein the antisense oligonucleotide or siRNA is linked to a functional moiety.

43. The nucleic acid, or the method, or the vector, or the composition of claim 42, wherein the functional moiety comprises or consists of a delivery moiety, a half-life extending moiety or a stabilising moiety.

44. The nucleic acid, or the method, or the vector, or the composition of claim 43, wherein the delivery moiety is selected from the group consisting of lipids, peptides, carbohydrates, and antibodies.

45. The nucleic acid, or the method, or the vector, or the composition of any one of claims 42 to 44, wherein the delivery moiety comprises a cell-penetrating peptide (CPP), a receptor binding domain (RBD), a N-acetylgalactosamine (GalNAc) moiety, a poly(ethylene glycol) (PEG) moiety, a fatty acid moiety, a carbohydrate moiety or a lipid moiety.

46. The nucleic acid, or the method, or the vector, or the composition of any one of claims 42 to 45, wherein the functional moiety is covalently or non-covalently linked to the antisense oligonucleotide.

47. The nucleic acid, or the method, or the vector, or the composition of any one of claims 42 to 46, wherein the functional moiety is linked to the 5' end of the antisense oligonucleotide or siRNA or is linked to the 3' end of the antisense oligonucleotide or siRNA.

48. The nucleic acid, or the method, or the vector, or the composition of any one of claims 1 to 47, wherein the nucleotide sequence of the nucleic acid is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% complementary to the nucleotide sequence of the targeted portion over the length of the nucleic acid.

49. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of PRPF31 pre-mRNA or mRNA and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 6 to 18193 or 41833 to 41849.

50. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of the PRPF31 gene 3’ UTR and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 7008 to 7103, 16098 to 16201, or 41844 to 41849.

51. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of the PRPF31 gene 3’ UTR and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 16125, 41848 or 41849.

52. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of the PRPF31 gene 5’ UTR and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 1672 to 1796, 10765 to 10886 or 41833 to 41843.

53. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of the PRPF31 gene 5’ UTR and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 41833, 41836, 41838, 41839, 41842, 41843, 10870, 10862 or 10843.

54. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of ncRNA and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NO: 18194 to 41831 or 41850 to 41860.

55. The nucleic acid, or the method, or the vector, or the composition of any one of claims 28 to 48, wherein the antisense oligonucleotide binds within a targeted portion of ncRNA and the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 31223, 41850, 41852, 41854, or 41855.

56. The nucleic acid, or the method, or the vector, or the composition of any one of claims 1 to 55, wherein the nucleic acid is complexed with a delivery nanocarrier.

57. The nucleic acid, or the method, or the vector, or the composition of claim 56, wherein the delivery nanocarrier is selected from the group consisting of: lipoplexes, liposomes, exosomes, inorganic nanoparticles, and DNA nanostructures.

58. The method of claim 57, wherein the delivery nanocarrier comprises a lipid nanoparticle (LNP) encapsulating the nucleic acid.

59. The nucleic acid, or the method, or the vector, or the composition of any one of claims 1 to 58, wherein the nucleic acid is formulated for a route of administration selected from the group consisting of intravitreal, suprachoroidal, subretinal, ciliary intramuscular, intravenous, intra-arterial, subcutaneous, and topical routes.

60. Use of a nucleic acid in the manufacture of a medicament for treating, preventing and / or delaying progression of a Pre-mRNA Processing Factor 31 (PRPF31) gene mediated disease or condition in a subject, wherein the nucleic acid binds to:(i) a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA; or(ii) a targeted portion of a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA, mRNA or ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell.

61. An antisense oligonucleotide that binds to a targeted portion of Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the pre-mRNA or mRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of PRPF31 pre-mRNA or mRNA corresponding to any one of SEQ ID NOs: 1, 41861 or 41862.

62. The antisense oligonucleotide according to claim 61, wherein the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs:6 to 18193 or 41833 to 41849.

63. An antisense oligonucleotide that binds to a targeted portion of a Pre-mRNA Processing Factor 31 (PRPF31) 3’ untranslated region (UTR), wherein binding of the antisense oligonucleotide to the targeted portion of the pre-mRNA or mRNA 3 ’UTR in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell, and wherein the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 7008 to 7103, 16098 to 16201, or 41844 to 41849.

64. The antisense oligonucleotide of claim 63, wherein the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 16125, 41848 or 41849.

65. An antisense oligonucleotide that binds to a targeted portion of a Pre-mRNA Processing Factor 31 (PRPF3P) 5’ untranslated region (UTR), wherein binding of the antisense oligonucleotide to the targeted portion of the pre-mRNA or mRNA 5 ’UTR in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell, and wherein the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 1672 to 1796, 10765 to 10886 or 41833 to 41843.

66. The antisense oligonucleotide of claim 65, wherein the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 41833, 41836, 41838, 41839, 41842, 41843, 10870, 10862 or 10843.

67. An antisense oligonucleotide that binds to a targeted portion of anon-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the nucleic acid to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the nucleic acid binds within a targeted portion of ncRNA corresponding to any one of SEQ ID NOs: 2 to 5.

68. The antisense oligonucleotide according to claim 67, wherein the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 18194 to 41831 or 41850 to 41860.

69. An antisense oligonucleotide that binds to a targeted portion of anon-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA, wherein binding of the antisense oligonucleotide to the targeted portion of the ncRNA in a cell increases the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell and wherein the antisense oligonucleotide comprises or consists of a sequence set forth in any one of SEQ ID NOs: 18194 to 41831 or 41850 to 41860.

70. The antisense oligonucleotide of claims 68 or 69, wherein the antisense oligonucleotide comprises a sequence set forth in any one of SEQ ID NOs: 31223, 41850, 41852, 41854, or 41855.

71. A method of genetically modifying a mammalian cell, the method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more doublestrand breaks within or near a DNA sequence encoding Pre-mRNA Processing Factor 31 (PRPF3P) pre-mRNA or mRNA, or a non-coding RNA (ncRNA) that is complementary to a portion of a Pre-mRNA Processing Factor 31 (PRPF31) pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

72. The method of claim 71, wherein the genetic modification is selected from the group consisting of:(i) small insertions and deletions (indels);(ii) insertion and / or deletion and / or replacement of one or more nucleotide bases within or near a targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;(iii) insertion of a RNA destabilizing element near a targeted portion of thePRPF31 pre-mRNA, mRNA and / or ncRNA;(iv) deletion of one or more exons within or near a targeted portion of thePRPF31 pre-mRNA, mRNA and / or ncRNA;(v) deletion of one or more introns within or near a targeted portion of thePRPF31 pre-mRNA, mRNA and / or ncRNA;(vi) deletion of one or more miRNA binding sites within or near a targeted portion of the PRPF31 pre-mRNA and / or mRNA; and(vii)combinations thereof.

73. The method of claim 71 or 72, wherein the genetic modification is:(i) deletion of an intronic sequence or part thereof within or near a targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA;(ii) deletion of an exon sequence or part thereof within or near a targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA; and / or(iii) deletion of an exon-exon boundary or part thereof within or near a targeted portion of the PRPF31 pre-mRNA, mRNA and / or ncRNA; wherein(i) the PRPF31 pre-mRNA or mRNA comprises a sequence set forth in SEQ ID NO: 1, 41861 or 41862; and / or(ii) the ncRNA comprises a sequence set forth in any one of SEQ ID NOs: 2 to 5.

74. The method of any one of claims 71 to 73, wherein the DNA endonuclease or endonuclease system is selected from the group consisting of a meganuclease, a zinc finger nuclease (ZFN), a transcription-activator like effector nuclease (TALEN) and a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas nuclease.

75. The method of any one of claims 71 to 74, wherein the genetic modification increases or decreases function of the PRPF31 pre-mRNA, mRNA and / or ncRNA.

76. The method of any one of claims 71 to 75, wherein the DNA endonuclease or endonuclease system is encoded in a viral vector selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus and anellovir.

77. A method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising method comprising introducing into the cell one or more deoxyribonucleic acid (DNA) endonucleases or endonuclease system to effect one or more single-strand breaks or one or more double-strand breaks within or near a DNA sequence comprisinga miRNA binding site within a 3 ’untranslated region (UTR) of a gene encoding the PRPF31 pre-mRNA or mRNA in a cell, such that the miRNA binding site or part thereof is deleted, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

78. The method of claim 77, wherein the DNA endonuclease or endonuclease system is selected from the group consisting of a meganuclease, a zinc finger nuclease (ZFN), a transcription-activator like effector nuclease (TALEN) and a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas nuclease.

79. The method of claims 77 or 78, wherein the DNA endonuclease or endonuclease system is encoded in a viral vector selected from the group consisting of adeno- associated virus (AAV), adenovirus, lentivirus and anellovir.

80. A method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising deleting a miRNA binding site or part thereof within a 3 ’untranslated region (UTR) of a gene encoding the PRPF31 pre-mRNA or mRNA in a cell, such that the miRNA is no longer able to bind to the miRNA binding site and wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased.

81. A method of increasing the level of PRPF31 mRNA in a cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in a cell the method comprising method comprising preventing a miRNA binding to a miRNA binding site within a 3 ’untranslated region (UTR) of a gene encoding the PRPF31 pre-mRNA or mRNA in a cell, wherein the level of PRPF31 mRNA in the cell and / or the amount of functional PRPF31 protein encoded by the PRPF31 mRNA in the cell is increased82. The method of any one of claims 77 to 81, wherein the miRNA binding site is a binding site of a miR-129-3p and / or miR-1251 -5p microRNA family member.

83. The method of claim 83, wherein the miR-129-3p microRNA family member is hsa-miR-129-l-3p and / or hsa-miR-129-2-3p.

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