Advanced compositions and methods for treatment of kidney disease

Abstract

Described herein are guide nucleic acids, gene editing systems, and related compositions and methods for increasing expression of Polycystin 1 protein and uses thereof for the treatment of autosomal dominant polycystic kidney disease (ADPKD).

Description

[0001] ADVANCED COMPOSITIONS AND METHODS FOR TREATMENT OF KIDNEY DISEASE Technical Field The present disclosure generally is directed to compositions and methods for gene editing for treatment of conditions associated with mutations in the Polycystic Kidney Disease 1 (PKD1) gene. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited nephropathy that leads to end-stage renal disease (ESRD). Approximately 1 in 500–2,500 individuals carry a mutation for this condition. ADPKD is a progressive disorder that is characterised by an abnormal expansion of renal tubule cells resulting in the growth of multiple cysts in the kidney. Cyst development starts early in life and in the more severe cases in utero and is commonly followed by a prolonged period of asymptomatic progression. Signs and symptoms of ADPKD usually present between the ages of 30 and 40. However, approximately 3% of ADPKD patients have either very-early-onset or unusually rapid progressive disease. Consistent with the decline in renal function patients present with various urinary complications such as cyst and urinary tract infections, a decline in glomerular filtration rate, chronic lower back pain and hypertension. ADPKD patients often present with additional extra-renal conditions including hepatic cysts (in >90% of patients aged >35 years), pancreatic cysts, intracranial aneurysms, colon diverticulosis, and heart valve defects. Overall, ADPKD is associated with significant morbidity a reduced life expectancy. ADPKD is predominantly caused by a mutation in one of the polycystin genes; PKD1 (Polycystin 1, Transient Receptor Potential Channel Interacting) (74–85% of patients) or PKD2 (15–26%). The phenotype of patients with a PKD1 mutation is usually more severe compared to those with PKD2 mutations, which is reflected in approximately 20 years difference in the mean age of ESRD (54.3 years in PKD1 vs 74.0 years in PKD2 disease). There is an ongoing need to provide new treatments or preventative measures for ADPKD. Summary PKD1 consists of 46 exons spanning approximately 50 kb of genomic DNA on the short arm of chromosome 16 (16p13.3). The canonical encoded Polycystin 1 protein is a 4,303 amino acid, glycosylated integral membrane protein that localises to primary cilia, endoplasmic reticulum, adherent and desmosomal junctions, apical membranes, plasma membrane and junctional complexes. Polycystin 1 contains a large N-terminal extracellular region, multiple transmembrane domains, and a cytoplasmic C- tail and functions as a regulator of calcium-permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell / matrix interactions and modulation of G-protein-coupled signal-transduction pathways. Splice variants encoding different isoforms have been noted for this gene. While not wishing to be bound by theory, it is believed that kidney cysts develop in ADPKD once the level of Polycystin 1 function falls below a specific level. Indeed, this is consistent with the fact that the level of residual Polycystin 1 function from the mutated gene directly correlates with disease severity. The median age at onset of ESRD was 55 years for carriers of a truncating mutation (complete loss of function) and 67 years for carriers of a non-truncating mutation (partial loss of function). The present disclosure provides guide nucleic acids, e.g., guide RNAs (gRNAs), hybrid guide RNAs, and prime editing guide RNAs and related compositions and methods for genetically editing the PKD1 gene or PKD1 gene mRNAs in vivo or ex vivo in order to increase Polycystin 1 protein levels by modulating the post-transcriptional or translational regulation of the 3' untranslated region (UTR) of PKD1 mRNA, e.g., by reducing or eliminating specific binding of mirR-17 family miRNAs (e.g., miR-17-5p, miR-106a-5p, miR-106b-5p, miR-20a-5p, miR-93-5p) or miR-200 family miRNAs (e.g., miR-200b, miR200c, or miR-429) to their cognate binding sites. Accordingly, in one aspect provided herein is a guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3’ untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; and (ii) a binding scaffold for a gene editor protein or component thereof (e.g., a deaminase). In another aspect provided herein is a guide nucleic acid comprising a spacer corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene and a binding scaffold for a Cas9 nickase, wherein the guide nucleic acid is a guide RNA (gRNA). In another aspect provided herein is a guide nucleic acid comprising (i) a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3’ untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a Cas9 nickase, wherein the guide nucleic acid is a prime editing guide RNA (pegRNA). In a relates aspect provided herein is a guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a gene editor protein or component thereof. In some examples, where the guide nucleic acid comprises a deoxyribonucleotide and a ribonucleotide, the 2' hydroxyl group of the ribose in the ribonucleotide is covalently linked to a methyl group (2'-OMe). In some examples, the binding scaffold binds to a gene editor protein or component thereof comprising a deaminase. In some examples, the binding scaffold binds to a gene editor protein or component thereof comprising a reverse-transcriptase or component thereof. In another aspect provided herein is a gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a guide RNA comprising (i) a spacer sequence, wherein the spacer sequence corresponds or is complementary to a protospacer sequence within a targeted portion of the 3' UTR of the PKD1 gene; and (ii) a binding scaffold for a gene editor protein or component thereof or (b) a prime editing guide RNA comprising (i) a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a gene editor protein or component thereof. In another aspect provided herein is a gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a guide nucleic acid comprising (i) a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a gene editor protein or component thereof. In some examples of a gene editing system provided herein, the gene editor protein comprises a deaminase or component thereof. In some examples of a gene editing system provided herein, the gene editor protein comprises a reverse-transcriptase or component thereof. In some examples a ribonucleotide in the guide nucleic acid sequence comprises a ribose, wherein the 2' hydroxyl group in a ribose is covalently linked to a methyl group (2'-OMe). In other examples the guide nucleic acid sequence comprises an unmodified ribonucleotide. In some examples where the guide nucleic acid sequence comprises a ribose with a 2' hydroxyl group in a ribose is covalently linked to a methyl group (2'-OMe), the ribose is located on position 1, 2 and / or 3 from the 5’ end and / or the 3’end of the guide nucleic acid sequence. In some examples the deoxyribonucleotide is located on position 3, 4, 6, 7, or 8 from the 5' end of the spacer sequence. In some examples of a hybrid guide nucleic acid or gene editing system utilizing a hybrid guide nucleic acid the spacer sequence comprises one to ten deoxyribonucleotides. In some examples the gene editing system comprises a nucleic acid encoding the gene editor protein or component thereof. In some examples the nucleic acid encoding the gene editor protein or the component thereof is a mRNA. In some examples the gene editor protein or component thereof comprises a single fusion protein. In some examples the DNA binding domain comprises a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) protein or a fragment thereof. In some examples the DNA binding domain comprises a catalytically impaired nuclease. In some examples the DNA binding domain comprises a base editing protein or a fragment thereof. In some examples the DNA binding domain comprises a prime editing protein or a fragment thereof. In some examples for any of the above-mentioned guide nucleic acids or gene editing systems, the spacer sequence comprises a phosphorothioate backbone modification (PS). In some examples the spacer sequence comprises a (2'-OMe)PS(2'- OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif. In other examples the spacer sequence comprises a (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif. In some examples either of the foregoing motifs is located at the 5' end of the spacer sequence. In some examples the guide nucleic acid comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one of SEQ ID NOs: 2-9 or 19-62. In some examples the spacer sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one SEQ ID NOs:2-7. In other examples the spacer sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to SEQ ID NO:4 or SEQ ID NO:7. In some examples the guide nucleic acid comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to SEQ ID NO:81 or SEQ ID NO:108. In other examples the extension sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one of SEQ ID NOs:19-62. In some examples, in a gene editing system disclosed herein, the nucleic acid binding domain of the gene editor protein is capable of binding to DNA. In a related aspect provided herein is a gene editing system comprising: (a) Cas9 nickase or a nucleic acid encoding the Cas9 nickase, and (b) a guide RNA comprising (i) a spacer corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene, and (ii) a binding scaffold for a gene editor protein or component thereof or (b) a prime editing guide RNA comprising a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and a binding scaffold for the Cas9 nickase. In some examples the Cas9 nickase comprises a mutation selected from the group consisting of: N692A, M694A, Q695A, H698A, K810A, K855A, K848A, K1003A, R1060A as compared to a Cas9 nickase comprising the amino acid sequence corresponding to SEQ ID NO:911. In some examples the just-mentioned gene editing system comprises a deaminase or component thereof. In other examples the gene editing system comprises a polymerase or component thereof. In some examples the polymerase is a reverse transcriptase. In some examples the Cas9 nickase comprises a single fusion protein with a deaminase or component thereof or with a reverse transcriptase or component thereof. In some examples a gene editing system comprises a Cas9 nickase, as a purified protein. In other examples a gene editing system comprises a nucleic acid encoding the Cas9 nickase. In some examples the encoding nucleic acid is a mRNA. In some examples the Cas9 nickase comprises an amino acid sequence having at least 90% identity to SEQ ID NO:911. In some examples in any of the gene editing systems provided herein component (a) and (b) are constituent components of a pharmaceutical composition that comprises a lipid nanoparticle (LNP) containing (a) and / or (b), wherein the LNP comprises an amino lipid, a phospholipid, a sterol (e.g., cholesterol) and a PEG lipid. In some examples the LNP comprises a delivery moiety. In some examples the delivery moiety is selected from the group consisting of: lipids, peptides, polyethers, carbohydrates, and antibodies. In some examples the delivery moiety comprises a receptor binding domain (RBD). In other examples the delivery moiety comprises a N-acetylgalactosamine (GalNAc) moiety, a poly(ethylene glycol) (PEG) moiety, a fatty acid moiety, or a lipid moiety. In other examples the delivery moiety comprises a cell-penetrating peptide (CPP). In some examples the amino acid sequence of the CPP comprises SEQ ID NO:914. In some examples the delivery moiety targets the LNP to kidney. In some examples the gene editing system is not provided in a human in vivo. In a related aspect provided herein is a pharmaceutical composition comprising any guide nucleic acid or gene editing system disclosed herein and a pharmaceutically acceptable excipient. In a further related aspect provided herein is a method for treating ADPKD, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein, whereby a level of Polycystin 1 protein is increased in a kidney in the subject. In another related aspect provided herein is the use of a guide nucleic acid or gene editing system disclosed herein in the manufacture of a medicament for treatment of ADPKD in a subject in need thereof. In a further related aspect provided herein is a guide nucleic acid or gene editing system provided herein for use in the treatment of ADPKD in a subject in need thereof. In some examples of the above-mentioned method or use, treatment of the subject introduces at least one nucleotide modification within a binding site sequence for a miR- 17 family member or a miR-200 family member within the targeted portion, whereby binding of the miR-17 or miR-200 family member is reduced or eliminated. In other examples of the above-mentioned method or use, treatment of the subject results in deletion of the seed sequence or a subsequence thereof for a miR-17 family member (e.g., miR-17-5p, miR-106a-5p, miR-106b-5p, miR-20a-5p, or miR-93-5p miRNA) or a miR- 200 family member (e.g., miR-200b, miR200c, or miR-429 miRNA), whereby binding of the miR-17 family or miR-200 family member is reduced or eliminated. Brief Description of the Accompanying Drawings Figure 1 – Schematic illustration of PKD1 exon-intron structure, miRNA binding sites in PKD 3' UTR, and relative binding positions of exemplary guide nucleic acids. Schematic illustration of PKD1 exon-intron structure of the canonical transcript ENST00000262304.9, miRNA binding sites in PKD 3' UTR. (A) Exon / -Intron map of human PKD1 pre-mRNA; (B) A segment of PKD1 mRNA 3' UTR sequence that includes binding site for miR-17 family miRNAs (in bold). Figure 2 – Vector map depicting a dual luciferase vector comprising essential elements for investigating the activity of the miR-17 binding site in modulating gene expression levels. The design of plasmid construct (Vector Builder, 6273 bp) with two luciferase reporter genes was used for the dual-luciferase assay, including plasmid replication gene (pUC ori), plasmid selection marker (ampicillin antibiotics), a primary reporter gene, Nanoluciferase (Nluc) the expression of which is driven by the eukaryotic elongation factor 1 alpha (EF1-alpha) promoter and terminated by the PKD13' UTR followed by a bovine growth hormone polyadenylation (bGA-polyA) signal; the construct also includes a control reporter gene, Firefly luciferase (“luciferase”) expression cassette under the control of a separate promoter (SV40) and terminator (SV40 late pA). Inclusion of the PKD1 3' UTR confers PKD13' UTR-dependent modulation of the Nluc luciferase signal as a proxy readout for the post-transcriptional regulation of the reporter transcript by the PKD1 3' UTR sequence. Figure 3 – Modulation of luciferase reporter activity based on the modification of the binding site of miR-17 within the PKD13' UTR. Plasmid construct(s) that comprised unmodified (WT) or modified PKD1-3' UTR sequence comprising the modified miR-17 binding sites shown in Table 1 was transfected in HEK-293 cells via lipofection in triplicate. Luciferase activity of the plasmids comprising various type of base modification within the seed sequences of miR- 17 in the PKD13' UTR was assessed. Results were reported as a fold change in primary gene expression normalised to reporter gene expression to demonstrate PKD13' UTR- dependent luciferase activity. Labelled bars in bar graph are shown from left to right representing the expression level of PKD13' UTR vector comprising the unmodified miR-17 seed binding sequence, which was set to a relative level of 1, and for modified PKD1 3' UTR constructs. The results indicated a significant increase in primary gene (NLuc) expression containing the modified PKD13' UTR by 1.3-2-fold compared to the signal observed from the unmodified PKD13' UTR construct (n=4). Complete deletion of the miR-17 seed sequence led to up to a 1.4-fold upregulation, suggesting the importance of this sequence element within the 3' UTR for gene expression regulation. Applying a deletion of 1-2 bases within the seed sequence, particularly at base positions 3 and 4, resulted in a 1.6-2.0-fold upregulation, indicating the potential significance of these bases for miR-17 binding-mediated gene repression. Additionally, base substitution within the seed sequence could facilitate upregulation of gene expression. These findings suggest that altering the sequence within the seed sequence for miRNA binding could modulate gene expression due to reduced or abolished miRNA binding to the target mRNA. Data are plotted as mean + standard deviation. Statistical significance is shown as *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001. Figure 4 – Base editing with CBE system successfully substituted target nucleotide on PKD1-3’UTR sequence. Plasmid construct that comprised sgRNAs (SEQ ID NOs:63 and 99, shown in Table 5), xCas9-ABE, puromycin resistant marker and PiggyBac transposon, as well as a plasmid expressed PiggyBac DNA transposase were co-transfected via lipofection in triplicates in HEK293 cells. Likewise, plasmids co-expressing sgRNAs (SEQ ID NOs:81 and 108, shown in Table 5) and xCas9-BE4 in the same PiggyBac DNA transportase system were also performed lipofectamine transfection in HEK293 cells. After 2 days post-transfection, cells were cultured in media with puromycin to select for edited cells. DNA samples were extracted at day 10-15 post puromycin selection and analysed for gene editing efficiency by PCR and Sanger sequencing. In contrast to HEK293 wild type sequence, CBE system positively edited the nucleotide target (C to T conversion). a) Transfection of SEQ ID NO:81 significantly substituted C to T by 60% at 10-days post-transfection and the editing efficiency sustained till day 15 (64%). b) Additionally, a moderate C-T conversion (SEQ ID NO:108, the second C at position 8, 5’-3’read) was detected with the transfection of SEQ ID NO:108, indicating by a time- dependent editing efficiency (36-46%) shown at the same transfection period. The first C at position 5 of SEQ ID NO:108 remained no change following transfection. These two sgRNAs were selected for mRNA and protein validation. c) Whereas SEQ ID NOs:63 and 99 (ABE system) were assessed as showing no editing at day 10 post- transfection. Figure 5 – Base editing with SEQ ID NO:81 up-regulated PKD1 mRNA expression at day-15 post-transfection. Plasmid construct that comprised sgRNAs (SEQ ID NOs:81 and 108, shown in Table 5) and xCas9-BE4 conjugated with PiggyBac transposon and plasmid expressed PiggyBac DNA transposase were co-transfected via lipofection in triplicates in HEK293 cells. Edited cells were selected in culture media containing puromycin at 2-days post- transfection. RNA samples were extracted at day 15 puromycin post-selection and mRNA expression was assessed by via PKD1 quantitative RT-PCR. Cells treated with siRNA (ORIGENE, catalogue number SR321327) via RNAiMAX (Thermofisher, catalogue number 3778075) for 5 days were used as negative controls for the assay. Following 15-days post-transfection, SEQ ID NO:81 increased PKD1 mRNA expression by 1.4-fold, while SEQ ID NO:108 had no significant change on PKD1 mRNA levels, by compared to wild type HEK293 cells. These data suggest SEQ ID NO:81-based editing enables upregulation of PKD1 mRNA levels while SEQ ID NO:108 had little effect on altering PKD1 transcriptional levels. Data are plotted as one biological replicate. Figure 6 – Base editing with SEQ ID NO:81 and SEQ ID NO:108 enhanced PC1 protein expression. Plasmid construct that comprised base editing spacer sequences (SEQ ID NOs:4 and 7, shown in Table 2) and xCas9-BE4 conjugated with PiggyBac transposon and plasmid expressed PiggyBac DNA transposase were co-transfected via lipofection in triplicate in HEK293 cells. Edited cells were selected in culture media containing puromycin at 2-days post-transfection. Protein lysates were harvested at day 15 of puromycin selection and assessed the protein expression via PC1 Western Blot. Cells treated with siRNA (ORIGENE, catalogue number SR321327) via RNAiMAX (Thermofisher, catalogue number 3778075) for 5 days were used as negative controls for the assay. Transfection with plasmids encoding sgRNAs corresponding to SEQ ID NOs:81 and 108 significantly enhanced PC1 protein expression by 1.5-fold and 1.3-fold at day 15 post-transfection, respectively. These data suggest that base editing utilizing SEQ ID NOs:81 and 108 enables up-regulation of PC1 protein expression, including SEQ ID NO:81 that translates the mRNA effect to protein levels and SEQ ID NO:108 with specific regulation on protein expression. Data are plotted in mean + standard deviation. Statistical significance is shown as *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001. Figure 7 – Base editing with SEQ ID NO:81 and SEQ ID NO:108 reduced cAMP production. HEK293 cells that were edited with SEQ ID NO:81 and SEQ ID NO:108 were selected to obtain homozygous monoclonal lines (100% of the monoclonal cell population having the edit). Monoclonal cells were seeded for 48-hours and assessed the PC1 protein function via cAMP assay. Forskolin (an adenylyl cyclase activator) was used as a positive control for the assay. Cells edited with SEQ ID NOs:81 and 108 significantly reduced cAMP levels by 40%, compared to the HEK293 cells transfected with an empty vector. These data suggest HEK293 cells edited using SEQ ID NOs:81 and 108 could enhance calcium signalling due to an increase in PC1 protein expression. Data are plotted in mean + standard deviation. Statistical significance is shown as ****p<0.0001. Detailed Description General 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. Each example of the present disclosure described herein is to be applied mutatis mutandis to each and every other example unless specifically stated otherwise. Those skilled in the art will appreciate that the disclosure herein 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. 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 disclosure, as described herein. The present disclosure is performed without undue experimentation using, unless otherwise indicated, conventional techniques of molecular biology, microbiology, virology, recombinant DNA technology, peptide synthesis in solution, solid phase peptide synthesis, and immunology. Such techniques are described and explained throughout the literature in sources such as Perbal 1984, Sambrook et al., 2001, Brown (editor) 1991, Glover and Hames (editors) 1995 and 1996, Ausubel et al. including all updates until present, Coligan et al. (editors) (including all updates until present), Maniatis et al. 1982, Gait (editor) 1984, Hames and Higgins (editors) 1984, Freshney (editor) 1986. 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. 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). 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. The term "nucleic acid," as used herein, refers to a polymer containing at least two nucleotides (i.e., deoxyribonucleotides or ribonucleotides) in either single- or double-stranded form and includes DNA and RNA, hybrids of DNA and RNA, and combinations thereof. The term "nucleic acid," as used herein, also refers to a polymer containing at least two chemically modified nucleotides (i.e., deoxyribonucleotides or ribonucleotides) in either single- or double-stranded form and includes DNA and RNA, hybrids of DNA and RNA, and combinations thereof. A nucleic acid includes any oligonucleotide or polynucleotide, with fragments containing up to 60 nucleotides generally termed oligonucleotides, and longer fragments termed polynucleotides. A deoxyribo-oligonucleotide consists of a 5-carbon sugar called deoxyribose joined covalently to phosphate at the 5' and 3' carbons of this sugar to form an alternating, unbranched polymer. A ribooligonucleotide consists of a similar repeating structure where the 5-carbon sugar is ribose. Accordingly, the terms "polynucleotide" and "oligonucleotide" can refer to a polymer or oligomer of nucleotide or nucleoside monomers consisting of naturally-occurring bases, sugars and inter-sugar (backbone) linkages. Additionally, nucleic acids include nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, nonstandard, and / or non-naturally occurring, and which have similar binding properties as the reference nucleic acid. The nucleic acid may be modified at the base moiety (e.g., at one or more atoms that typically are available to form a hydrogen bond with a complementary nucleotide and / or at one or more atoms that are not typically capable of forming a hydrogen bond with a complementary nucleotide), sugar moiety, or phosphate backbone. Backbone modifications can include, but are not limited to, a phosphorothioate, a phosphorodithioate, a phosphoroselenoate, a phosphorodiselenoate, a phosphoroanilothioate, a phosphoraniladate, a phosphoramidate, and a phosphorodiamidate linkage. A phosphorothioate linkage substitutes a sulfur atom for a non-bridging oxygen in the phosphate backbone and delays nuclease degradation of oligonucleotides. A phosphorodiamidate linkage (N3′→P5′) reduces or prevents nuclease recognition and degradation. Backbone modifications can also include having peptide bonds instead of phosphorous in the backbone structure (e.g., N-(2- aminoethyl)glycine units linked by peptide bonds in a peptide nucleic acid), or linking groups including carbamate, amides, and linear and cyclic hydrocarbon groups. Nucleic acid molecules described herein may contain a sugar moiety that comprises ribose or deoxyribose, as present in naturally occurring nucleotides, or a modified sugar moiety or sugar analog. The examples of modified sugar moieties include, but are not limited to, 2'-O-methyl, 2'-O-methoxyethyl, 2'-O-aminoethyl, 2' - Fluoro, N3′→P5′ phosphoramidate, 2'dimethylaminooxyethoxy, 2' 2'dimethylaminoethoxyethoxy, 2'-guanidinidium, 2'-O-guanidinium ethyl, carbamate modified sugars, and bi cyclic modified sugars. 2'-O-methyl or 2'-O-methoxyethyl modifications promote the A-form or RNA-like conformation in oligonucleotides, increase binding affinity to RNA, and have enhanced nuclease resistance. Modified sugar moieties can also include having an extra bridge bond (e.g., a methylene bridge joining the 2'-O and 4'-C atoms of the ribose in a locked nucleic acid) or sugar analog such as a morpholine ring (e.g., as in a phosphorodiamidate morpholino). Examples of such analogs and / or modified residues include, but are not limited to diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5- carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5--methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2- methylthio-N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5- oxyacetic acid methylester, 5-methyl-2-thiouracil, 3-(3-amino- 3- N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, methyl phosphonates, chiral- methyl phosphonates, 2'-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like. In some cases, nucleotides may include modifications in their phosphate moieties, including modifications to a triphosphate moiety. Non-limiting examples of such modifications include phosphate chains of greater length (e.g., a phosphate chain having, 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications with thiol moieties (e.g., alpha-thiotriphosphate and beta-thiotriphosphates). Such modified or substituted oligonucleotides are often preferred over native forms because of properties such as, for example, enhanced cellular uptake, reduced immunogenicity, and increased stability in the presence of nucleases. Thus, the terms "polynucleotide" and "oligonucleotide" can also include polymers or oligomers comprising non-naturally occurring monomers, or portions thereof, which function similarly. The term "nucleoside" refers to a compound that consists of a base combined with deoxyribose or ribose. Nucleosides include but not limited to, ribonucleoside and deoxyribonucleoside. Nucleosides are phosphorylated to give nucleotides. Ribonucleosides include adenosine (A), guanosine (G), 5-methyluridine (m5U), uridine (U), and cytidine (C). Deoxyribonucleosides include deoxyadenosine (dA), deoxyguanosine (dG), deoxythymidine (dT), deoxyuridine (dU), deoxycytidine (dC). The deoxyribose or ribose (i.e., sugar moieties) can be modified. The examples of modified sugar moieties include, but are not limited to, 2'-O-methyl, 2'-O-methoxyethyl, 2'-O-aminoethyl, 2'-Fluoro, N3′→P5′ phosphoramidate, 2'dimethylaminooxyethoxy, 2' 2'dimethylaminoethoxyethoxy, 2'-guanidinidium, 2'-O-guanidinium ethyl, carbamate modified sugars, and bi cyclic modified sugars. 2'-O-methyl or 2'-O-methoxyethyl modifications promote the A-form or RNA-like conformation in oligonucleotides, increase binding affinity to RNA, and have enhanced nuclease resistance. Modified sugar moieties can also include having an extra bridge bond (e.g., a methylene bridge joining the 2'-O and 4'-C atoms of the ribose in a locked nucleic acid) or sugar analog such as a morpholine ring (e.g., as in a phosphorodiamidate morpholino). Examples of such analogs and / or modified residues include, but are not limited to diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5- carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1- methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5- methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio- N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5- methyluracil, uracil-5- oxyacetic acid methylester, 5-methyl-2-thiouracil, 3-(3-amino- 3- N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, methyl phosphonates, chiral- methyl phosphonates, 2'-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like. The term “nucleotide deaminase” or“deaminase,” as used herein, refers to an enzyme that catalyzes deamination of adenine or cytidine, or a polypeptide fragment of such an enzyme that retains such function. The term "motif," as used herein, refers to a pattern or an arrangement of specific nucleotides, for example, a motif can refers to (i) one or more 2'-deoxyribonucleotides within a spacer, (ii) a combination of one or more 2'-deoxyribonucleotides and one or more ribonucleotides within the spacer, (iii) a combination of one or more 2' - deoxyribonucleotides, one or more ribonucleotides, and one or more 2'-O-Me ribonucleotides within the spacer, wherein the 2'-OMe ribonucleotide can be at the 5'- end or at the 3'-end of a 2'-deoxyribonucletide, (iv) a combination of one or more 2'- deoxyribonucleotides and one or more 2'-OMe ribonucleotides within the spacer, wherein the 2'-OMe ribonucleotide can be placed / located at the 5' -end or at the 3'-end of the 2'deoxynucleotides, or (v) any of the motifs disclosed earlier (i-iv) further comprising a phosphonothioate backbone. The term "nucleotide" refers to a molecule that contains a sugar deoxyribose (DNA) or ribose (RNA), a base, and a phosphate group. Nucleotides are linked together through the phosphate groups. "Bases" include purines and pyrimidines, which further include natural compounds adenine, thymine, guanine, cytosine, uracil, inosine, and natural analogs, and synthetic derivatives of purines and pyrimidines, which include, but are not limited to, modifications which place new reactive groups such as, but not limited to, amines, alcohols, thiols, carboxylates, and alkylhalides. The term "off-targeting," "off-site targeting," or "off-target effect" as used herein refers to when the spacer of the guide nucleic acid binds to a sequence of the genome other than the target sequence to which the spacer was specifically designed to bind. The resulting unintentional binding would lead to unintentional editing of genes other than the target gene. The phrase “binds to a targeted portion” or “binds within a targeted portion,” in reference to a guide nucleic acid, as used herein, refers to specific hybridization between the guide 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 guide nucleic acid, under such ex vivo conditions, hybridizes 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 ºC. The skilled person will appreciate that under in vivo conditions, the specificity of hybridization between a guide nucleic acid and its target sequence is defined in terms of the level of complementarity between the guide nucleic acid and the target sequence to which it hybridizes within a cell. 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. 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. 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 (Orn), 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 glycine. Peptides may be linear peptides or cyclic peptides. 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. 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. 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. A CPP may direct a molecule of interest, such as a guide nucleic acid disclosed herein, from outside a cell through the plasma membrane, and into the cytoplasm or a desired subcellular compartment. In other examples a CPP is associated with a lipid nanoparticle (LNP) that encapsulated a guide nucleic acid, a gene editor protein, or a gene editing system. Alternatively, or in addition, a CPP may direct a molecule of interest or an LNP across the, epithelial, endothelial, basement membrane, trans- mucosal, cardiovascular, skin, gastrointestinal and / or pulmonary barriers. In some examples the CPP is selectively targeted to or taken up by the kidneys. 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. A peptide ligand via its binding to a target receptor may direct a molecule of interest, such as a guide nucleic acid or LNP 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 or LNP across a relevant biological barrier, e.g., the renal basement membrane, blood-brain, trans-mucosal, hematoretinal, cardiovascular, skin, gastrointestinal, and / or pulmonary barriers. The term "protospacer," or "target sequence" and their grammatical equivalents as used herein can refer to a DNA sequence of a target gene. In the native state, a protospacer is adjacent to a PAM (protospacer adjacent motif). The site of cleavage by an RNA-guided nuclease is within a protospacer sequence. The term "spacer" or "spacer sequence" refers to a guide nucleic acid sequence (e.g., in a gRNA or perRNA) that is complementary and binds to the its target sequence. In some examples the target sequence is on the sense strand of a target gene. In other examples the target sequence is on the antisense strand of the target gene. Typically, selection of the sense strand or antisense strand for targeting will depend on the location / availability of a protospacer adjacent motif (PAM). The term "extension" and its grammatical equivalents as used herein can refer to a nucleotide acid sequence that provides a template (i.e., acts to “template” or “templates” for short) the synthesis of the desired edit in the form of a replacement DNA strand. The term "base editing," "prime editing," "gene editing," "genome editing," or "gene modification" and its grammatical equivalents as used herein can refer to genetic engineering in which one or more nucleotides are modified, inserted, replaced, or removed from a genome. Gene editing can be performed using a nuclease (e.g., a natural- existing nuclease or an artificially engineered nuclease). Gene modification can include introducing a double stranded break, a non-sense mutation, a frameshift mutation, a splice site alteration, or an inversion in a polynucleotide sequence, e.g., a target region sequence such as a miRNA binding site in the 3′ UTR region of PKD1. The term "base editor" as used herein can refer to an agent that binds a polynucleotide and has nucleobase modifying activity. The base editor can comprise a nucleobase modifying polypeptide (e.g., a deaminase) and a nucleic acid programmable nucleotide binding domain in conjunction with a guide polynucleotide (e.g., gRNA), or nucleic acids encoding the programmable nucleotide binding domain and the deaminase. The agent can be a biomolecular complex comprising a protein domain having base editing activity, i.e., a domain capable of modifying a base (e.g., A, T, C, G, or U) within a nucleic acid molecule (e.g., DNA), or a nucleic acid encoding the same. The polynucleotide programmable DNA binding domain can be fused or linked to a deaminase domain, resulting in a base editor fusion protein. The base editor can comprise a nucleic acid encoding the base editor fusion protein, e.g., a mRNA encoding the base editor fusion protein. The base editor fusion protein can comprise one or more linkers, for example, peptide linkers. The agent can be a fusion protein comprising a domain having base editing activity. The protein domain having base editing activity can be linked to the guide RNA (e.g., via an RNA binding motif on the guide RNA and an RNA binding domain fused to the deaminase). In some examples, the domain having base editing activity is capable of deaminating a base within a nucleic acid molecule. In some examples, the base editor is capable of deaminating one or more bases within a DNA molecule. In some examples, the base editor is capable of deaminating an adenosine (A) within DNA (an adenosine base editor (ABE)). In some examples, the base editor is capable of deaminating a cytosine (C) within DNA (a cytosine base editor (CBE)). The term "base editor system," as used herein, refers to a gene editing system for editing a single nucleobase of a target nucleotide sequence. In various examples, the base editor system comprises (1) a nucleic acid-programmable nucleotide binding domain (e.g., from Cas9); (2) a deaminase domain (e.g., an adenosine deaminase or a cytidine deaminase) for deaminating said nucleobase; and (3) one or more guide nucleic acids (e.g., gRNAs). In some examples, the base editor system comprises a base editor fusion protein comprising (1) and (2). In some examples, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some examples, the base editor is an adenine or adenosine base editor (ABE). In some examples, the base editor is a cytosine base editor (CBE). The term "prime editing," as used herein, refers to a form of precise genome editing that enables direct, irreversible targeted small insertions, deletions, and base swapping without requiring double- stranded DNA breaks (DSBs), or donor DNA templates. In some examples, DNA prime editors comprise a catalytically disabled Cas9 nuclease fused to a reverse transcriptase. Prime editing comprises the use of a prime editing guide RNA (pegRNA) that is substantially larger than a standard sgRNA used for CRISPR Cas9 editing. The pegRNA comprises a primer binding sequence (PBS) and a template containing the desired RNA sequence added at the 3' end. The term "CRISPR RNA" (crRNA) herein refers to an RNA sequence that can form a complex with one or more Cas proteins (e.g., Cas9) and provides DNA binding specificity to the complex. A crRNA provides DNA binding specificity since it contains a "spacer sequence" that is complementary to a strand of a DNA target sequence. A crRNA further comprises a "repeat sequence" ("tracr RNA mate sequence") encoded by a repeat region of the CRISPR locus from which the crRNA was derived. A repeat sequence of a crRNA can anneal to sequence at the 5'end of a tracrRNA crRNA in native CRISPR systems is derived from a "pre-crRNA" transcribed from a CRISPR locus. A pre-crRNA comprises spacer regions and repeat regions; spacer regions contain unique sequence complementary to a DNA target site sequence. Pre-crRNA in native systems is processed to multiple different crRNAs, each with a guide sequence along with a portion of repeat sequence. CRISPR systems utilize crRNA, for example, for DNA targeting specificity. The term "trans-activating CRISPR RNA" (tracrRNA) herein refers to a non-coding RNA used in type II CRISPR systems, and contains, in the 5'-to-3' direction, (i) a sequence that anneals with the repeat region of CRISPR type II crRNA and (ii) a stem loop-containing portion (Deltcheva et al., 2011, Nature, 471 :602-607). A modified tracrRNA refers to a tracrRNA with modified ribonucleotide (e.g., 2'-OMe modified RNA). As used herein, the term "guide nucleic acid", refers to a polynucleotide sequence that can form a complex with a Cas endonuclease and enables the Cas endonuclease to recognize and optionally cleave a DNA target site. The guide nucleic acid can be a single molecule or a double molecule. The guide nucleic acid sequence can be DNA only (gDNA). The DNA can be modified or unmodified. The guide nucleic acid sequence can be RNA only (gRNA or pegRNA). The RNA can be modified or unmodified. The guide nucleic acid sequence can be a combination of DNA and RNA. Optionally, the guide nucleic acid can comprise at least one nucleotide, phosphodiester bond or linkage modification such as, but not limited, to Locked Nucleic Acid (LNA), 5-methyl dC, 2,6- Diaminopurine, 2'-Fluoro A, 2'-Fluoro U, 2'-O-Methyl RNA, Phosphorothioate bond, linkage to a cholesterol molecule, linkage to a polyethylene glycol molecule, linkage to a spacer 18 (hexaethylene glycol chain) molecule, or 5' to 3' covalent linkage resulting in circularization. A guide nucleic acid that solely comprises ribonucleic acids is referred to as a "guide RNA." A guide nucleic acid that comprises both RNA and DNA is referred to as a "guide RDNA" or “hybrid guide nucleic acid.” Compositions for Increasing Polycystin 1 Protein Levels 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. In the case of the Polycystic Kidney Disease 1 (PKD1) gene that encodes Polycystin 1 protein, miRNAs that bind to the 3' UTR and of the encoding mRNA transcript include miR-17 family miRNAs (e.g., miR-17-5p, miR-106a-5p, miR-106b- 5p, miR-20a-5p, miR-93-5p) and miR-200 family miRNAs (e.g., miR-200b, miR200c, or miR-429). While not wishing to be bound by theory, it is believed that by mutating or deleting binding sites for microRNAs located within the PKD1 mRNA 3' UTR binding of the corresponding miRNAs to these locations on the PKD13' UTR will be reduced or eliminated, ultimately resulting in increases in Polycystin 1 protein levels. A number of advanced genetic editing systems are available to introduce desired changes in the desired target regions of PKD1. Several of such systems are summarised below. CRISPR / Cas Systems There are several different CRISPR / Cas systems. The CRISPR / Cas system presents a number of number of advantages compared to other methods of genome editing involving endonucleases, meganucleases, zinc finger nucleases, and transcription activator-like effector nucleases (TALENs), which may require de novo protein engineering for every new target locus. Based upon the genes encoding the effector module (i.e., the proteins involved in the interference stage), the CRISPR / Cas systems can be placed in either Class 1 or Class 2. Class 1 systems have a multi-subunit crRNA-effector complex, whereas Class 2 systems have a single protein, such as Cas 9, Cpfl, C2cl, C2c2, C2c3, or a crRNA-effector complex. Class 1 systems comprise Type I, Type III and Type IV systems. Class 2 systems comprise Type II and Type V systems (Makarova et al., 2015, Nature Review Microbiology, 13: 1-15). Type I systems all have a Cas3 protein with helicase activity and cleavage activity. Type I systems are divided into seven sub-types (I-A to I-F and I-U). Type III systems possess a casJO gene, which encodes a multi domain protein containing a Palm domain (a variant of the RNA recognition motif (RRM)) that is homologous to the core domain of numerous nucleic acid polymerases and cyclases and that is the largest subunit of type III crRNA-effector complexes. All type III loci also encode the small subunit protein, one Cas5 protein and typically several Cas7 proteins. Type III can be divided into four sub-types, III-A to III-D. Sub-type III-A has a csm2 gene encoding a small subunit and also has casl, cas2 and cas6 genes. Sub-type III-B has a cmr5 gene encoding a small subunit and also typically lacks casl, cas2 and cas6 genes. Sub-type III-C has a Casl0 protein with an inactive cyclase-like domain and lacks a casl and cas2 gene. Sub-type III-D has a Casl10 protein that lacks the HD domain, it lacks a casl and cas2 gene and has a cas5-like gene known as csx10. Type IV systems encode a minimal multisubunit crRNA effector complex comprising a partially degraded large subunit, Csfl, Cas5, Cas7, and in some cases, a putative small subunit. Type IV systems lack casl and cas2 genes. Type IV systems do not have sub-types, but there are two distinct variants. One variant has a DinG family helicase, while the other variant lacks a DinG family helicase, but has a gene encoding a small α-helical protein. Type II systems have casl, cas2 and cas9 genes. cas9 encodes a multidomain protein that combines the functions of the crRNA-effector complex with target DNA cleavage. Type II systems also encode a tracrRNA. Type II systems are divided into three sub-types, subtypes II-A, II-B and II-C. Sub-type II-A contains an additional gene, csn2. Sub-type II-B lacks csn2, but has cas4. Sub-type II-C is the most common Type II system found in bacteria and has only three proteins, Casl, Cas2 and Cas9. Type V systems have a cpfl gene and casl and cas2 genes. The cpfl gene encodes a protein, Cpfl, that has a RuvC-like nuclease domain that is homologous to the respective domain of Cas9, but lacks the HNH nuclease domain that is present in Cas9 proteins. In Class 1 systems, the expression and interference stages involve multisubunit CRISPR RNA (crRNA)-effector complexes. In these systems, pre-crRNA is bound to the multisubunit crRNA-effector complex and processed into a mature crRNA. In Type I and III systems this involves an RNA endonuclease, e.g., Cas6. In Class 1 systems the crRNA is associated with the crRNA-effector complex and achieves interference by combining nuclease activity with RNA-binding domains and base pair formation between the crRNA and a target nucleic acid. In Type I systems, the crRNA and target binding of the crRNA-effector complex involves Cas7, Cas5, and Cas8 fused to a small subunit protein. The target nucleic acid cleavage of Type I systems involves the HD nuclease domain, which is either fused to the superfamily 2 helicase Cas3' or is encoded by a separate gene, cas3. In Type III systems, the crRNA and target binding of the crRNA-effector complex involves Cas7, Cas5, Cas10 and a small subunit protein. The target nucleic acid cleavage of Type III systems involves the combined action of the Cas7 and Cas 10 proteins, with a distinct HD nuclease domain fused to Cas 10, which is thought to cleave single- stranded DNA during interferences. In Class 2 systems, the expression and interference stages involve a single large protein, e.g., Cas9, Cpfl, C2Cl, C2C2, or C2C3. In most Class 2 Type II systems, pre- crRNA is bound to Cas9 and processed into a mature crRNA in a step that involves RNase III and a tracrRNA. In Class 2 systems the crRNA is associated with a single protein and achieves interference by combining nuclease activity with RNA-binding domains and base pair formation between the crRNA and a target nucleic acid. In Type II systems, the crRNA and target binding involves Cas9 as does the target nucleic acid cleavage. In Type II systems, the RuvC-like nuclease (RNase H fold) domain and the HNH (McrA-like) nuclease domain of Cas9 each cleave one of the strands of the target nucleic acid. The Cas9 cleavage activity of Type II systems also requires hybridization of crRNA to tracrRNA to form a duplex that facilitates the crRNA and target binding by the Cas9. In Type V systems, the crRNA and target binding involves Cpfl as does the target nucleic acid cleavage. In Type V systems, the RuvC-like nuclease domain of Cpfl cleaves both strands of the target nucleic acid in a staggered configuration, producing 5' overhangs, which is in contrast to the blunt ends generated by Cas9 cleavage. These 5' overhangs may facilitate insertion of DNA through non-homologous end-joining (NHEJ) methods. The Cpfl cleavage activity of Type V systems also does not require hybridization of crRNA to tracrRNA to form a duplex, rather the crRNA of Type V systems use a single crRNA that has a stem loop structure forming an internal duplex. Cpfl binds the crRNA in a sequence and structure specific manner, that recognizes the stem loop and sequences adjacent to the stem loop, most notably, the nucleotide 5' of the spacer sequences that hybridizes to the target nucleic acid. This stem loop structure is typically in the range of 15 to 19 nucleotides in length. Substitutions that disrupt this stem loop duplex abolish cleavage activity, whereas other substitutions that do not disrupt the stem loop duplex do not abolish cleavage activity. In Type V systems, the crRNA forms a stem loop structure at the 5' end and the sequence at the 3' end is complementary to a sequence in a target nucleic acid. Other proteins associated with Type V crRNA and target binding and cleavage include Class 2 candidate I (C2c1) and Class 2 candidate 3 (C2c3). C2c1 and C2c3 proteins are similar in length to Cas9 and Cpf1 proteins, ranging from approximately 1,100 amino acids to approximately 1,500 amino acids. C2c1 and C2c3 proteins also contain RuvC-like nuclease domains and have an architecture similar to Cpfl. C2c1 proteins are similar to Cas9 proteins in requiring a crRNA and a tracrRNA for target binding and cleavage, but have an optimal cleavage temperature of 50°C. C2c1 proteins target an AT-rich PAM, which similar to Cpf1, is 5' of the target sequence. Class 2 candidate 2 (C2c2) does not share sequence similarity to other CRISPR effector proteins, and therefore may be in a putative Type VI system. C2c2 proteins have two HEPN domains and are predicted to have RNase activity, and therefore may target and cleave mRNA. C2c2 proteins appear similar to Cpf1 proteins in requiring crRNA for target binding and cleavage, while not requiring tracrRNA. Also like Cpfl, the crRNA for C2c2 proteins forms a stable hairpin, or stem loop structure, that may aid in association with the C2c2 protein. The gene editing systems provided herein may comprise Class I or Class 2 system components, including ribonucleic acid protein complexes. The Class 2 Cas nuclease families of proteins are enzymes with DNA endonuclease activity, and they can be directed to cleave a desired nucleic acid target by designing an appropriate guide RNA, as described further herein. A Class 2 CRISPR / Cas system component may be from a Type II, Type IIA, Type IIB, Type IIC, Type V, or Type VI system. Class 2 Cas nucleases include, for example, Cas9 (also known as Csnl or Csxl2), Csn2, Cas4, Casl2a (Cpfl), Casl2b (C2cl), Casl2c (C2c3), Casl3a (C2c2), Cas13b, Cas13c, and Cas13d proteins. In some examples, the Cas protein is from a Type II CRISPR / Cas system, i.e., a Cas9 protein from a CRISPR / Cas9 system, or a Type V CRISPR / Cas system, e.g., a Casl2a protein. In some examples, the Cas protein is from a Class 2 CRISPR / Cas system, i.e., a single-protein Cas nuclease such as a Cas9 protein or a Casl2a protein. Other non- limiting examples of Cas proteins can include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas10, Csyl, Csy2, Csy3, Cse1, Cse2, Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csf1, Csf2, CsO, Csf4, Cpf1, Cas9HiFi, homologues thereof, or modified versions thereof. Base Editing / Base Editing Systems Class 2 CRISPR / Cas systems, particularly CRISPR / Cas9 systems, have been used for precision genome editing. Through the use of a guide RNA (gRNA) with a sequence homologous to that of a sequence of DNA in the target genome (known as the protospacer) adjacent to a specific protospacer-adjacent motif (PAM) comprising the sequence NGG (N is any standard base) in the DNA, Cas9 can be used to create a double- strand break (DSB) at the targeted sequence. NHEJ at DSBs can be used to create indels and knock out genes at genetic loci; likewise, homology-directed repair (HDR) can be used, with an introduced template DNA, to insert genes or modify the targeted sequence. In some examples, provided herein are base editor systems capable of nucleobase modifications in the PKD1 gene. In some examples, the base editor system comprises (i) a guide nucleic acid directed to a targeted portion of the PKD13' untranslated region (UTR) or a nucleic acid encoding same, and (ii) a base editor fusion protein comprising a programmable DNA binding domain (e.g., Cas9 or dCas9) and a deaminase or component thereof, or a nucleic acid encoding same. In some examples, the base editor system comprises a guide polynucleotide. In some examples, the base editor system comprises a nucleic acid encoding a guide polynucleotide. In some examples, the base editor system comprises a base editor fusion protein comprising a programmable DNA binding domain and a deaminase. In some examples, the base editor system comprises a nucleic acid encoding a base editor fusion protein comprising a programmable DNA binding domain and a deaminase. Prime Editing The disclosed gene editing systems can encompass a prime editing CRISPR system or a component thereof. Prime editing is a variation on CRISPR systems which expands the guide RNA's responsibility to serve two purposes: to guide Cas9 to a targeted genomic location, and to serve as an RNA template to copy new sequences into the DNA genome (Anzalone AV et al., 2019, Nature, 576:149-157). Similar to CRISPR, prime editing requires the presence of a catalytically modified Cas endonuclease and a single guide RNA. The Cas9 endonuclease is catalytically modified to be a Cas9 nickase which nicks the DNA rather than generating a double-strand break. The Cas9 nickase is fused to a reverse transcriptase or component thereof. The prime editing guide RNA (pegRNA), is substantially larger than standard sgRNA. The pegRNA is a sgRNA with a primer binding sequence (PBS) and the template containing the desired RNA sequence added at the 3' end (RTT). Additional information about prime editing can be found in published PCT publication WO2020191245. The hybrid guide gene editing systems disclosed herein can comprise a polymerase or component thereof. A polymerase functions to catalyze the polymerization of a nucleic acid strand using an existing nucleic acid as a template. Examples of useful polymerases include DNA polymerases and RNA polymerases. The polymerase can work with a nucleic acid programmable nucleotide binding domain or a nucleic acid programmable DNA binding protein (e.g., in the form of fusion proteins or coupled or associated in trans with the hybrid guide nucleic acid sequences). The polymerase can be a RNA-dependent DNA polymerase (e.g., reverse transcriptase) or a DNA-dependent DNA polymerase (e.g., a prokaryotic polymerase, including Pol I, Pol II, or Pol III, or a eukaryotic polymerase, including Pol a, Pol b, Pol g, Pol d, Pol e, or Pol z). Guide Nucleic Acids for PKD1 A guide nucleic acid sequence can exist as a single polynucleotide molecule and comprises two regions: (1) a region that shares homology to the PKD1 gene (or RNA) sequence, particularly regions encompassing the 3′ UTR and directs binding of a guide nucleic acid-gene editor protein to the targeted PKD1 gene sequence; (2) a region that binds a guide nucleotide sequence-gene editor protein Prime editing guide nucleotide acids include region (1), (2) and (3) a nucleic acid extension that templates the synthesis of the desired edit in the form of a replacement DNA strand. Region (1) can comprise a spacer sequence. Region (3) comprises a primer binding site (PBS) and a reverse transcriptase template (RTT). Region (2) can be referred to as a tracrRNA sequence or equivalent such as a modified tracrRNA. Region (2) may comprise a stem-loop structure. For example, region (2) can be identical or homologous to a tracrRNA as provided in Jinek et al., 2012, Science 337:816- 821. Other examples of gRNAs (e.g., those including domain (2)) can be found in U.S. Patent Application Publication US20160208288 and U.S. Patent Application Publication US20160200779. Methods of using guide nucleotide sequence-gene editor protein, such as Cas9, for site-specific cleavage (e.g., to modify a genome) are known in the art. In some examples, guide nucleic acids of the PKD1 gene editing systems disclosed herein can comprise a DNA-RNA chimeric guide (i.e., chRDNA). The chRDNA can be a single guide RDNA. As used herein, the term "RDNA" refers to a nucleic acid comprising a mixture of ribonucleotide (RNA) and deoxynucleotide (DNA). That is, an RDNA comprises at least one ribonucleotide and at least one deoxynucleotide. As used herein, the term "sgchRDNA," "sgRDNA," "single guide chRDNA," and "single guide RDNA" are used interchangeably and refer to a polynucleotide comprising a spacer sequence, wherein the spacer sequence comprises a mixture of DNA and RNA nucleotides that is complementary to a sequence in a target nucleic acid. The spacer sequence comprises at least one deoxyribonucleotide and at least one ribonucleotide. The ribose of the ribonucleotide of the spacer sequence can be modified. For example, the ribose can comprise a 2' hydroxyl group covalently linked to a methyl group (2'-O- Methyl). As used herein, the term "sgRNA," and "single guide RNA" are used interchangeably and refer to a polynucleotide comprising a spacer sequence, wherein the spacer sequence comprises solely RNA that is complementary to a sequence in a target nucleic acid. The spacer sequence comprises only ribonucleotide. The ribose of the ribonucleotide of the spacer sequence can be modified. For example, the ribose can comprise a 2' hydroxyl group covalently linked to a methyl group (2'-O-Methyl). In some examples a guide nucleic acid disclosed herein comprises a deoxyribonucleotide-deoxyribonucleotide-ribonucleotide- deoxyribonucleotidedeoxyribonucleotide (dN-dN-N-dN-dN) motif. In other examples a guide nucleic acid disclosed herein comprises a deoxyribonucleotide- deoxyribonucleotide-ribonucleotidedeoxyribonucleotide--deoxyribonucleotide- deoxyribonucleotide (dN-dN-N-dN-dN-dN) motif. In various examples a guide nucleic acid comprises a spacer sequence. In some examples the spacer sequence comprises at least one deoxyribonucleotide. In some examples the spacer sequence comprises one to ten deoxyribonucleotides (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deoxyribonucleotides). In some examples the locations where the ribonucleotide are replaced with a deoxyribonucleotide comprise, from the 5' end of the spacer sequence, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, or position 20. In some examples, the deoxyribonucleotide is located at one or more of positions 3, 4, 6, 7, or 8 from the 5' end of the spacer sequence. In some examples the spacer sequence comprises deoxyribonucleotides at one or more of positions 4, 5, 6, 7, 9, 10, 13, or 14 from the 5' end of the spacer sequence. In some examples the spacer sequence disclosed herein comprises at least one modified ribonucleotide. In some examples the ribonucleotide is modified at a 2' hydroxyl group to be covalently linked to a methyl group (i.e., 2'-O-methyl). In some examples the spacer sequence comprises one to three modified ribonucleotides. In other examples the spacer sequence comprises one or two modified ribonucleotides. In other examples, the spacer sequence does not comprise a modified ribonucleotide. The spacer sequence can have only unmodified ribonucleotides. In some examples the spacer sequence comprises only unmodified ribonucleotides and 2' - deoxyribonucleotides. In some examples a modified ribonucleotide is located on the 5' end of the spacer sequence. In some examples a modified ribonucleotide is located at position 1, 2, and 3 from the 5' end of the spacer sequence. In some examples a modified ribonucleotide is located at position 1, 3, and 4 from the 5' end of the spacer sequence. In some examples a modified ribonucleotide is located at position 1 and 2 from the 5' end of the spacer sequence. In some examples a modified ribonucleotide is located at position 1 and 3 from the 5' end of the spacer sequence. In some examples a modified ribonucleotide is located at position 2 and 3 from the 5' end of the spacer sequence. In other examples the modified ribonucleotide is located at position 3 and 4 from the 5' end of the spacer sequence. In other examples a modified ribonucleotide is located at position 1 from the 5' end of the spacer sequence. In some instances, the spacer sequence has three modified ribonucleotides located at position 1, 2, and 3 from the 5' end of the spacer sequence. In some examples the spacer sequence comprises three modified ribonucleotides located at positions 1, 3, and 4 from the 5' end of the spacer sequence. In other examples the spacer sequence has two modified ribonucleotides located at position 1 and 2 from the 5' end of the spacer sequence. In some examples the spacer sequence has two modified ribonucleotides located at positions 1 and 3 from the 5' end of the spacer sequence. In some examples the spacer sequence has two modified ribonucleotides located on position 2 and 3 from the 5' end of the spacer sequence. The spacer sequence can have two modified ribonucleotides located on position 3 and 4 from the 5' end of the spacer sequence. The spacer sequence can have one modified ribonucleotide located on position 1 from the 5' end of the spacer sequence. In some examples, the spacer sequence comprises five deoxyribonucleotides and two 2'-OMe ribonucleotides. In some examples the spacer sequence comprises five deoxyribonucleotides located on positions 3, 4, 5, 6, and 7 from the 5' end of the spacer sequence and two 2'-OMe ribonucleotides located at positions 1 and 2 from the 5' end of the spacer sequence. In other examples the spacer comprises eight deoxyribonucleotides located at positions 4, 5, 6, 7, 9, 10, 13, and 14 from the 5' end of the spacer sequence and three 2'-OMe ribonucleotides located at positions 1, 2, and 3 from the 5' end of the spacer sequence. In other examples the spacer comprises four deoxyribonucleotides located on positions 3, 4, 6, and 7 from the 5' end of the spacer sequence and two 2' -OMe ribonucleotides located on positions 1 and 2 from the 5' end of the spacer sequence. In other examples the spacer comprises five deoxyribonucleotides located on positions 3, 4, 6, 7, and 8 from the 5' end of the spacer sequence and two 2'-OMe ribonucleotides located on positions 1 and 2 from the 5' end of the spacer sequence. In some examples the spacer sequence further comprises a phosphorothioate backbone modification (PS). In some examples the spacer sequence comprises at least one phosphorothioate backbone modification. In some examples the spacer sequence comprises at least two phosphorothioate backbone modifications. In other examples the spacer sequence comprises at least three phosphorothioate backbone modifications. In some examples the spacer sequence comprises two or three phosphorothioate backbone modifications. The nucleotide residue of the 5' terminal of the spacer can comprise a phosphorothioate backbone modification. The phosphorothioate backbone modification can be between position 1 and position 2 from the 5' end of the spacer sequence. In some examples the phosphorothioate backbone modification is between position 2 and position 3 from the 5' end of the spacer sequence. In other examples the phosphorothioate backbone modification is between position 3 and position 4 from the 5' end of the spacer sequence. The spacer sequence can comprise three phosphorothioate backbone modifications and the phosphorothioate backbone modifications are located between position 1 and 2, between position 2 and 3, and between position 3 and 4 from the 5' end of the spacer sequence. In some examples the spacer sequence comprises two phosphorothioate backbone modifications and the phosphorothioate backbone modifications are located between position 1 and 2 and between positions 2 and 3 from the 5' end of the spacer sequence. In some examples the spacer sequence comprises a (2'- OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif. In other examples the spacer sequence comprises a (2'-OMe)PS(2'- OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif. In some examples the spacer sequence comprises a (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif. In some examples the spacer sequence comprises a (2’-Ome)PS(2’Ome) PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA)(DNA) motif. As used herein, "2-OMe" refers to a modified RNA in which the 2' hydroxyl group of the ribose of the RNA is covalently linked to a methyl group; "RNA" refers to an unmodified RNA; "DNA" refers to an unmodified DNA. In some examples of guide nucleic acids disclosed herein for editing of the PKD1 gene, the sequence of the guide nucleic acid comprises or consists of a sequence comprising at least about 80% to 100% to any one of SEQ ID NOs:2-9 or 19-62, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% identical to any one of SEQ ID NOs:2-9 or 19-62. In some examples the sequence comprises the sequence corresponding to any one of SEQ ID NOs:2-9 or 19-62. In other examples the sequence consists of the sequence corresponding to any one of SEQ ID NOs:2-9 or 19-62. In some examples of guide nucleic acids disclosed herein for editing of the PKD1 gene the sequence of the guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to any one of SEQ ID NOs:2-9 or 19-62, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to any one of SEQ ID NOs: 2-9 or 19-62. In some examples the sequence of the guide nucleic acid sequence comprises the sequence corresponding to any one of SEQ ID NOs:2-9 or 19-62. In other examples the spacer sequence consists of the sequence corresponding to any one of SEQ ID NOs:2-9. In some examples the sequence of a base editing guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to any one of SEQ ID NOs:2-7, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to any one of SEQ ID NOs: 2-7. In other examples the sequence of a prime editing guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to SEQ ID NO:8 or SEQ ID NO:9, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to SEQ ID NO:8 or SEQ ID NO:9. In other examples the extension sequence of a prime editing guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to any one of SEQ ID NOs:19-62, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to SEQ ID NOs:19-62. A guide nucleic acid as disclosed herein can be a single guide nucleic acid comprising a spacer sequence at the 5' -end and a tracrRNA at the 3 '-end. The tracrRNA may be modified. For example, some of the ribonucleotides of the tracrRNA can have one or more 2'-OMe modifications. A tracr nucleic acid (e.g., tracrRNA) can have a length of from about 50 nucleotides to about 150 nucleotides. A tracrRNA sequence can comprise more than one duplexed region (e.g., hairpin, hybridized region). A tracrRNA sequence can comprise two duplexed regions. A tracrRNA may comprise a secondary structure. A tracrRNA may contain more than one secondary structure. A tracrRNA sequence may comprise a first secondary structure and a second secondary structure and a first secondary structure comprises more nucleotides than a second secondary structure. A tracrRNA may comprise a first secondary structure, a second secondary structure, and a third secondary structure where the first secondary structure includes fewer nucleotides than the second secondary structure and the second secondary structure includes more nucleotides than the third secondary structure. In some examples a tracrRNA is a modified tracrRNA, e.g., one that includes 2-OMe modification. In some examples the tracrRNA sequence is GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAA CUUGAAAAAGUGGCACCGAGUCGGUGCUsususu (SEQ ID NO:909) (where “s” is G or C). In other examples the tracrRNA is gUUUUAGagcuaGaaauagcaaGUU aAaAuAaggcuaGU ccGUU AucAAcuuGaaaaagugGcaccgagucggugcusususu (SEQ ID NO:910). A target nucleic acid can comprise DNA, RNA, or combinations thereof and can be a double-stranded nucleic acid or a single-stranded nucleic acid. A spacer sequence can hybridize to a target nucleic acid that is located 5' or 3' of a protospacer adjacent motif (PAM), depending upon the particular gene editor protein to be used. A PAM can vary depending upon the gene editor protein to be used. For example, when using Cas9 from S. pyogenes, the PAM can be a sequence in the target nucleic acid that comprises the sequence 5' -NRR-3 ', wherein R can be either A or G, and where N is any nucleotide, and N is immediately 3' of the target nucleic acid sequence targeted by the targeting region sequence. A gene editor protein can be modified such that a PAM is different compared to a PAM for an unmodified gene editor protein. For example, when using Cas9 from S. pyogenes, the Cas9 may be modified such that the PAM no longer comprises the sequence 5' -NRR-3 ', but instead comprises the sequence 5' -NNR-3 ', where R can be either A or G, wherein N is any nucleotide, and N is immediately 3' of the target nucleic acid sequence targeted by the spacer sequence. Other gene editor proteins may recognize other PAMs and one of skill in the art is able to determine the PAM for any particular gene editor protein. The polynucleotides and CRISPR systems described in the present application may be used with a Cpfl protein (e.g., from Francisella novicida) directed to a site on a target nucleic acid proximal to a 5'-TTTN-3' PAM. A target nucleic acid sequence can be 20 nucleotides. A target nucleic acid can be less than 20 nucleotides. A target nucleotide can comprise ranges of nucleotides between about 10 to 30 nucleotides, e.g., 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or another number of nucleotides from about 10 nucleotides to 30 nucleotides. The selection of a specific PAMs is within the knowledge of those of skill in the art based on the particular gene editor protein to be used in a given instance. In some examples, where a space sequence in a guide nucleic acid includes both DNA and RNA on the same strand, the guide nucleic acid can be chemically synthesized. Chemical synthesis of polynucleotides is well understood and practiced routinely in the art. Chemical synthesis of polynucleotides of the present disclosure can be conducted in solution or on a solid support. In some examples solid phase synthesis is used as a method of making a guide nucleic acid for early evaluation. A guide nucleic acid containing DNA (“hybrid RNA-DNA” or chRDNA guides) may provide the advantage of increased specificity of targeting target nucleic acids such as DNA. See, e.g., Donohue et al., (2021), Molecular Cell, 81(17):3637-3649. In some examples spacer sequences of the guide nucleic acids disclosed herein include modifications that, e.g., increase stability of the polynucleotide. Such modifications may include phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates such as 3 '-alkylene phosphonates, 5'-alkylene phosphonates, chiral phosphonates, phosphinates, phosphoramidates including 3 '-amino phosphoramidate and amino alkylphosphoramidates, phosphorodiamidates, thionophosphoramidates, thiono alkylpho sphonates, thionoalkylpho sphotriesters, selenophosphates, and boranophosphates having normal 3'-5' linkages, 2 -5' linked analogs, and those having inverted polarity wherein one or more internucleotide linkages is a 3' to 3', a 5' to 5' or a 2' to 2' linkage. In some examples, suitable targeting nucleic acids have inverted polarity and include a single 3' to 3' linkage at the 3 '-most internucleotide linkage (i.e., a single inverted nucleoside residue in which the nucleobase is missing or has a hydroxyl group in place thereof). In some examples, deoxyribose or ribose on the deoxynucleotide or nucleotide of the spacer sequences are modified. The examples of modified sugar moieties include, but are not limited to, 2'-O-methyl, 2'-O-methoxyethyl, 2'-O-aminoethyl, 2' -Fluoro, N3 phosphoramidate, 2'dimethylaminooxyethoxy, 2' 2'dimethylaminoethoxyethoxy, 2'guanidinidium, 2'-O-guanidinium ethyl, carbamate modified sugars, and bicyclic modified sugars. 2'-O-methyl or 2'-O-methoxyethyl modifications promote the A-form or RNA-like conformation in oligonucleotides, increase binding affinity to RNA, and have enhanced nuclease resistance. Modified sugar moieties can also include having an extra bridge bond (e.g., a methylene bridge joining the 2'-O and 4'-C atoms of the ribose in a locked nucleic acid) or sugar analog such as a morpholine ring (e.g., as in a phosphorodiamidate morpholino). Examples of such analogs and / or modified residues include, but are not limited to diaminopurine, 5-fluorouracil, 5-bromouracil, 5- chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5- (carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6--isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7- methylguanine, 5--methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5' -methoxycarboxymethyluracil, 5-methoxyuracil, 2- methylthio-N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2--thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5- oxyacetic acid methylester, 5--methyl-2-thiouracil, 3-(3-amino- 3- N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, methyl phosphonates, chiral- methyl phosphonates, 2'-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like. A spacer sequence in a guide nucleic acid “specifically hybridizes” to or is “specific” to a target nucleic acid or a targeted portion of the PKD1 gene, e.g., the 3' UTR sequence. At a given ionic strength and pH, the Tmis the temperature at which 50% of a target sequence hybridizes to a complementary oligonucleotide. Spacer 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. Linkers In some examples the gene editing systems disclosed herein include linkers that connect one or more components of a gene editing system. In some examples a linker is used to link any of the proteins or protein domains described herein. In some examples a linker may be as simple as a covalent bond, or it may be a polymeric linker many atoms in length. In some preferred examples a linker is a peptide, a polypeptide. In some examples the linker is not peptide-like. The linker can be carbon bond, disulfide bond, carbonheteroatom bond, etc. The linker can be a carbon-nitrogen bond of an amide linkage. The linker can be a cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic or heteroaliphatic linker. The linker can be polymeric (e.g., polyethylene, polyethylene glycol, polyamide, polyester, etc.). The linker can comprise a monomer, dimer, or polymer of aminoalkanoic acid. The linker can comprise an aminoalkanoic acid (e.g., glycine, ethanoic acid, alanine, beta-alanine, 3-aminopropanoic acid, 4-aminobutanoic acid, 5-pentanoic acid, etc.). The linker can comprise a monomer, dimer, or polymer of aminohexanoic acid (Ahx). The linker can be based on a carbocyclic moiety (e.g., cyclopentane, cyclohexane). The linker can comprise a polyethylene glycol moiety (PEG). In some examples the linker comprises a peptide. The linker can comprise an aryl or heteroaryl moiety. The linker can be based on a phenyl ring. The linker may include functionalized moieties to facilitate attachment of a nucleophile (e.g., thiol, amino) from the peptide to the linker. Any electrophile may be used as part of the linker. Exemplary electrophiles include, but are not limited to, activated esters, activated amides, alkyl halides, aryl halides, acyl halides, and isothiocyanates. In some examples a linker is an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some examples a linker is be 5 to 200 amino acids in length, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 to 25, 26, 27, 28, 29, 30, 35, 40, 50, 55, 70, 76, 80, 95, 120, 130, 150, 170, 180, 190, or another number of amino acids from 5 to 200 amino acids in length. In some examples the linker comprises the amino acid sequence SGSETPGTSESATPES (SEQ ID NO:915), AKA the “XTEN” linker. In other examples a linker comprises the amino acid sequence SGGS (SEQ ID NO:916), GGGS (SEQ ID NO:917), EAAAK (SEQ ID NO:918), or multimers and / or combinations thereof. In some examples, where the linker comprises multimers of a linker amino acid sequence the multimer is from 2 to 15 repeats of one of the foregoing linker sequences. Where multiple different linker sequences are repeated the number of repeats for each linker sequence can be different, e.g., (EAAK)3and (GGGS)5. In some examples a linker comprises the amino acid sequence SGGSSGSETPGTSESATPESSGGS (SEQ ID NO:919). In some examples the linkers provided herein are used to link a first adenosine deaminase and a second adenosine deaminase. In other examples the linker links a deaminase (e.g., a first or a second adenosine deaminase) and a gene editor protein comprising a nucleic acid-binding domain (e.g., dCas9). In some examples a linker links a gene editor protein and a nuclear localization signal (NLS). In other examples a linker links a deaminase and a NLS. In some examples a linker can be a bond (e.g., a covalent bond), an organic molecule, group, non-amino acid sequence polymer, or chemical moiety. PKD1 Guide Nucleic Acids and Gene Editing Systems The target gene for modification using the compositions, systems, and methods disclosed herein is PKD1 gene encoding Polycystin 1. In some examples disclosed herein are compositions and systems to mutate or delete sequences within a targeted portion of the 3' untranslated region (UTR) that comprising binding sites for miR-17 family member or a miR-200 family member. Mutation or deletion of one or more of such binding sites in a wild type PKD1 allele leads to the production of PKD1 mRNA transcripts to which miR-200 and / or miR-17 miRNAs cannot bind or which exhibit reduced binding. As a consequence, overall levels of Polycystin 1 protein are increased. For reference, the sequence of the human PKD1 gene is publicly available through the online Ensembl database under record ENSG00000008710. The nucleotide sequence of canonical human PKD13' UTR sequence located within exon 46 is provided herein as SEQ ID NO:1. For reference, the sequence of the canonical human PKD1 mRNA transcript (“PKD-201”) is publicly available through the online Ensembl database under record ENST00000262304.9. The nucleotide sequence of the canonical human PKD1 mRNA 3' UTR sequence is provided herein as SEQ ID NO:1. Accordingly, provided herein are guide nucleic acids (e.g., a guide RNA, prime editing guide RNA or hybrid RNA-DNA guide) targeting the PKD1 gene or PKD1 pre- mRNA or mRNA. In some examples provided here is a guide nucleic acid that includes a spacer corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of human PKD1 gene and a binding scaffold for a Cas9 nickase, wherein the guide nucleic acid is a guide RNA (gRNA). In other examples the guide nucleic acid includes (i) spacer sequence that contains a deoxyribonucleotide and a ribonucleotide, where the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the PKD1 gene; and (ii) a binding scaffold for a gene editor protein or component thereof. In other examples the guide nucleic acid includes (i) spacer sequence that contains a deoxyribonucleotide and a ribonucleotide, where the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the PKD1 gene; a nucleic acid extension that templates the synthesis of the desired edit in the form of a replacement DNA strand, and (iii) a binding scaffold for a gene editor protein or component thereof In some examples, in a ribonucleic acid in the sequence, the 2' hydroxyl group of a ribose is covalently linked to a methyl group (2'-OMe). In some examples the binding scaffold binds to a gene editor protein or component thereof comprising a deaminase. Also provided herein is a system for editing the PKD1 gene that includes: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the PKD1 gene, and (ii) a binding scaffold for the gene editor protein or component thereof; or (c) a guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the PKD1 gene, a nucleic acid extension that templates the synthesis of the desired edit in the form of a replacement DNA strand, and (iii) a binding scaffold for the gene editor protein or component thereof. In some examples the gene editor protein or component thereof comprises a deaminase or component thereof. Optionally, ribose in the ribonucleotide can be a modified ribose that is a ribose covalently linked at the 2' hydroxyl group to a methyl group. In some examples the sequence comprises a phosphorothioate backbone modification (PS). In some examples of the foregoing gene editing system the nucleic acid encoding the gene editor protein or component thereof is a mRNA. In some examples in a hybrid RNA-DNA guide nucleic acid the spacer sequence comprises a (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif. In some examples in a hybrid RNA-DNA guide nucleic acid the spacer sequence comprises a (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif. In some examples any of the foregoing motifs is located at the 5' end of the spacer sequence. In some examples the spacer sequence comprises one to ten deoxyribonucleotides. In some examples the deoxyribonucleotide is located on position 3, 4, 6, 7 or 8 from the 5' end of the spacer sequence. In some examples in a guide nucleic acid provided herein (either alone or as part of a gene editing system disclosed herein), the sequence comprises a sequence at least 80% identical to the sequence corresponding to any one of SEQ ID NOs:2-9 or 19-62, e.g., 85%, 87%, 90%, 92%, 93%, 95%, 97%, 99%, or another percentage identity to any one of SEQ ID NOs: 2-9. In some examples the sequence of a base editing guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to any one of SEQ ID NOs:2-7, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to any one of SEQ ID NOs: 2-7. In other examples the sequence of a prime editing guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to SEQ ID NO:8 or SEQ ID NO:9, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to SEQ ID NO:8 or SEQ ID NO:9. In other examples the extension sequence of a prime editing guide nucleic acid comprises or consists of a sequence at least about 80% to 100% to any one of SEQ ID NOs:19-62, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence identity from at least about 80% to 100% to SEQ ID NOs:19-62. In some examples a base editing guide nucleic acid comprises a sequence at least 80% identical to the sequence corresponding to any one of SEQ ID NOs:63-116, e.g., 85%, 87%, 90%, 92%, 93%, 95%, 97%, 99%, or another percentage identity to any one of SEQ ID NOs:63-116. In other examples a primer editing guide (PEG) nucleic acid comprises a sequence at least 80% identical to the sequence corresponding to any one of SEQ ID NOs:117-908, e.g., 85%, 87%, 90%, 92%, 93%, 95%, 97%, 99%, or another percentage identity to any one of SEQ ID NOs:117-908. In some examples the gene editor protein or the component thereof comprises a single fusion protein or two or more proteins. In some examples of a gene editing system disclosed herein the nucleic acid binding domain of a gene editor protein is capable of binding to DNA. In other examples the nucleic acid binding domain is capable of binding to RNA. In some examples the DNA binding domain of the gene editor protein or the component thereof comprises a CRISPR protein or a fragment thereof. In some examples the DNA binding domain of the gene editor protein comprises a catalytically impaired nuclease. In some examples the DNA binding domain comprises a prime editing protein or a fragment thereof. Also provided herein is a system for editing the PKD1 gene that includes: (a) Cas9 nickase or a nucleic acid encoding the Cas9 nickase, and (b) a guide RNA comprising a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the PKD1 gene, and a scaffold sequence for the Cas9 nickase; or (c) a prime editing guide RNA comprising a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the PKD1 gene, an extension sequence that templates the desired edit, and a scaffold sequence for the Cas9 nickase. In some preferred examples, in the gene editing systems disclosed herein, the gene editor protein comprises a nucleobase editor or a base editor (BE) refers to an agent comprising a polypeptide that is capable of making a modification to a base (e.g., A, T, C, G, or U) within a nucleic acid sequence (e.g., DNA or RNA). In some examples, the base editor is capable of deaminating a base within a nucleic acid. In some examples, the base editor is capable of deaminating a base within a DNA molecule. In some examples, the base editor is capable of deaminating an adenine (A) in DNA. In some examples, a base editor comprises a fusion protein comprising a programmable DNA binding protein fused to an adenosine deaminase. In some examples, the base editor comprises a fusion protein comprising a Cas9 protein and an adenosine deaminase. In some examples, the base editor is a Cas9 nickase (nCas9) fused to an adenosine deaminase. In some examples, the base editor is a nuclease-inactive Cas9 (dCas9) fused to an adenosine deaminase or components thereof. In other examples, a base editor comprises a fusion protein comprising a programmable DNA binding protein fused to a cytidine deaminase. In some examples, the base editor comprises a fusion protein comprising a Cas9 protein and a cytidine deaminase. In some examples, the base editor is a Cas9 nickase (nCas9) fused to a cytidine deaminase. In some examples, the base editor is a nuclease-inactive Cas9 (dCas9) fused to a cytidine deaminase. In some examples, a base editor further comprises, an inhibitor of base excision repair, for example, a UGI domain. In some examples, a base editor fusion protein comprises a Cas9 nickase fused to a deaminase and an inhibitor of base excision repair, such as a UGI. In some examples, the dCas9 domain of the fusion protein comprises a D10A and a H840A mutation as numbered in the wild type Cas9 Nickase amino acid sequence (SEQ ID NO:911). In some examples, the UGI comprises the amino acid sequence corresponding to SEQ ID NO:912. In some examples, a base editor system provided herein comprises a base editor fusion protein. For example, a base editor fusion protein comprises a programmable DNA binding protein and a deaminase, e.g., an adenosine deaminase. In some examples the amino acid sequence of an adenosine deaminase corresponds to SEQ ID NO:913. In some examples, any of the fusion proteins provided herein are base editors. In some examples, the programmable DNA binding protein is a Cas9 domain, a Cpf1 domain, a CasX domain, a CasY domain, a Casl2b domain, a C2c2 domain, or an aC2c3 domain. In some examples, the programmable DNA binding protein is a Cas9 domain. In some examples, the Cas9 domain is one selected from any of the Cas9 domains or Cas9 proteins (e.g., nuclease inactive Cas9 or Cas9 nickase, or a Cas9 variant from any species) provided herein. In some examples, any of the Cas9 domains or Cas9 proteins provided herein may be fused with any of the deaminases provided herein. In some examples, the base editor comprises a deaminase, e.g., an adenosine deaminase and a programmable DNA binding protein, e.g., a Cas9 domain joined via a linker. In some examples, the base editor comprises a fusion protein comprising a deaminase, e.g., an adenosine deaminase and a programmable DNA binding protein, e.g., a Cas9 domain joined via a linker. In some examples, the linker is a peptide linker. In some examples, a linker is present between the deaminase domain and the Cas9 domain. In some examples, a deaminase and a programmable DNA binding domain are fused via any of the peptide linkers provided herein. In some examples, a base editor system provided herein comprises a base editor comprising a fusion protein comprising an inhibitor of base repair. In some examples, a base editor comprises a fusion protein comprising a cytidine deaminase and a programmable DNA binding domain, e.g., a Cas9 domain. In some examples, a base editor comprises a fusion protein comprising an adenosine deaminase and a programmable DNA binding domain, e.g., a Cas9 domain. In some examples, the base editor or the fusion protein further comprises an inhibitor of base repair (IBR). In some examples, the IBR comprises an inhibitor of inosine base repair. In some examples, the IBR is an inhibitor of inosine base excision repair. In some examples, the inhibitor of inosine base excision repair is a catalytically inactive inosine specific nuclease (dISN). Thus, this disclosure contemplates a fusion protein comprising a programmable DNA binding protein and an adenosine deaminase further fused to a dISN. This disclosure contemplates a fusion protein comprising any Cas9 domain, for example, a Cas9 nickase (nCas9) domain, a catalytically inactive Cas9 (dCas9) domain, a high fidelity Cas9 domain, or a Cas9 domain with reduced PAM exclusivity. It should be understood that the use of a dISN may increase the editing efficiency of a adenosine deaminase that is capable of catalyzing a A to I change. For example, fusion proteins comprising a dISN domain may be more efficient in deaminating A residues. In some preferred examples, in the gene editing systems disclosed herein, the gene editor protein comprises a prime editor (PE), which refers to a polypeptide capable of transcribing single-stranded RNA into DNA. In some examples, a prime editor comprises a fusion protein comprising a programmable DNA binding protein fused to a reverse transcriptase. In some examples, the base prime comprises a fusion protein comprising a Cas9 protein and a reverse transcriptase. In some examples, the prime editor is a Cas9 nickase (nCas9) fused to a reverse transcriptase. In some examples, the prime editor is a nuclease-inactive Cas9 (dCas9) fused to a reverse transcriptase or components thereof. In some examples, a prime editor further comprises, an inhibitor of DNA mismatch repair, for example, a MLH1 mutant (MLH1dn). In some examples, a prime editor fusion protein comprises a Cas9 nickase fused to a reverse transcriptase and an inhibitor of DNA mismatch repair, such asMLH1dn. In some examples, the dCas9 domain of the fusion protein comprises a D10A and a H840A mutation as numbered in the wild type Cas9 Nickase amino acid sequence (SEQ ID NO:911). In some examples, the MLH1dn comprises the amino acid sequence corresponding to SEQ ID NO:921. In some examples, the gene editors provided herein comprise fusion proteins that further comprise one or more nuclear targeting sequences, for example, a nuclear localization sequence (NLS). In some examples, the fusion protein comprises multiple NLSs. In some examples, the fusion protein comprises a NLS at the N-terminus and the C-terminus of the fusion protein. In some examples, a NLS comprises an amino acid sequence that facilitates the importation of a protein, that comprises an NLS, into the cell nucleus. In some examples, the NLS is fused to the N-terminus of the fusion protein. In some examples, the NLS is fused to the C-terminus of the fusion protein. In some examples, the NLS is fused to the N terminus of the programmable DNA binding protein, e.g. the Cas9. In some examples, the NLS is fused to the C-terminus of the programmable DNA binding protein. In some examples, the NLS is fused to the N-terminus of the adenosine deaminase. In some examples, the NLS is fused to the C-terminus of the adenosine deaminase. In some examples, the NLS is fused to the C-terminus of the reverse transcriptase. In some examples, the NLS is fused to the fusion protein via one or more linkers. In some examples, the NLS is fused to the fusion protein without a linker. A number of suitable NLS amino acid sequences are known in the art, e.g., PKKKRKV (SEQ ID NO:920). In some examples, the fusion proteins provided herein do not comprise a linker. In some examples, a linker is present between one or more of the domains or proteins (e.g., adenosine deaminase-programmable DNA binding protein-NLS-IBR). In some examples, the "-" used in the general architecture above indicates the presence of an optional linker. In some examples a fusion protein provided for use herein comprises programmable DNA binding protein and two adenosine deaminase domains, as it believed that dimerization of adenosine deaminases could improve the ability (e.g., efficiency) of the fusion protein to modify a nucleic acid base, for example to deaminate adenine. In some examples, a fusion protein comprises 2, 3, 4 or 5 adenosine deaminase domains. In some examples, any of the fusion proteins provided herein comprise two adenosine deaminases. In some examples, any of the fusion proteins provided herein contain only two adenosine deaminases. In some examples, the adenosine deaminases are the same. In some examples, the adenosine deaminases are any of the adenosine deaminases are different from each other. In some examples, an adenosine deaminase comprises an amino acid sequence that is at least 70% identical to SEQ ID NO:913, e.g., 75%, 80%, 82%, 85%, 88%, 90%, 92%, 94%, 96%, 97%, 99%, or another percent identity from at least 70% to 100% identical to the amino acid sequence corresponding to SEQ ID NO:913. Other fusion proteins comprising a programmable DNA binding domain and an adenosine deaminase, as well as sequences of various adenosine deaminases are known in the art, as exemplified in, e.g., WO2023 / 049299. Base Editing of PKD1 A base editor system provided herein comprises a programmable DNA binding protein and a deaminase. As used herein, a deaminase refers to an enzyme that catalyzes the removal of an amine group from a molecule, or deamination, for example through hydrolysis. In some examples, the deaminase is a cytidine deaminase, catalyzing the deamination of cytidine (C) to uridine (U), deoxycytidine (dC) to deoxyuridine (dU), or 5-methyl-cytidine to thymidine (T, 5-methyl-U), respectively. Subsequent DNA repair mechanisms ensure that a dU is replaced by T (see Komor et al., 2016, Nature, 533:420- 424). In some examples the deaminase is a cytosine deaminase, which catalyzes the conversion of cytosine to thymine (e.g., in DNA). In other examples, the deaminase is an adenosine deaminase, which converts adenine to guanine. In some examples, the deaminase is a naturally-occurring deaminase. In other examples, the deaminase is a sequence variant of a naturally-occurring deaminase from an organism. In some examples an adenosine deaminase for use in the systems and methods disclosed herein is at least 80% identical to the sequence corresponding to SEQ ID NO:913, e.g., 85%, 87%, 90%, 92%, 95%, 97%, 99%, or another percent sequence from at least 80% to 100% identical to SEQ ID NO:913. Suitable examples of cytosine deaminases are known in the art as exemplified in, e.g., Li et al., (2022), Nature Communications, 13:4531; and Yuan et al., (2023), Nucleic Acids Research, 51(20):e105. In some examples a fusion protein provided herein comprises a linker between at least two domains of the fusion protein (e.g., between an adenosine deaminase and a programmable DNA binding protein). In other examples the fusion protein does not comprise a linker. Prime Editing In some examples of editing of the PKD1 a prime editing CRISPR system or a component thereof is used. Prime editing is a variation on CRISPR systems in which a guide nucleic acid encompasses two separate functions: (1) guiding Cas9 to a targeted genomic location, and (2) to serve as an RNA template to copy a desired new sequences into the genome, as described in Anzalone et al., (2019), Nature, 576:149-157). Prime editing utilizes a catalytically modified Cas endonuclease and a single guide RNA. The catalytically modified is a Cas9 nickase which nicks the DNA rather than generating a double-strand break. The Cas9 nickase is fused to a reverse transcriptase. The “prime editing guide RNA” (pegRNA) is substantially longer than standard sgRNA. The pegRNA is a sgRNA with a primer binding sequence (PBS) and the template containing the desired RNA sequence added at the 3' end (RTT). Additional information about prime editing can be found in published PCT application WO2020191245. In some examples the hybrid guide gene editing systems disclosed comprise a polymerase. Examples of suitable polymerases include DNA polymerases and RNA polymerases. The polymerase can work with a nucleic acid programmable DNA binding protein (e.g., in the form of fusion proteins or coupled or associated in trans with the hybrid guide nucleic acid sequences). The polymerase can be a RNA-dependent DNA polymerase (e.g., reverse transcriptase) or a DNA-dependent DNA polymerase (e.g., a prokaryotic polymerase, including Pol I, Pol II, or Pol III, or a eukaryotic polymerase, including Pol a, Pol b, Pol g, Pol d, Pole, or Pol z). Gene Editor Proteins In some examples the gene editing systems and methods provided herein utilize a gene editor protein. A gene editor protein comprises a nucleic acid-binding domain. In some preferred examples the nucleic acid-binding domain binds DNA. In some examples the nucleic acid-binding domain is a Cas9 domain. The term "Cas9" refers to an RNA guided nuclease comprising a Cas9 protein, or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). In some examples Cas9 refers to a polypeptide comprising an amino acid sequence having at least 80% identity to a wild type Cas9 from S. pyogenes), e.g., 82%, 85%, 86%, 88%, 90%, 92%, 95%, 97% or another percent sequence identity to a wild type Cas9 polypeptide (e.g., Cas9 from S. pyogenes). Cas9 can refer to a polypeptide with at most or at most about 50%, 60%, 70%, 80%, 90%, 100% sequence identity and / or sequence similarity to a wild type exemplary Cas9 polypeptide (e.g., from S. pyogenes). In some examples the utilized Cas9 is a wild type Cas9. In some preferred examples the utilized Cas9 is a modified form of the Cas9 protein that comprising an amino acid change such as a deletion, insertion, or substitution. Cas9 nuclease sequences and structures of variant Cas9 orthologs have been described for a range of species. Exemplary species from which a Cas9 amino acid sequence can be obtained include, but are not limited to, Streptococcus pyogenes, Streptococcus thermophilus, Streptococcus sp., Staphylococcus aureus, Listeria innocua, Lactobacillus gasseri, Bacillus pseudomycoides, Lactobacillus salivariu, Streptomyces pristinaespiralis, or Campylobacter jejuni. In some examples, the Cas9 protein is from Streptococcus pyogenes. In other examples, the Cas9 protein is from Streptococcus thermophilus. Other suitable Cas9 nucleases and amino acid sequences are publically available and known to those of skill in the art based, e.g., Cas9 sequences from the organisms and loci disclosed in Chylinski et al., (2013) RNA Biology 10:5, 726-737. In preferred examples the PKD1 gene editing systems provided herein comprise a gene editor protein, e.g., a Cas nuclease, with reduced or abolished nuclease activity. For example, a Cas9 protein may be nuclease inactive or may be a Cas9 nickase. Methods for generating a Cas9 protein (or a fragment thereof) having an inactive DNA cleavage domain are known. For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvC 1 subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvC 1 subdomain cleaves the non-complementary strand. Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations Dl0A and H840A have been shown to completely inactivate the nuclease activity of S. pyogenes Cas9. In some preferred examples Cas9 nickase suitable for use in the PKD1 gene editing systems and the methods disclosed herein has an active HNH domain and an inactive RuvC domain and is able to cleave only the strand of the target DNA that is bound by the sgRNA (which is the opposite strand of the strand that is being edited). In some examples the Cas9 nickase comprises mutations that inactivate the RuvC domain, e.g., a D10A mutation. In various examples, any mutation that inactivates the RuvC domain is included in a Cas9 nickase, e.g., insertion, deletion, or single or multiple amino acid substitution in the RuvC domain. In some preferred examples a Cas9 nickase for use as described herein, the RuvC domain is inactivated, but the HNH domain remains activate. Other exemplary suitable nuclease-inactive Cas9 domains include, but are not limited to, those comprising mutations: D839A, N863A, or K603R. Cas9, dCas9, or Cas9 variant also encompasses Cas9, dCas9, or Cas9 variants from any organism. A gene editor protein can comprise a CasX or CasY, or a variant thereof, which have been described in, for example, Burstein et al., Cell Res. 2017 Feb 21. doi: 10.1038 / cr.2017.21. The gene editor proteins can comprise high fidelity Cas9 domains. High fidelity Cas9 domains are engineered Cas9 domains comprising one or more mutations that decrease electrostatic interactions between the Cas9 domain and the sugar-phosphate backbone of DNA. Exemplary Cas9 domains with high fidelity are known in the art as described in, e.g., Kleinstiver et al., (2016)., Nature 529:490-495 (2016); and in Slaymaker et al., (2015), Science, 351, 84-88 (2015). In some examples a high fidelity Cas9 domain is a nuclease-inactive Cas9 domain. In other examples a high fidelity Cas9 domain is a nickase domain. Suitable examples of a gene editor protein include, but are not limited to, a Cas9 protein, a Cpf1 protein, a C2cl protein, a C2c2 protein, a C2c3 protein, Cas3, Cas 5, Cas7, Cas8, or Cas10. In some preferred examples a gene editor protein is a Cas9 protein. In other preferred examples a gene editor protein is a Cpf1 protein. In some preferred examples the editor protein is a nickase, i.e., it cleaves one strand of a target nucleic acid duplex. Pharmaceutical Compositions Also provided herein are pharmaceutical compositions comprising any of the guide nucleic acids, gene editor proteins, or gene editing systems provided herein collectively referred to as “gene editing compositions”, and formulated with at least a pharmaceutically acceptable excipient, including a carrier, filler, preservative, adjuvant, solubilizer and / or diluent. Pharmaceutical compositions containing any of the gene editing compositions described herein, for use in the methods disclosed herein, can be prepared according to conventional techniques 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 guide nucleic acid or gene editing system disclosed herein. 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, benzenesulfonate, 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. In some examples, pharmaceutical compositions are formulated into any of a number of possible dosage forms including, but not limited to, topical ointments, solutions for intravenous administration, subcutaneous injection, intrathecal administration, intracisterna 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). In some examples, pharmaceutical formulations comprising any of the gene editing compositions 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. In some examples a pharmaceutical composition comprises a guide nucleic acid and a nucleic acid sequence (e.g., a mRNA) encoding a gene editor protein disclosed herein. In some examples, a pharmaceutical composition comprises a dose of a guide nucleic acid and a gene editing protein-encoding nucleic acid that when administered results in a plasma Cmax of the guide nucleic acid (e.g., a gRNA, pegRNA and mRNA) from about 0.02 µg / ml to about 10 µg / ml, e.g., 0.03, 0.05, 0.07 , 0.10, 0.2, 0.4, 0.6, 0.8, 1.00, 1.2, 1.5, 1.8 , 2.1, 2.2, 2.5, 2.7, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.5, 4.8, 5.2, 5.5, , 6.2, 6.5, 7.0, 7.2, 7.4, 7.7, 8.3, 8.5, 9.0, 0.5, or another Cmax of the guide nucleic acid from about 0.02 µg / ml to about 10 µg / ml. In some examples a pharmaceutical composition is effective to provide a total dose of guide nucleic acid plus encoding nucleic acid of about 0.01 mg / kg to about 10 mg / kg, e.g., 0.2 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.7 mg / kg, 4.2 mg / kg, 5.0 mg / kg, 6.0 mg / kg,7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, or another total dose of guide nucleic acid plus encoding nucleic acid of about 0.01 mg / kg to about 10 mg / kg. In some preferred examples a pharmaceutical composition disclosed herein is provided in the form of a lipid nanoparticle (LNP) composition. LNP formulations and methods for preparing them are established in the art as describe in, e.g., Conway et al., (2019), Mol. Ther., 27, 866-877 and Villiger et al., (2021), Nature Biomedical Engineering, 5(2):179-189. In some examples LNPs are composed of an amino lipid, a monomethoxypolyethylene glycol (or methoxypoluyethyle glycol) of average molecular weight 2 kDa conjugated to a lipid called PEG-Lipid, cholesterol and 1,2- distearoylsn-glycero-3-phosphocholine (DSPC). Suitable examples of LNP formulations are described in, e.g., international patent application publication WO 2023 / 049299. In some examples an LNP comprises a delivery moiety. In some examples the delivery moiety is selected from the group consisting of: lipids, peptides, polyethers, carbohydrates, and antibodies. In some examples, the delivery moiety includes a cell-penetrating peptide (CPP). Suitable examples of CPPs are described in, e.g., PCT / AU2020 / 051397. In some examples the amino acid sequence of the CPP comprises or consists of: RRSRTARAGRPGRNSSRPSAPR (SEQ ID NO:914). In one example, the CPP comprises the sequence RRSRTARAGRPGRNSSRPSAPR (SEQ ID NO:914), optionally wherein any amino acid other than glycine is a D amino acid. In some examples the delivery moiety targets the LNP to kidney. See, e.g., Wang et al., (2022), Nature Protocols, 18:265-291. In other examples, the delivery moiety includes a receptor binding domain. In other examples, the delivery moiety includes a carbohydrate. 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. 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 examples 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 further examples, the delivery moiety includes an antibody. See, e.g., Lee et al., (2023), Nanoscale Adv., 5:3834-3856. Methods As described herein, ADPKD is associated with insufficient levels of functional Polycystin 1. Accordingly, the methods described herein include a method for treating ADPKD by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising any of the guide nucleic acids or gene editing systems disclosed herein, whereby a level of functional Polycystin 1 protein is increased in the subject. Likewise, in some examples, any of the guide nucleic acids or gene editing systems disclosed herein are used in the manufacture of a medicament for treatment of ADPKD. In some preferred examples the treatment introduces at least one point mutation within a binding site sequence for a miR-17 family member or a miR-200 family member within the targeted portion, whereby binding of the miR-17 or miR-200 family member is reduced or eliminated. In other examples the treatment results in deletion of a binding site sequence for a miR-17 family member or a miR-200 family member within the targeted portion, whereby binding of the miR-17 or miR-200 family member is reduced or eliminated. In some examples, administration to a subject or contact with cells with any of the pharmaceutical compositions disclosed herein increases the level of Polycystin 1 protein about 1.1 to about 3-fold, e.g., 1.3 to about 2.7-fold, about 1.4 to about 2.6-fold, about 1.5 to about 2.5-fold, about 1.6 to about 2.4-fold, about 1.7 to about 2.3-fold, about 1.8 to about 2.2-fold, or another increased level of Polycystin 1 protein about 1.1 to about 3-fold compared to the level in the tissue without the administration or contact. Suitable routes of administration for treatment with the compositions, pharmaceutical compositions, or medicaments disclosed herein include, but are not limited to, intravenous, intraperitoneal, intraarterial, subcutaneous, intrathecal, oral, and topical. In some examples the route of administration is intravenous. In some examples any of the treatment methods disclosed herein can, optionally, include the step of determining a level PKD1 mRNA, Polycystin 1 protein in the subject before and / or following the treatment. In some examples the subject to be treated is a mammal selected from the group consisting of: humans, non-human primates, mice, or rats. In some preferred examples the subject to be treated is a human subject. 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 gene editing system being administered to relieve to some extent one or more of the symptoms and / or clinical indicia associated with kidney dysfunction in ADPKD, e.g., the presence and number of kidney cysts as detected by, e.g., ultrasound imaging. In some examples, an "effective amount" for therapeutic uses is the amount of a pharmaceutical composition disclosed herein required to provide a clinically significant decrease in disease symptoms 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. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. 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. In some examples an assessment of the treatment can include an assessment of expression of functional Polycystin 1 protein levels in the kidney before and after treatment, e.g., by comparing the level of Polycystin 1 protein in a kidney biopsy taken after treatment versus the level observed in a kidney biopsy obtained before treatment. 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. Combination Treatments The pharmaceutical compositions comprising any of the guide nucleic acids or gene editing systems, disclosed herein, can also be used in combination with other agents of therapeutic value in the treatment of a condition associated with ADPKD. 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, preferably 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. Pharmaceutical compositions comprising guide nucleic acids and / or gene editing systems, 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 inflammatory 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. 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. For combination therapies, dosages of co-administered therapeutic agents will of course vary depending on the type of co-agents employed and the disease stage of the patient to be treated. In some examples a combination treatment will comprise the separate administration of: (i) a pharmaceutical composition comprising a gene editing protein or a nucleic acid encoding a gene editing protein (e.g., a Cas9 nickase); and (ii) a pharmaceutical composition comprising a guide nucleic acid against the PKD1 gene target region. In some examples (i) is administered prior to (ii). In other examples (ii) is administered prior to (i). In some preferred examples a gene editing protein and a guide nucleic acid are co-administered substantially at the same time. In some preferred examples the gene editing protein and guide nucleic acid, collectively referred to as a “gene editing system” are formulated within the same pharmaceutical composition, whereby (i) and (ii) are co-administered simultaneously. In some examples pharmaceutical compositions comprising a gene editing protein, a guide nucleic acid, a gene editing system, and an additional therapeutic agent that make up a combination therapy disclosed herein are in 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. Examples of suitable therapeutic agents for co-administration with a composition or a pharmaceutical composition disclosed herein include, but are not limited to, vasopressin V2 receptor antagonists (e.g., Tolvaptan), Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptor blockers, paracetamol, opioids and antibiotics. EXAMPLES Example 1: Sequence selection of PKD13' UTR target sequence. Mutations in PKD1 result in the dysregulation or inadequate levels of functional Polycystin 1, which are linked to the onset and severity of ADPKD. miRNAs from the miR-17 family (e.g., miR-17-5p, miR-106a-5p, miR-106b-5p, miR-20a-5p, miR-93-5p) are known to bind to the 3' UTR of the PKD1 mRNA leading to decreased Polycystin 1 protein. In order to address this, the upregulation of PKD1 gene expression was designed to interrupt the binding of specific miRNAs to the 3' UTR of PKD1. This was accomplished by modifying (via substitution, insertion, or deletion) cis sequence within the PKD13' UTR to prevent effective binding of respective miRNAs to the 3' UTR. A segment of the 3' UTR of the PKD1 transcript sequence is shown in SEQ ID NO:1. Figure 1 illustrates the seed sequence within the 3' UTR of the PKD1 gene respective to miR-17 binding and relative location within the PKD1 mRNA. Example 2: Dual luciferase vector design to modify the seed sequence of miR-17 within the 3' UTR of the PKD1 gene. Dual luciferase vectors were engineered to compare gene expression levels among vectors harboring distinct patterns of base modifications within the miR-17 seed sequences located in the 3' UTR of the PKD1 gene. Figure 2 depicts the design of the plasmid construct, where Nanoluciferase (Nluc) serves as the primary indicator of gene expression, while firefly luciferase (luciferase) functions as a control gene expression marker for data normalisation. Base modifications were employed within the seed sequences of miR-17 binding sites of the PKD1 3' UTR are illustrated in Table 1 (Appendix). Example 3: Proof-of-concept study comparing gene expression upregulation with and without base modification within the 3' UTR of the PKD1 gene using a dual- luciferase assay HEK-293 cells (CRL-1573, ATCC) were seeded 5,000 cells per well with 200 µL of cell culture media (high-glucose Eagle’s Minimum Essential Medium supplemented with 10% (v / v) non-heat inactivated FBS) overnight in a white wall, clear bottom 96- well plate pre-coated with Geltrex (1 in 100 dilution, A1413302, Thermo Fisher). On the next day, cells were replaced with 90 µL of fresh Opti-MEM media and transfected with 10 µL of transfection mixture via lipofectamine 3000 according to the manufacturer’s manual (L3000015, Thermo Fisher). The transfection reagent was mixed with an equal volume of diluted lipofectamine 3000 (0.15 µL per well) and diluted plasmid DNA (5 or 10 ng of the PKD13' UTR contained custom plasmid construct, Vector Builder, sequence detail described in Table 1, seed binding region sequences A- H). At 48-hours post-transfection, cells (80 µl supernatant) were combined with the substrates from Nano-Glo dual luciferase reporter assay kit (N1620, Promega) to measure the dual-luciferase activity using a VICTOR Nivo microplate reader (PerkinElmer). Cells were initially added with the same volume of ONE-Glo Ex reagent, shake at 600 rpm in the dark for 10 minutes to detect the control reporter Firefly luciferase signal (default luminescence measurement setting with Z-focus at 16 mm). Following the Firefly luciferase read, an equal volume (80 µL) of Nano DLR Stop and Glo reagent was added to the well, incubated with the same shaking speed to detect the primary reporter Nanoluciferase signal at the Z-focus of 4 mm. All luciferase signals were blanked to the average of untreated wells to remove the background noise. The primary luciferase signal was subsequently normalised to the same well of the control luciferase signal. A fold change of PKD13' UTR dependent luciferase activity was calculated by dividing the normalised signal over the average signal of the wild type (WT) that expressed the same amounts of plasmid construct. Statistical analysis was performed in ordinary one-way ANOVA via Prism 10, and p value below 0.05 was considered as statistical significance. The data are shown in Figure 3. Example 4: Screening of base editing to the 3'UTR of the PKD1 gene to increase PKD1 mRNA expression and PC1 protein expression Base editing guide RNAs comprise a spacer sequence and a scaffold sequence. Suitable base editing spacer sequences (SEQ ID NOs:2, 4, 6, and 7 listed in Table 2) and a scaffold sequence (SEQ ID NO:10 listed in Table 3) were designed to facilitate base(s) editing within the 3' UTR of the PKD1 gene. Sequences of entire base editing guide RNAs are listed in Table 5 as SEQ ID NOs:63, 81, 99, and 108. Designed gRNAs were screened in HEK293 cells using plasmid vector. Guide RNA vectors containing a subset of gRNA sequences corresponding to SEQ ID NOs:63, 81, 99, and 108 were co- transfected with xCas9-ABE plasmids encoding PiggyBac DNA transportase into a HEK293 cells to induce A to G base editing. Likewise, co-transfection with xCas9-BE4 plasmids co-expressed with PiggyBac DNA transportase was performed to induce C to T base editing. Transfection with Lipofectamine 3000 was followed by an incubation period of 10-15 days with the addition of puromycin for selection of base-edited clones. DNA samples were harvested and the efficacy of edited bases were verified through PCR and subsequent Sanger sequencing. The resulting data are shown in Figure 4. The results demonstrated that the use of gRNAs comprising SEQ ID NO:81 or SEQ ID NO:108 resulted in the successful substitution of C to T by 64% and 46%, respectively. Subsequently, the resulting functional impact of PKD1 base editing was validated through assessment of PKD1 mRNA expression and PC1 protein expression. The expression of PKD1 mRNA was determined by reverse transcription- quantitative PCR (RT-qPCR) using PKD1 Taqman probe (Thermofisher, catalogue number Hs00947394_g1, FAM, 20x) at a dilution of 1:2.5. The mRNA expression fold- change was calculated by the PKD1 value of 2-∆∆Ctnormalized with the housekeeping gene (DHX57 probe, Thermofisher, catalogue number Hs00376574_m1, VIC, 20x and TRAPPC11 probe, Thermofisher, catalogue number Hs00934895_m1, VIC, 20x) average value of 2-∆∆Ct. The data presented in Figure 5 show that the point mutations effected by gRNAs corresponding to SEQ ID NO:81 and SEQ ID NO:108 upregulate PKD1 mRNA expression by 1.4-fold and 1.1-fold, respectively. Polycystin 1 protein was assessed by western blot assay using mouse anti- Polycystin 1 polyclonal antibody (Santa-Cruz, catalogue number sc130554) at a dilution of 1:250 in 5% BSA in TBST buffer followed by Secondary Antibody Solution IRDye 800 (Anti-Mouse) (Licor, catalogue number 926-32210) diluted 1:10000 in 5% BSA in TBST buffer. Total Protein Stain serves as a loading control and was detected using REVERT 700 Total Protein stain (Licor, catalogue number 926-11021) followed by a wash of pre-made Wash Solution (6.7% glacial acetic acid, 30% Methanol, in MilliQ water), rinsed with MilliQ water and destained by a ready-to-use Destaining solutions (0.1 M NaOH, 30% Methanol, in MilliQ water). The fold change of PC1 protein was calculated by normalized PC1 protein intensity of the testing sample divided by the average of the normalized PC1 protein level of the untreated group. The data presented in Figure 6 demonstrate that the use of gRNAs corresponding to SEQ ID NOs:81 and 108 to effect point mutations significantly enhanced PC1 protein expression by 1.5-fold and 1.3-fold at day 15 post-transfection, respectively. Example 5: Functional validation of PKD1 gene editing in a cyclic adenosine monophosphate (cAMP) assay. Guide RNAs that demonstrated significant Polycystin-1 protein upregulation, as per Examples 4 and 5, were selected for functional validation in a cAMP assay (revvity, catalogue number 62AM4PEB). Under normal physiological conditions, PC1, in a complex with PC2, facilitates calcium influx to suppress adenylyl cyclase and therefore reduce cAMP levels In ADPKD patients, loss of PC1 protein distrupt this regulation, resulting in elevated cAMP levels that drive abnormal cell proliferation and fluid secretion in kidney tubules, contributing to cyst formation and growth. Increasing PC1 protein by base editing is therefore expected to lower cAMP levels. In order to evaluate the effect of the gRNA-mediated base edits on cAMP levels, polyclonal cells edited with gRNAs corresponding to SEQ ID NOs: 81 and 109 underwent monoclonal selection to isolate homozygous (100%) edited clones, with successful editing confirmed by Sanger sequencing. Monoclonal cells were subsequently seeded at five thousand cells (10 µL cells suspension per well) into a 384-well plate and incubated at 37 °C, 5% CO2for 48-hours. Following the incubation, a half volume (5 µL) of Dynamic cAMP-d2 reagent was added to the cells, followed with the addition of an equal volume (5 µL) of Dynamic cAMP-Eu Cryptate antibody. After one hour incubation at room temperature, the assay plate(s) were measured on EnVision Homogeneous Time- Resolved Fluorescence (HTRF) plate reader with excitation at 320 nm and emission at two separate wavelengths (665 nm and 620 nm). Data were calculated as a ratio by using the fluorescence at 320 nm / 665 nm divided by the fluorescence at 320 nm / 620 nm. The concentration of cAMP was plotted against a standard curve. The fold changes of cAMP for base-edited cell samples were normalized to the average of empty vector transfection (mock untreated) cell samples. The data are shown in Figure 7. The results demonstrate that HEK293 cells edited with SEQ ID NOs:81 and 108 show significantly reduced cAMP levels (40% reduction). These data suggest HEK293 cells edited with gRNAs corresponding to SEQ ID NOs:81 and 108 could rescue calcium signalling in ADPKD1 patients by increasing PC1 protein expression. It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the invention as shown in the specific examples without departing from the spirit or scope of the invention as broadly described. The present examples are, therefore, to be considered in all respects as illustrative and not restrictive. This application claims priority from Australian Provisional Application Nos. 2024900920 filed on 4 April 2025 and 2024901296 filed on 6 May 2024 entitled “Advanced compositions and methods for treatment of kidney disease”, the entire contents of which are hereby incorporated by reference. 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. 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. References de Carvalho Ribeiro et al., 2020, Stem Cells International, doi.org / 10.1155 / 2020 / 8894590. Dugal-Tessier et al., (2021), J Clin Med., 10(4):838. Osafune et al., 2021, Clinical and Experimental Nephrology, 25(6) :574-584. Prakash et al., 2019, Nucleic Acids Research, 47(12) :6029-6044. Sharma et al., 2019, Methods Cell Biol., doi.org / 10.1016 / bs.mcb.2019.05.008

[0002] Appendix 1: Sequences and SEQ ID NOs SEQ ID NO:1 Human PKD1 transcript 3′ UTR (PKD-201 canonical transcript ENST00000262304.9) TCCTCCTTCCTGGCGGGGGTGGGCCGTGGAGTCGGAGTGGACACCGCTCAGTATTACTTTCTGCCGCTGT CAAGGCCGAGGGCCAGGCAGAATGGCTGCACGTAGGTTCCCCAGAGAGCAGGCAGGGGCATCTGTCTGTC TGTGGGCTTCAGCACTTTAAAGAGGCTGTGTGGCCAACCAGGACCCAGGGTCCCCTCCCCAGCTCCCTTG GGAAGGACACAGCAGTATTGGACGGTTTCTAGCCTCTGAGATGCTAATTTATTTCCCCGAGTCCTCAGGT ACAGCGGGCTGTGCCCGGCCCCACCCCCTGGGCAGATGTCCCCCACTGCTAAGGCTGCTGGCTTCAGGGA GGGTTAGCCTGCACCGCCGCCACCCTGCCCCTAAGTTATTACCTCTCCAGTTCCTACCGTACTCCCTGCA CCGTCTCACTGTGTGTCTCGTGTCAGTAATTTATATGGTGTTAAAATGTGTATATTTTTGTATGTCACTA TTTTCACTAGGGCTGAGGGGCCTGCGCCCAGAGCTGGCCTCCCCCAACACCTGCTGCGCTTGGTAGGTGT GGTGGCGTTATGGCAGCCCGGCTGCTGCTTGGATGCGAGCTTGGCCTTGGGCCGGTGCTGGGGGCACAGC TGTCTGCCAGGCACTCTCATCACCCCAGAGGCCTTGTCATCCTCCCTTGCCCCAGGCCAGGTAGCAAGAG AGCAGCGCCCAGGCCTGCTGGCATCAGGTCTGGGCAAGTAGCAGGACTAGGCATGTCAGAGGACCCCAGG GTGGTTAGAGGAAAAGACTCCTCCTGGGGGCTGGCTCCCAGGGTGGAGGAAGGTGACTGTGTGTGTGTGT GTGTGCGCGCGCGCACGCGCGAGTGTGCTGTATGGCCCAGGCAGCCTCAAGGCCCTCGGAGCTGGCTGTG CCTGCTTCTGTGTACCACTTCTGTGGGCATGGCCGCTTCTAGAGCCTCGACACCCCCCCAACCCCCGCAC CAAGCAGACAAAGTCAATAAAAGAGCTGTCTGACTGCAA Table 2: Exemplary Guide Nucleic Acid Base Editing and Prime Editing Spacer Sequences Targeting PKD13′ UTR Sequences. Table 3: Exemplary Scaffold Sequences for Base Editing and Prime Editing Guide Nucleic Acids Targeting PKD13′ UTR Sequences. Table 4: Exemplary Extension Sequences for Prime Editing Guide Nucleic Acids Targeting PKD1 3′ UTR Sequences Table 5: Exemplary Full Sequences for Base Editing Guide Nucleic Acids Targeting PKD13′ UTR Sequences (spacer sequence + scaffold sequence) Table 6: Exemplary Full Sequences for Prime Editing Guide (PEG) Nucleic Acids Targeting PKD13′ UTR Sequences (spacer sequence + scaffold sequence + extension sequence) SEQ ID NO:909 Exemplary tracrRNA nucleotide sequence GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAA CUUGAAAAAGUGGCACCGAGUCGGUGCUsususu SEQ ID NO:910 Exemplary tracrRNA nucleotide sequence gUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugG caccgagucggugcusususu SEQ ID NO:911 Amino acid sequence of Cas9 Nickase DKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKR TARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEK YPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLF EENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDA KLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDE HHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLV KLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLAR GNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVY NELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVED RFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQ LKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVS GQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNS RERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHI VPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAE RGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKD FQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKA TAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKK TEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFESPTVAYSVLVVAKVEKGKSKKLKSV KELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNEL ALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVL SAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYE TRIDLSQLGGD SEQ ID NO:912 Amino acid sequence of uracil-DNA glycosylase inhibitor MTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYK PWALVIQDS NGENKIKML SEQ ID NO:913 Amino acid sequence of adenosine deaminase MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDVLHHP GMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD SEQ ID NO:914 Amino acid sequence of CPP RRSRTARAGRPGRNSSRPSAPR SEQ ID NO:915 Amino acid sequence of an exemplary linker SGSETPGTSESATPES SEQ ID NO:916 Amino acid sequence of an exemplary linker SGGS SEQ ID NO:917 Amino acid sequence of an exemplary linker GGGS SEQ ID NO:918 Amino acid sequence of an exemplary linker EAAAK SEQ ID NO:919 Amino acid sequence of an exemplary linker SGGSSGSETPGTSESATPESSGGS SEQ ID NO:920 Amino acid sequence of an exemplary nuclear localisation signal PKKKRKV SEQ ID NO:921 Amino acid sequence of an exemplary inhibitor of DNA mismatch repair MSFVAGVIRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTSIQVIVKEG GLKLIQIQDNGTGIRKEDLDIVCERFTTSKLQSFEDLASISTYGFRGEALASISHV AHVTITTKTADGKCAYRASYSDGKLKAPPKPCAGNQGTQITVEDLFYNIATRR KALKNPSEEYGKILEVVGRYSVHNAGISFSVKKQGETVADVRTLPNASTVDNI RSIFGNAVSRELIEIGCEDKTLAFKMNGYISNANYSVKKCIFLLFINHRLVESTSL RKAIETVYAAYLPKNTHPFLYLSLEISPQNVDVNVHPTKHEVHFLHEESILERV QQHIESKLLGSNSSRMYFTQTLLPGLAGPSGEMVKSTTSLTSSSTSGSSDKVYA HQMVRTDSREQKLDAFLQPLSKPLSSQPQAIVTEDKTDISSGRARQQDEEMLEL PAPAEVAAKNQSLEGDTTKGTSEMSEKRGPTSSNPRKRHREDSDVEMVEDDSR KEMTAACTPRRRIINLTSVLSLQEEINEQGHEVLREMLHNHSFVGCVNPQWAL AQHQTKLYLLNTTKLSEELFYQILIYDFANFGVLRLSEPAPLFDLAMLALDSPES GWTEEDGPKEGLAEYIVEFLKKKAEMLADYFSLEIDEEGNLIGLPLLIDNYVPP LEGLPIFILRLATEVNWDEEKECFESLSKECAMFYSIRKQYISEESTLSGQQSEVP GSIPNSWKWTVEHIVYKALRSHILPPKHFTEDGNILQLANLPDLYKVF

Claims

CLAIMS:

1. A guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; and (ii) a binding scaffold for a gene editor protein or component thereof.

2. A guide nucleic acid comprising a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene and a binding scaffold for a Cas9 nickase, wherein the guide nucleic acid is a guide RNA (gRNA).

3. A guide nucleic acid comprising (i) a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a Cas9 nickase, wherein the guide nucleic acid is a prime editing guide RNA (pegRNA).

4. A guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a gene editor protein or component thereof.

5. The guide nucleic acid according to claim 1 or claim 4, wherein the ribonucleotide comprises a ribose, and wherein the 2' hydroxyl group of the ribose is covalently linked to a methyl group (2'-OMe).

6. The guide nucleic acid according to any one of claims 1 or 3 to 5, wherein the binding scaffold binds to a gene editor protein or component thereof comprising a deaminase or component thereof.

7. The guide nucleic acid according to any one of claims 4 to 6, wherein the binding scaffold binds to a gene editor protein or component thereof comprising a reverse transcriptase or component thereof.

8. A gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a guide RNA comprising (i) a spacer sequence, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; and (ii) a binding scaffold for a gene editor protein or component thereof.

9. A gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a prime editing guide RNA comprising (i) a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a gene editor protein or component thereof.

10. A gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene, and (ii) a binding scaffold for the gene editor protein or component thereof.

11. A gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a guide nucleic acid comprising (i) a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; (ii) an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and (iii) a binding scaffold for a gene editor protein or component thereof.

12. The gene editing system according to claim 10, wherein the gene editor protein or the component thereof comprises a deaminase or component thereof.

13. The gene editing system according to claim 11, wherein the gene editor protein or the component thereof comprises a reverse transcriptase or component thereof.

14. The gene editing system according to any one of claims 8 to 13, wherein the ribonucleotide of the guide nucleic acid comprises a ribose, and, and wherein the 2' hydroxyl group in a ribose is covalently linked to a methyl group (2'-OMe).

15. The gene editing system according to any one of claims 8 to 14, wherein the guide nucleic acid sequence comprises an unmodified ribonucleotide.

16. The gene editing system according to any one of claims 8 to 15, wherein the nucleic acid encoding the gene editor protein or the component thereof is a mRNA.

17. The gene editing system according to any one of claims 8 to 16, wherein the gene editor protein or the component thereof comprises a single fusion protein.

18. The guide nucleic acid according to any one of claims 1 to 7; or the gene editing system according to any one of claims 8 to 17, wherein the spacer sequence comprises a phosphorothioate backbone modification (PS).

19. The guide nucleic acid according to any one of claim 2 or claims 4 to 7; or the gene editing system according to any one of claims 8 to18, wherein the spacer sequence comprises a (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif.

20. The guide nucleic acid or the gene editing system according to claim 19, wherein the (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif is located at the 5' end of the spacer sequence.

21. The guide nucleic acid according to any one of claim 2 or claims 4 to 7; or the gene editing system according to any one of claims 8 to 20, wherein the guide nucleic acid sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one SEQ ID NOs:2-9 or 19-62.

22. The guide nucleic acid according to claim 21, wherein the spacer sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one of SEQ ID NOs:2-7.

23. The guide nucleic acid according to claim 21, wherein the spacer sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to SEQ ID NO:4 or SEQ ID NO:

7.

24. The guide nucleic acid according to claim 23, wherein the guide nucleic acid comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to SEQ ID NO:81 or SEQ ID NO:

108.

25. The guide nucleic acid according to claim 21, wherein the guide nucleic acid comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one of SEQ ID NOs:19-62.

26. The guide nucleic acid according to any one of claims 2 or 4 to 7; or the gene editing system according to any one of claims 8 to 18, wherein the spacer sequence comprises a (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif.

27. The guide nucleic acid or the guide gene editing system according to claim 26, wherein the (2'-OMe)PS(2'-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif is located at the 5' end of the spacer sequence.

28. The gene editing system according to any one of claims 10 to 27, wherein the nucleic acid binding domain is capable of binding to DNA.

29. The gene editing system according to any one of claims 10 to 18, wherein the deoxyribonucleotide is located on position 3, 4, 6, 7, or 8 from the 5' end of the spacer sequence.

30. The hybrid guide nucleic acid according to any one of claims 2 or 4 to 7, or the gene editing system according to any one of claims 10 to 29, wherein the spacer sequence comprises one to ten deoxyribonucleotides.

31. The gene editing system according to any one of claims 10 to 30, wherein the DNA binding domain comprises a CRISPR protein or a fragment thereof.

32. The gene editing system according to any one of claims 10 to 30, wherein the DNA binding domain comprises a catalytically impaired nuclease.

33. A gene editing system comprising: (a) Cas9 nickase or a nucleic acid encoding the Cas9 nickase, and (b) a guide RNA comprising a spacer corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene, and a scaffold for the Cas9 nickase.

34. A gene editing system comprising: (a) Cas9 nickase or a nucleic acid encoding the Cas9 nickase, and (b) a prime editing guide RNA comprising a spacer sequence corresponding to a protospacer sequence within a targeted portion of the 3' untranslated region (UTR) of the Polycystic Kidney Disease 1 (PKD1) gene; an extension sequence that templates synthesis of an edited sequence as a replacement DNA strand for the corresponding region of the targeted portion; and a binding scaffold for the Cas9 nickase.

35. The gene editing system according to claim 33 or claim 34, wherein the Cas9 nickase comprises a mutation, wherein the mutation is selected from the group consisting of: N692A, M694A, Q695A, H698A, K810A, K855A, K848A, Kl003A, Rl060A as compared to a Cas9 nickase comprising the amino acid sequence corresponding to SEQ ID NO:

911.

36. The gene editing system according to claim 35, wherein the gene editing system comprises a deaminase.

37. The gene editing system according to claim 35, wherein the gene editing system comprises a polymerase.

38. The gene editing system according to claim 37, wherein the polymerase is a reverse transcriptase.

39. The gene editing system according to any one of claims 36 to 38, wherein the Cas9 nickase comprises a single fusion protein with the deaminase or with the polymerase.

40. The gene editing system according to any one of claims 33 to 39, wherein (a) comprises the Cas9 nickase.

41. The gene editing system according to any one of claims 33 to 39, wherein (a) comprises the nucleic acid encoding the Cas9 nickase.

42. The gene editing system according to claim 41, wherein the nucleic acid is a mRNA.

43. The gene editing system according to any one of claims 33 to 42, wherein the Cas9 nickase comprises an amino acid sequence having at least 90% identity to SEQ ID NO:

911.

44. The gene editing system according to any one of claims 33 to 43, wherein the guide nucleic acid sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one of SEQ ID NOs:2-9 or 19-62.

45. The gene editing system according to claim 44, wherein the spacer sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one SEQ ID NOs:2-7.

46. The gene editing system according to claim 44, wherein the spacer sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to SEQ ID NO:4 or SEQ ID NO:

7.

47. The gene editing system according to claim 46, wherein the guide nucleic acid comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to SEQ ID NO:81 or SEQ ID NO:

108.

48. The gene editing system according to claim 44, wherein the extension sequence comprises a sequence at least 80%, 90%, 95%, 99%, or 100% identical to the sequence corresponding to any one of SEQ ID NOs:19-62.

49. The gene editing system according to any one of claims 10 to 48, wherein (a) and (b) are constituent components of a pharmaceutical composition that comprises a lipid nanoparticle (LNP) containing (a) or (b), wherein the LNP comprises an amino lipid, a phospholipid, a sterol and a PEG lipid.

50. The gene editing system according to claim 49, wherein the LNP comprises a delivery moiety.

51. The gene editing system according to claim 50, wherein the delivery moiety is selected from the group consisting of: lipids, peptides, polyethers, carbohydrates, and antibodies.

52. The in vivo hybrid guide gene editing system according to claim 50, wherein the delivery moiety comprises a receptor binding domain (RBD).

53. The gene editing system according to claim 50, wherein the delivery moiety comprises a N-acetylgalactosamine (GalNAc) moiety, a poly(ethylene glycol) (PEG) moiety, a fatty acid moiety, or a lipid moiety.

54. The gene editing system according to claim 50, wherein the delivery moiety comprises a cell-penetrating peptide (CPP).

55. The gene editing system according to claim 54, wherein the amino acid sequence of the CPP comprises SEQ ID NO:

914.

56. The gene editing system according to any one of claims 50 to 55, wherein the delivery moiety targets the LNP to kidney.

57. The gene editing system according to any one of claims 10 to 56, wherein the gene editing system is not in a human in vivo.

58. A pharmaceutical composition comprising the guide nucleic acid according to any one of claims 1 to 7, or the gene editing system according to any one of claims 10 to 56, and a pharmaceutically acceptable excipient.

59. A method for treating autosomal dominant polycystic kidney disease (ADPKD), the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 57, whereby a level of Polycystin 1 protein is increased in a kidney in the subject.

60. Use of the guide nucleic acid according to any one of claims 1 to 7, or the gene editing system according to any one of claims 10 to 57 in the manufacture of a medicament for treatment of ADPKD in a subject in need thereof.

61. The guide nucleic acid according to any one of claims 1 to 7, or the gene editing system according to any one of claims 10 to 57 for use in the treatment of ADPKD in a subject in need thereof.

62. The method according to claim 59 or the use according claim 60 or claim 61, wherein the treatment introduces at least one point mutation within a binding site sequence for a miR-17 family member or a miR-200 family member within the targeted portion, whereby binding of the miR-17 or miR-200 family member is reduced or eliminated.

63. The method or use according to claim 62, wherein the at least one point mutation is within a binding site sequence for the miR-17 family member.

64. The method according to claim 59 or the use according claim 60 or claim 61, wherein the treatment results in deletion of a binding site sequence for a miR-17 family member or a miR-200 family member within the targeted portion, whereby binding of the miR-17 or miR-200 family member is reduced or eliminated.

65. The method or use according to claim 62, wherein the treatment results in deletion of a binding site sequence for a miR-17 family member.

66. The method or use according to any one of claims 59 to 65, wherein the subject is human.

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