Methods of recombinant adeno-associated virus kidney administration

Abstract

The technology described herein is directed to methods of administering a therapeutic composition, such as recombinant adeno-associated virus (rAAV), to a kidney of a subject using a retrograde ureter route, for example, to at least renal papilla of the kidney. Such administration methods can be used to treat a kidney-associated disorder in a subject in need thereof. Also described herein are pharmaceutical compositions comprising a recombinant adeno-associated virus (rAAV) for administration to the kidney.

Description

Attorney Docket No: 046192-000134WOPTMETHODS OF RECOMBINANT ADENO-ASSOCIATED VIRUS KIDNEY ADMINISTRATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U. S. C. § 119(e) of U. S. Provisional Application No. 63 / 726,021 filed November 27, 2024, the contents of which are incorporated herein by reference in their entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted in XML format via Patent Center and is hereby incorporated by reference in its entirety. Said XML copy, created on November 24, 2025, is named 046192-000134WOPT_SL.xml and is 51,478 bytes in size.TECHNICAL FIELD

[0003] The technology described herein relates to methods of administering recombinant adeno-associated virus rAAV to the kidney and pharmaceutical compositions comprising rAAV for administration to the kidney.BACKGROUND

[0004] The primary job of the kidney is to filter the blood, removing waste products and excess fluid. The kidneys maintain a healthy balance of water, salts, and minerals. The kidneys also control blood pressure in the body. Kidneys are perfused by approximately 1500L of blood per day in humans, which translates to 180L of glomerular filtrate (primary urine) per day and 1 to 2L of final urine per day.

[0005] Kidneys are made up of greater than 1 million filtering units known as nephrons. The nephron comprises the following regions in order of filtrate passage: glomerulus, glomerular capsule (Bowman’s capsule), proximal tubule, loop of Henle, distal tubule, and collecting duct. The glomerulus is the site of blood filtration; small fenestrations allow fluids and small molecules to pass through, keeping blood cells and proteins out of the kidney tubules; the filtrate is captured by the glomerular capsule. The proximal tubule (also referred to interchangeably as proximal convoluted tubule (PCT)) filters 65% of primary urine; reabsorbs glucose, amino acids, solutes, and low molecular weight proteins; and maintains acid-base balance by reabsorbing bicarbonate. The loop of Henle reabsorbs water and salts; its descending thin limb reabsorbs water concentrating urine, and its ascending thick limb is permeable to ion exchange. The distal tubule (also referred to interchangeably as distal convoluted tubule (DCT)) regulates extracellular fluid volume and electrolyte homeostasis. The collecting duct reabsorbs more water, with fine tuning to the final urine product. Urine flows out14903-3015-35943Attorney Docket No: 046192-000134WOPTof the collecting duct through a renal papilla at the apex of a renal pyramid into minor and major renal calyxes. The urine then travels through the renal pelvis and ureter, is stored in the urinary bladder, and is excreted through the urethra. The speed of fluid flow through the kidneys is about 120 mL per minute in a healthy adult, measured as the glomerular filtration rate (GFR).

[0006] Kidney-associated disorders can be treated using genetic vectors, such as a recombinant adeno-associated virus (rAAV). However, it is not beneficial to administer rAAV using the intravenous (IV) route since the virus would transduce other organs (e.g., liver), and the high GFR can reduce transduction efficiency of nephrons. One alternative administration method is to needle puncture the kidney multiple times; however, this administration method is not clinically favorable. A urologist would likely exclude performing such kidney needle punctures because the kidney is highly vascularized and a puncture may result in excessive bleeding. As the kidney is accessible by vascular tract, another method is to cannulate the renal artery, cannulate the renal vein, attach the cannulas to a pump, and circulate an agent (e.g., rAAV) through the resulting isolated and cannulated vasculature. However, this is a complex surgical procedure that can result in complications and discomfort. There is great need for clinically relevant administration methods to efficiently deliver rAAV or other therapeutic compositions to kidneys. There is also need of rAAV that demonstrate tropism and / or efficiency in the kidneys.SUMMARY

[0007] Embodiments of the technology described herein relate to methods of administering a therapeutic composition, including but not limited to recombinant adeno-associated virus (rAAV), to at least one part of the kidney, such as a nephron or a papilla of a kidney of a subject. This can be accomplished using a retrograde ureter route. The renal papilla is the apex of a renal pyramid in the kidney where urine flows from the collecting ducts into the renal calyxes, renal pelvis, and ureter. Such administration methods can be used to treat a kidney-associated disorder in a subject in need thereof. Also described herein are pharmaceutical compositions comprising a recombinant adeno-associated virus (rAAV) for administration to the kidney.

[0008] Also described herein are specific rAAVs that showed high transduction in the kidneys following retrograde ureter administration, including but not limited to an rAAV comprising a capsid selected from Table 1 or Fig. 4. Furthermore, described herein are exemplary parameters for the retrograde ureter administration, such as to at least one papilla of a kidney, including administration volume, timings, and / or renal vessel(s) occlusion.

[0009] In one aspect, the retrograde ureter administration can further comprise occlusion, such as with clamps or a balloon catheter, partial occlusion, or non-occlusion of at least one of the renal artery, renal vein, and / or ureter.24903-3015-35943Attorney Docket No: 046192-000134WOPT

[0010] In multiple aspects, described herein are methods of transducing a sufficient number of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV) to obtain an effective level of expression (e.g., of the rAAV, of a transgene comprised by the rAAV) in the kidney.

[0011] In one aspect, described herein is a method of transducing nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, wherein nephrons of the kidney are transduced at a therapeutically effective level, wherein none of the renal artery, renal vein, and ureter are occluded during administration of the solution comprising the rAAV.

[0012] In one aspect, described herein is a method of transducing nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject, wherein kidney nephrons comprising nephron cells are transduced with the rAAV at a therapeutically effective level.

[0013] In some embodiments of any of the aspects, delivery device (e.g., a ureteroscope, a catheter) is 0 mm to about 10mm away from the at least one renal papilla while administering the rAAV.

[0014] In some embodiments of any of the aspects, the solution comprising the rAAV is selectively administered to the at least one renal papilla for about 1 minute to about 2 minutes per renal papilla.

[0015] In some embodiments of any of the aspects, about 1 mL to about 5 mL of the solution comprising the rAAV is selectively administered to each targeted renal papilla of the kidney.

[0016] In some embodiments of any of the aspects, further comprising maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O while the rAAV is being administered. In some embodiments of any of the aspects, further comprising maintaining an intra-renal pressure of from about 27 cm H2O to about 80 cm H2O while the rAAV is being administered.

[0017] In some embodiments of any of the aspects, the method results in the transduction of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or more of the nephrons in the kidney with the rAAV.

[0018] In some embodiments of any of the aspects, the transduction efficiency of the rAAV of the nephrons in the kidney is at least 2-fold, at least 5 -fold, at least 10-fold, at least 50-fold, at least34903-3015-35943Attorney Docket No: 046192-000134WOPT100-fold, at least 400-fold, at least 1000-fold, or at least 3500-fold increased compared to a corresponding transduction efficiency of corresponding nephrons in another kidney treated by intravenous administration of the solution comprising the rAAV.

[0019] In some embodiments of any of the aspects, the rAAV is not AAV9, and the transduction efficiency of the rAAV of the nephrons in the kidney is at least 2-fold, at least 5 -fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 400-fold, at least 1000-fold, or at least 3500-fold increased compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

[0020] In some embodiments, the nephrons are transduced with an efficiency index that is greater than 1.

[0021] In some embodiments of any of the aspects, the rAAV does not comprise an AAV9 capsid, and the transduction efficiency of the rAAV in proximal tubule cells of the nephrons in the kidney is at least 2-fold, at least 5 -fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 400-fold, at least 1000-fold, or at least 3500-fold increased compared to a corresponding transduction efficiency in proximal tubule cells achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

[0022] In some embodiments of any of the aspects, the method further comprises a step of blocking or occluding a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof, prior to administering the solution comprising the rAAV.

[0023] In some embodiments of any of the aspects, the method further comprises a step of occluding at least one of the following: a renal artery, a renal vein, and / or a ureter of the kidney, prior to administering the solution comprising the rAAV.

[0024] In some embodiments of any of the aspects, the method further comprises a step of unoccluding the renal artery, the renal vein, and / or the ureter after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV.

[0025] In some embodiments of any of the aspects, the method further comprises a step of unblocking or occluding the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV.

[0026] In some embodiments of any of the aspects, the method further comprises the kidney is not isolated from systemic circulation.

[0027] In some embodiments of any of the aspects, the method further comprises a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney is not blocked or occluded during performance of the method.

[0028] In some embodiments of any of the aspects, none of the renal artery, renal vein, and ureter are occluded during administration of the solution comprising the rAAV44903-3015-35943Attorney Docket No: 046192-000134WOPT

[0029] In some embodiments of any of the aspects, the solution comprising the rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O. In some embodiments of any of the aspects, the solution comprising the rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 27 cm H2O to about 80 cm H2O.

[0030] In some embodiments of any of the aspects, the subject is a human, a non-human primate, a horse, a dog, or a pig.

[0031] In some embodiments of any of the aspects, at least about 30% of the nephrons of the kidney are transduced with the rAAV.

[0032] In some embodiments of any of the aspects, the volume of the solution comprising the rAAV administered to the subject is from about 0.2 mL / kg to about 0.27 mL / kg.

[0033] In some embodiments of any of the aspects, the volume of the solution comprising the rAAV administered to the subject is from about 0.27 mL / kg to about 0.33 mL / mg.

[0034] In some embodiments of any of the aspects, the volume of the solution comprising the rAAV administered to the subject is from about 0.20 mL / kg to about 1.25 mL / mg.

[0035] In some embodiments of any of the aspects, the solution comprising the rAAV is administered using a balloon catheter.

[0036] In some embodiments of any of the aspects, the renal blood vessel and / or the ureter is occluded or blocked using a balloon catheter.

[0037] In some embodiments of any of the aspects, the renal blood vessel and / or the ureter is occluded or blocked using a clamp, e.g., after laparoscopy, or using an intraarterial balloon, e.g., endovascular delivery.

[0038] In some embodiments of any of the aspects, only one of the renal artery or renal vein of the kidney is blocked or occluded.

[0039] In some embodiments of any of the aspects, the renal vein of the kidney is not blocked or occluded.

[0040] In some embodiments of any of the aspects, the method does not comprise a continuous perfusion of an isolated kidney.

[0041] In some embodiments of any of the aspects, the method does not comprise a closed circuit comprising the kidney.

[0042] In some embodiments of any of the aspects, the method does not comprise a substantially closed system comprising the kidney.

[0043] In some embodiments of any of the aspects, the method does not comprise diverting circulation from the kidney.

[0044] In some embodiments of any of the aspects, the method does not comprise bypassing the kidney.54903-3015-35943Attorney Docket No: 046192-000134WOPT

[0045] In some embodiments of any of the aspects, the method is performed in vivo.

[0046] In some embodiments of any of the aspects, the method is not performed ex vivo.

[0047] In some embodiments of any of the aspects, the period of time for occluding or blocking the at least one renal blood vessel and / or the ureter is 15-45 minutes subsequent to the occluding or blocking.

[0048] In some embodiments of any of the aspects, the period of time for occluding or blocking the at least one renal blood vessel and / or the ureter is 20-40 minutes subsequent to the occluding or blocking.

[0049] In some embodiments of any of the aspects, the period of time for occluding or blocking the at least one renal blood vessel and / or the ureter is about 15-30 minutes subsequent to the occluding or blocking.

[0050] In some embodiments of any of the aspects, the period of time for occluding or blocking the at least one renal blood vessel and / or the ureter is about 30 minutes subsequent to the occluding or blocking.

[0051] In some embodiments of any of the aspects, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.33 mL / kg, and wherein the period of time for occluding or blocking the renal blood vessel and / or the ureter is about 15-30 minutes subsequent to the occluding or blocking.

[0052] In some embodiments of any of the aspects, the volume of the solution comprising the rAAV is from about 0.2 mL / kg to about 0.27 mL / kg, and wherein the period of time for occluding or blocking the renal blood vessel and / or the ureter is about 15-30 minutes subsequent to the occluding or blocking.

[0053] In some embodiments of any of the aspects, the volume of the solution comprising the rAAV is from about 0.2 mL / kg to about 0.27 mL / kg, and wherein the period of time for occluding or blocking the renal blood vessel and / or the ureter is about 30 minutes subsequent to the occluding or blocking.

[0054] In some embodiments of any of the aspects, the rAAV comprises an AAV capsid protein selected from a serotype provided in Table 1. In some embodiments of any of the aspects, the rAAV comprises an AAV capsid protein selected from serotype AAV1, AAV2, AAV3a, AAV3b, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV2G9, AAV2.5G9, AAV2.5, AAVrh8, AAVrh10, AAVrh74, AAV 10, AAV11, and AAVDJ.

[0055] In some embodiments of any of the aspects, the rAAV comprises a capsid protein selected from the group consisting of AAV2G9, AAV2.5, AAVDJ, and AAV2.

[0056] In some embodiments of any of the aspects, the capsid protein is AAV2G9.

[0057] In some embodiments of any of the aspects, the rAAV comprises a rational polyploid.64903-3015-35943Attorney Docket No: 046192-000134WOPT

[0058] In some embodiments of any of the aspects, the solution comprises the rAAV at a concentration of 108viral genomes per mL (vg / mL) to 1015vg / mL.

[0059] In some embodiments of any of the aspects, the solution comprises the rAAV at a concentration of 108vg / mL to 1013vg / mL.

[0060] In some embodiments of any of the aspects, the solution comprises the rAAV at a concentration of IxlO13to 5xl013vg / mL.

[0061] In some embodiments of any of the aspects, the solution comprises IxlO14to 2.5xl015rAAV viral genomes total

[0062] In some embodiments of any of the aspects, the solution comprises IxlO13to 2xl013rAAV viral genomes total.

[0063] In some embodiments of any of the aspects, the solution comprises 5xl013to 6xl013rAAV viral genomes total.

[0064] In some embodiments of any of the aspects, the solution comprises IxlO10viral genomes total.

[0065] In some embodiments of any of the aspects, the rAAV comprises a transgene.

[0066] In some embodiments of any of the aspects, the transgene is selected from the group consisting of 4-Hydroxy-2-Oxoglutarate Aldolase 1 (H0GA1; e.g., type III); Alanine -Glyoxylate Aminotransferase (AGXT; e.g., type I); Aquaporin 2 (AQP2); ATPase Na+ / K+ Transporting Subunit Alpha 1 (ATP 1 Al); Arginine Vasopressin Receptor 2 (AVPR2); ATPase H+ Transporting V0 Subunit A4 (ATP6V0A4); ATPase H+ Transporting V1 Subunit B1 (ATP6V1B1); Barrier Syndrome, Infantile, With Sensorineural Deafness (BSND; e.g., type IV); Barttin CLCNK (chloride channel K) Type Accessory Subunit Beta (BSND); Calcium Sensing Receptor (CaSR); Carbonic Anhydrase 2 (CA2); Chloride Voltage-Gated Channel 5 (CLCN5; e.g., type I); Chloride Voltage-Gated Channel Ka (CLCNKA; e.g., type IV); Chloride Voltage-Gated Channel Kb (CLCNKB; e.g., type III and IV); Claudin 16 (CLDN16); Claudin 19 (CLDN19); CLCNKA (Chloride Voltage-Gated Channel Ka); Collagen Type IV Alpha 3 Chain (COL4A3); Collagen Type IV Alpha 4 Chain (COL4A4); Collagen Type IV Alpha 5 Chain (COL4A5); Cullin 3 (CUL3); Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2 (CNNM2); Cytochrome P450 Family 11 Subfamily B Member 1 (CYP11B1); Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2); Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1); Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2); Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (EHHADH); Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); FAM111 (family 111) Trypsin Like Peptidase A (FAM111A); Forkhead Box II (FOXI1); FXYD Domain / Motif Containing Ion Transport Regulator 2 (FXYD2); Glucosidase II Alpha Subunit (GANAB); Glycine Amidinotransferase (GATM); Glyoxylate And Hydroxypyruvate Reductase (GRHPR; e.g., type II); Guanine nucleotide binding protein alpha stimulating (GNAS); Hepatocyte nuclear factor 1 (HNF1)74903-3015-35943Attorney Docket No: 046192-000134WOPTHomeobox B (HNF1B); Hepatocyte Nuclear Factor 4 Alpha (HNF4A); Hydroxy-Delta-5 -Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2); Hydroxysteroid 11-Beta Dehydrogenase 2 (HSD11B2); Inositol Polyphosphate-5-Phosphatase (OCRL; e.g., type II); Kelch Like Family Member 3 (KLHL3); MAGED2 (type V); Mucin 1 (MUC1; e.g., type I); Melanoma Antigen Gene Family Member D2 (MAGED2); Nephrin (NPHS1); Nephrocystin 1 (NPHP1);Nephrosis 2 (NPHS2; Podocin); Nuclear Receptor Subfamily 3 Group C Member 2 (NR3C2); Oculocerebrorenal Syndrome Of Lowe (OCRL) Inositol Polyphosphate-5-Phosphatase; Phosphate Regulating Endopeptidase X-Linked (PHEX); Polycystic Kidney And Hepatic Disease 1 (PKHD1); Polycystin 1 (PKD1); Polycystin 2 (PKD2; Potassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1; e.g., type II); Potassium Inwardly Rectifying Channel Subfamily J Member 10 (KCNJ10); Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1); Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1); Pterin-4 Alpha-Carbinolamine Dehydratase 1 (PCBD1); Sodium Channel Epithelial 1 Subunit Alpha (SCNN1 A); Sodium Channel Epithelial 1 Subunit Beta (SCNN1B); Sodium Channel Epithelial 1 Subunit Gamma (SCNN1G); Solute Carrier Family 1 Member 1 (SLC1A1); Solute Carrier Family 2 Member 2 (SLC2A2); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 34 Member 1 (SLC34A1); Solute Carrier Family 34 Member 3 (SLC34A3); Solute Carrier Family 36 Member 2 (SLC36A2); Solute Carrier Family 4 Member 1 (SLC4A1); Solute Carrier Family 6 Member 19 (SLC6A19); Solute Carrier Family 6 Member 20 (SLC6A20); Solute Carrier Family 7 Member 7 (SLC7A7); Solute Carrier Family 7 Member 9 (SLC7A9); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6); Von Hippel-Lindau Tumor Suppressor (VHL); WD Repeat Domain 72 (WDR72); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 1 (WNK1); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 4 (WNK4); and combinations thereof.

[0067] In some embodiments of any of the aspects, the transgene comprises an inhibitor of a gene or protein selected from the group consisting of: Renin (REN), Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A), Sodium Channel Epithelial 1 Subunit Beta (SCNN1B), and Uromodulin (UMOD).

[0068] In some embodiments of any of the aspects, circulating serum of the subject does not neutralize the rAAV upon administration.

[0069] In some embodiments of any of the aspects, the subject has antibodies that neutralize the rAAV to be administered in the circulating serum and the antibodies do not neutralize the rAAV in the kidney upon administration.

[0070] In some embodiments of any of the aspects, a subsequent administration of the rAAV is performed without resulting in a substantial inflammatory response in the kidney.84903-3015-35943Attorney Docket No: 046192-000134WOPT

[0071] In some embodiments of any of the aspects, the subsequent administration is at least one day later. In some embodiments of any of the aspects, the subsequent administration is at least one month later.

[0072] In some embodiments of any of the aspects, the method transduces proximal tubules of the kidney with the rAAV.

[0073] In some embodiments of any of the aspects, the method transduces at least one cell population of a glomerulus, a glomerular capsule, a proximal convoluted tubule, the loop of Henle, a distal convoluted tubule, or the collecting duct of the kidney with the rAAV. In some embodiments of any of the aspects, the method transduces at least one of a glomerulus, a glomerular capsule, a proximal convoluted tubule, the loop of Henle, or a distal convoluted tubule of the kidney with the rAAV.

[0074] In some embodiments of any of the aspects, the rAAV comprises a kidney-specific promoter.

[0075] In some embodiments of any of the aspects, the kidney-specific promoter is selected from the group consisting of: kidney-specific cadherin (KSPC) gene promoter; Na+ / glucose co-transporter (SGLT2) gene promoter; sodium potassium, 2 chloride co-transporter (NKCC2) gene promoter; and E-cadherin (ECAD) gene promoter.

[0076] In some embodiments of any of the aspects, the kidney-specific promoter is a synthetic promoter.

[0077] In some embodiments of any of the aspects, the rAAV has a genome comprising a promoter specific to proximal convoluted tubules and / or collecting ducts.

[0078] In one aspect, described herein is a method of treating a kidney-associated disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) to the subject by performing a method as described herein.

[0079] In some embodiments of any of the aspects, the kidney-associated disorder is selected from the group consisting of: Alport syndrome; Autosomal dominant polycystic kidney disease (ADPKD); Autosomal dominant tubulointerstitial kidney disease (ADTKD); Autosomal recessive polycystic kidney disease (ARPKD); Apparent mineralocorticoid excess; Autosomal dominant hypocalcemia; Autosomal dominant hypomagnesemia; Bartter Syndrome (e.g., Barttertype 1; Bartter type 2; Barttertype 3; Barttertype 4a; Barttertype 4b; Barttertype 5); Congenital adrenal hyperplasia (e.g., Congenital adrenal hyperplasia type 1; Congenital adrenal hyperplasia type 2; Congenital adrenal hyperplasia type 4; Congenital adrenal hyperplasia type 5); Cystinosis; Cystinuria (e.g., Cystinuria A; Cystinuria B); Dent disease (e.g., Dent disease type 1; Dent disease type 2 / Lowe syndrome); Dicarboxylic aminoaciduria; Distal RTA; EAST / SeSAME syndrome; Fanconi Bickel syndrome; Fanconi renotubular syndrome (e.g., Fanconi renotubular syndrome 1; Fanconi renotubular94903-3015-35943Attorney Docket No: 046192-000134WOPTsyndrome 2; Fanconi renotubular syndrome 3; Fanconi renotubular syndrome 4); Gitelman syndrome; Glucocorticoid remediable aldosteronism; Hartnup disorder; Hereditary hypophosphatemic rickets with hypercalciuria; HNF IB-related kidney disease; Hyperphenylalaninemia BH4-deficient;Hypomagnesemia (e.g., Hypomagnesemia type 1 / hypomagnesemia with secondary hypocalcemia; Hypomagnesemia type 2; Hypomagnesemia type 3 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia type 4; Hypomagnesemia type 5 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia, seizures, and mental retardation type 1; Hypomagnesemia, seizures, and mental retardation type 2); Iminoglycinuria; Kenny-Caffey syndrome type 2; Liddle syndrome; Lysinuric protein intolerance; Medullary cystic kidney disease; Neonatal inflammatory skin and bowel disease type 2; Nephrogenic diabetes insipidus; Nephrogenic syndrome of inappropriate antidiuresis; Nephronophthisis; Papillorenal syndrome; Primary hyperoxaluria; Pseudohypoaldosteronism (e.g., Pseudohypoaldosteronism type 1;Pseudohypoaldosteronism type 1A; Pseudohypoaldosteronism type 2b; Pseudohypoaldosteronism type 2c; Pseudohypoaldosteronism type 2d; Pseudohypoaldosteronism type 2e); Renal tubular acidosis type 3; Thin Basement Membrane Nephropathy; Von Hippel-Lindau syndrome; and X-linked hypophosphatemic rickets.

[0080] In some embodiments of any of the aspects, the kidney-associated disorder is Cystinuria, and the transgene is SLC3A1 and / or SLC7A9.

[0081] In some embodiments of any of the aspects, the kidney-associated disorder is autosomal dominant polycystic kidney disease (ADPKD), and the transgene is PKD1, PKD2, and / or GANAB.

[0082] In one aspect, described herein is a method of transducing at least about 10% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 0.33 mL / kg, the kg being the weight of the subject; and (d) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 10% of the nephrons in the kidney with the rAAV.

[0083] In one aspect described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively104903-3015-35943Attorney Docket No: 046192-000134WOPTadministering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and (d) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

[0084] In one aspect, described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal artery of the kidney and not blocking a renal vein of the kidney; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device; and (d) unblocking the renal artery after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

[0085] In one aspect, described herein is a method of transducing nephrons in a kidney of a subject, the method comprising: (a) blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising rAAV to at least one targeted renal papilla of the kidney through the delivery device, the rAAV not being rAAV9; and (d) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV, wherein the method results in a transduction efficiency that is at least 2-fold higher compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

[0086] In some embodiments of any of the aspects, the rAAV comprises a capsid protein selected from Table 1, excluding AAV9.

[0087] In some embodiments of any of the aspects, the rAAV has at least 2-fold higher transduction efficiency in the kidney compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

[0088] In some embodiments of any of the aspects, the rAAV has 400-fold higher transduction efficiency in the kidney compared to AAV9. In some embodiments of any of the aspects, the rAAV has 3500-fold higher transduction efficiency in the kidney compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.114903-3015-35943Attorney Docket No: 046192-000134WOPT

[0089] In one aspect, described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) isolating the kidney from systemic circulation; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and (d) re-establishing the kidney into systemic circulation after a period of time of from about 10 minutes to about 60 minutes after the isolating and / or after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

[0090] In one aspect, described herein is a method of treating a kidney disorder in a subject in need thereof, the method comprising: administering to a kidney of the subject a therapeutically effective amount of a first recombinant adeno-associated virus (rAAV) encoding a transgene that is therapeutic toward the kidney disorder; and subsequent to administering the first rAAV, administering to the kidney or a different kidney of the subject a therapeutically effective amount of a second rAAV encoding the transgene or a different transgene that is therapeutic toward to the kidney disorder, wherein the first rAAV and the second rAAV are cross seroreactive, and wherein the subject does not elicit a significant immune response to the second rAAV in the kidney.

[0091] In some embodiments of any of the aspects, at least one solution comprising the first and / or second rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O. In some embodiments of any of the aspects, at least one solution comprising the first and / or second rAAV is administered to the while maintaining at an intrarenal pressure of from about 27 cm H2O to about 80 cm H2O.

[0092] In some embodiments of any of the aspects, a solution comprising the second rAAV is administered after about a week.

[0093] In some embodiments of any of the aspects, the first and second rAAVs are administered by an administration method comprising: guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the first or second rAAV through the delivery device to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject.

[0094] In some embodiments of any of the aspects, the first and / or second rAAVs are administered by an administration method comprising: (a) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising the rAAV through the124903-3015-35943Attorney Docket No: 046192-000134WOPTdelivery device to at least one targeted renal papilla of the kidney or a different kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and (d) unblocking renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV.

[0095] In some embodiments of any of the aspects, the administration method results in at least about 25% of the nephrons in the kidney being transduced with the rAAV.

[0096] In some embodiments of any of the aspects, the subject has neutralizing antibodies toward the first rAAV therapeutic prior to the administering.

[0097] In some embodiments of any of the aspects, the capsid protein of the first rAAV is the same serotype as the capsid protein of the second rAAV.

[0098] In some embodiments of any of the aspects, the capsid protein of the first rAAV is a different serotype as the capsid protein of the second rAAV.

[0099] In some embodiments of any of the aspects, the time period for subsequent administration of the second rAAV is determined based on the efficacy or longevity of the administration of the first rAAV.

[0100] In some embodiments of any of the aspects, the first rAAV is administered to a first kidney of the subject, and the second rAAV is administered to a second kidney of the subject.

[0101] In some embodiments of any of the aspects, the first rAAV is administered to a first kidney of the subject, and the second rAAV is administered to the first kidney of the subject.

[0102] In some embodiments of any of the aspects, the first rAAV is administered to both kidneys of the subject, and the second rAAV is administered to both kidneys of the subject.

[0103] In one aspect, described herein is a method of treating a kidney disorder in a subject in need thereof, the subject being seropositive for a recombinant adeno-associated virus (rAAV) therapeutic, the method comprising: selectively administering to at least one targeted renal papilla of a kidney of the subject the rAAV therapeutic encoding a transgene that is therapeutic toward the kidney disorder, wherein the subject does not elicit a significant immune response to the rAAV therapeutic in the kidney.

[0104] In some embodiments of any of the aspects, the subject has neutralizing antibodies toward the rAAV therapeutic prior to the administering.

[0105] In some embodiments of any of the aspects, the rAAV is administered by an administration method comprising: guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV through the delivery device to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject.134903-3015-35943Attorney Docket No: 046192-000134WOPT

[0106] In some embodiments of any of the aspects, the rAAV is administered by an administration method comprising: (a) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising the rAAV through the delivery device to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and (d) unblocking renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV, wherein the administration method results in at least about 25% of the nephrons in the kidney being transduced with the rAAV.

[0107] In one aspect, described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney; (b) guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; (c) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject, wherein the rAAV comprises a capsid protein selected from Table 1; and (d) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

[0108] In one aspect, described herein is a method of treating a kidney-associated disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the 2G9 rAAV to the subject by performing a retrograde ureter (e.g., trans-papilla) administration method as described herein.

[0109] In some embodiments of any of the aspects, the rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O. In some embodiments of any of the aspects, the rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 27 cm H2O to about 80 cm H2O.

[0110] In some embodiments of any of the aspects, the volume of the solution is 0.13 mL / kg to 1.25 mL / kg. In some embodiments of any of the aspects, the volume of the solution is 0.27 mL / kg to 0.33 mL / kg. In some embodiments of any of the aspects, the volume of the solution is 0.2 mL / kg to 1.25 mL / kg. In some embodiments of any of the aspects, the volume of the solution is 0.13 mL / kg to 0.33 mL / kg.144903-3015-35943Attorney Docket No: 046192-000134WOPT

[0111] In some embodiments of any of the aspects, the period of time is 30-60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV.

[0112] In some embodiments of any of the aspects, the subject is seropositive for the rAAV prior to the administration of the solution comprising the rAAV.

[0113] In some embodiments of any of the aspects, the rAAV is administered in liposomes, nanocapsules, microparticles, microspheres, lipid particles, lipid nanoparticles, or vesicles.

[0114] In some embodiments of any of the aspects, the rAAV is administered in lipid nanoparticles (LNPs).

[0115] In one aspect, described herein is a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) comprising: (a) an AAV capsid protein selected from Table 1; (b) a transgene comprising: (i) a gene selected from the group consisting of 4-Hydroxy-2-Oxoglutarate Aldolase 1 (H0GA1; e.g., type III); Alanine -Glyoxylate Aminotransferase (AGXT; e.g., type I); Aquaporin 2 (AQP2); ATPase Na+ / K+ Transporting Subunit Alpha 1 (ATP1A1); Arginine Vasopressin Receptor 2 (AVPR2); ATPase H+ Transporting V0 Subunit A4 (ATP6V0A4); ATPase H+ Transporting V1 Subunit B1 (ATP6V1B1); Bartter Syndrome, Infantile, With Sensorineural Deafness (BSND; e.g., type IV); Barttin CLCNK (chloride channel K) Type Accessory Subunit Beta (BSND); Calcium Sensing Receptor (CaSR); Carbonic Anhydrase 2 (CA2); Chloride Voltage-Gated Channel 5 (CLCN5; e.g., type I); Chloride Voltage-Gated Channel Ka (CLCNKA; e.g., type IV); Chloride Voltage-Gated Channel Kb (CLCNKB; e.g., type III and IV); Claudin 16 (CLDN16);Claudin 19 (CLDN19); CLCNKA (Chloride Voltage-Gated Channel Ka); Collagen Type IV Alpha 3 Chain (COL4A3); Collagen Type IV Alpha 4 Chain (COL4A4); Collagen Type IV Alpha 5 Chain (COL4A5); Cullin 3 (CUL3); Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2 (CNNM2); Cytochrome P450 Family 11 Subfamily B Member 1 (CYP11B1); Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2); Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1); Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2); Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (EHHADH); Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); FAM111 (family 111) Trypsin Like Peptidase A (FAM111A); Forkhead Box II (FOXI1); FXYD Domain / Motif Containing Ion Transport Regulator 2 (FXYD2); Glucosidase II Alpha Subunit (GANAB); Glycine Amidinotransferase (GATM);Glyoxylate And Hydroxypyruvate Reductase (GRHPR; e.g., type II); Guanine nucleotide binding protein alpha stimulating (GNAS); Hepatocyte nuclear factor 1 (HNF1) Homeobox B (HNF1B); Hepatocyte Nuclear Factor 4 Alpha (HNF4A); Hydroxy-Delta-5 -Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2); Hydroxysteroid 11-Beta Dehydrogenase 2 (HSD11B2);Inositol Polyphosphate-5 -Phosphatase (OCRL; e.g., type II); Kelch Like Family Member 3 (KLHL3); MAGED2 (type V); Mucin 1 (MUC1; e.g., type I); Melanoma Antigen Gene Family Member D2 (MAGED2); Nephrin (NPHS1); Nephrocystin 1 (NPHP1); Nephrosis 2 (NPHS2; Podocin); Nuclear154903-3015-35943Attorney Docket No: 046192-000134WOPTReceptor Subfamily 3 Group C Member 2 (NR3C2); Oculocerebrorenal Syndrome Of Lowe (OCRL) Inositol Polyphosphate-5-Phosphatase; Phosphate Regulating Endopeptidase X-Linked (PHEX); Polycystic Kidney And Hepatic Disease 1 (PKHD1); Polycystin 1 (PKD1); Polycystin 2 (PKD2; Potassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1; e.g., type II); Potassium Inwardly Rectifying Channel Subfamily J Member 10 (KCNJ10); Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1); Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1); Pterin-4 Alpha-Carbinolamine Dehydratase 1 (PCBD1); Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A); Sodium Channel Epithelial 1 Subunit Beta (SCNN1B); Sodium Channel Epithelial 1 Subunit Gamma (SCNN1G); Solute Carrier Family 1 Member 1 (SLC1A1); Solute Carrier Family 2 Member 2 (SLC2A2); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 34 Member 1 (SLC34A1); Solute Carrier Family 34 Member 3 (SLC34A3); Solute Carrier Family 36 Member 2 (SLC36A2); Solute Carrier Family 4 Member 1 (SLC4A1); Solute Carrier Family 6 Member 19 (SLC6A19); Solute Carrier Family 6 Member 20 (SLC6A20); Solute Carrier Family 7 Member 7 (SLC7A7); Solute Carrier Family 7 Member 9 (SLC7A9); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6); Von Hippel-Lindau Tumor Suppressor (VHL); WD Repeat Domain 72 (WDR72); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 1 (WNK1); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 4 (WNK4); and combinations thereof; or (ii) an inhibitor of a gene or protein selected from the group consisting of: Renin (REN), Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A), Sodium Channel Epithelial 1 Subunit Beta (SCNN1B), and Uromodulin (UMOD); and (c) a pharmaceutically acceptable carrier.

[0116] In some embodiments of any of the aspects, the pharmaceutically acceptable carrier comprises mannitol.

[0117] In some embodiments of any of the aspects, the AAV comprises a capsid protein of AAV2G9.

[0118] In some embodiments of any of the aspects, the solution that comprises the rAAV is at a concentration of I08viral genomes per mL (vg / mL) to IO15vg / mL.

[0119] In some embodiments of any of the aspects, the solution that comprises the rAAV is at a concentration of I08viral genomes per mL (vg / mL) to I014vg / mL.

[0120] In some embodiments of any of the aspects, the solution that comprises the rAAV is at a concentration of I08vg / mL to IO13vg / mL.

[0121] In some embodiments of any of the aspects, the solution that comprises the rAAV is at a concentration of IxlO13to 5xl013vg / mL.

[0122] In some embodiments of any of the aspects, the pharmaceutical composition comprises IxlO14to 2.5xl015rAAV viral genomes total.164903-3015-35943Attorney Docket No: 046192-000134WOPT

[0123] In some embodiments of any of the aspects, the pharmaceutical composition comprises IxlO13to 2xl013rAAV viral genomes total.

[0124] In some embodiments of any of the aspects, the pharmaceutical composition comprises 5xl013to 6xl013rAAV viral genomes total.

[0125] In some embodiments of any of the aspects, the pharmaceutical composition is in a unit dose of from about 0.13 mL / kg to about 0.33 mL / kg, the kg being the weight of the subject.

[0126] In some embodiments of any of the aspects, the pharmaceutical composition is in a unit dose of from about 0.27 mL / kg to about 0.33 mL / kg.

[0127] In some embodiments of any of the aspects, the pharmaceutical composition is in a unit dose of from about 0.27 mL / kg to about 1.25 mL / kg.

[0128] In some embodiments of any of the aspects, the transgene comprises a reporter protein.

[0129] In some embodiments of any of the aspects, the genome of the rAAV comprises a kidneyspecific promoter.

[0130] In some embodiments of any of the aspects, the kidney-specific promoter is selected from the group consisting of: kidney-specific cadherin (KSPC) gene promoter; Na+ / glucose co-transporter (SGLT2) gene promoter; sodium potassium, 2 chloride co-transporter (NKCC2) gene promoter; and E-cadherin (ECAD) gene promoter.

[0131] In some embodiments of any of the aspects, the kidney-specific promoter is a synthetic promoter.

[0132] In some embodiments of any of the aspects, the genome of the rAAV comprises a promoter specific to proximal convoluted tubules and / or collecting ducts.

[0133] In some embodiments of any of the aspects, the rAAV is formulated for delivery to at least one renal papilla.

[0134] In some embodiments of any of the aspects, the rAAV is formulated for delivery in liposomes, nanocapsules, microparticles, microspheres, lipid particles, lipid nanoparticles, or vesicles.

[0135] In some embodiments of any of the aspects, the rAAV is formulated for delivery in lipid nanoparticles (LNPs).

[0136] In one aspect, described herein is a method of transducing nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject, wherein the rAAV comprises AAV2G9, and wherein nephrons of the kidney are transduced with the rAAV at a therapeutically effective level.174903-3015-35943Attorney Docket No: 046192-000134WOPTBRIEF DESCRIPTION OF THE DRAWINGS

[0137] Fig. 1 shows histological sections of rat kidneys following retrograde ureter administration of a rAAV library. The top panel shows YFP expression (stained brown) in the library exposed left kidney and the bottom panel shows no detectable YFP expression in the unexposed right kidney.

[0138] Fig. 2 shows magnified images from Fig. 1. These images show that the kidney tubules were heavily transduced by the library compared to the negative control.

[0139] Fig. 3 shows a nephron schematic and an image illustrating the multiple paths for transduction.

[0140] Fig. 4 is a bar graph showing the efficiency index of rAAVs normalized to AAV9 in the kidney medulla (e.g., substantially comprising glomeruli, proximal tubules, and distal tubules) or kidney cortex (e.g., substantially comprising glomeruli, proximal tubules, and distal tubules). The efficiency index of each tested rAAV normalized to AAV9 was calculated as follows in Formula I: (cDNA reads [%] / input [%]) / (cDNA AAV9 reads [%] / input AAV9 [%]).

[0141] Fig. 5 is a schematic showing administration of AAV to a papilla of a kidney using an ureteroscope. Neither the renal artery nor renal vein are clamped or otherwise occluded.DETAILED DESCRIPTION

[0142] Embodiments of the technology described herein relate to methods of administering a therapeutic composition, such as recombinant adeno-associated virus (rAAV), to a kidney of a subject using a retrograde ureter route. While rAAV is used as an exemplary therapeutic composition herein, it is understood that other therapeutic compositions can be administered using the methods described herein. Accordingly in one aspect, described herein is a method of administering a therapeutic composition to a kidney of a subject, the method comprising: guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the therapeutic composition to at least one targeted renal papilla of the kidney through the delivery device. In some embodiments, the solution has a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject. In some embodiments, a kidney-associated disease or disorder is effectively treated through administration of the therapeutic to the at least one targeted renal papilla. In some embodiments, the therapeutic composition comprises a viral vector (e.g., adenovirus, lentivirus, AAV, etc.), liposomes, micelles, lipid nanoparticles (LNPs), small molecules, nanoparticles, antibodies, nucleic acids, polypeptides, or analogues thereof, or any combination thereof.

[0143] As used herein, “retrograde ureter route” or “retro-ureteral (RU)” or “retrograde route” or “retrograde route to the ureter” or “retrograde injection through ureter” or “retrograde administration” or “retrograde ureter administration” etc. are used interchangeably and refer to directing a delivery 184903-3015-35943Attorney Docket No: 046192-000134WOPTdevice against the flow of urine out of the kidney through the subjects urethra, bladder, and ureter, and into the renal pelvis, and administering a solution comprising the rAAV, i.e., by injecting the solution into the renal pelvis, where the solution flows into the nephrons of the kidney, including to the nephron tubules, such as the proximal tubules, loops of Henle, distal tubules, and / or collecting ducts.

[0144] In some embodiments, the retrograde ureter route comprises administering the rAAV through a delivery device in contact with, or close to contact with (e.g., 0-20 mm away from), at least one target papilla (e.g., at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all) of at least one kidney. The target papilla is a specific papilla to which the solution is to be selectively delivered. It is understood that while the solution is intended to be delivered to a specific target papilla, the renal pelvis is typically filled with a fluid; thus, a small portion of the solution may inadvertently diffuse to another papilla. In some embodiments, less than 75%, less than 70%, less than 60%, less than 50%, less than 40%, or less than 30% of the solution delivered to an unintended non-target papilla. In other embodiments, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% of the solution is delivered to the intended target papilla. The delivery device can be any delivery device known in the art for administering a solution the renal pelvis, including a catheter (without a balloon), a balloon catheter, or a ureteroscope, as nonlimiting examples. The number of papillae to administer to can depend on the condition being treated. A human kidney typically contains 6 to 10 papillae, which can vary due to anatomical variations such as papillae fusion. Such administration is referred herein as “trans-papilla” or “trans-papillary” administration. In a preferred embodiment, the retrograde ureter route described herein consists of trans-papilla administration to at least one, at least two, at least three, or at least four renal papillae, or more, or to all (each and every) of the renal papillae.

[0145] In some embodiments, the solution comprising the rAAV is administered in contact with or in close proximity to the renal papilla. In some embodiments, the distal end of the delivery device (e.g., catheter, ureteroscope, or other device) for administering the solution comprising the rAAV is positioned in a renal calyx and in close proximity to the renal papilla, e.g., from 0 to 30 mm, from 0 to 20 mm, from 0 to 15 mm, from 0 to 10 mm, from 0.5 to 30 mm, from 0.5 to 20 mm, from 0.5 to 15 mm, from 0.5 to 10 mm. In other embodiments, the distal end of the delivery device is positioned in close proximity to the renal papilla at a distance of less than or equal to 30 mm, less than or equal to 25 mm, less than or equal to 20 mm, less than or equal to 15 mm, less than or equal to 10 mm, less than or equal to 5 mm, or less than or equal to 1 mm. In yet other embodiments, the distal end of the delivery device is positioned in close proximity to the renal papilla at a distance of about 0 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2.0 mm, about 2.5 mm, about 3.0, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.5 mm, about 6.0 mm, about 6.5 mm, about 7.0 mm, about 7.5 mm, about 8.0 mm, about 8.5 mm, about 9.0 mm, about 9.5 mm, about 10.0 mm, about 10.5194903-3015-35943Attorney Docket No: 046192-000134WOPTmm, about 11.0 mm, about 11.5 mm, about 12.0 mm, about 12.5 mm, about 13.0, about 13.5 mm, about 14.0 mm, about 14.5 mm, about 15.0 mm, about 15.5 mm, about 16.0 mm, about 16.5 mm, about 17.0 mm, about 17.5 mm, about 18.0 mm, about 18.5 mm, about 19.0 mm, about 19.5 mm, about 20.0 mm, or more away from the surface of the renal papilla. In other embodiments, the distal end of the delivery device is positioned less than or equal to 0 mm to 10 mm. It is understood that each of the individual distances described herein can be used to define lower and upper values of a distance range. It should be understood that by increasing the pressure used even larger distances away from the surface of the renal papilla, for example up to 1 cm or 2 cm or more, can be used. Such adjustments are well within the skill of the artisan based on the disclosure herein. Thus, in one embodiment the distance can be in direct contact to 2 cm depending on the pressure used.

[0146] In some embodiments, the rAAV solution comprises from IxlO10to IxlO15, from IxlO11to 5xl014, from IxlO11to IxlO14, from IxlO13to 5xl013vg / mL, or about IxlO10vg / mL, about 2xlO10vg / mL, about 3xl010vg / mL, about 4xlO10vg / mL, about 5xlOlovg / mL, about 6xlOlovg / mL, about 7xlOlovg / mL, about 8xlOlovg / mL, about 9xlOlovg / mL, about 10xl010vg / mL, IxlO11vg / mL, about 2xlOnvg / mL, about 3xl0nvg / mL, about 4xlOnvg / mL, about 5xl0nvg / mL, about 6xlOnvg / mL, about 7xlOnvg / mL, about 8xl0nvg / mL, about 9xlOnvg / mL, about lOxlO11vg / mL, IxlO12vg / mL, about 2xl012vg / mL, about 3xl012vg / mL, about 4xl012vg / mL, about 5xl012vg / mL, about 6xl012vg / mL, about 7xlO12vg / mL, about 8xlO12vg / mL, about 9xlO12vg / mL, about 10xl012vg / mL, about IxlO13vg / mL, about 2xl013vg / mL, about 3xl013vg / mL, about 4xl013vg / mL, about 5xl013vg / mL, about 6xl013vg / mL, about 7xl013vg / mL, about 8xl013vg / mL, about 9xl013vg / mL, about lOxlO13vg / mL, IxlO14vg / mL, about 2xl014vg / mL, about 3xl014vg / mL, about 4xl014vg / mL, about 5xl014vg / mL, about 6xl014vg / mL, about 7xl014vg / mL, about 8xlO14vg / mL, about 9xl014vg / mL, about 10xl014vg / mLlxl015vg / mL, about 2xl015vg / mL, about 3xl015vg / mL, about 4xl015vg / mL, about 5xl015vg / mL, about 6xl015vg / mL, about 7xl015vg / mL, about 8xl015vg / mL, about 9xl015vg / mL, about lOxlO15vg / mL, or more, rAAV. It is understood that each of the individual concentrations described herein can be used to define lower and upper values of a concentration range.

[0147] In some embodiments, the total volume of the solution to be delivered to the kidney is from 0.13 mL / kg to about 0.35 mL / kg, about 0.2 mL / kg to about 0.35 mL / kg, from about 0.25 mL / kg to about 0.35 mL / kg, from about 0.3 mL / kg to about 0.35 mL / kg, from about 0.2 mL / kg to about 0.30 mL / kg, or from about 0.2 mL / kg to about 0.25 mL / kg. The total volume can be, for example, from about 5 mL to about 75 mL, from about 10 mL to about 50 mL, or about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, or about 75 mL. Therefore, a portion of the total volume is administered to each selectively targeted papilla. In various embodiments, the total volume of the solution is about equally divided between each papilla that is selectively targeted, wherein every papilla of the kidney is selectively targeted or a portion of the total number of papillae204903-3015-35943Attorney Docket No: 046192-000134WOPTof the kidney are selectively targeted. In other embodiments, a fraction of the total volume is about evenly delivered to each specifically targeted papilla, and a remaining fraction of the total volume is administered to the renal pelvis, e.g., outside of a calyx. In some embodiments, from about 1 mL to about 5 mL, or about 0.5 mb, about 1 mb, about 2 mb, about 3, mb, about 5 mb, about 6 mb, about 7 mb, about 8 mb, about 9 mb, about 10 mb, or more of the solution comprising the rAAV is selectively administered to each target renal papilla. It is understood that each of the individual volumes described herein can be used to define lower and upper values of a volume range.

[0148] In some embodiments, the solution comprising the rAAV is administered for about 1 min to 2 min, about 0.5 min, about 1 min, about 1.25 min, about 1.5 min, about 1.75 min, about 2, or more to each renal papilla. It is understood that each of the individual volumes described herein can be used to define lower and upper values of a volume range.

[0149] In some embodiments, 1 ml to 5 mb of the solution comprising the rAAV is administered for about 1 minute to about 2 minutes to each renal papilla, resulting in a flow rate of about 0.5 mL / min to 5 mL / min. In some embodiments, the solution comprising the rAAV is administered at a flow rate of about 0.5 mL / min, about 0.5 mL / min, about 0.6 mL / min, about 0.7 mL / min, about 0.8 mL / min, about 0.9 mL / min, about 1 mL / min, about 1.1 mL / min, about 1.2 mL / min, about 1.3 mL / min, about 1.4 mL / min, about 1.5 mL / min, about 1.6 mL / min, about 1.7 mL / min, about 1.8 mL / min, about 1.9 mL / min, about 2 mL / min, about 2.1 mL / min, about 2.2 mL / min, about 2.3 mL / min, about 2.4 mL / min, about 2.5 mL / min, about 2.6 mL / min, about 2.7 mL / min, about 2.8 mL / min, about 2.9 mL / min, about 3 mL / min, about 3.1 mL / min, about 3.2 mL / min, about 3.3 mL / min, about 3.4 mL / min, about 3.5 mL / min, about 3.6 mL / min, about 3.7 mL / min, about 3.8 mL / min, about 3.9 mL / min, about 4 mL / min, about 4.1 mL / min, about 4.2 mL / min, about 4.3 mL / min, about 4.4 mL / min, about 4.5 mL / min, about 4.6 mL / min, about 4.7 mL / min, about 4.8 mL / min, about 4.9 mL / min, about 5 mL / min, about 0.5-1.0 mL / min, about 1.0-1.5 mL / min, about 1.5-2.0 mL / min, about 2.0-2.5 mL / min, about 2.5-3.0 mL / min, about 3.0-3.5 mL / min, about 3.5-4.0 mL / min, about 4.0-4.5 mL / min, about 4.5-5.0 mL / min, about 1.0-2.5 mL / min, about 2.5-5.0 mL / min, about 2.0-3.0 mL / min, about 1.5-3.5 mL / min, or about 1.0-4.0 mL / min. It is understood that each of the individual flow rates described herein can be used to define lower and upper values of a flow rate.

[0150] In some embodiment, the method comprises positioning the delivery device at or near a first selectively targeted papilla, administering a first portion of the total volume of the solution to the first selectively targeted papilla, positioning the delivery device at or near a second selectively targeted papilla, administering a second portion of the total volume of the solution to the second selectively targeted papilla, and repeating the positioning and administering until a last portion of the total volume of the solution is administered to a last selectively targeted papilla.214903-3015-35943Attorney Docket No: 046192-000134WOPT

[0151] In some embodiments, at least one of the renal artery, renal vein, and / or ureter are not occluded, whereas in other embodiments, at least one of the renal artery, renal vein, and / or ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration. Such occlusion can be performed using a clamp or ballon catheter. In some embodiments, the renal artery is occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, the renal vein is occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, the ureter is occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, the renal artery and renal vein are occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, the renal artery and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, the renal vein and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, the renal artery, renal vein, and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, at least one of the renal artery, renal vein, and / or ureter are not occluded during the retrograde ureter (e.g., trans-papilla) administration. In some embodiments, none of the renal artery, renal vein, and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration.

[0152] In some embodiments, at least one of the renal artery, renal vein, and / or ureter are occluded for at least 1 min, at least 1 min, at least 2 min, at least 3 min, at least 4 min, at least 5 min, at least 6 min, at least 7 min, at least 8 min, at least 9 min, at least 10 min, at least 11 min, at least 12 min, at least 13 min, at least 14 min, at least 15 min, at least 16 min, at least 17 min, at least 18 min, at least 19 min, at least 20 min, at least 21 min, at least 22 min, at least 23 min, at least 24 min, at least 25 min, at least 26 min, at least 27 min, at least 28 min, at least 29 min, at least 30 min, at least 31 min, at least 32 min, at least 33 min, at least 34 min, at least 35 min, at least 36 min, at least 37 min, at least 38 min, at least 39 min, at least 40 min, at least 41 min, at least 42 min, at least 43 min, at least 44 min, at least 45 min, at least 46 min, at least 47 min, at least 48 min, at least 49 min, at least 50 min, at least 51 min, at least 52 min, at least 53 min, at least 54 min, at least 55 min, at least 56 min, at least 57 min, at least 58 min, or at least 59 min during the retrograde ureter (e.g., trans-papilla) administration. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range. As noted above, there are some embodiments where none of the renal artery, renal vein, and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration.

[0153] In some embodiments, at least one of the renal artery, renal vein, and / or ureter are occluded for at most 1 min, at most 1 min, at most 2 min, at most 3 min, at most 4 min, at most 5 min, at most 6 min, at most 7 min, at most 8 min, at most 9 min, at most 10 min, at most 11 min, at most 12 min, at most 13 min, at most 14 min, at most 15 min, at most 16 min, at most 17 min, at most 18 min, at most 19 min, at most 20 min, at most 21 min, at most 22 min, at most 23 min, at most 24 min, at224903-3015-35943Attorney Docket No: 046192-000134WOPTmost 25 min, at most 26 min, at most 27 min, at most 28 min, at most 29 min, at most 30 min, at most 31 min, at most 32 min, at most 33 min, at most 34 min, at most 35 min, at most 36 min, at most 37 min, at most 38 min, at most 39 min, at most 40 min, at most 41 min, at most 42 min, at most 43 min, at most 44 min, at most 45 min, at most 46 min, at most 47 min, at most 48 min, at most 49 min, at most 50 min, at most 51 min, at most 52 min, at most 53 min, at most 54 min, at most 55 min, at most 56 min, at most 57 min, at most 58 min, at most 59 min, or at most 60 min during the retrograde ureter (e.g., trans-papilla) administration. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range. As noted above, there are some embodiments where none of the renal artery, renal vein, and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration.

[0154] In some embodiments, at least one of the renal artery, renal vein, and / or ureter are occluded for about 1 min, about 1 min, about 2 min, about 3 min, about 4 min, about 5 min, about 6 min, about 7 min, about 8 min, about 9 min, about 10 min, about 11 min, about 12 min, about 13 min, about 14 min, about 15 min, about 16 min, about 17 min, about 18 min, about 19 min, about 20 min, about 21 min, about 22 min, about 23 min, about 24 min, about 25 min, about 26 min, about 27 min, about 28 min, about 29 min, about 30 min, about 31 min, about 32 min, about 33 min, about 34 min, about 35 min, about 36 min, about 37 min, about 38 min, about 39 min, about 40 min, about 41 min, about 42 min, about 43 min, about 44 min, about 45 min, about 46 min, about 47 min, about 48 min, about 49 min, about 50 min, about 51 min, about 52 min, about 53 min, about 54 min, about 55 min, about 56 min, about 57 min, about 58 min, about 59 min, or about 60 min during the retrograde ureter (e.g., trans-papilla) administration. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range. As noted above, there are some embodiments where none of the renal artery, renal vein, and ureter are occluded during the retrograde ureter (e.g., trans-papilla) administration.

[0155] In some embodiments, the method further comprises directing a renal pressure probe through the urethra, bladder, and ureter of the subject and to the renal pelvis and controlling and / or monitoring the intrarenal pressure during the administration. In some embodiments, the intrarenal pressure is controlled using the delivery device (e.g., catheter, ureteroscope). The intrarenal pressure applied to and maintained within the kidney during the administration is from about 20 to about 60 cm H2O, from about 25 to about 50 cm H2O or about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 cm H2O.

[0156] In some embodiments, the method further comprises administering a contrast agent (e.g., for imaging, e.g., using CT scan, X-ray, etc.) before, during, and / or after the administration of the rAAV solution. In some embodiments, the contrast agent is removed at least partially before the administration of the rAAV solution. In some embodiments, the contrast agent is a radio-opaque and / or x-ray opaque. In some embodiments, the contrast agent comprises an iodinated contrast media234903-3015-35943Attorney Docket No: 046192-000134WOPT(ICM), non-limiting examples of which include, iodixanol, iohexol, ioxilan, iothalamate meglumine, iopamidol, iopromide, ethiodized oil, and the like.

[0157] Such administration methods can be used to treat a kidney-associated disorder in a subject in need thereof. Also described herein are pharmaceutical compositions comprising a recombinant adeno-associated virus (rAAV) for administration to the kidney.

[0158] Also described herein are specific rAAVs that showed high transduction in the kidneys following retrograde ureter (e.g., trans-papilla) administration, including but not limited to an rAAV comprising a capsid selected from those described in Table 1 and Fig. 4 (see also International Patent Application PCT / US2024 / 031768 filed May 30, 2024, the contents of which are incorporated herein by reference in their entirety). Such specific rAAVs (e.g., AAV2G9, AAV2.5, AAVDJ, AAV2, AAVKP1, AAVKP2, AAVKP3, and AAV2.7m8) have increased levels of kidney transduction compared to AAV9. Furthermore, described herein are exemplary parameters for the retrograde ureter administration, including administration volume, timings, and renal vessel(s) occlusion. The retrograde ureter administration results in increased levels of kidney transduction compared to other administration routes (e.g., intravenous).Administration and Treatment Methods

[0159] In multiple aspects, described herein are methods of administering a recombinant adeno-associated virus (rAAV) to a kidney of a subject and methods of treating a kidney-associated disorder in a subject in need thereof. In one aspect, described herein is a method of transducing a sufficient number of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV) to obtain an effective level of expression in the kidney, the method comprising administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, wherein a solution comprising the rAAV is administered to the kidney for a time sufficient and / or at an intra-renal pressure sufficient to result in a pharmaceutically effective level of rAAV transduction in the nephrons of the kidney.

[0160] In one aspect, described herein is a method of transducing nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter; and administering a solution comprising the rAAV to the renal pelvis (e.g., to at least one papilla) of the kidney at a volume of from about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg), the kg being the weight of the subject, wherein the kidney nephrons comprising nephron cells are transduced with the rAAV at a therapeutically effective level and / or high efficiency.

[0161] In one aspect, described herein is a method of transducing at least about 15% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least244903-3015-35943Attorney Docket No: 046192-000134WOPTone papilla) of the kidney in a retrograde route, wherein the volume is from about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg), the kg being the weight of the subject. In some embodiments, a solution comprising the rAAV is administered over a period of time from about 0.5 minutes to about 2 minutes. In some embodiments, a solution comprising the rAAV is administered over a period of time from about 1 minute to 60 minutes. In some embodiments, the method further comprises a step of blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof, prior to administering the rAAV. In some embodiments, the method further comprises unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV.

[0162] In one aspect, described herein is a method of transducing at least about 15% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof; (b) administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, wherein the volume is from about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg), the kg being the weight of the subject; and (c) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV.

[0163] In one aspect, described herein is a method of transducing at least about 20% of the nephrons in a kidney of a subject with the rAAV.

[0164] In one aspect, described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with the rAAV.

[0165] In one aspect, described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal artery of the kidney and not blocking a renal vein of the kidney; (c) administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route; and (c) unblocking the renal artery after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV. In some embodiments, the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

[0166] In one aspect, described herein is a method of transducing nephrons in a kidney of a subject, the method comprising: (a) blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney; (b) administering a volume of a solution comprising rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, the rAAV not being rAAV9; and (c) unblocking the renal blood vessel after a period of time of254903-3015-35943Attorney Docket No: 046192-000134WOPTfrom about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV. In some embodiments, the method results in a transduction efficiency that is at least 2-fold higher than a corresponding administration using rAAV9 instead of the rAAV. In some embodiments, the rAAV has at least 400-fold or at least 3500-fold higher transduction efficiency than AAV9.

[0167] In one aspect, described herein is a method of transducing at least about 30% of the nephrons in a kidney of a subject with the rAAV. In one aspect, described herein is a method of administering a recombinant adeno-associated virus (rAAV) to a kidney of a subject and / or treating a kidney-associated disorder in a subject in need thereof, the method comprising: (a) blocking at least one renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney; (b) administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, wherein the volume is no more than 1.25 ml / kg (e.g., no more than 0.33 mL / kg); and (c) unblocking the at least one renal blood vessel after a period of time subsequent to the blocking and / or after administering the solution comprising the rAAV.

[0168] In one aspect, described herein is a method of transducing at least about 15% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney; (b) administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, wherein the volume is from about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg), the kg being the weight of the subject, wherein the rAAV comprises a capsid protein from serotype AAV2G9; and (c) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV. In some embodiments, the method results in the transduction of at least about 25% of the nephrons in the kidney with the 2G9 rAAV.

[0169] In one aspect, described herein is a method of administering a recombinant adeno-associated virus (rAAV) to a kidney of a subject and / or treating a kidney-associated disorder in a subject in need thereof, the method comprising: (a) blocking at least one renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney; (b) administering a volume of about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg) of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, wherein the rAAV comprises a capsid protein from serotype AAV2G9; and (c) unblocking the at least one of the renal blood vessel after a period of time subsequent to the blocking and / or after administering the solution comprising the rAAV.264903-3015-35943Attorney Docket No: 046192-000134WOPT

[0170] In some embodiments of any of the aspects, the step of “blocking at least one renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney” or “blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof’ or “blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney” or the like is replaced with a step of “isolating the kidney from systemic circulation.”

[0171] In some embodiments of any of the aspects, the step of “unblocking the at least one of the renal blood vessel after a period of time” or “unblocking the renal blood vessel after a period of time” or “unblocking the at least one renal blood vessel after a period of time” or the like subsequent to the blocking is replaced with a step of “re-establishing the kidney into systemic circulation after a period of time” subsequent to the isolating.

[0172] In one aspect, described herein is a method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising: (a) isolating the kidney from systemic circulation; (b) administering a volume of a solution comprising the rAAV via a ureter (e.g., to at least one papilla) of the kidney in a retrograde route, wherein the volume is from about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg), the kg being the weight of the subject; and (c) re-establishing the kidney into systemic circulation after a period of time of from about 10 minutes to about 60 minutes subsequent to the isolating. In some embodiments, the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

[0173] In some aspects, described herein is a method of transducing nephrons of a kidney in a subject with a rAAV comprising an AAV2g9 capsid. The method comprises guiding a delivery device (e.g., a ureteroscope, a catheter) through the subject’s urethra, bladder, and ureter, and administering a solution comprising the rAAV to the renal pelvis (e.g., to at least one papilla) of the kidney at a volume of from about 0.13 mL / kg to about 1.25 mL / kg (e.g., about 0.13 mL / kg to about 0.33 mL / kg, the kg being the weight of the subject). In some embodiments, an end of the catheter through which the solution is delivered is positioned in close proximity to a renal papilla, and the solution is administered into the collecting ducts of the renal papilla. In various embodiments, an end of the catheter through which the solution is delivered is positioned in the ureter, and the solution is administered in the ureter and flushed into the renal pelvis of the kidney. In other embodiments, an end of the catheter through which the solution is delivered is positioned in the renal pelvis and the solution is administered directly to the renal pelvis of the kidney. As a result of the administration, nephrons of the kidney are transduced with the rAAV at a therapeutically effective level and / or high efficiency.

[0174] In some aspects, described herein is a method of transducing nephrons of a kidney in a subject with a rAAV. The method comprises guiding a delivery device (e.g., a ureteroscope, a274903-3015-35943Attorney Docket No: 046192-000134WOPTcatheter) through the subject’s urethra, bladder, and ureter, and administering a solution comprising the rAAV to the renal pelvis (e.g., to at least one papilla) of the kidney at a volume of from about 0.13 mL / kg to about 1.25 mL / kg (e.g., 0.13 mL / kg to about 0.33 mL / kg, the kg being the weight of the subject). In some embodiments, an end of the catheter through which the solution is delivered is positioned in close proximity to a renal papilla, and the solution is administered into the collecting ducts of the renal papilla. In various embodiments, an end of the catheter through which the solution is delivered is positioned in the ureter and the solution is administered in the ureter and flushed into the renal pelvis of the kidney. In other embodiments, an end of the catheter through which the solution is delivered is positioned in the renal pelvis and the solution is administered directly to the renal pelvis of the kidney. As a result of the administration, nephrons of the kidney are transduced with the rAAV at a therapeutically effective level and / or high efficiency.

[0175] As used here, a “high efficiency” means a level of transduction, e.g., a nephron transduction efficiency or nephron component transduction efficiency, that results in detectable and / or measurable levels of rAAV in cells of the kidney. In various embodiments, a high efficiency corresponds to a nephron transduction efficiency or nephron component transduction efficiency of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, or more. In some embodiments, a high efficiency corresponds to an efficiency index (as defined herein; see e.g., Formula I) that is greater than 1, e.g., having efficiency higher than what is achieved by administering rAAV comprising an AAV9 capsid. For example, the efficiency index is greater than 1, greater than 2, greater than 3, greater than 4, greater than 5, greater than 6, greater than 7, greater than 8, greater than 9, greater than 10, greater than 20, greater than 30, greater than 40, greater than 50, greater than 60, greater than 70, greater than 80, greater than 90, greater than 100, greater than 200, greater than 300, greater than 400, greater than 500, greater than 600, greater than 700, greater than 800, greater than 900, greater than 1000, greater than 2000, greater than 3000, greater than 4000, greater than 5000. It is understood that each of the individual efficiency indices described herein can be used to define lower and upper values of an efficiency index range. In some embodiments, the efficiency index is between 1 and 6000, between 1 and 5000, between 1 and 4000, between 1 and 3000, between 1 and 2000, between 1 and 1000, between 1 and 900, between 1 and 800, between 1 and 700, between 1 and 600, between 1 and 500, between 1 and 400, between 1 and 300, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, between 1 and 10, between 1 and 9, between 1 and 8, between 1 and 7, between 1 and 6, between 1 and 5, between 1 and 4, between 1 and 3, or between 1 and 2. Such high efficiencies corresponds to a clinically relevant level of transduction. In various embodiments, a clinically relevant level is a therapeutically and / or pharmaceutically effective level.284903-3015-35943Attorney Docket No: 046192-000134WOPT

[0176] In some embodiments, the method results in a therapeutically and / or pharmaceutically effective level of a therapeutic composition in the nephrons of the kidney, for example a therapeutically and / or pharmaceutically effective level of rAAV transduction in the nephrons of the kidney, which can vary depending on the specific disease and / or location in the kidney of the transduction. The terms “therapeutically effective” or “pharmaceutically effective” level of transduction refer to the level of transduction sufficient to provide transgene expression (e.g., a transgene encoded by the rAAV genome) in the transduced kidney cells that is sufficient to treat or ameliorate at least one symptom caused by or resulting from a kidney-associated disorder in the subject or to inhibit, slow, minimize, or reverse the progression of a kidney-associated disorder in the subject. In various embodiments, a therapeutically and / or pharmaceutically effective level corresponds to a nephron transduction efficiency or nephron component transduction efficiency of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0177] In some embodiments, the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV. For example, by blocking (e.g., clamping) the renal artery or isolating the kidney from systemic circulation, administering 20 mb to kidney via ureter, holding for 15-30 min, and unblocking (e.g., unclamping) or re-establishing the kidney into systemic circulation, rAAV transduction of the nephrons is at least 30%, which had not previously been described.

[0178] As used herein, the terms “transducing a nephron” or “transducing nephrons” interchangeably refer to transducing at least one cell of a nephron, the at least one cell being: a glomerulus cell (including cells of Bowman’s capsule); a proximal tubule (also referred to as a proximal convoluted tubule) cell; a cell of the loop of Henle (including descending and / or ascending limbs, and thick and / or thin regions thereof); a distal tubule (also referred to as a distal convoluted tubule) cell; a collecting duct cell; or a combination thereof. Similarly, the terms “transducing a nephron ‘component’” or “transducing nephron ‘components’” interchangeably refer to transducing at least one cell of a nephron component, the nephron component being: a glomerulus (including Bowman’s capsule); a proximal tubule (also referred to as a proximal convoluted tubule); the loop of Henle (including descending and / or ascending limbs, and thick and / or thin regions thereof); a distal tubule (also referred to as a distal convoluted tubule); or a collecting duct.

[0179] As used herein, the phrases “administering to at least one papilla” or “administering to at least one renal papilla” refer to administering the rAAV to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or all, of the papilla in one or both of the subject’s kidneys.

[0180] The terms “nephron transduction efficiency” and “nephron component transduction efficiency” refer to a number of transduced nephrons or nephron components relative to the total294903-3015-35943Attorney Docket No: 046192-000134WOPTnumber of nephrons or total number of nephron components in a kidney, respectively. Accordingly, a nephron transduction efficiency of 10% means that 10% of the total number of nephrons in the kidney are transduced. For example, in a hypothetical kidney having exactly 1 million (1,000,000) nephrons, a nephron transduction efficiency of 10% means that 100,000 of the 1,000,000 nephrons are transduced. Put another way, in the hypothetical kidney having exactly 1 million (1,000,000) nephrons, the nephron transduction efficiency of 10% means that at least one cell in each of 100,000 individual nephrons of the 1,000,000 total individual nephrons is transduced. Similarly, a proximal tubule transduction percentage of 10% means that 10% of the total number of proximal tubules in the kidney are transduced. For example, in a hypothetical kidney having exactly 1 million (1,000,000) proximal tubules (e.g., one proximal tubule per nephron), a proximal tubule transduction efficiency of 10% means that 100,000 of the 1,000,000 proximal tubules are transduced. Put another way, in the hypothetical kidney having exactly 1 million (1,000,000) nephrons (thus 1,000,0000 proximal tubules), the proximal tubule transduction efficiency of 10% means that at least one cell in each of 100,000 individual proximal tubules of the 1,000,000 total individual proximal tubules is transduced.

[0181] In some embodiments, the rAAV is administered to at least one renal papilla of at least one kidney. The transduction efficiencies described herein are understood to refer to the percentage transduced of the total nephrons, tubules, or cells to which the rAAV was administered. For example, if the rAAV is administered to one renal papilla, the transduction efficiency can be determined for the nephrons, tubules, or cells connected to the administered papilla, for example found in the renal pyramid associated with the administered papilla.

[0182] Because a transduced nephron component can have more than one cell that is transduced, this aspect can be discussed in terms of a “cellular transduction efficiency.” For example, a single nephron can have a nephron cellular transduction efficiency of 30%, which means that 30% of the total number cells making up that single nephron are transduced. Similarly, a single proximal tubule may have a proximal tubule cellular transduction efficiency of 30%, which means 30% of the total number cells in that single proximal tubule are transduced. It is understood that even though 30% of the total number cells in the proximal tubule are transduced, this aspect does not preclude transduction of other components of the same nephron. For example, a cell can have a proximal tubule cellular transduction efficiency of 30% along with specified or unspecified cellular efficiency relating to cells of the loop of Henle (ascending and / or descending limbs, and thick and / or thin regions thereof), cells of the distal tubule, and / or cells of the corresponding collecting duct.

[0183] Accordingly, in some aspects, the current technology provides for both a nephron transduction efficiency and a cellular transduction efficiency. As an example, the term “a proximal tubule transduction efficiency of at least 20% and a proximal tubule cellular transduction efficiency of at least 30%” means that at least 20% of the of the total number of proximal tubules in a kidney are transduced and at least 30% of the proximal tubule cells in each of the transduced proximal tubules304903-3015-35943Attorney Docket No: 046192-000134WOPTare transduced, or to put it another way, at least 30% of the proximal tubule cells in at least 20% of the total number proximal tubules in the kidney are transduced.

[0184] Descriptions herein, for example, of transduction of a percentage of nephrons in a kidney may refer to a nephron transduction efficiency, a nephron component transduction efficiency, and / or a cellular transduction efficiency.

[0185] In some embodiments, the method results in a proximal tubule transduction efficiency of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0186] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule transduction efficiency of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more, determined as the percentage of transduced proximal tubules of the total number of proximal tubules connected to the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0187] In some embodiments, the method results in a proximal tubule cellular transduction efficiency of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0188] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule cellular transduction efficiency of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more, determined as the percentage of transduced proximal314903-3015-35943Attorney Docket No: 046192-000134WOPTtubule cells of the total number of proximal tubule cells associated with the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0189] In some embodiments, the method results in a proximal tubule transduction efficiency of at least 30% and a proximal tubule cellular transduction efficiency of at least 30%. In some embodiments, the method results in a proximal tubule transduction efficiency of at least 20% and a proximal tubule cellular transduction efficiency of at least 30%. In some embodiments, the method results in a proximal tubule transduction efficiency of at least 30% and a proximal tubule cellular transduction efficiency of at least 20%. In some embodiments, the method results in a proximal tubule transduction efficiency of at least 20% and a proximal tubule cellular transduction efficiency of at least 20%. In some embodiments, the method results in a proximal tubule transduction efficiency of at least 25% and a proximal tubule cellular transduction efficiency of at least 25%.

[0190] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule transduction efficiency of at least 30% of the proximal tubules connected to the administered papilla(e) and a proximal tubule cellular transduction efficiency of at least 30% of the proximal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule transduction efficiency of at least 20% of the proximal tubules connected to the administered papilla(e) and a proximal tubule cellular transduction efficiency of at least 30% of the proximal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule transduction efficiency of at least 30% of the proximal tubules connected to the administered papilla(e) and a proximal tubule cellular transduction efficiency of at least 20% of the proximal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule transduction efficiency of at least 20% of the proximal tubules connected to the administered papilla(e) and a proximal tubule cellular transduction efficiency of at least 20% of the proximal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a proximal tubule transduction efficiency of at least 25% of the proximal tubules connected to the administered papilla(e) and a proximal tubule cellular transduction efficiency of at least 25% of the proximal tubule cells associated with the administered papilla(e).

[0191] In some embodiments, the method results in the transduction of about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at324903-3015-35943Attorney Docket No: 046192-000134WOPTleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or more of the nephrons in the kidney with the rAAV, or in other words about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the total number of “nephron cells” (cells of the nephron) in the kidney with the rAAV. In some embodiments, the transduced cells are epithelial cells. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0192] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in transduction of about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or more of the nephrons connected to the administered papilla(e) in the kidney with the rAAV, or in other words about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the total number of “nephron cells” (cells of the nephron) associated with the administered papilla(e) in the kidney with the rAAV. In some embodiments, the transduced cells are epithelial cells. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0193] In some embodiments, the method results in the transduction of about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or more of the nephrons in the kidney with the rAAV, or in other words about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the total number of “nephron cells” (e.g., proximal convoluted tubule cells, loop of Henle cells, distal convoluted tubule cells, collecting duct cells, or any combination thereof) in the kidney with the rAAV. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.334903-3015-35943Attorney Docket No: 046192-000134WOPT

[0194] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in the transduction of about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or more of the nephrons connected to the administered papilla(e) in the kidney with the rAAV, or in other words about at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the total number of “nephron cells” (e.g., proximal convoluted tubule cells, loop of Henle cells, distal convoluted tubule cells, collecting duct cells, or any combination thereof) associated with the administered papilla(e) in the kidney with the rAAV. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0195] In some embodiments, the transduced cells are epithelial cells from the proximal tubule. In some embodiments, the transduced cells are epithelial cells from the loop of Henle. In some embodiments, the transduced cells are epithelial cells from the distal convoluted tubule. In some embodiments, the transduced cells are epithelial cells from the collecting duct. In some embodiments, the transduced cells are epithelial cells from the distal convoluted tubule and collecting duct.

[0196] In some embodiments, the transduced cells of the nephrons are epithelial cells from the proximal tubules. Accordingly, the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the proximal tubules of the kidney or epithelial cells of the proximal tubules of the kidney. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0197] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the proximal tubules of the kidney connected to the administered papilla(e) or epithelial cells of the proximal tubules of the kidney associated with the administered papilla(e).344903-3015-35943Attorney Docket No: 046192-000134WOPT

[0198] Transduction of the proximal tubules or epithelial cells of the proximal tubules can be measured using a variety of methods known in the art. As a non-limiting example, the colocalization of the thick brush border (typical and unique to the proximal tubule) and the rAAV reporter gene can be quantified compared to the total number of thick brush border cells. Additional non-limiting examples of markers for proximal tubule epithelial cells include megalin, cubilin, sodium-glucose cotransport 1 (SGLT1), sodium-glucose cotransport 2 (SGLT2), vimentin, Kim-1, Na / Pi, PDZ domain containing 1 (PDZK1), Solute Carrier Family 3 Member 1 (SLC3A1; also referred to as NaSl), stem cells antigen-1 (Sca-1), CD13, and / or aquaporin; see e.g., Agarwal et al. “Renal cell markers: lighthouses for managing renal diseases,” Am J Physiol Renal Physiol. 2021 Dec 1;321(6): F715-F739, the contents of which are incorporated herein by reference in their entirety.

[0199] In some embodiments, the transduced cells of the nephrons are epithelial cells from the loops of Henle. Accordingly, the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the loops of Henle. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0200] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the loops of Henle connected to the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0201] In some embodiments, the method results in a loop of Henle transduction efficiency of at least 30% and a loop of Henle cellular transduction efficiency of at least 30%. In some embodiments, the method results in a loop of Henle transduction efficiency of at least 20% and a loop of Henle cellular transduction efficiency of at least 30%. In some embodiments, the method results in a loop of Henle transduction efficiency of at least 30% and a loop of Henle cellular transduction efficiency of at least 20%. In some embodiments, the method results in a loop of Henle transduction efficiency of at least 20% and a loop of Henle cellular transduction efficiency of at least 20%. In some embodiments, the method results in a loop of Henle transduction efficiency of at least 25% and a loop of Henle cellular transduction efficiency of at least 25%.354903-3015-35943Attorney Docket No: 046192-000134WOPT

[0202] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a loop of Henle transduction efficiency of at least 30% of the loops of Henle connected to the administered papilla(e) and a loop of Henle cellular transduction efficiency of at least 30% efficiency of the loop of Henle cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, the method results in a loop of Henle transduction efficiency of at least 20% of the loops of Henle connected to the administered papilla(e) and a loop of Henle cellular transduction efficiency of at least 30% of the loop of Henle cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, the method results in a loop of Henle transduction efficiency of at least 30% of the loops of Henle connected to the administered papilla(e) and a loop of Henle cellular transduction efficiency of at least 20% of the loop of Henle cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, the method results in a loop of Henle transduction efficiency of at least 20% of the loops of Henle connected to the administered papilla(e) and a loop of Henle cellular transduction efficiency of at least 20% of the loop of Henle cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, the method results in a loop of Henle transduction efficiency of at least 25% of the loops of Henle connected to the administered papilla(e) and a loop of Henle cellular transduction efficiency of at least 25% of the loop of Henle cells associated with the administered papilla(e).

[0203] In some embodiments, the transduced cells of the nephrons are epithelial cells from the distal convoluted tubules. Accordingly, the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the distal convoluted tubules of the kidney. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0204] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or364903-3015-35943Attorney Docket No: 046192-000134WOPTmore of the epithelial cells of the distal convoluted tubules of the kidney connected to the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0205] In some embodiments, the method results in a distal tubule transduction efficiency of at least 30% and a distal tubule cellular transduction efficiency of at least 30%. In some embodiments, the method results in a distal tubule transduction efficiency of at least 20% and a distal tubule cellular transduction efficiency of at least 30%. In some embodiments, the method results in a distal tubule transduction efficiency of at least 30% and a distal tubule cellular transduction efficiency of at least 20%. In some embodiments, the method results in a distal tubule transduction efficiency of at least 20% and a distal tubule cellular transduction efficiency of at least 20%. In some embodiments, the method results in a distal tubule transduction efficiency of at least 25% and a distal tubule cellular transduction efficiency of at least 25%.

[0206] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and method results in a distal tubule transduction efficiency of at least 30% of the distal tubules connected to the administered papilla(e) and a distal tubule cellular transduction efficiency of at least 30% of the distal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal tubule transduction efficiency of at least 20% of the distal tubules connected to the administered papilla(e) and a distal tubule cellular transduction efficiency of at least 30% of the distal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal tubule transduction efficiency of at least 30% of the distal tubules connected to the administered papilla(e) and a distal tubule cellular transduction efficiency of at least 20% of the distal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal tubule transduction efficiency of at least 20% of the distal tubules connected to the administered papilla(e) and a distal tubule cellular transduction efficiency of at least 20% of the distal tubule cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal tubule transduction efficiency of at least 25% of the distal tubules connected to the administered papilla(e) and a distal tubule cellular transduction efficiency of at least 25% of the distal tubule cells associated with the administered papilla(e).

[0207] In some embodiments, the transduced cells of the nephrons are epithelial cells from the collecting ducts. Accordingly, the method can include transducing at least 5%, at least 10%, at least374903-3015-35943Attorney Docket No: 046192-000134WOPT15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the collecting ducts of the kidney. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0208] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the collecting ducts of the kidney connected to the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0209] In some embodiments, the method results in a collecting duct transduction efficiency of at least 30% and a collecting duct cellular transduction efficiency of at least 30%. In some embodiments, the method results in a collecting duct transduction efficiency of at least 20% and a collecting duct cellular transduction efficiency of at least 30%. In some embodiments, the method results in a collecting duct transduction efficiency of at least 30% and a collecting duct cellular transduction efficiency of at least 20%. In some embodiments, the method results in a collecting duct transduction efficiency of at least 20% and a collecting duct cellular transduction efficiency of at least 20%. In some embodiments, the method results in a collecting duct transduction efficiency of at least 25% and a collecting duct cellular transduction efficiency of at least 25%.

[0210] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and method results in a collecting duct transduction efficiency of at least 30% of the collecting ducts connected to the administered papilla(e) and a collecting duct cellular transduction efficiency of at least 30% of the collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a collecting duct transduction efficiency of at least 20% of the collecting ducts connected to the administered papilla(e) and a collecting duct cellular transduction efficiency of at least 30% of the collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a collecting duct transduction efficiency of at least 30% of the collecting ducts connected to the administered papilla(e) and a384903-3015-35943Attorney Docket No: 046192-000134WOPTcollecting duct cellular transduction efficiency of at least 20% of the collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a collecting duct transduction efficiency of at least 20% of the collecting ducts connected to the administered papilla(e) and a collecting duct cellular transduction efficiency of at least 20% of the collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a collecting duct transduction efficiency of at least 25% of the collecting ducts connected to the administered papilla(e) and a collecting duct cellular transduction efficiency of at least 25% of the collecting duct cells associated with the administered papilla(e).

[0211] In some embodiments, the transduced cells of the nephrons are epithelial cells from the distal convoluted tubules and / or collecting ducts. Accordingly, the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the distal convoluted tubules and / or collecting ducts of the kidney. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0212] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method can include transducing at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the epithelial cells of the distal convoluted tubules and / or collecting ducts of the kidney connected to the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0213] In some embodiments, the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 30% and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 30%. In some embodiments, the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 20% and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 30%. In some embodiments, the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 30% and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 20%. In some embodiments, the method results in a distal convoluted tubule394903-3015-35943Attorney Docket No: 046192-000134WOPTand / or collecting duct transduction efficiency of at least 20% and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 20%. In some embodiments, the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 25% and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 25%.

[0214] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 30% of the distal convoluted tubules and / or collecting ducts connected to the administered papilla(e) and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 30% of at least 25% of the distal convoluted tubule cells and / or collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 20% of the distal convoluted tubules and / or collecting ducts connected to the administered papilla(e) and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 30% of the distal convoluted tubule cells and / or collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 30% of the distal convoluted tubules and / or collecting ducts connected to the administered papilla(e) and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 20% of the distal convoluted tubule cells and / or collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 20% of the distal convoluted tubules and / or collecting ducts connected to the administered papilla(e) and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 20% of the distal convoluted tubule cells and / or collecting duct cells associated with the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in a distal convoluted tubule and / or collecting duct transduction efficiency of at least 25% of the distal convoluted tubules and / or collecting ducts connected to the administered papilla(e) and a distal convoluted tubule and / or collecting duct cellular transduction efficiency of at least 25% of the distal convoluted tubule cells and / or collecting duct cells associated with the administered papilla(e).

[0215] In some embodiments, the transduction percentage of the nephrons can represent transduction percentage of all the proximal tubules in the kidney. As a non-limiting example, transduction of 30% of the nephrons refers to transduction of 30% of the proximal tubules or proximal404903-3015-35943Attorney Docket No: 046192-000134WOPTtubule cells per treated kidney. In some embodiments, at least 30% of the nephrons or nephron cells per treated kidney are transduced, and other nephrons can be transduced at locations other than the proximal tubule. In some embodiments, the nephron transduction percentage in a kidney can be higher than the proximal tubules transduction percentage, e.g., when accounting for transduction in the proximal tubules and other locations of the nephron.

[0216] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and transduction of 30% of the nephrons refers to transduction of 30% of the proximal tubules connected to the administered papilla(e) or 30% of proximal tubule cells associated with the administered papilla(e) per treated kidney. In some embodiments, at least 30% of the proximal tubules connected to the administered papilla(e) or 30% of proximal tubule cells associated with the administered papilla(e) per treated kidney are transduced, and other nephrons can be transduced at locations other than the proximal tubule. In some embodiments, the nephron transduction percentage in a kidney can be higher than the proximal tubules transduction percentage associated with the administered papilla(e), e.g., when accounting for transduction in the proximal tubules and other locations of the nephron.

[0217] In some embodiments, the method results in the transduction of cells and / or nephrons in at least one pyramid and / or associated cortex region of the kidney. Renal pyramids are kidney tissues that are shaped like cones in the medulla; a kidney can contain between 7 and 18 pyramids. Each pyramid ends in a papilla, where collecting ducts drain urine into the minor and major calyxes, which combine into the renal pelvis and then ureter. The superficial cortex region includes proximal and distal tubules connected to loops of Henle and collecting ducts in the deeper medullary pyramids. In some embodiments, the method results in the transduction of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or more of cells and / or nephrons in at least one pyramid and / or associated cortex region of the kidney. In some embodiments, the method results in the transduction of at least one cell or at least one nephron in at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the pyramids and / or associated cortex regions of the kidney. It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0218] In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in the transduction414903-3015-35943Attorney Docket No: 046192-000134WOPTof at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or more of cells and / or nephrons in at least one pyramid and / or associated cortex region of the kidney associated with or connected to the administered papilla(e). In some embodiments, the rAAV is administered to at least one renal papilla (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, or all) of at least one kidney, and the method results in the transduction of at least one cell or at least one nephron in at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75-85%, 80-90%, 85-95%, 90-100%, 95-100%, or more of the pyramids and / or associated cortex regions of the kidney associated with or connected to the administered papilla(e). It is understood that each of the individual percentages described herein can be used to define lower and upper values of a percentage range.

[0219] In some embodiments, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 1.25 mL / kg of the subject. In some embodiments, the volume of the solution comprising the rAAV is from about 0.2 mL / kg to about 1.25 mL / kg of the subject. In some embodiments, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.33 mL / kg of the subject. The “kg” (kilograms) indicates the weight of the subject. The volume of 0.13 mL / kg to about 0.33 mL / kg is equivalent to 10 mL to 25 mL in a 75 kg subject. In some embodiments, the volume can be adjusted according to the weight of the subject. For example, instead of administering 25 mL maximal volume to a 75 kg subject, 30 mL maximal volume can be administered to a 90 kg subject. In some embodiments, the subject weighs 60 kg to 90 kg. Volumes below 0.13 mL / kg may not be sufficient to elicit sufficient transduction in the kidney. On the other hand, volumes above 0.33 mL / kg may damage the kidney.

[0220] In some embodiments, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.35 mL / kg. In some embodiments, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.33 mL / kg, from about 0.15 mL / kg to about 0.30 mL / kg, or from about 0.2 mL / kg to about 0.25 mL / kg. In some embodiments, the volume of the solution comprising the rAAV is from about 0.27 mL / kg to about 0.33 mL / kg. In some embodiments, the volume of the solution comprising the rAAV is from about 0.2 mL / kg to about 0.27 mL / kg. In some embodiments, the volume of the solution comprising the rAAV is about 0.24 mL / kg. In some embodiments, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.35 mL / kg, about 0.15 mL / kg to about 0.35 mL / kg, about 0.2 mL / kg to about 0.35 mL / kg, from about 0.25 mL / kg to about 0.35 mL / kg, from about 0.3 mL / kg to about 0.35 mL / kg, from about 0.13424903-3015-35943Attorney Docket No: 046192-000134WOPTmL / kg to about 0.30 mL / kg, from about 0.13 mL / kg to about 0.25 mL / kg, or from about 0.13 mL / kg to about 0.2 mL / kg. In some embodiments, the volume of the solution comprising the rAAV is 0.13 mL / kg, 0.14 mL / kg, 0.15 mL / kg, 0.16 mL / kg, 0.17 mL / kg, 0.18 mL / kg, 0.19 mL / kg, 0.2 mL / kg, 0.21 mL / kg, 0.22 mL / kg, 0.23 mL / kg, 0.24 mL / kg, 0.25 mL / kg, 0.26 mL / kg, 0.27 mL / kg, 0.28 mL / kg, 0.29 mL / kg, 0.3 mL / kg, 0.31 mL / kg, 0.32 mL / kg, 0.33 mL / kg, 0.34 mL / kg, 0.35 mL / kg, 0.36 mL / kg, 0.37 mL / kg, 0.38 mL / kg, 0.39 mL / kg, 0.4 mL / kg, 0.41 mL / kg, 0.42 mL / kg, 0.43 mL / kg, 0.44 mL / kg, 0.45 mL / kg, 0.46 mL / kg, 0.47 mL / kg, 0.48 mL / kg, 0.49 mL / kg, 0.5 mL / kg, 0.51 mL / kg, 0.52 mL / kg, 0.53 mL / kg, 0.54 mL / kg, 0.55 mL / kg, 0.56 mL / kg, 0.57 mL / kg, 0.58 mL / kg, 0.59 mL / kg, 0.6 mL / kg, 0.61 mL / kg, 0.62 mL / kg, 0.63 mL / kg, 0.64 mL / kg, 0.65 mL / kg, 0.66 mL / kg, 0.67 mL / kg, 0.68 mL / kg, 0.69 mL / kg, 0.7 mL / kg, 0.71 mL / kg, 0.72 mL / kg, 0.73 mL / kg, 0.74 mL / kg, 0.75 mL / kg, 0.76 mL / kg, 0.77 mL / kg, 0.78 mL / kg, 0.79 mL / kg, 0.8 mL / kg, 0.81 mL / kg, 0.82 mL / kg, 0.83 mL / kg, 0.84 mL / kg, 0.85 mL / kg, 0.86 mL / kg, 0.87 mL / kg, 0.88 mL / kg, 0.89 mL / kg, 0.9 mL / kg, 0.91 mL / kg, 0.92 mL / kg, 0.93 mL / kg, 0.94 mL / kg, 0.95 mL / kg, 0.96 mL / kg, 0.97 mL / kg, 0.98 mL / kg, 0.99 mL / kg, 1.0 mL / kg, 1.01 mL / kg, 1.02 mL / kg, 1.03 mL / kg, 1.04 mL / kg, 1.05 mL / kg, 1.06 mL / kg, 1.07 mL / kg, 1.08 mL / kg, 1.09 mL / kg, 1.1 mL / kg, 1.11 mL / kg, 1.12 mL / kg, 1.13 mL / kg, 1.14 mL / kg, 1.15 mL / kg, 1.16 mL / kg, 1.17 mL / kg, 1.18 mL / kg, 1.19 mL / kg, 1.2 mL / kg, 1.21 mL / kg, 1.22 mL / kg, 1.23 mL / kg, 1.24 mL / kg, 1.25 mL / kg, 1.26 mL / kg, 1.27 mL / kg, 1.28 mL / kg, 1.29 mL / kg, 1.3 mL / kg, 0.05-0.15 mL / kg, 0.10-0.20 mL / kg, 0.15-0.25 mL / kg, 0.20-0.30 mL / kg, 0.25-0.35 mL / kg, 0.05-0.10 mL / kg, 0.10-0.15 mL / kg, 0.15-0.20 mL / kg, 0.20-0.25 mL / kg, 0.25-0.30 mL / kg, 0.30-0.35 mL / kg, 0.35-0.4 mL / kg, 0.4-0.5 mL / kg, 0.5-0.6 mL / kg, 0.6-0.7 mL / kg, 0.7-0.8 mL / kg, 0.8-0.9 mL / kg, 0.9-1.0 mL / kg, 1.0-1.1 mL / kg, 1.1-1.2 mL / kg, 1.2-1.3 mL / kg, 0.05-0.35 mL / kg, 0.10-0.35 mL / kg, 0.15-0.35 mL / kg, 0.20-0.35 mL / kg, 0.05-0.20 mL / kg, 0.05-0.25 mL / kg, or 0.05-0.30 mL / kg. It is understood that each of the individual volumes described herein can be used to define lower and upper values of a volume range.

[0221] In some embodiments, the volume of the solution comprising the rAAV is a volume selected from the group consisting of at least 0.05 mL / kg, at least 0.1 mL / kg, at least 0.13 mL / kg, at least 0.14 mL / kg, at least 0.15 mL / kg, at least 0.16 mL / kg, at least 0.17 mL / kg, at least 0.18 mL / kg, at least 0.19 mL / kg, at least 0.20 mL / kg, at least 0.21 mL / kg, at least 0.22 mL / kg, at least 0.23 mL / kg, at least 0.24 mL / kg, at least 0.25 mL / kg, at least 0.26 mL / kg, at least 0.27 mL / kg, at least 0.28 mL / kg, at least 0.29 mL / kg, at least 0.30 mL / kg, at least 0.31 mL / kg, at least 0.32 mL / kg, at least 0.33 mL / kg, at least 0.34 mL / kg, at least 0.35 mL / kg, at least 0.4 mL / kg, at least 0.5 mL / kg, at least 0.6 mL / kg, at least 0.7 mL / kg, at least 0.8 mL / kg, at least 0.9 mL / kg, at least 1.0 mL / kg, at least 1.1 mL / kg, at least 1.2 mL / kg, at least 1.25 mL / kg, or more. In some embodiments, the volume of the solution comprising the rAAV is a volume selected from the group consisting of at most 0.30 mL / kg, at most 0.31 mL / kg, at most 0.32 mL / kg, at most 0.33 mL / kg, at most 0.34 mL / kg, at most 0.35 mL / kg, at most 0.4 mL / kg, at most 0.5 mL / kg, at most 0.6 mL / kg, at most 0.7 mL / kg, at most 0.8 mL / kg, at434903-3015-35943Attorney Docket No: 046192-000134WOPTmost 0.9 mL / kg, at most 1.0 mL / kg, at most 1.1 mL / kg, at most 1.2 mL / kg, or at most 1.25 mL / kg. It is understood that each of the individual volumes described herein can be used to define lower and upper values of a volume range.

[0222] In some embodiments, heparin is administered to the subject prior to, during, or after the retrograde rAAV administration, e.g., to prevent blood coagulation during the procedure. In some embodiments, the heparin can be used in combination with administration to individual papillae, without blocking of the renal artery, renal vein, and / or ureter.

[0223] In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure that results in pyelotubular reflux and pyelovenous backflow with no fornix rupture. The term “pyelotubular reflux” (also referred to interchangeably as “intrarenal reflux”) refers to urinary reflux (i.e., a backward or return flow) from renal pelvis and calyces into the collecting ducts; pyelotubular reflux can be seen as a blush of the renal pyramid on voiding cystourethrography. The term “pyelovenous backflow” (also referred to as “pyelovenous reflux”) refers to drainage of fluid from the renal pelvis of a kidney into the renal venous system; pyelovenous backflow can occur when abnormal amounts of intra-renal pressure occur in a direction opposite to normal. The term “renal fornix” (or “fornix”) refers to the thin pointed projections, arising from the lateral aspects of each minor calyx, and extending a short distance into the renal columns; each fornix contacts the renal pyramid on its inner surface. Rupture of the renal fornix can be due to increased renal pelvis pressure; rupture of one or more renal fornices can lead to peri-renal or retro-peritoneal extravasation (leakage) of urine.

[0224] The normal intrarenal pressure (IRP) range is 0 cm H2O to 20 cm H2O. An IRP between 27 cm H2O to 41 cm H2O results in pyelotubular reflux. An IRP between 41 cm H2O to 68 cm H2O results in pyelovenous backflow. An IRP below 27 cm H2O does not result in pyelotubular reflux or pyelovenous backflow and is thus not an effective IRP for the methods described herein. An IRP between 81 cm H2O to 95 cm H2O can result in fornix rupture. As such, the methods described herein use an IRP that is 80 cm H2O or less. An above-normal IRP (e.g., for an extended time period, e.g., multiple days) can be associated with infectious and hemorrhagic complications, as well as kidney damage. See e.g., Pauchard et al. “A Practical Guide for Intra-Renal Temperature and Pressure Management during Rirs: What Is the Evidence Telling Us,” J Clin Med. 2022 Jun; 11(12): 3429; the contents of which are incorporated herein by reference in its entirety.

[0225] In some embodiments, the administered volume and resultant intrarenal pressure are determined in a subject, such as a human, a non-human primate, or a pig, which is a relevant animal model for human translation due to their anatomical and physiological similarities to humans.Intrarenal pressure can be measured by methods known in the art, such as a sensor wire (e.g., a wire including a pressure sensor; e.g., placed into the renal cavities) and the like.444903-3015-35943Attorney Docket No: 046192-000134WOPT

[0226] When working with an irrigation flow (i.e., flow rate) greater than 6 mL / min, the ureter behaves like an open tube, resulting in a linear relationship between flow and pressure. In some embodiments, about 0.13 mL / kg to about 0.35 mL / kg of the rAAV solution are administered over a time period from about 0.5 minutes (30 seconds) to about 2 minutes (120 seconds). The time for administration of the rAAV can be shorter for smaller volumes and / or smaller subjects (e.g., 5 mL / min for 2.5 mL in about 0.5-1.0 minutes for an 8-12 kg subject) or longer for larger volumes and / or larger subjects (e.g., 9 mL / min for 18 mL in about 1-2 minutes for a 60-80 kg subject). A shorter time period for administration of the rAAV can reduce risk of damage to the fornix structure of the kidney. In some embodiments, a solution comprising the rAAV is administered for a time sufficient to reach a desired intrarenal pressure (e.g., from about 25 cm H2O to about 55 cm H2O, or from about 27 cm H2O to about 80 cm H2O). In some embodiments, about 0.13 mL / kg to about 0.35 mL / kg of the rAAV solution are administered over a time period from about 10 minutes to about 60 minutes, resulting in a flow rate from between about 0.167 mL / min to about 2.5 mL / min. In some embodiments, the flow rate is below 6 mL / min. In some embodiments, the ureter does not behave like an open tube when the rAAV solution is administered. In some embodiments, the volume of the administered solution significantly affects efficacy of the treatment, while the flow rate does not significantly affect efficacy of the treatment.

[0227] In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of about 46 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intrarenal pressure of about 45 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of from about 27 cm H2O to about 80 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of from about 27 cm H2O to about 41 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of from about 41 cm H2O to about 68 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of from about 68 cm H2O to about 80 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of about at least 20 cm H2O, at least 25 cm H2O, at least 30 cm H2O, at least 35 cm H2O, at least 40 cm H2O, at least 45 cm H2O, at least 50 cm H2O, at least 55 cm H2O, at least 60 cm H2O, at least 65 cm H2O, at least 70 cm H2O, or at least 75 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-renal pressure of about at most 25 cm H2O, at most 30 cm H2O, at most 35 cm H2O, at most 40 cm H2O, at most 45 cm H2O, at most 50 cm H2O, at most 55 cm H2O, at most 60 cm H2O, at most 65 cm H2O, at most 70 cm H2O, at most 75 cm H2O, or at most 80 cm H2O. In some embodiments, a solution comprising the rAAV is administered to the kidney at an intra-454903-3015-35943Attorney Docket No: 046192-000134WOPTrenal pressure range of about 20-30 cm H2O, 25-35 cm H2O, 30-40 cm H2O, 35-45 cm H2O, 40-50 cm H2O, 45-55 cm H2O, 50-60 cm H2O, 55-65 cm H2O, 60-70 cm H2O, 65-75 cm H2O, 70-80 cm H2O, 20-40 cm H2O, 20-50 cm H2O, 20-60 cm H2O, 20-70 cm H2O, 20-80 cm H2O, 25-85 cm H2O, 30-80 cm H2O, 40-80 cm H2O, 50-80 cm H2O, or 60-80 cm H2O. It is understood that each of the individual intrarenal pressures described herein can be used to define lower and upper values of an intrarenal pressure range.

[0228] In some embodiments, the solution comprising the rAAV is administered in the retrograde route to, for example at least one papilla, via the ureter using a catheter or cannula. As used herein, the terms “catheter” and “cannula” are used interchangeably to refer to a hollow tube that can inserted into, for example, a body cavity, a blood vessel, the urethra, the ureter, etc.; in some embodiments, the catheter is thin (e.g., at most 5, 6, 7, 8, 9, 10, 11, 12 mm in diameter) and / or flexible. In some embodiments, the catheter is made from a material that does not trigger an immune response (e.g., latex, silicone, TEFLON, polyvinyl chloride, etc.) and / or is treated to reduce infection (e.g., silver-coated catheter). In some embodiments, any solutions or pharmaceutical composition described herein (e.g., comprising at least one rAAV) can be manually delivered via the ureter (e.g., to at least one papilla) using a plunger associated with a catheter or cannula. In some embodiments, any solutions or pharmaceutical composition described herein (e.g., comprising at least one rAAV) can be manually delivered via the ureter (e.g., to at least one papilla) using an automatic injection, e.g., pump (syringe pump, peristaltic pump, etc.).

[0229] In some embodiments, a catheter can be used to administer the rAAV solution to the kidney. The catheter can be inserted through the subject’s urethra, through the bladder, and up through a ureter of the kidney to a desired location within the ureter, e.g., at, near, or in the renal pelvis. In some embodiments, the catheter used to administer the solution comprising the rAAV is a balloon catheter. In some embodiments, the balloon catheter is inflated to block the ureter and prevent, inhibit, or minimize urine and / or rAAV backflow downstream of the balloon, e.g., from the bladder, back toward the kidney, before, during, and / or after administration of the solution comprising the rAAV. In some embodiments, the balloon catheter is deflated to unblock the ureter after the period of time, e.g., after 10-60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV. In some embodiments, the catheter used to administer the solution comprising the rAAV is a non-balloon catheter and / or the ureter is not blocked during administration of the solution comprising the rAAV.

[0230] In some embodiments, the administering the volume of the solution comprising rAAV via the ureter of the kidney in the retrograde route is performed by injecting the rAAV, e.g., a composition comprising the rAAV, into at least one renal papilla. The injecting can be performed using a syringe coupled to and in fluid communication with the catheter. The injecting is performed over an injection time period of from about 1 second (s) to about 5 minutes (min), from about 1464903-3015-35943Attorney Docket No: 046192-000134WOPTsecond to about 4 minutes, from about 1 second to about 3 minutes, from about 1 second to about 2 minutes, from about 1 second to about 1 minute, from about 0.5 minutes (30 seconds) to about 0.75 minutes (45 seconds), from about 0.5 minutes (30 seconds) to about 1 minute (60 seconds), from about 1 minute (60 seconds) to about 2 minutes (120 seconds), from about 0.5 minutes (30 seconds) to about 2 minutes (120 seconds), for example, for about 1 s, about 2 s, about 3 s, about 4 s, about 5 s, about 6 s, about 7 s, about 8 s, about 9 s, about 10 s, about 11 s, about 12 s, about 13 s, about 14 s, about 15 s, about 16 s, about 17 s, about 18 s, about 19 s, about 20 s, about 21 s, about 22 s, about 23 s, about 24 s, about 25 s, about 26 s, about 27 s, about 28 s, about 29 s, about 30 s, about 31 s, about 32 s, about 33 s, about 34 s, about 35 s, about 36 s, about 37 s, about 38 s, about 39 s, about 40 s, about 41 s, about 42 s, about 43 s, about 44 s, about 45 s, about 46 s, about 47 s, about 48 s, about 49 s, about 50 s, about 51 s, about 52 s, about 53 s, about 54 s, about 55 s, about 56 s, about 57 s, about 58 s, about 59 s, about 1 min, about 1.25 min, about 1.5 min, about 1.75 min, about 2 min, about 2.25 min, about 2.5 min, about 2.75 min, about 3 min, about 3.25 min, about 3.5 min, about 3.75 min, about 4 min, about 4.25 min, about 4.5 min, about 4.75 min, or about 5 min. In some embodiments, the injection time period is less than or equal to about 5 min, less than or equal to about 4 min, less than or equal to about 3 min, less than or equal to about 2 min, or less than or equal to about 1 min. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range.

[0231] In other embodiments, the administering the volume of the solution comprising rAAV does not comprise a continuous perfusion of the composition comprising rAAV that extends beyond about 5 minutes. In some embodiments, a solution comprising the rAAV is administered using a retrograde ureter route (e.g., using a syringe coupled to and in fluid communication with a catheter in the ureter) to a kidney reversibly, i.e., temporarily, isolated from systemic circulation over a time period of at most 5 minutes, and the isolated kidney is re-established into systemic circulation after a period of time of from about 10 minutes to about 60 minutes after the isolating. In some embodiments, the isolation period is replaced with a blocking period (e.g., using a balloon catheter or clamp) of about of from about 10 minutes to about 60 minutes after the blocking, and a solution comprising the rAAV is administered using a retrograde ureter route (e.g., using a syringe coupled to and in fluid communication with a catheter in the ureter) to the blocked kidney over a time period of at most 5 minutes. The at most 5 -minute administration of the rAAV can be performed at any time during the 10-minute to 60-minute isolation or blocking period of the kidney. For example, the rAAV administration is performed at about minutes 0-5, about minutes 5-10, about minutes 10-15, about minutes 15-20, about minutes 20-25, about minutes 25-30, about minutes 30-35, about minutes 35-40, about minutes 40-45, about minutes 45-50, about minutes 50-55, or about minutes 55-60 of the 10 minute to 60 minute kidney isolation or blocking period. In some embodiments, a solution comprising the rAAV is administered in discontinuous increments, e.g., about 1 -minute injection followed by474903-3015-35943Attorney Docket No: 046192-000134WOPTabout 1 -minute of isolation or blocking without injection, rejected iteratively until the entire rAAV volume has been administered.

[0232] As described herein, prior to and during administration of the solution comprising the rAAV to the kidney, the kidney is reversibly isolated from the subject’s systemic circulation. As used herein, the term “systemic circulation” refers to a flow of blood through a subject’s vascular system from the heart to organs and tissues throughout the body (including kidneys) and back to the heart. Via beating of the heart, oxygenated blood is carried through arteries to organs and tissues where the arteries transition into arterioles and then to capillaries where gas exchange occurs. Deoxygenated blood is then transferred from the capillaries to venules, which transition into veins, and then back to the heart. With specific regard to a kidney, the vascular system includes a renal artery, which supplies oxygenated blood to the kidney, and a renal vein, which carries deoxygenated blood away from the kidney. By “isolating the kidney from systemic circulation,” it is meant that blood flow through a particular kidney is slowed, minimized, substantially stopped, or stopped. Isolating a kidney from systemic circulation can be achieved by blocking at least one renal blood vessel (i.e., the renal artery and / or renal vein) of the kidney and / or by diverting the circulation away from the kidney, for example, by way of an external circuit, such that systemic blood flow does not continuously enter the “isolated kidney” by way of the renal artery. Accordingly, any agent delivered to the systemic circulation will not enter and / or circulate through the kidney when the kidney is “isolated.” Isolating a kidney from systemic circulation results in reduced or no urine production in nephrons of the kidney, thus in the kidney itself. Accordingly, urine production is minimized or decreased relative to a kidney that has not been isolated from systemic circulation or stopped, which allows for a more effective backflow of the retrograde ureter rAAV administration in the urinary tract.

[0233] In some embodiments, the method can involve no blocking of renal vessels, particularly when there is direct administration to at least one papilla. In some embodiments, the method comprises blocking at least one renal blood vessel of the kidney. By blocking at least one renal blood vessel, the kidney is isolated from systemic circulation. In some embodiments, only the renal artery is blocked and the renal vein is not blocked. In other embodiments, only the renal vein is blocked and the renal artery is not blocked. In yet other embodiments, both the renal artery and the renal vein are blocked. Accordingly, only one of the renal blood vessels can be blocked or both of the renal blood vessels can be blocked. Blocking a renal blood vessel can be performed by methods known in the art, including by occluding or clamping. Blocking a renal blood vessel by occluding or clamping isolates the kidney from systemic circulation without the formation or introduction of an external or secondary circuit. Accordingly, in some embodiments, the at least one kidney is isolated from systemic circulation without an external or secondary circuit. In some embodiments, neither the renal artery nor the renal vein are blocked.484903-3015-35943Attorney Docket No: 046192-000134WOPT

[0234] Occluding the at least one renal blood vessel comprises introducing an occlusion into the at least one blood vessel, such that the flow of blood through the at least one renal blood vessel is slowed, minimized, substantially stopped, or stopped. Such an occlusion can be introduced by use of a catheter, such as a dilation catheter, a balloon catheter, or a perfusion catheter as non-limiting examples. In some embodiments, the catheter is inserted into an accessible artery or vein, such as the femoral artery, femoral vein, internal jugular vein, and the like, as determined by a medical professional. In some embodiments, the catheter is inserted percutaneously. Accordingly, the catheter can be directed internally to a desired location of a targeted blood vessel, such as the renal artery or renal vein. For example, in some embodiments, a balloon catheter is percutaneously directed to a desired renal blood vessel and is then inflated to block the renal blood vessel, which slows, minimizes, substantially stops, or stops blood supply to the kidney and isolates the kidney from systemic circulation. When both renal blood vessels are to be blocked, separate balloon catheters are directed to each individual renal blood vessel. Blocking the at least one renal blood vessel is performed prior to administration of the solution comprising the rAAV. As discussed herein, the at least one renal blood vessel is unblocked after a time period of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV. The blocking period and the isolating period, whichever period is implied, are measured from moment of blocking or isolating, i.e., subsequent to the blocking or isolating and / or after administering the solution comprising the rAAV. Unblocking the at least one renal blood vessel is performed by, for example, deflating the balloon of the catheter, which reestablishes blood flow to the kidney and reintroduces the kidney to systemic circulation.

[0235] Clamping the at least one renal blood vessel comprises clamping the at least one blood vessel, such that the flow of blood through the at least one renal blood vessel is slowed, minimized, substantially stopped, or stopped. Non-limiting examples of suitable clamps include renal artery clamps, artery clamps, vascular clamps, artery clips, vascular clips, renal vein clamps, renal vein clips, Dieffenbach clamps, and hemostats. Such a clamp can be introduced through an incision made in the subject. For example, in some embodiments, a clamp is directed to and placed on a desired renal blood vessel. The clamp squeezes and blocks the renal blood vessel, which slows, minimizes, substantially stops, or stops blood supply to the kidney and isolates the kidney from systemic circulation. When both renal blood vessels are to be blocked, separate clamps are directed to each individual renal blood vessel. Blocking the at least one renal blood vessel is performed prior to administration of the solution comprising the rAAV. As discussed herein, the at least one renal blood vessel is unblocked after a time period of from about 10 minutes to about 60 minutes subsequent to the blocking and / or after administering the solution comprising the rAAV. Unblocking the at least one renal blood vessel is performed by, for example, unclamping or releasing the clamp, which reestablishes blood flow to the kidney and reintroduces the kidney to systemic circulation.494903-3015-35943Attorney Docket No: 046192-000134WOPT

[0236] In some embodiments, the method comprises introducing an external or secondary circuit to isolate the kidney from systemic circulation. In some embodiments, the method for using an external circuit to isolate the kidney comprises: (a) positioning a perfusion catheter in the renal artery of the kidney; (b) positioning a recovery catheter in the renal vein of the kidney, wherein the perfusion catheter and the recovery catheter together with a membrane oxygenation device form a closed external perfusion circuit through the kidney; and (c) causing a perfusate to flow through the external circuit, wherein the external circuit isolates perfusion through the kidney from the systemic circulation of the subject. Positioning the perfusion and recovery catheters can include blocking the renal artery and / or the renal vein, respectively, for example, by use of a balloon catheter. See e.g., International Patent Publication WO2022175546A1, the contents of which are incorporated herein by reference in their entirety. The perfusate can be, for example, blood donated from the subject or from another subject prior to the performance of the method. Such a use of an external circuit to isolate the kidney from systemic circulation can also be referred to as an “isolated perfused kidney (IPK).” In some embodiments, the IPK is maintained in a physiological environment without ischemia. In some embodiments, the flow rate of the perfusate circulated through the closed circuit does not deviate significantly from the patient’s own blood flow rate in order to avoid ischemia and / or under perfusion. In some embodiments, the blood from the recovery catheter in the renal vein is recirculated back to the perfusion catheter in the renal artery to form an external circuit. The rAAV can be administered via a retrograde route through a ureter while the kidney is isolated from systemic circulation by way of the external circuit.

[0237] In some embodiments, the method for re-establishing the kidney into systemic circulation comprises disassembling the external circuit, for example, by: (a) removing the perfusion catheter from the renal artery of the kidney; (b) removing the recovery catheter from the renal vein of the kidney; and (c) allowing blood from systemic circulation to flow into the renal artery and out of the renal vein back into systemic circulation. Because the external circuit allows for a continuous supply of oxygen to the kidney, re-establishing the kidney to the systemic circulation can be performed at a time period longer than kidney isolation methods that impart ischemia to the kidney.

[0238] In some embodiments, the method does not comprise a continuous perfusion of the kidney. In some embodiments, the method does not comprise a closed circuit comprising the kidney. In some embodiments, the method does not comprise a substantially closed system comprising the kidney. In some embodiments, the method does not comprise diverting circulation from the kidney. In some embodiments, the method does not comprise bypassing the kidney. In some embodiments, the method is performed in vivo. In some embodiments, the method is not performed ex vivo.

[0239] In some embodiments, the method comprises a continuous perfusion of the kidney.In some embodiments, the method comprises a closed circuit comprising the kidney. In some embodiments, the method comprises a substantially closed system comprising the kidney. In some504903-3015-35943Attorney Docket No: 046192-000134WOPTembodiments, the method comprises diverting circulation from the kidney. In some embodiments, the method comprises bypassing the kidney. In some embodiments, the method is not performed in vivo. In some embodiments, the method is performed ex vivo.

[0240] In some embodiments, during the period of time of isolating the kidney from systemic circulation, for example, by blocking the at least one renal blood vessel, the isolated kidney is maintained under normothermic “warm” conditions (i.e., body temperature). Non-limiting examples of normothermic conditions for the isolated kidney include about 36°C, about 36.1°C, about 36.2°C, about 36.3°C, about 36.4°C, about 36.5°C, about 36.6°C, about 36.7°C, about 36.8°C, about 36.9°C, about 37°C, about 37.1°C, about 37.2° C, about 37.3°C, about 37.4°C, about 37.5°C, about 37.6° C, about 37.7°C, about 37.8°C, about 37.9°C, or about 36.0°C-38.0°C.

[0241] In some embodiments, the period of time for isolating the kidney from systemic circulation, for example, by blocking the at least one renal blood vessel, is such that the kidney does not undergo substantial ischemic damage (e.g., build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and / or leakage of autolyzing proteolytic enzymes into the kidney cell and surrounding kidney tissues). In some embodiments, the period of time for isolating the kidney from systemic circulation is about 15 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is 10-60 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is 30-60 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is 30-45 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is 15-45 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is 20-40 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is about 15-30 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is about 30 minutes subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is no more than 45 minutes (min) subsequent to the isolating. In some embodiments, the period of time for isolating the kidney from systemic circulation is at least 10 min, at least 11 min, at least 12 min, at least 13 min, at least 14 min, at least 15 min, at least 16 min, at least 17 min, at least 18 min, at least 19 min, at least 20 min, at least 21 min, at least 22 min, at least 23 min, at least 24 min, at least 25 min, at least 26 min, at least 27 min, at least 28 min, at least 29 min, at least 30 min, at least 31 min, at least 32 min, at least 33 min, at least 34 min, at least 35 min, at least 36 min, at least 37 min, at least 38 min, at least 39 min, at least 40 min, at least 41 min, at least 42 min, at least 43 min, at least 44 min, at least 45 min, at least 46 min, at least 47 min, at least 48 min, at least 49 min, at least 50 min, at least 51 min, at least 52 min, at least 53 min, at least 54 min, at least 55 min, at least 56 min, at least 57 min, at least 58 min, or at least 59 min514903-3015-35943Attorney Docket No: 046192-000134WOPTsubsequent to the isolating. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range.

[0242] In some embodiments, the period of time for isolating the kidney from systemic circulation is at most 10 min, at most 11 min, at most 12 min, at most 13 min, at most 14 min, at most 15 min, at most 16 min, at most 17 min, at most 18 min, at most 19 min, at most 20 min, at most 21 min, at most 22 min, at most 23 min, at most 24 min, at most 25 min, at most 26 min, at most 27 min, at most 28 min, at most 29 min, at most 30 min, at most 31 min, at most 32 min, at most 33 min, at most 34 min, at most 35 min, at most 36 min, at most 37 min, at most 38 min, at most 39 min, at most 40 min, at most 41 min, at most 42 min, at most 43 min, at most 44 min, at most 45 min, at most 46 min, at most 47 min, at most 48 min, at most 49 min, at most 50 min, at most 51 min, at most 52 min, at most 53 min, at most 54 min, at most 55 min, at most 56 min, at most 57 min, at most 58 min, at most 59 min, or at most 60 min subsequent to the isolating. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range.

[0243] In some embodiments, the period of time for isolating the kidney from systemic circulation is about 10 min, about 11 min, about 12 min, about 13 min, about 14 min, about 15 min, about 16 min, about 17 min, about 18 min, about 19 min, about 20 min, about 21 min, about 22 min, about 23 min, about 24 min, about 25 min, about 26 min, about 27 min, about 28 min, about 29 min, about 30 min, about 31 min, about 32 min, about 33 min, about 34 min, about 35 min, about 36 min, about 37 min, about 38 min, about 39 min, about 40 min, about 41 min, about 42 min, about 43 min, about 44 min, about 45 min, about 46 min, about 47 min, about 48 min, about 49 min, about 50 min, about 51 min, about 52 min, about 53 min, about 54 min, about 55 min, about 56 min, about 57 min, about 58 min, about 59 min, or about 60 min subsequent to the isolating. It is understood that each of the individual times described herein can be used to define lower and upper values of a time range.

[0244] In some embodiments, the volume of the solution comprising the rAAV is from 0.13 mL / kg to about 0.35 mL / kg, about 0.2 mL / kg to about 0.35 mL / kg, from about 0.25 mL / kg to about 0.35 mL / kg, from about 0.3 mL / kg to about 0.35 mL / kg, from about 0.2 mL / kg to about 0.30 mL / kg, or from about 0.2 mL / kg to about 0.25 mL / kg; and the period of time for isolating the kidney from systemic circulation, for example, by blocking the at least one renal blood vessel or establishing an external circuit comprising the kidney, is 10-60 minutes subsequent to the isolating. In some embodiments, the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.35 mL / kg, about 0.2 mL / kg to about 0.35 mL / kg, from about 0.25 mL / kg to about 0.35 mL / kg, from about 0.3 mL / kg to about 0.35 mL / kg, from about 0.2 mL / kg to about 0.30 mL / kg, or from about 0.2 mL / kg to about 0.25 mL / kg; and the period of time for isolating the kidney from systemic circulation, for example, by blocking the at least one renal blood vessel or establishing an external circuit comprising the kidney, is about 30 minutes subsequent to the isolating, or about 15-30 minutes subsequent to the isolating.524903-3015-35943Attorney Docket No: 046192-000134WOPT

[0245] In some embodiments, the method of treatment can comprise first diagnosing a subject or patient who can benefit from treatment by the methods described herein and / or a pharmaceutical composition described herein. In some embodiments, such diagnosis comprises detecting or measuring an abnormal level of an analyte in a sample from the subject or patient associated with a kidney-associated disorder. In some embodiments, the method further comprises administering an rAAV to the kidney of the subject.

[0246] In some embodiments, the subject has previously been determined to have an abnormal level of an analyte or marker described herein relative to a reference. In some embodiments, the reference level can be the level in a sample of similar cell type, sample type, sample processing, and / or obtained from a subject of similar age, sex and other demographic parameters as the sample / subject. In some embodiments, the test sample and control reference sample are of the same type, that is, obtained from the same biological source, and comprising the same composition, e.g., the same number and type of cells.

[0247] The term “sample” or “test sample” as used herein denotes a sample taken or isolated from a biological organism, e.g., a blood or plasma sample from a subject. In some embodiments of any of the aspects, the technology described herein encompasses several examples of a biological sample. In some embodiments of any of the aspects, the biological sample is cells, or tissue, or peripheral blood, or bodily fluid. Exemplary biological samples include, but are not limited to, a biopsy (e.g., from the kidney); blood; serum; plasma; or urine. The term also includes a mixture of the above-mentioned samples. The term “test sample” also includes untreated or pretreated (or pre-processed) biological samples. In some embodiments of any of the aspects, a test sample can comprise cells from a subject.

[0248] In some embodiments, the reference can be a level of the analyte in a population of subjects who do not have or are not diagnosed as having, and / or do not exhibit signs or symptoms of a kidney-associated disorder. In some embodiments, the reference can also be a level of expression of the analyte in a control sample, a pooled sample of control individuals or a numeric value or range of values based on the same. In some embodiments of any of the aspects, the reference can be the level of an analyte in a sample obtained from the same subject at an earlier point in time, e.g., the methods described herein can be used to determine if a subject’s sensitivity or response to the rAAV therapy is changing overtime.

[0249] In some embodiments of any of the aspects, the step of determining if the subject has an abnormal level of an analyte described herein can comprise i) obtaining or having obtained a sample from the subject and ii) performing or having performed an assay on the sample obtained from the subject to determine / measure the level of the analyte in the subject. In some embodiments of any of the aspects, the step of determining if the subject has an abnormal level of an analyte described herein can comprise performing or having performed an assay on a sample obtained from the subject to534903-3015-35943Attorney Docket No: 046192-000134WOPTdetermine / measure the level of analyte in the subject. In some embodiments of any of the aspects, the step of determining if the subject has an abnormal level of an analyte described herein can comprise ordering or requesting an assay on a sample obtained from the subject to determine / measure the level of the analyte in the subject. In some embodiments of any of the aspects, the step of determining if the subject has an abnormal level of an analyte described herein can comprise receiving the results of an assay on a sample obtained from the subject to determine / measure the level of the analyte in the subject. In some embodiments of any of the aspects, the step of determining if the subject has an abnormal level of an analyte described herein can comprise receiving a report, results, or other means of identifying the subject as a subject with a decreased level of the analyte.

[0250] In one aspect of any of the embodiments, described herein is a method of treating a kidney-associated disorder in a subject in need thereof, the method comprising: a) determining if the subject has an abnormal level of an analyte described herein; and b) instructing or directing that the subject be administered a solution comprising an rAAV or a pharmaceutical composition as described herein if the level of the analyte is abnormal relative to a reference. In some embodiments of any of the aspects, the step of instructing or directing that the subject be administered a particular treatment can comprise providing a report of the assay results. In some embodiments of any of the aspects, the step of instructing or directing that the subject be administered a particular treatment can comprise providing a report of the assay results and / or treatment recommendations in view of the assay results.

[0251] In some embodiments of any of the aspects, the solution (or pharmaceutical composition) comprising the rAAV described herein is administered as a monotherapy, e.g., another treatment for the kidney-associated disorder is not administered to the subject.

[0252] In some embodiments of any of the aspects, the methods described herein can further comprise administering a second agent and / or treatment to the subject, e.g., as part of a combinatorial therapy. Non-limiting examples of a second agent and / or treatment can include a treatment for a kidney-associated disorder, such as blood pressure medication (e.g., angiotensin converting enzyme (ACE) such as ramipril, enalapril and lisinopril); medication for diabetes or a high albumin to creatinine ratio (ACR) (e.g., dapagliflozin); medication for cardiovascular disease (e.g., a statin such as atorvastatin or simvastatin); medication to lower potassium (e.g., sodium zirconium cyclosilicate); reduced fluid intake; diuretics (e.g., furosemide); anemia medication (e.g., erythropoietin); calcium supplements; steroids (e.g., cyclophosphamide); dialysis (e.g., hemodialysis, peritoneal dialysis); lifestyle changes (e.g., ceasing smoking; eating a healthy, balanced diet; restricting salt intake, e.g., to less than 6g a day; doing regular exercise, e g., at least 150 minutes a week; reducing alcohol intake, e.g., no more than the recommended limit of 14 units of alcohol a week; losing weight if overweight or obese; avoiding over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen); and / or a kidney transplant (e.g., of a kidney not transduced by the rAAV).544903-3015-35943Attorney Docket No: 046192-000134WOPT

[0253] By way of non-limiting example, if a subject is to be treated for pain or inflammation according to the methods described herein, the subject can also be administered a second agent and / or treatment known to be beneficial for subjects suffering from pain or inflammation. Examples of such agents and / or treatments include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs - such as aspirin, ibuprofen, or naproxen); corticosteroids, including glucocorticoids (e.g. cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone); methotrexate; sulfasalazine; leflunomide; anti-TNF medications; cyclophosphamide; pro-resolving drugs; my cophenolate; or opiates (e.g. endorphins, enkephalins, and dynorphin), steroids, analgesics, barbiturates, oxycodone, morphine, lidocaine, and the like.

[0254] In some embodiments of any of the aspects, the methods described herein can further comprise administering a second agent and / or treatment to the subject, e.g., as part of an immune suppression therapy. In some embodiments, at least one immune suppression agent is DEPO-MEDROL® (methylprednisolone acetate) and / or Tacrolimus (calcineurin-inhibitor). In some embodiments, the at least one immune suppression agent is selected from the group consisting of: Prednisone, Cyclosporine, Tacrolimus, Azathioprine, Mycophenolate mofetil, Sirolimus, Everolimus, Alemtuzumab, and is DEPO-MEDROL® (methylprednisolone acetate). In some embodiments, the at least one immune suppression agent is administered about 7 days prior to, about 6 days prior to, about 5 days prior to, about 4 days prior to, about 3 days prior to, about 2 days prior to, about 1 day prior to, the same day as, about 1 day after, about 2 days after, about 3 days after, about 4 days after, about 5 days after, about 6 days after, about 7 days after, about 8 days after, about 9 days after, about 10 days after, about 11 days after, about 12 days after, about 13 days after, about 14 days after, about 15 days after, about 16 days after, about 17 days after, about 18 days after, about 19 days after, about 20 days, or more, after retro-ureteral administration of the rAAV. In some embodiments, the at least one immune suppression agent is administered if at least one transgene is immunogenic; as non-limiting examples, GFP, mCherry, HA1, and luciferase, and some variants thereof are known to be immunogenic. In some embodiments, the transgene(s) are not immunogenic and do not comprise immunogenic markers, and at least one immune suppression agent is not administered.Recombinant Adeno-Associated Virus (rAAV)

[0255] Described herein are methods of administering a recombinant adeno-associated virus (rAAV) to a kidney of a subject. Recombinant AAV (rAAV) vectors are typically composed of, at a minimum, a transgene and its regulatory sequences, and 5' and 3' AAV inverted terminal repeats (ITRs). The transgene can comprise, as described further herein, one or more regions that encode one or more inhibitory RNAs (e.g., miRNAs) comprising a nucleic acid that targets an endogenous mRNA of a subject. The transgene can also comprise a region encoding, for example, a protein and / or an expression control sequence (e.g., a poly-A tail), as described further herein. The isolated nucleic acid554903-3015-35943Attorney Docket No: 046192-000134WOPT(e.g., the recombinant AAV vector) can be packaged into a capsid protein and administered to a subject (e.g., using retrograde ureter administration) and / or delivered to a selected target cell, such as a kidney cells.

[0256] In some embodiments, the rAAV comprises a capsid selected from the capsids described in Table 1. In other embodiments, the rAAV comprises a capsid selected from the capsids described in Table 1, but excluding AAV9. The exemplary capsids provided in Table 1 include representative AAV VP1 sequences, which further contain the respective VP2 and VP3 sequences, as is known in the art. Each of the references that is recited in Table 1 (including non-patent literature and patent literature) is herein incorporated by reference in its entirety.TABLE 1: Exemplary descriptions of capsids and sequences (patent and non-patent references are i i incorporated herein by reference in their entireties)[ Serotype and where capsid sequence is [ Serotype and where capsid sequence is: published and / or described ] published and / or described AAV1 (see SEQ ID NO: 11 in US20150159173 AAV1 (see SEQ ID NOT in US20160017295, and SEQ ID NO:202 in US20150315612) § SEQ ID NO:64 in US20030138772, SEQ ID NO:27 in US20150159173, and SEQ ID NO:5 in i US7198951) AAV1 (see SEQ ID NO:6 in US20030138772) 1 AAV1.3 (see SEQ ID NO: 14 in L S20030138772) i AAV2 (see SEQ ID NO:7 in US20150159173 AAV2 (see SEQ ID NO:70 in US20030138772, i and SEQ ID NO:211 in US20150315612) SEQ ID NO:23 in US20150159173, and SEQ ID!NO:4 in LS6I56303): AAV2 (sec SEQ ID NO:8 in US6156303) AAV2 (sec SEQ ID NO:7 in US20030138772) i AAV2 (see SEQ ID NO:3 in US6156303) ii AAV2.5T (see SEQ ID NO:42 in US9233131) i AAV3 (see SEQ ID NO: 12 in I J S2() 1501591 "13 ) AAV3 (see SEQ ID NO: 71 in LS20030138772. i § SEQ ID NO:28 in US20150159173, and SEQ ID \O:6 in LS7I9895 I) i AA V3.3b (See SEQ ID NO: 72 in | AAV3-3 (See SEQ ID NO: 200 US20150315612) i | US20030138772) AAV3-3 (Sec SEQ ID NO 217 US20150315612) AAV3a ((Scc SEQ ID NO 5 in US6156303) i AAV3a (Scc SEQ ID NO: 9 in US6156303) AAV3b (Sec SEQ ID NO: 6 in US6156303) AAV3b (See SEQ ID NO: 10 in US6156303) | AAV3b (See SEQ ID NO: 1 in US6156303) i AAV4 (Sec SEQ ib NO: 17 I. §20140348794) 1 AAV4 '((Sec SEQ ID N():5 in L §20140348794) i AAV4 (Sec SEQ ID NO: 3 in US20140348794) AAV4 (Sec SEQ ID NO: 14 in US20140348794) i A A V4 (See SEQ ID NO: 15 in US20140348794) i A A V4 (See SEQ ID NO: 1 in US20140348794) i AAV4 (Sec SEQ ib NO: 12 in I. §20140348794) 1 AAV4 (Sec SEQ ID NO: 1 in L S20140348794) AAV4 (Sec SEQ ID NO: 7 in US20140348794) i: AAV4 (Sec SEQ ID NO: 8 in US20140348794) i AAV4 (See SEQ ID NO: 9 in US20140348794) | AAV4 (See SEQ ID NO: 2 in US20140348794) i AAV4 "(Sec SEQ ID NO: 1 () in L §20140348794) 1 AAV4 (§cc §EQ ID NO: 1 1 in I. §20140348794) i AAV4 (See SEQ ID NO: 18 in US20140348794) AAV4 (See SEQ ID NO:63 in US20030138772 and SliQ ID NO:4 in I. S20I600I 7295) AAV4 (§cc §EQ ID NO: 4 in I. §20140348794) i AAV4 (See SEQ ID NO: 16 in I. §20140348794) i AAV4 (Sec SEQ ID NO 20 in US20140348794) AAV4 (Sec SEQ ID NO 6 in US20140348794) i A A V4 (See SEQ ID NO: 1 in US20140348794) AAV42.2 (See SEQ ID NO: 9 in US20030138772) i AAV42.2 (See SEQ ID NO: 102 in § AAV42.3b (See SEQ ID NO: 36 in iUS20030138772) ] US20030138772)564903-3015-35943Attorney Docket No: 046192-000134WOPTAAV42.3B (See SEQ ID NO: 107 in AAV42.4 (See SEQ ID NO: 33 in J US20030138772) S US20030138772) i AAV42.4 (See SEQ ID NO: 88 in AAV42.8 (See SEQ ID NO: 27 in US20030138772) § US20030138772) AAV42.8 (See SEQ ID NO: 85 in | AAV43.1 (See SEQ ID NO: 39 in J US20030138772) 1 L S20030138772) i AAV43.1 (See SEQ ID NO: 92 in:: AAV43.12 (See SEQ ID NO: 41 in i US20030138772) | I S20030138772) i AAV43.12 (See SEQ ID NO: 93 in AAV5 (see SEQ ID NO: 1 in US7427396) US20030138772) i AAV5 (see SEQ ID NO: 114 in 0826630138772) | AAV5 (see SEQ ID N0:5 in US20 "160017295,§ SEQ ID N0:2 in US7427396, and SEQ ID NO:2 I6 in LS20I503 I56I2) i AAV5 (see SEQ ID NO: 199 in US2015031'5612) | AAV6 (see SEQ ID NO:65 in LS20()30138772. i § SEQ ID NO:29 in US20150159173, SEQ ID 1 N0:6 in US20160017295, and SEQ ID NO: 7 in US6156303) AAV6 (see SEQ ID NOS:2, 7, and 11 in i: AAV6 (see SEQ ID NOS:203 and 220 in J US6156303) | L 820150315612) i AAV7 (see SEQ ID NO:14 in US20150159173) | AAV7 (see SEQ ID NO: 183 in US20150315612) i i AAV7 (see SEQ ID NO:2 in US20030138772, | AAV7 (see SEQ ID N0:3 in US20030138772) J SEQ ID NO:30 in US20150159173, SEQ ID | NO: 181 in I. S20I50315612. and SEQ ID NO:7 An US20160017295) i AAV7 (see SEQ ID N(): l in 0820030138772 | AAV7 (see SEQ ID NO:213 0820150315612) Lind SEQ H) NO: 180 in LS20I50315612) i AAV7 (see SEQ ID N():222 in LS20I50315612) AAV7 (see SEQ ID N():2 in LS8906675) AAV8 (Sec SEQ ID NO: 15 in US20150159173) AAV8 (Sec SEQ ID NO: 7 in US20150376240) i AAV8 (See SEQ ID N0:4 in OS20030138772; AAV8 (See SEQ ID NO: 95 in OS20030138772, i SEQ ID NO: 182 in OS20150315612) SEQ ID NO: 1 in OS20140359799) i AAV8 (See SEQ ID NO: 31 in 0820150159173) | AA V8 (See, e.g., SEQ ID NO: 8 in § OS20160017295, or SEQ ID N0:7 in § OS7198951, or SEQ ID NO: 223 in OS20150315612) i A A V8 (See SEQ ID NO: 8 in OS20150376240) | AAV8 (See SEQ ID NO: 214 in j OS20150315612) i AA V-8b (See SEQ ID NO: 5 in | AA V-8b (See SEQ ID NO: 3 in i OS20150376240) OS20150376240) AAV-8h (See SEQ ID NO: 6 in AAV-8h (See SEQ ID NO: 4 in OS20150376240) US20150376240) i AAV9 (See SEQ ID NO: 5 in US20030138772) § AAV9 (Sec SEQ ID NO: 1 or 2 in US7198951) i AAV9 (See SEQ ID NO: 9 in OS20160017295):: AAV9 (See SEQ ID NO: 100 in OS20030138772 i and SEQ ID NO:2 in OS7198951) AAV9 (See SEQ ID NO: 3 in OS7198951) i: AAV9 (AAVhu.14) (See SEQ ID NO: 3 in S OS20150315612) i AAV9 (AAVhu.14) (See SEQ ID NO: 123 in | AAV 10 (see SEQ ID NO: 1 17 in i OS20150315612) § OS20030138772) i AAV10 (SEQ ID NO:9 in WO261L121561) AAV10 (SEQ ID NO:8 in WO2015121501) i AAVi 1 (SEQ ID NO: 1 18 in US26636138772) 1 AAV I2 (SEQ ID NO: 1 19 in LS20030138772) i AAVA3.1 (See SEQ ID NO: 120 in: AAVA3.3 (See SEQ ID NO: 57 in US20030138772) US20030138772) AAVA3.3 (See SEQ ID NO: 66 in AAVA3.4 (See SEQ ID NO: 54 in JUS20030138772) S US20030138772)574903-3015-35943Attorney Docket No: 046192-000134WOPTAAVA3.4 (See SEQ ID NO: 68 in AAVA3.5 (See SEQ ID NO: 55 in J US20030138772) S US20030138772) i AAVA3.5 (See SEQ ID NO: 69 in AAVA3.7 (See SEQ ID NO: 56 in US20030138772) § US20030138772) AAVA3.7 (Sec SEQ ID NO: 67 in | AAV29. (See SEQ ID NO: 11 in (AAVbb. 1) 161 i J US20030138772) 1 L JS20030138772) AAVC2 (See SEQ ID NO: 61 in § AAVCh.5 (See SEQ ID NO:46 in US20030138772) i: US20150159173); SEQ ID NO: 234 in US20150315612) AAV24.1 (See SEQ ID NO: 101 in:: AAVcy.2 (AAV13.3) (See SEQ ID NO: 15 in US20030138772) | L JS20030138772) i AAV27.3 (See SEQ ID NO: 104 in | AAVcy.3 (AAV24.1) (See SEQ ID NO: 16 in J US20030138772) j US20030138772) i AAVcy.5 (See SEQ ID NO: 227 in | AAVcy.4 (AAV27.3 j (See SEQ ID NO: 17 in | US20150315612) J US20030138772) i AAVcy.5 (AAV7.2) (See SEQ ID NO: 18 in AAV7.2 (See SliQ ID NO: 103 in US20030138772) J US20030138772) i AAVcy.6 (AAV 16.3) (See SEQ ID NO: 10 in AAV 16.3 (See SEQ ID NO: 105 in US20030138772) US20030138772) i AAVcy.5 (See SEQ ID NO: 24 in AAVcy.5 (See SEQ ID NO: 8 in US20150159173) US20150159173): AAVCy.5R2 (See SEQ ID NO: 24 modified with s AAVCy.5Rl (See SEQ ID NO: 24 modified with | G13D and D403N in US20150159173) GI3D in US20150159173): AAVCy.5R4 (See SEQ ID NO: 24 modified with s AAVCy.5R3 (See SEQ ID NO: 24 modified with: G13D, D403N, R51K, N158K, and P161Q in G13D, D403N, and R51K in US20150159173) J US20150159173) i AAVDJ (See SEQ ID NO: 2 in US20140359799) AAVDJ (See SEQ ID NO: 3 in US20140359799 i and SEQ ID NO: 2 in US7588772) AAVDJ-8 (See SEQ ID NO: 1 modified with i: AAVDJ (See SEQ ID NO: 1 in US7588772) J R587Q and R590T in US7588772) i AAVH2 (See SEQ ID NO: 26 in | AAVF5 (See SEQ ID NO: 110 in i US20030138772) § US20030138772) i AAVhEl. 1 (See SEQ ID NO: 44 in US9233131) | AA VI 16 (See SEQ ID NO: 25 in j US20030138772) i AAVhEri.16 (See SEQ ID NO: 48 in. VAVhErl.14 (See SEQ ID NO: 46 in | US9233131) J US9233131) i AAVhErl.23 (AAVhEr2.'29) (See SEQ ID NO: | AAVhErl.18 (See SEQ ID NO: 49 in 53 in US9233131) LS9233I3I) AAVhErl.36 (See SEQ ID NO: 52 in AAVhErl.35 (See SEQ ID NO: 50 in US9233131) US9233131) i AAVhErl.7 (Sec SEQ ID NO: 51 in US9233I3I) AAVhErl.5 (Sec SEQ ID NO: 45 in US9233I3I) i AAVhEr2.16 (See SEQ IDNO: 55 in 1 AAVhErl.8 (See SEQ ID NO: 47 in US9233131) i i US9233131) i A A Vhl j-2.31 (See SEQ ID NO: 58 in 1 A A VhEr2.30 (See SEQ ID NO: 56 in J US9233131) S US9233131) i AAVhEr2.4 (See SEQ IDNO: 54 in US9233131) | AAVhEr2.36 (See SEQ IDNO: 57 in j US9233131) i AAVhu.l (See SEQ ID NO: 46 in | AAVhErS. I (See SEQ IDNO: 59 in US9233131) US20150315612) i AAVhu.i'O (AAV 16.8) (See SEQ ID NO: 56 in AAVhu.l (See SEQ ID NO: 144 in US20150315612) US20150315612) i AAVhu.l 1 (AAV16.12) (See SEQ ID NO: 57 in AAVhu.lO (AAV16.8) (See SEQ ID NO: 156 in i iUS20150315612) § I. S20I50315612)584903-3015-35943Attorney Docket No: 046192-000134WOPT AAVhu.12 (See SEQ IDNO: 59 in AAVhu.l 1 (AAV16.12) (See SEQ ID NO: 153 in! US20150315612) ' US20150315612) AAVhu.13 (See SEQ IDNO: 16 in AAVhu.12 (See SEQ ID NO: 154 in US2015015917 and ID NO: 71 in US20150315612) J US20150315612) AAVhu.13 (See SEQ IDNO: 32 in AAVhu.136.1 (See SEQ ID NO: 165 in US20150159173 and IDNO: 129 § US20150315612) J US20150315612) i AAVhu.140.2 (See SEQ ID NO: 167 in | AAVhu.140.1 (See SEQ ID NO: 166 in i US20150315612) § I. S20I50315612) AAVhu.15 (See SEQ IDNO: 147 in AAVhu.145.6 (See SEQ ID NO: 178 in J US20150315612) S I. S20I50315612) i AAVhu.156.1 (See SEQ IDNO: 179 in | AAVhu.15 (AAV33.4) (See SEQ ID NO: 50 in i US20150315612) § I. S20I50315612) AAVhu.16 (AAV33.8) (See SEQ IDNO: 51 in AAVhu.16 (See SEQ ID NO: 148 in J US20150315612) S I. S20I50315612) i AAVhu.17 (AAV33.12) (See SEQ ID NO: 4 in | AAVhu.17 (See SEQ ID NO: 83 in | US20150315612) J I. S20I50315612) i AAVhu.l7i2 (See SEQibNO: 172 in AAVhu.172.1 (See SEQ ID NO: 171 in US20150315612) j I. S20I50315612) i AAVhu.173.8 (See SEQ ID NO: 175 in | AAVhu.173.4 (See SEQ ID NO: 173 in J US20150315612) § US20150315612) i AAVhu.18 (See SEQ IDNO: 149 in | AAVhu.18 (See SEQ ID NO: 52 in i US20150315612) § I. S20I50315612) i AAVhu.19 (See SEQ IDNO: 133 in | AAVhu.19 (See SEQ ID NO: 62 in US20150315612)!US20150315612) AAVhu.2 (See SEQ ID NO: 143 in § AAVhu.2 (See SEQ ID NO: 48 in US20150315612) US20150315612) AAVhu.20 (See SEQ ID NO: 134 in i: AAVhu.20 (See SEQ ID NO: 63 in J US20150315612) | I. S20I50315612) i AAVhu.21 (See SEQ ID NO: 135 in | AAVhu.21 (See SEQ ID NO: 65 in i US20150315612) § I. S20I50315612) i AAVhu.22239 (See SEQ ID NO: 138 in | AAVhu.22 (See SEQ ID NO: 67 in US20150315612) i I. S20I50315612) i AAVhu.23.2 (See SEQ IDNO: 137 in | AAVhu.23 (See SEQ ID NO: 60 in | US20150315612) J I. S20I50315612) i A A Vhu.24 (See SEQ ID NO: 136 in | A A Vhu.24 (See SEQ ID NO: 66 in i US20150315612) I. S20I50315612) AAVhu.25 (See SEQ ID NO: 146 in AAVhu.25 (See SEQ ID NO: 49 in US20150315612) US20150315612) AAVhu.26 (See SEQ ID NO: 33 in § AAVhu.26 (See SEQ ID NO: 17 in US20150159173, and SEQ ID NOS: 61 and 139 ii US20150159173 and SEQ ID NO: 61 in Hn US20150315612) I. S20I50315612) i A A Vhu.27 (See SEQ ID NO: 140 in | A A Vhu.27 (See SEQ ID NO: 64 in i US20150315612) § I. S20I50315612) AAVhu.28 (See SEQ ID NO: 130 in AAVhu.28 (See SEQ ID NO: 68 in J US20150315612) S I. S20I50315612) AAVhu.29 (See SEQ ID NO: 42 in AAVhu.29 (See SEQ ID NO: 69 in US20150159173 and SEQ IDNO: 132 in i: US20150315612) J US20150315612) AAVhu.29 (See SEQ ID NO: 225 in AAVhu.29R (See SEQ ID NO: 42 with G396E in! iUS20150315612) § I. S20150159173)594903-3015-35943Attorney Docket No: 046192-000134WOPTAAVhu.3 (See SEQ ID NO: 44 in AAVhu.3 (See SEQ ID NO: 145 in US20150315612) S US20150315612)AAVhu.30 (See SEQ ID NO: 70 in AAVhu.30 (See SEQ ID NO: 131 in US20150315612) § US20150315612)AAVhu.31 (See SEQ ID NO: 1 in | AAVhu.31 (See SEQ ID NO: 121 in US20150315612) § US20150315612)AAVhu.32 (See SEQ ID NO: 2 in:: AAVhu.32 (See SEQ ID NO: 122 in US20150315612) § US20150315612)i A A Vhu.33 (See SEQ ID NO: 75 in | A A Vhu.33 (See SEQ ID NO: 124 in US20150315612) US20150315612)i A A Vhu.34 (See SEQ ID NO: 72 in | A A Vhii.34 (See SEQ ID NO: 125 inJ US20150315612) § US20150315612)i AAVhu.35 (See SEQ ID NO: 73 in | AAVhu.35 (See SEQ ID NO: 164 in US20150315612) J I. S20I50315612)i A A Vhu.36 (See SEQ ID NO: 74 in | A A Vhii.36 (See SEQ ID NO: 126 in US20150315612) § US20150315612)i AAVhu.37 (See SEQ ID NO: 34 in | AAVhu.37 (AAV 106.1) (See SEQ ID NO: 16in US20150159173 and SEQ ID NO: 88 in § US20150315612 and SEQ ID NO: 18 in US20150315612) § US20150159173)AAVhu.38 (See SEQ ID NO: 161 in AAVhu.39 (See SEQ ID NO: 102 in US20150315612) § US20150315612)AAVhu.39 (AAVLG-9) (See SEQ ID NO: 24 in AAVhu.4 (See SEQ ID NO: 47 inJ US20150315612 S I. S20I50315612)i AAVhu.4 (See SEQ ID NO: 141 in I AAVhu.40 (See SEQ ID NO: 87 in US20150315612) US20150315612)AAVhu.40 (AAV114.3) (See SEQ ID NO: 11 in AAVhu.41 (See SEQ ID NO: 91 in US20150315612) US20150315612)| AAVhu.41 (AAV 127.2) (See SEQ ID NO: 6 in § AAVhu.42 (See SEQ ID NO: 85 in US20150315612) § US20150315612)i AAVhu.42 ( AA V 127.5) (See SEQ ID NO:8 in | AAVhu.43 (See SEQ ID NO: 160 in US20150315612) j I. S20I50315612)i AAVhu.43 (See SEQ ID NO: 236 in | AAVhu.43 (AAV 128.1) (See SEQ ID NO: 80 in | US20150315612) J I. S20I50315612): AAVhu.44 (See SEQ ID NO: 45 in AAVhu.44Rl (See SEQ ID NO: 45 modified with US20150159173 and SEQ ID NO: 158 in § E137K in US20150159173)| US20150315612)i AAVhu.44 (AAV 128.3) (See SEQ ID NO: 81 in | AAVhu.44R3 (See SEQ ID NO: 45 modified US20150315612) § with E137K, P446L, and G609D inj US20150159173)i A A Vhu.44R2 (See SEQ ID NO: 45 modified | A A Vhu.45 (See SEQ ID NO: 127 inwith E137K and P446L in US20150159173) § US20150315612)i A A Vhu.45 (See SEQ ID NO: 76 in | A A Vhii.46 (See SEQ ID NO: 159 in US20150315612) § US20150315612)i A A Vhu.46 (See SEQ ID NO: 82 in | A A Vhu.47 (See SEQ ID NO: 77 in US20150315612) § US20150315612)AA Vhu.46 (See SEQ ID NO: 224 in AAVhu.48 (See SEQ ID NO: 38 in US20150315612) S US20150159173)AA Vhu.47 (See SEQ ID NO: 128 in AAVhu.48 (AAV130.4) (See SEQ ID NO: 78 in US20150315612) US20150315612)AAVhu.48 (See SEQ ID NO: 157 in:: AAVhu.48R2 (See SEQ ID NO: 38 modified US20150315612) * with G277S and E322K in US20150159173) i AAVhu.48Rl (See SEQ ID NO: 38 modified with | AAVhu.49 (See SEQ ID NO: 209 inG277S in US20150159173) US20150315612)604903-3015-35943Attorney Docket No: 046192-000134WOPTAAVhu.48R3 (See SEQ ID NO: 38 modified AAVhu.5 (See SEQ ID NO: 45 inwith G277S, E322K, and S552N in US20150315612)US20150159173)AAVhu.49 (See SEQ ID NO: 189 in AAVhu.51 (See SEQ ID NO: 208 in US20150315612) US20150315612)AAVhu.5 (See SEQ ID NO: 142 in AAVhu.52 (See SEQ ID NO: 210 in US20150315612) US20150315612)AAVhu.51 (See SEQ ID NO: 190 in AAVhu.53 (See SEQ ID NO: 19 in US20150315612) US20150159173)AAVhu.52 (See SEQ ID NO: 191 in AAVhu.53 (AAV145.1) (See SEQ ID NO: 176 in i US20150315612) US20150315612)i AAVhu.53 (See SEQ ID NO: 35 in AAVhu.54 (AAV145.5) (See SEQ ID NO: 177 in! US20150159173) US20150315612)AAVhu.54 (See SEQ ID NO: 188 in AAVhu.56 (See SEQ ID NO: 205 in US20150315612) US20150315612)i AAVhu.55 (See SEQ ID NO: 187 in AAVhu.56 (AAV145.6) (See SEQ ID NO: 192 in i US20150315612) US20150315612)AAVhu.56 (AAV145.6) (See SEQ ID NO: 168 in AAVhu.57 (See SEQ ID NO: 169 in US20150315612) US20150315612)AAVhu.57 (See SEQ ID NO: 206 in AAVhu.58 (See SEQ ID NO: 207 in US20150315612) US20150315612)AAVhu.57 (See SEQ ID NO: 193 in AAVhu.6 (AAV3.1) (See SEQ ID NO: 5 in US20150315612) US20150315612)i AAVhu.58 (See SEQ ID NO: 194 in AAVhu.60 (See SEQ ID NO: 184 in US20150315612) US20150315612)AAVhu.6 (AAV3.1) (See SEQ ID NO: 84 in AAVhu.61 (See SEQ ID NO: 185 in US20150315612) US20150315612)i AAVhu.60 (AAV 161.10) (See SEQ ID NO: 170 AAVhu.63 (See SEQ ID NO: 204 inin US20150315612) US20150315612)i AAVhu.61 (AAV 161.6) (See SEQ ID NO: 174 in AAVhu.64 (See SEQ ID NO: 212 in! US20150315612) US20150315612)i AAVhu.63 (See SEQ ID NO: 195 in AAVhu.66 (See SEQ ID NO: 197 in US20150315612) US20150315612)i AAVhu.64 (See SEQ ID NO: 196 in AAVhu.67 (See SEQ ID NO: 198 in US20150315612) US20150315612)AAVhu.67 (See SEQ ID NO: 215 in AAVhu.7 (See SEQ ID NO: 150 in US20150315612) US20150315612)AAVhu.7 (See SEQ ID NO: 226 in AAVhu.71 (See SEQ ID NO: 79 in US20150315612) US20150315612)i AAVhu.7 ( AAV7.3) (See SEQ ID NO: 55 in AAVhu.8 (See SEQ ID NO: 12 in US20150315612) US20150315612)AAVhu.8 (See SEQ ID NO: 53 in AAVhu.9 (AAV3.1) (See SEQ ID NO: 58 in US20150315612) US20150315612)i AAVhu.8 (See SEQ ID NO: 151 in AAV-LK01 (See SEQ ID NO: 2 in US20150315612) US20150376607)i AAVhu.9 (AAV3.1) (See SEQ ID NO: 155 in AAV-LK02 (See SEQ ID NO: 3 in US20150315612) US20150376607)i AAV-I. K01 (See SEQ ID NO: 29 in AAV-LK03 (See SEQ ID NO: 4 in US20150376607) US20150376607)i AAV-I.k()2 (See SEQ I D NO: 30 in AAV-LK04 (See SEQ ID NO: 32 inUS20150376607) US20150376607)614903-3015-35943Attorney Docket No: 046192-000134WOPTAAV-LK03 (See SEQ ID NO: 12 in AAV-LK05 (See SEQ ID NO: 33 in WO2015121501 and SEQ ID NO: 31 in US20150376607)US20150376607)i AAV-LK04 (See SEQ ID NO: 5 in AAV-LK06 (See SEQ ID NO: 34 in US20150376607) US20150376607)AAV-LK05 (See SEQ ID NO: 6 in AAV-LK07 (See SEQ ID NO: 35 in US20150376607) US20150376607)AAV-LK06 (See SEQ ID NO: 7 in AAV-LK08 (See SEQ ID NO: 36 in US20150376607) US20150376607)AAV-LK07 (See SEQ ID NO: 8 in AAV-LK09 (See SEQ ID NO: 37 in US20150376607) US20150376607)i AAV-I. K08 (See SEQ ID NO: 9 in AAV-LK10 (See SEQ ID NO: 38 in US20150376607) US20150376607)i AAV-LkO9 (See SEQ I D NO: 10 in AAV-LK11 (See SEQ ID NO: 39 in US20150376607) US20150376607)i AA V-I. K 10 (See SEQ ID NO: 11 in AAV-LK12 (See SEQ ID NO: 40 in US20150376607) US20150376607)AAV-LK11 (See SEQ ID NO: 12 in AAV-LK13 (See SEQ ID NO: 41 in US20150376607) US20150376607)AAV-LK12 (See SEQ ID NO: 13 in AAV-LK14 (See SEQ ID NO: 42 in US20150376607) US20150376607)AAV-LK13 (See SEQ ID NO: 14 in AAV-LK15 (See SEQ ID NO: 43 in US20150376607) t S20150376607)i AAV-I. K 14 (See SEQ ID NO: 15 in AAV-LK16 (See SEQ ID NO: 44 in US20150376607) US20150376607)AAV-LK15 (See SEQ ID NO: 16 in AAV-LK17 (See SEQ ID NO: 45 in US20150376607) US20150376607)i A A V-I. K 16 (See SEQ ID NO: 17 in AAV-LK18 (See SEQ ID NO: 46 in US20150376607) US20150376607)i AAV-EK 17 (See SEQ I D NO: 18 in AAV-LK19 (See SEQ ID NO: 47 in! US20150376607) US20150376607)i AAV-I. KI 8 (See SEQ I D NO: 19 in AAV-PAEC (See SEQ ID NO: 48 in US20150376607) US20150376607)i AAV-EK 19 (See SEQ I D NO: 20 in AAV-PAEC 11 (See SEQ ID NO: 54 in US20150376607) US20150376607)AAV-PAEC (See SEQ ID NO: 1 in AAV-PAEC 12 (See SEQ ID NO: 51 in US20150376607) US20150376607)AAV-PAEC 11 (See SEQ ID NO: 26 in AAV-PAEC 13 (See SEQ ID NO: 49 in US20150376607) US20150376607)i AAV-PAEC 12 (See SEQ ID NO: 27 in AAV-PAEC2 (See SEQ ID NO: 56 in US20150376607) US20150376607)AAV-PAEC 13 (See SEQ ID NO: 28 in AAV-PAEC4 (See SEQ ID NO: 55 in US20150376607) US20150376607)i AAV-PAEC2 (See SEQ ID NO: 21 in AAV-PAEC6 (See SEQ ID NO: 52 in US20150376607) US20150376607)i AAV-PAEC4 (See SEQ ID NO: 22 in AAV-PAEC7 (See SEQ ID NO: 53 in US20150376607) US20150376607)i AAV-PAEC6 (See SEQ ID NO: 23 in AAV-PAEC8 (See SEQ ID NO: 50 in US20150376607) US20150376607)i AAV-PAEC7 (See SEQ ID NO: 24 in AAVpi.l (See SEQ ID NO: 93 in US20150376607) US20150315612)AAV-PAEC8 (See SEQ ID NO: 25 in AAVpi.2 (see SEQ ID NO: 30 inUS20150376607) US20150315612)624903-3015-35943Attorney Docket No: 046192-000134WOPTAAVpi.l (See SEQ ID NO: 28 in AAVpi.3 (See SEQ ID NO: 29 in US20150315612) US20150315612)AAVpi.2 (See SEQ ID NO: 95 in AAVrh.10 (See SEQ ID NO: 9 in US20150315612) US20150159173)AAVpi.3 (See SEQ ID NO: 94 in AAV44.2 (See SEQ ID NO: 59 in US20150315612) LS20030I38772)AAVrh.10 (See SEQ ID NO: 25 in AAV42. IB (See SEQ ID NO: 90 in US20150159173) US20030138772)i AAVrh.10 (AAV44.2) (See SEQ ID NO: 81 in AAVrh.13 (See SEQ ID NO: 10 in US20030138772) US20150159173)AAVrh.12 (AAV42. lb) (See SEQ ID NO: 30 in AAVrh.13 (See SEQ ID NO: 228 in US20030138772) US20150315612)i AAVrh.13 (See SEQ ID NO: 26 in AAV42.3A (See SEQ ID NO: 87 in US20150159173) US20030138772): AAVrh.l3R (See SEQ ID NO: 26 modified with AAV42.5A (See SEQ ID NO: 89 inE538K in US20150159173 US20030138772)i AA Vrh.14 ( AA V42.3a) (See SEQ ID NO: 32 in AAV42.5B (See SEQ ID NO: 91 in US20030138772) US20030138772)AAVrh.17 (AAV42.5a) (See SEQ ID NO: 34 in AAV42.6B (See SEQ ID NO: 112 in US20030138772) US20030138772)i AAVrh.18 (AAV42.5b) (See SEQ ID NO: 29 in AAVrh.2 (See SEQ ID NO: 39 in US20030138772) US20150159173)AAVrh.19 (AAV42.6b) (See SEQ ID NO: 38 in AAVrh.20 (See SEQ ID NO: 1 in US20030138772) US20150159173)i AAVrh.2 (See SEQ ID NO: 231 in AAVrh.21 (AAV42.10) (See SEQ ID NO: 35 in i US20150315612) US20030138772)i AAV42.10 (See SEQ ID NO: 106 in AAVrh.22 (AAV42.il) (See SEQ ID NO: 37 in i US20030138772) US20030138772)i AAV42.il (See SEQ ID NO: 108 in AAVrh.23 (AAV42.12) (See SEQ ID NO: 58 in i US20030138772) US20030138772)i AAV42.12 "(See SEQ ID NO: 1'13 in AAVrh.24 (AAV42.13) (See SEQ ID NO: 31 in i US20030138772) US20030138772)i AAV42.13 (See SEQ ID NO: 86 in AAVrh.25 (AAV42.15) (See SEQ ID NO: 28 in i US20030138772) LS20030I38772)AAV42.15 (See SEQ ID NO: 84 in AAVrh.31 (AAV223.1) (See SEQ ID NO: 48 in i US20030138772) US20030138772): AAVrh.2R (See SEQ ID NO: 39 modified with AAVrh.32 (AAVC1) (See SEQ ID NO: 19 in V651I in US20150159173) US20030138772)AAVC1 (See SEQ ID NO: 60 in AAVrh.51 (AAV2-5) (See SEQ ID NO: 104 in US20030138772) US20150315612)i AAVrh.32 / 33 (See SEQ ID NO: 2 in AAVrh.52 (AAV3-9) (See SEQ ID NO: 96 in US20150159173) US20150315612)i AAVrh.52 (AAV3-9) (See SEQ ID NO: 18 in AAVrh.53 (AAV3-11) (See SEQ ID NO: 17 in US20150315612) US20150315612)i AAVrh.53 (See SEQ ID NO: 97 in AAVrh.54 (See SEQ ID NO: 40 in US20150315612) US20150315612)i AAVrh.53 (AAV3-I 1) (See SEQ ID NO: 186 in AAVrh.55 (AAV4-19) (See SEQ ID NO: 117 in i US20150315612) US20150315612)AAVrh.54 (See SEQ ID NO: 49 in AAVrh.56 (See SEQ ID NO: 152 in US20150159173 and SEQ ID NO: 116 in US20150315612)US20150315612)AAVrh.55 (See SEQ ID NO: 37 in AAVrh.57 (See SEQ ID NO: 105 inUS20150315612) US20150315612)634903-3015-35943Attorney Docket No: 046192-000134WOPTAAVrh.56 (See SEQ ID NO: 54 in AAVrh.58 (See SEQ ID NO: 48 in US20150315612) US20150159173 and SEQ ID NO: 106 in US20150315612)AAVrh.57 (See SEQ ID NO: 26 in AAVrh.58 (See SEQ ID NO: 232 in US20150315612) US20150315612)AAVrh.58 (See SEQ ID NO: 27 in AAVrh.59 (See SEQ ID NO: 110 in US20150315612) US20150315612)AAVrh.59 (See SEQ ID NO: 42 in AAVrh.60 (See SEQ ID NO: 120 in US20150315612) US20150315612)AAVrh.60 (See SEQ ID NO: 31 in AAVrh.61 (AAV2-3) (See SEQ ID NO: 21 in US20150315612) US20150315612)i AAVrh.6l (See SEQ ID NO: 107 in AAVrh.62 (AAV2-15) (See SEQ ID NO: 114 in! US20150315612) US20150315612)AAVrh.62 (AAV2-15) (See SEQ ID NO: 33 in AAVrh.64 (See SEQ ID NO: 43 in US20150315612) US20150159173 and SEQ ID NO: 99 in US20150315612)AAVrh.64 (See SEQ ID NO: 15 in AAVrh.64 (See SEQ ID NO: 233 in US20150315612) US20150315612)i AAVRh.64RI (See SEQ ID NO: 43 modified AAVRh.64R2 (See SEQ ID NO: 43 modified with R697W in US20150159173 with R697W and V686E in US20150159173 AAVrh.65 (See SEQ ID NO: 35 in AAVrh.65 (See SEQ ID NO: 112 in US20150315612) US20150315612)i AAVrh.67 (See SEQ ID NO: 36 in AAVrh.67 (See SEQ ID NO: 230 in US20150315612) US20150315612)i AAVrh.67 (See SEQ ID NO: 47 in AAVrh.68 (See SEQ ID NO: 100 in US20150159173 and SEQ ID NO: 47 in US20150315612)US20150315612)i AAVrh.68 (See SEQ ID NO: 16 in AAVrh.69 (See SEQ ID NO: 119 in US20150315612) US20150315612)AAVrh.69 (See SEQ ID NO: 39 in AAVrh.70 (See SEQ ID NO: 98 in US20150315612) US20150315612)i AAVrh.70 (See SEQ ID NO: 20 in AAVrh.72 (See SEQ ID NO: 9 in US20150315612) US20150315612)AAVrh.71 (See SEQ ID NO: 162 in AAVrh.74 (See SEQ ID NO: 6 in US20150315612) US20150159173)i AAVrh.73 (See SEQ ID NO: 5 in AAVrh.8 (See SEQ ID NO: 235 in! US20150159173) US20150315612)i AAVrh.8 (See SEQ ID NO: 41 in AAVrh.8R A586R mutant (See SEQ ID NO: 10! US20150159173) in WO2015168666)i AA Vrh.8R (See SEQ I D NO: 9 in BAAV (bovine AAV) (See SEQ ID NO: 8 in US20150159173, WO2015168666) US9193769)i AA Vrh.8R R533A mutant (See SEQ ID NO: 11 BAAV (bovine AAV) (See SEQ ID NO: 4 in in WO2015168666) US9193769)i BAAV (bovine AAV) (See SEQ ID NO: 10 in BAAV (bovine AAV) (See SEQ ID NO: 6 in US9193769) US9193769)BAAV (bovine AAV) (See SEQ ID NO: 2 in BAAV (bovine AAV) (See SEQ ID NO: 5 in US9193769) US9193769)BAAV (bovine AAV) (See SEQ ID NO: 1 in BAAV (bovine AAV) (See SEQ ID NO: 11 in i US9193769) US9193769)BAAV (bovine AAV) (See SEQ ID NO: 3 in BAAV (bovine AAV) (See SEQ ID NO: 6 in US9193769) US7427396): BAAV (bovine AAV) (See SEQ ID NO: 5 in BAAV (bovine AAV) (See SEQ ID NO: 9 inUS7427396) US9193769)644903-3015-35943Attorney Docket No: 046192-000134WOPT BAAV (bovine AAV) (See SEQ ID NO: 7 in BNP61 AAV (See SEQ ID NO: 2 in J US9193769) S US20150238550) BNP61 AAV (See SEQ ID NO: 1 in BNP63 AAV (See SEQ ID NO: 4 in US20150238550) § US20150238550) i BNP62 AAV (See SEQ ID NO: 3 in | caprine AAV (See SEQ ID NO: 4 in US7427396) J US20150238550) caprine AAV (See SEQ ID NO: 3 in US7427396) AAAV (Avian AAV) (See SEQ ID NO: 12 in | US9238800): true type AAV (ttAAV) (See SEQ ID NO: 2 in AAAV (Avian AAV) (See SEQ ID NO: 6 in W02015121501) j US9238800) i AAAV (Avian AAV) (See SEQ ID NO: 2 in | AAAV (Avian AAV) (See SEQ ID NO: 8 in J US9238800) § US9238800) i AAAV (Avian AAV) (See SEQ ID NO: 4 in | AAAV (Avian AAV) (See SEQ ID NO: 10 in US9238800) J US9238800) i AAAV (Avian AAV) (See SEQ ID NO: 14 in | AAAV (Avian AAV) (See SEQ ID NO: 5 in J US9238800) § US9238800) i AAAV (Avian AAV) (See SEQ ID NO: 15 in | AAAV (Avian AAV) (See SEQ ID NO: 3 in i US9238800) § US9238800) AAAV (Avian AAV) (See SEQ ID NO: 9 in AAAV (Avian AAV) (See SEQ ID NO: 11 in J US9238800) S US9238800) i AAAV (Avian AAV) (See SEQ ID NO: 7 in | AAAV (Avian AAV) (See SEQ ID NO: 1 in i US9238800) § US9238800) AAAV (Avian AAV) (See US9238800) AAV Shuffle 100-1 (See SEQ ID NO: 11 in S US20160017295) AAV Shuffle 166-1 (See SEQ ID NO: 23 in | AAV Shuffle 100-2 (See SEQ ID NO: 29 in i US20160017295) | US20160017295) i AAV Shuffle 100-2 (See SEQ ID NO: 37 in | AAV Shuffle 100-3 (See SEQ ID NO: 12 in US20160017295) j US20160017295) i AAV Shuffle 100-3 (See SEQ ID NO: 24 in | AAV Shuffle 100-7 (See SEQ ID NO: 13 in J US20160017295) § US20160017295) i AAV Shuffle 100-7 (See SEQ ID NO: 25 in | AAV Shuffle 10-2 (See SEQ ID NO: 26 in i US20160017295) § US20160017295) i AAV Shuffle 10-2 (See SEQ ID NO: 34 in | AAV Shuffle 10-6 (See SEQ ID NO: 27 in US20160017295)!US20160017295) AAV Shuffle 10-6 (See SEQ ID NO: 35 in AAV Shuffle 10-8 (See SEQ ID NO: 28 in US20160017295) US20160017295) AAV Shuffle 10-8 (See SEQ ID NO: 36 in i: AAV SM 100-10 (See SEQ ID NO: 33 in J US20160017295) | US20160017295) AAV SM 100-10 (See SEQ ID NO: 41 in AAV SM 100-3 (See SEQ ID NO: 32 in i US20160017295) § US20160017295) i AAV SM 100-3 (See SEQ ID NO: 40 in AAV SM 10-1 (See SEQ ID NO: 30 in US20160017295) i US20160017295) i AAV SM 10- 1 (See SEQ ID NO: 38 in | AAV SM 16-2 (See SEQ ID NO: 22 in | US20160017295) J US20160017295) i AAV SM 16-2 (See SEQ ID NO: 10 in | AAV SM 10-8 (See SEQ ID NO: 31 in US20160017295) J US20160017295) i AAV SM 10-8 (See SEQ ID NO: 39 in AAV CBr-7.1 (See SEQ ID NO: 54 in US20160017295) W02016065001) AAV CBr-7.1 (See SEQ ID NO: 4 in § AAV CBr-7.10 (See SEQ ID NO: 61 in i WO2016065001) | W02016065001) AAV CBr-7.10 (See SEQ ID NO: 11 in AAV CBr-7.2 (See SEQ ID NO: 55 in JWO2016065001) S WO2016065001)654903-3015-35943Attorney Docket No: 046192-000134WOPTAAV CBr-7.2 (See SEQ ID NO: 5 in AAV CBr-7.3 (See SEQ ID NO: 56 inJ WO2016065001) S WO2016065001)AAV CBr-7.3 (See SEQ ID NO: 6 in AAV CBr-7.4 (See SEQ ID NO: 57 in WO2016065001) § WO2016065001)i AAV CBr-7.4 (See SEQ ID NO: 7 in AAV CHt-6.6 (See SEQ ID NO: 35 inJ WO2016065001) S WO2016065001)AAV CBr-7.5 (See SEQ ID NO: 8 in AAV CHt-6.7 (See SEQ ID NO: 36 ini WO2016065001) § WO2016065001)i AAV CHt-6.6 (See SEQ ID NO: 85 in AAV CHt-6.8 (See SEQ ID NO: 37 in WO2016065001) i WO2016065001)i AAV CHt-6.7 (See SEQ ID NO: 86 in AAV ( lit- PI (See SEQ ID NO: 29 inJ WO2016065001) § WO2016065001)i AAV CHt-6.8 (See SEQ ID NO: 87 in AAV ( Ht-P2 (See SEQ ID NO: 1 inWO2016065001) J WO2016065001)i AAV ( 1 It- PI (See SEQ ID NO: 79 in AAV CHt-1’5 (See SEQ ID NO: 2 inJ WO2016065001) § WO2016065001)i AAV CHt-1’2 (See SEQ ID NO: 51 in AAV CHt-1’6 (See SEQ ID NO: 30 ini WO2016065001) § WO2016065001)AAV CHt-P5 (See SEQ ID NO: 52 in AAV CHt-P8 (See SEQ ID NO: 31 inJ WO2016065001) S WO2016065001)i AAV CHt-P6 (See SEQ ID NO: 80 in AAV CIH-P9 (See SEQ ID NO: 3 inW02016065001) ' W02016065001)AAV CHt-P8 (See SEQ ID NO: 81 in AAV CKd-1 (See SEQ ID NO: 57 inJ WO2016065001) US8734809)i AAV CHI-P9 (See SEQ ID NO: 53 in AAV CKd-10 (See SEQ ID NO: 58 ini WO2016065001) | US8734809)i AAV CKd-1 (See SEQ I D NO: 131 in AAV CKd-2 (See SEQ ID NO: 59 in US8734809) j US8734809)AAV CKd-10 (See SEQ ID NO: 132 in AAV CKd-3 (See SEQ ID NO: 60 inJ US8734809) § US8734809)i AAV CKd-2 (See SEQ I D NO: 133 in AAV CKd-4 (See SEQ ID NO: 61 ini US8734809) § US8734809)i AAV CKd-3 (See SEQ ID NO: 134 in AAV CKd-6 (See SEQ ID NO: 62 inJ US8734809) ‘ US8734809)AAV CKd-4 (See SEQ ID NO: 135 in § AAV CKd-7 (See SEQ ID NO: 63 inUS8734809) US8734809)AAV CKd-6 (See SEQ ID NO: 136 in i: AAV CKd-8 (See SEQ ID NO: 64 inJ US8734809) US8734809)AAV CKd-7 (See SEQ ID NO: 137 in AAV CKd-B 1 (See SEQ ID NO: 73 ini US8734809) § US8734809)i AAV CKd-8 (See SEQ ID NO: 138 in AAV CKd-B2 (See SEQ ID NO: 74 in US8734809) i US8734809)i AAV CKd-B 1 (See SEQ ID NO: 147 in AAV CKd-B3 (See SEQ ID NO: 75 in| US8734809) J US8734809)i AAV CKd-B2 (See SEQ ID NO: 148 in AAV CKd-B3 (See SEQ ID NO: 149 in US8734809) J US8734809)AAV CLv-1 (See SEQ ID NO: 139 inUS8734809)AAV CLv-1 (See SEQ ID NO: 65 in AAV Civ 1-10 (See SEQ ID NO: 178 in i US8734809) 1 US8734809) AAV CLvl-1 (See SEQ ID NO: 171 in AAV CLv-12 (See SEQ ID NO: 66 in US8734809)US8734809)664903-3015-35943Attorney Docket No: 046192-000134WOPTAAV CLvl-2 (See SEQ ID NO: 172 in AAV CLvl-3 (See SEQ ID NO: 173 in US8734809) US8734809)AAV CLv-12 (See SEQ ID NO: 140 in AAV CLv-13 (See SEQ ID NO: 141 in US8734809) US8734809)i AAV CLv-13 (See SEQ ID NO: 67 in AAV Civ 1-7 (See SEQ ID NO: 175 in US8734809) LS8734809)AAV CLvl-4 (See SEQ ID NO: 174 in AAV Civ 1-9 (See SEQ ID NO: 177 in US8734809) US8734809)i AAV Civ 1-8 (See SEQ ID NO: 176 in AAV CLv-2 (See SEQ ID NO: 142 in US8734809) US8734809)i AAV CLv-2 (See SEQ I D NO: 68 in AAV CLv-3 (See SEQ ID NO: 143 in US8734809) US8734809)i AAV CLv-3 (See SEQ ID NO: 69 in AAV CLv-4 (See SEQ ID NO: 144 in US8734809) US8734809)i AAV CLv-4 (See SEQ ID NO: 70 in AAV CLv-6 (See SEQ ID NO: 145 in US8734809) US8734809)i AAV CLv-6 (See SEQ ID NO: 71 in AAV CLv-8 (See SEQ ID NO: 146 in US8734809) US8734809)AAV CLv-8 (See SEQ ID NO: 72 in AAV CLv-Dl (See SEQ ID NO: 96 in US8734809) US8734809)i AAV CLv-Dl (See SEQ ID NO: 22 in AAV CLv-D2 (See SEQ ID NO: 97 in US8734809) US8734809)AAV CLv-D2 (See SEQ ID NO: 23 in AAV CLv-D3 (See SEQ ID NO: 98 in US8734809) US8734809)i AAV CLv-D3 (See SEQ ID NO: 24 in AAV CLv-D4 (See SEQ ID NO: 99 in US8734809) US8734809)i AAV CLv-D4 (See SEQ ID NO: 25 in AAV CLv-D5 (See SEQ ID NO: 100 in US8734809) US8734809)i AAV CLv-D5 (See SEQ ID NO: 26 in AAV CLv-D6 (See SEQ ID NO: 101 in US8734809) US8734809)i AAV CLv-D6 (See SEQ ID NO: 27 in AAV CLv-D7 (See SEQ ID NO: 102 in US8734809) US8734809)i AAV ( l.\ -D7 (See SEQ ID NO: 28 in AAV CLv-D8 (See SEQ ID NO: 103 in US8734809) U S8734809); AAV CLv-Kl 762, see SEQ ID NO: 18 in W02016065001)AAV CLv-D8 (See SEQ ID NO: 29 in AAV CLv-K3 (See SEQ ID NO: 19 in US8734809) W02016065001)AAV CLv-Kl (See SEQ ID NO: 68 in AAV CLv-K6 (See SEQ ID NO: 20 in W02016065001) W02016065001)i AAV CLv-K3 (See SEQ ID NO: 69 in AAV CLv-L4 (See SEQ ID NO: 15 in W02016065001) W02016065001)AAV CLv-K6 (See SEQ ID NO: 70 in AAV CLv-L5 (See SEQ ID NO: 16 in W02016065001) W02016065001)i AAV Cl. \ -1.4 (See SEQ ID NO: 65 in AAV Cl.\ -1.6 (See SEQ ID NO: 17 in W02016065001) W02016065001)i AAV CL\ -1.5 (See SEQ ID NO: 66 in AAV CLv-Ml (See SEQ ID NO: 21 in W02016065001) W02016065001)i AAV Cl. \ -1.6 (See SEQ ID NO: 67 in AAV CLv-Mll (See SEQ ID NO: 22 in W02016065001) W02016065001)i AAV CLv-Ml (See SEQ ID NO: 71 in AAV CLv-M2 (See SEQ ID NO: 23 in W02016065001) W02016065001)AAV CLv-Ml 1 (See SEQ ID NO: 72 in AAV CLv-M5 (See SEQ ID NO: 24 inW02016065001) W02016065001)674903-3015-35943Attorney Docket No: 046192-000134WOPTAAV CLv-M2 (See SEQ ID NO: 73 in AAV CLv-M6 (See SEQ ID NO: 25 in W02016065001) W02016065001)AAV CLv-M5 (See SEQ ID NO: 74 in AAV CLv-M7 (See SEQ ID NO: 26 in W02016065001) W02016065001)AAV CLv-M6 (See SEQ ID NO: 75 in AAV CLv-M8 (See SEQ ID NO: 27 in W02016065001) W02016065001)AAV CLv-M7 (See SEQ ID NO: 76 in AAV CLv-M9 (See SEQ ID NO: 28 in W02016065001) W02016065001)AAV CLv-M8 (See SEQ ID NO: 77 in AAV CLv-Rl (See SEQ ID NO: 30 in W02016065001) US8734809)AAV CLv-M9 (See SEQ ID NO: 78 in AAV CLv-R2 (See SEQ ID NO: 31 in W02016065001) US8734809)AAV CLv-Rl (See SEQ ID NO: 104 in AAV CLv-R3 (See SEQ ID NO: 32 in | US8734809) US8734809)AAV CLv-R2 (See SEQ ID NO: 105 in AAV CLv-R4 (See SEQ ID NO: 33 in US8734809) US8734809)AAV CLv-R3 (See SEQ ID NO: 106 in AAV CLv-R5 (See SEQ ID NO: 34 in US8734809) US8734809)AAV CLv-R4 (See SEQ ID NO: 107 in AAV CLv-R6 (See SEQ ID NO: 35 in US8734809) US8734809)AAV CLv-R5 (See SEQ ID NO: 108 in AAV CLv-R7 (See SEQ ID NO: 110 in US8734809) US8734809)AAV CLv-R6 (See SEQ ID NO: 109 in AAV CLv-R8 (See SEQ ID NO: 111 in US8734809); AAV CLv-R7802 (see SEQ ID US8734809)NO: 36 in US8734809)AAV CLv-R8 (See SEQ ID NO: 37 in AAV CLv-R9 (See SEQ ID NO: 112 in US8734809) US8734809)AAV CLv-R9 (See SEQ ID NO: 38 in AAV CSp-1 (See SEQ ID NO: 119 in US8734809) US8734809)AAV CSp-1 (See SEQ ID NO: 45 in US8734809) AAV CSp-10 (See SEQ I D NO: 120 in US8734809)AAV CSp-10 (See SEQ ID NO: 46 in AAV CSp-11 (See SEQ ID NO: 121 in US8734809) US8734809)AAV CSp-11 (See SEQ ID NO: 47 in AAV CSp-2 (See SEQ ID NO: 122 in US8734809) US8734809)AAV CSp-2 (See SEQ ID NO: 48 in US87348O9) AAV CSp-3 (See SEQ ID NO: 123 in US8734809)AAV CSp-3 (See SEQ ID NO: 49 in US8734809) AAV CSp-4 (See SEQ ID NO: 124 in US8734809)AAV CSp-4 (See SEQ ID NO: 50 in US8734809) AAV CSp-6 (See SEQ ID NO: 125 in US8734809)AAV CSp-6 (See SEQ ID NO: 51 in US8734809) AAV CSp-7 (See SEQ ID NO: 126 in US8734809)| AAV CSp-7 (See SEQ ID NO: 52 in US8734809) AAV CSp-8 (See SEQ ID NO: 127 in US8734809)AAV CSp-8 (See SEQ ID NO: 53 in US8734809) AAV CSp-8.10 (See SEQ ID NO: 88 in W02016065001)AAV CSp-8.10 (See SEQ ID NO: 38 in AAV CSp-8.2 (See SEQ ID NO: 89 in W02016065001) W02016065001)AAV CSp-8.2 (See SEQ ID NO: 39 in AAV CSp-8.4 (See SEQ ID NO: 90 in W02016065001) W02016065001)AAV CSp-8.4 (See SEQ ID NO: 40 in AAV CSp-8.5 (See SEQ ID NO: 91 inW02016065001) W02016065001)684903-3015-35943Atorney Docket No: 046192-000134WOPTi AAV CSp-8.5 (See SEQ ID NO: 41 in AAV CSp-8.6 (See SEQ ID NO: 92 in W02016065001) W02016065001) J AAV CSp-8.6 (Sec SEQ ID XO: 42 in AAV CSp-8.7 (See SEQ ID NO: 93 in i W02016065001) W02016065001) AAV CSp-8.7 (See SEQ ID XO: 43 in AAV CSp-8.8 (See SEQ ID NO: 94 in J W02016065001) W02016065001) L\ AV CSp-8.8 (Sec SliQ ID XO: 44 in AAV CSp-8.9 (See SEQ ID NO: 95 in W02016065001) W02016065001) f AAV CSp-8.9 (See SEQ ID XO: 45 in AAV CSp-9 (See SEQ ID NO: 128 in W02016065001) US8734809) fAAV ( Sp-9842 (Scc^S AAV. VR-355 (See SEQ ID NO: 181 in i US8734809) US8734809)rAAv'hu'48R3 (See SEQ ID X(): 183 in. AAV3B (See SEQ ID NO: 98 in| US8734809). W02016065001)AAV4 (See SEQ ID NO: 99 in W02016065001) W02016065001) PAAV4 (See SEQ ID NO: 49 in WO2016065001) AAV5 (See SEQ ID NO: 100 in W02016065001) L\AV5 (Sec SEQ ID XO: 50 in \V020l606500l) AAVF1 / HSC1 (See SEQ ID NO: 2 in W02016049230) LAAVI' I / HSC I (Sec SliQ ID XO: 20 in AAVF11 / HSC11 (See SEQ ID NO: 4 in i WO2016049230) W02016049230) LAAVI' I l / IISCI I (Sec SliQ ID XO: 26 in AAVF12 / HSC12 (See SEQ ID NO: 12 in W02016049230) F AAVFT2 / HSC12 (See SEQ O. AAVF13 / HSC13 (See SEQ ID NO: 14 in W02016049230) W02016049230) P AJWF 13 / HSC 13 (See SEQ ID NO: 31 in. AAVF14 / HSC14 (See SEQ ID NO: 15 in W02016049230) W02016049230) i AWF 14i«SC 14 (See SEQ O. AAVF15 / HSC15 (See SEQ ID NO: 16 in W02016049230) W02016049230) rAAVFI57nSCI5 (See SIXflD X(): 33 in. AAVF16 / HSC16 (See SEQ ID NO: 17 in W02016049230) W02016049230) AAVF 16 / 1 ISC 16 (See SEQ ID XO: 34 in AAVF17 / HSC17 (See SEQ ID NO: 13 in J WO2016049230) W02016049230) J AAVI'I7 / HSCI7 (Sec SliQ ID XO: 35 in AAVF2 / HSC2 (See SEQ ID NO: 3 in i WO2016049230) W02016049230) LAAVF2 / HSC2 (Sec SEQ ID XO: 21 in AAVF3 / HSC3 (See SEQ ID NO: 5 in J W02016049230) W02016049230) L\AVF3 / IISC3 (See SliQ ID XO: 22 in AAVF4 / HSC4 (See SEQ ID NO: 6 in i W02016049230) W02016049230) 7 AAVF4 / HSC4 (See SEQ ID XO: 23 in AAVF5 / HSC5 (See SEQ ID NO: 11 in W02016049230) W02016049230) f AAVIA / I ISC5 (See'SEQ iDNd:'25 in. AAVF6 / HSC6 (See SEQ ID NO: 7 in W02016049230) W02016049230) LAAVI'6 / I ISC6 (Sec SliQ ID XO: 24 in AAVF7 / HSC7 (See SEQ ID NO: 8 in W02016049230). W02016049230)AAVF8 / HSC8 (See SEQ ID NOV in i W02016049230) W02016049230) J AAVI'8 / I ISC8 (Sec SliQ ID XO: 28 in AAVF9 / HSC9882 (see SEQ ID NO: 29 in i WO2016049230) W02016049230) LAAVI'9 / HSC9 (SCC SliQ ID XO: 10 in AAV Anc80L65 (see SEQ ID NO:23 in JWO2016049230) WO / 2017 / 019994)694903-3015-35943Attorney Docket No: 046192-000134WOPT>LXAVpol (see SEQ ID XO: 24 in LS8420372). AAV I P ii (see Mol. Then 2020 April 8;.§ 28(4): 1016-1032 and SEQ ID NOS:5 and 11 in US20200370039 with corresponding description) L\AVIA6ii (scc.t / o / . 77 / I. 2020 April 8: AAV7P4i (see A / o / . / BIT. 2020 April 8:28(4): 1016-1032 and SEQ ID NOS:8 and 14 in § 28(4): 1016-1032 and SEQ ID NOS:4 and 10 in US20200370039 with corresponding description) US20200370039 with corresponding description) AAV4Alii (see Mol. Then 2020 April 8; i: AAV9A2i (see Mol. Then 2020 April 8;28(4): 1016-1032 and SEQ ID NOS:6 and 12 in § 28(4): 1016-1032 and SEQ ID NOS:7 and 13 in i US20200370039 with corresponding description) US20200370039 with corresponding description) pAAVOAl! (sec^. " AAV9)> TF^.28(4): 1016-1032 and SEQ ID NOS:6 and 12 in § 28(4): 1016-1032) US20200370039 with corresponding description) F'AAV9A6r(see'^'^. " AAV9)> N^.28(4): 1016-1032 and SEQ ID NOS:8 and 14 in § 28(4): 1016-1032 and SEQ ID NOS:5 and 11 in US20200370039 with corresponding description) US20200370039 with corresponding description) F'AAV9P2F(seeAfoZ'^ AAVrh l()A2i (sec Mol. / Bcr. 2()2() April 8:.28(4): 1016-1032 and SEQ ID NOS:3 and 9 in § 28(4): 1016-1032 and SEQ ID NOS:7 and 13 in US20200370039 with corresponding description) US20200370039 with corresponding description) LXAVrhIOAIi (see.t / o / . / BI. 2020 April 8: AAVS I0PI i (see A / o / . / BIT. 2020 April 8:28(4): 1016-1032 and SEQ ID NOS:6 and 12 in § 28(4): 1016-1032)\ US20200370039 with corresponding description)rZXAVrhiopii (scc ^. FAAV23xA P2i ( "seeMo 77? I 2()2()ZApril 8:. 28(4): 1016-1032) § 28(4): 1016-1032 and SEQ ID NOS:3 and 9 in:: US20200370039 with corresponding description) rAAVI2P2ii > AAVDJ P2i (see Mo / Mhen April..............28(4): 1016-1032 and SEQ ID NOS:3 and 9 in § 28(4): 1016-1032 and SEQ ID NOS:3 and 9 in US20200370039 with corresponding description):: US20200370039 with corresponding description) f AAV2i8g9 (See " J BioZ C e / «Z 2013 Oct 4: f AAV 2i8 (see SEQ ID NO: 29 in US 10548947) " ' i 288(40): 28814-28823) AAV2g9 (See "descriptions in \\ 020I4I44229.1' AAV2.5 (See SEQ ID NO-'i'in. and J Biol Chem. 2013 Oct 4: 288(40): 28814- j WO / 2022 / I5987I, SEQ IDNO: 16 in 28823; and SEQ ID NO: 24 US20220354969 § US9012224, and SEQ ID NO: 1 in US 11639509) (without A266S)) rAAV2.5g9 (see SEQ ID NO: 2 "in US 639509 [ AAV 2il() (see SEQ ID NO: l l'andits. and SEQ ID NO: 2 in WO / 2020 / 219656) i: corresponding description in US9475845) AAV2i9 (see SEQ ID NO: 10 and its MyoAAV3A (see SEQ ID X():22 and corresponding description in US9475845) corresponding description in WO / 2022 / 020616) > MyoAAVlA (see SEQ ID NO: 12 and MyoAAV3C (see SEQ ID NO: 24 and corresponding description in WO / 2022 / 020616) corresponding description in WO / 2022 / 020616) MyoAAV3B (see SEQ ID X(): 23 and. Xh oAAV3E (see SEQ ID NO: 26 and corresponding description in WO / 2022 / 020616) corresponding description in WO / 2022 / 020616) MyoAAV3D (see SEQ ID X():25 and MyoAAV4A (see SEQ ID NO:28 and corresponding description in WO / 2022 / 020616) corresponding description in WO / 2022 / 020616) MyoAAV3F (sec SEQ ID NO: 27 and My oAAV4C (see SEQ ID NO: 30 and corresponding description in WO / 2022 / 020616) corresponding description in WO / 2022 / 020616) MyoAAV4B (see SEQ ID X():29 and " MyoAAV4E (see SEQ ID NO:32 and corresponding description in WO / 2022 / 020616) corresponding description in WO / 2022 / 020616) MyoAAV4D (see SEQ ID XO:3I and AAV9-P | (589) (AAVXIYO) (see SEQ ID NO: 16; corresponding description in WO / 2022 / 020616) in US20210363193)L\AV9-PI(588) (AAVXIYO) (see SEQ ID XO: 12 AAV9-P3(589 (see SEQ ID NO: 20 inAn LS20210363193) US20210363193)704903-3015-35943Attorney Docket No: 046192-000134WOPTAAV9-P3(588) (see SEQ ID NO:18 in AAVS1-P1 (see SEQ ID NO:30 in 20210363193) i J US20210363193)i AAVS1 (see SEQ ID NO:30 without Pl peptide AAVS10-P1 (see SEQ ID NO:28 in An 20210363193) 20210363193): AAVS10 (see SEQ ID NO:28 without Pl peptide AAV.cc44 (see SEQ ID NO:5 in An 20210363193) WO2021226267) AAV.cc47 (see SEQ ID NO: 8 in AAV.cc84 (see SEQ ID NO: 14 in WO2021226267) § WO2021226267) AAV.cc51 (see SEQ ID NO: 11 in AAVRec3 (see SEQ ID NO:3 in WO2021226267) i US20210371880) AAVRec2 (see SEQ ID NO:2 in | AAV-Olig001 (see SEQ ID NO:2 in US9636370) i J US20210371880) i AAVLC. Vl (see SEQ ID NO:6 in | AAV-Olig003 (see SEQ ID NO:4 in US9636370)WO2022051633) i AAV-Olig002 (see SEQ ID NO:3 in US9636370) AAV.PHP.B (see SEQ ID NO:3 in US11149256 and SEQ ID NO: 7 in WO2019200016) i AAV.PHP.S (see SEQ ID NO:4 in US11149256) AAV9.24 (AAV9 with W503R; see Table 6 in ' US9409953)AAV9-PHP.eB (See SEQ ID NOS:4 and 46 in i: AAV9.47 (AAV9 with S414N, G453D, K557E, i US20170166926 and SEQ ID NO:5 in and T582I; see Table 6 in US9409953)i USl 1149256)AAV9.45 (AAV9 with N498Y and L602F; see i: AAV9.68 (AAV9 with P504T; see Table 6 in Table 6 in US9409953) US9409953) i AAV9.61 ( A A V9 with N498Y; see Table 6 in | AAVXL12 (see SEQ ID NOS: 1 and 4 inUS9409953) US20210246467) AAV9.84 (AAV9 with P468T and E500D; see i AAVXL32.1 (see SEQ ID NOS:3 and 6 in J Table 6 in US9409953) US20210246467)AAVXL32 (see SEQ ID NOS:2 and 5 in AAVKP1 (see JCIInsight. 2019 Nov 14; 4(22): i US20210246467) e 131610: SEQ ID NOS: 1 and 14 inUS11608510; and SEQ ID NO:39 in§ US20220354969)i AAVKP2 (see JCIInsight. 2019 Nov 14; 4(22): AAVKP3 (see JCIInsight. 2019 Nov 14; 4(22): el31610; SEQ ID NOS: 5 and 18 in c 131610: SEQ ID NOS: 2 and 15 inUS11608510; and SEQ ID NO:40 in US11608510; and SEQ ID NO:41 inJ US20220354969) § US20220354969)AAVLK03 (see SEQ ID NO: 20 in | AAVrh20 (see SEQ ID NO: 17 in i US20220354969) § US20220354969) AAVhu37 (see SEQ ID NO: 16 in AAVrh10 (see SEQ ID NO: 13 in J US20220354969) S US20220354969) i AAV2.7m8 (see Sei Transl Med. 2013 Jun 12; AAVNP40 (see SEQ ID NO: 25 in 5(189): 189ra76-189ra76 and SEQ ID NO: 13 and § US20220354969): its corresponding description in US9193956; i SEQ ID NO: 13 in US20230057380; and SEQ ID § J NO: 34 in US20220354969) i AAVSh10 (see SEQ ID NO: 35 US20220354969) | AAVrh8 (see SEQ ID NO: 12 in § US20220354969) i AAV2i8 (see SEQ ID NO: 22 US20220354969) | AAVhu 13 (see SEQ ID NO: 15 in S US20220354969) i AAV2G9 (see SEQ ID NO: 24 in US20220354969) AAVAnc80 (see SEQ ID NO: 33 in § US20220354969) AAVPHPB (see SEQ ID NO: 27 in AAVPHPeB (see SEQ ID NO: 28 in JUS20220354969) S US20220354969)714903-3015-35943Attorney Docket No: 046192-000134WOPTAAVbovine (see SEQ ID NO. 12 in AAV2R585E (see US 11866462)US20220184227

[0257] In some embodiments, the rAAV comprises one or more AAV capsid protein selected from serotype AAV1, AAV2, AAV3a, AAV3b, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV2G9, AAV2.5G9, AAV2.5, AAVrh8, AAVrh10, AAVrh74, AAV10, AAV11, and AAVDJ.

[0258] In some embodiments, the rAAV comprises one or more AAV capsid protein selected from serotype AAV1, AAV2, AAV3a, AAV3b, AAV4, AAV5, AAV6, AAV7, AAV8, AAV2G9, AAV2.5G9, AAV2.5, AAVrh8, AAVrh10, AAVrh74, AAV10, AAV11, and AAVDJ.

[0259] In some embodiments, the rAAV comprises one or more AAV capsid protein selected from serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAVrh74, AAVrh10, pol, AAV9-PHP. B, AAV9-PHP.eB, AAVLK03, AAVAnc80L65, AAVDJ, AAVlA6ii, AAVlP5ii, AAV4Alii, AAV7P4i, AAV9Ali, AAV9A2i, AAV9A6i, AAV9Pli, AAV9P2i, AAV9P5i, AAVrh10Ali, AAVrh10A2i, AAVrh10Pli, AAV12P2ii, AAVSIOPli, AAV JEA, AAV23xA P2i, AAVDJ P2i, AAV 2i8, AAV2G9, AAV2.5, AAV4E, and AAV4A.

[0260] In some embodiments, the rAAV comprises an AAV capsid protein selected from AAV2, AAV6, AAVLK03, AAVDJ, AAV9A2i, AAV9A6i, AAVrh10A2i, AAV2g9, or AAV2.5 (see e.g., Fig.4). In some embodiments, the rAAV comprises an AAV capsid protein selected from AAV2, AAVDJ, AAVJEA (minimal), AAV2g9, or AAV2.5.

[0261] In some embodiments, the rAAV comprises a capsid selected from the group consisting of: AAV2G9, AAV2.5, AAVDJ, and AAV2. In some embodiments, the rAAV does not comprise a capsid protein from serotype AAV9. In some embodiments, the rAAV is not rAAV9. In some embodiments, the rAAV demonstrates tropism for the kidneys, in that it has the ability to preferentially and productively infect kidney cells and / or tissues.

[0262] In some embodiments, the rAAV comprises an AAV capsid protein selected from AAV2, AAV6, AAVLK03, AAVDJ, AAV9A2i, AAV9A6i, AAVrh10A2i, AAV2g9, AAV2.5, AAVKP1, AAVKP2, AAVKP3, and AAV2.7m8.

[0263] In some embodiments, the rAAV does not comprise an AAV9 capsid.

[0264] In some embodiments, the rAAV comprises a capsid selected from the group consisting of: AAV2G9, AAV2.5, AAVDJ, AAV2, AAVKP1, AAVKP2, AAVKP3, and AAV2.7m8. In some embodiments, the rAAV comprises a capsid selected from the group consisting of: AAVKP1, AAVKP2, AAVKP3, AAVDJ, AAV2G9, and AAV2.7m8. In some embodiments, the rAAV comprises a capsid selected from the group consisting of: AAVKP1, AAVKP2, and AAVKP3. In some embodiments, the rAAV comprises a capsid of AAV2.7m8. In some embodiments, the rAAV comprises a capsid of AAV-DJ.724903-3015-35943Attorney Docket No: 046192-000134WOPT

[0265] In some embodiments, the rAAV administered using the retrograde ureter route has at least 10-fold higher transduction efficiency in the kidneys (e.g., cells of the nephrons, proximal tubules, loops of Henle, distal convoluted tubules, and / or collecting ducts) as compared to transduction efficiency in the kidneys of the rAAV administered using another route, such intravenously, intraperitoneally, via an intrarenal artery or intrarenal vein route, retro-orbitally, via direct kidney injection, or subcapsularly. In some embodiments, the rAAV administered using the retrograde ureter route has at least 2-fold, at least 5 -fold, at least 10-fold, at least 25 -fold, at least 50-fold, at least 75 -fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 600-fold, at least 700-fold, at least 800-fold, at least 900-fold, at least 1000-fold, at least 1100-fold, at least 1200-fold, at least 1300-fold, at least 1400-fold, at least 1500-fold, at least 1600-fold, at least 1700-fold, at least 1800-fold, at least 1900-fold, at least 2000-fold, at least 2100-fold, at least 2200-fold, at least 2300-fold, at least 2400-fold, at least 2500-fold, at least 2600-fold, at least 2700-fold, at least 2800-fold, at least 2900-fold, at least 3000-fold, at least 3100-fold, at least 3200-fold, at least 3300-fold, at least 3400-fold, or at least 3500-fold higher transduction efficiency in the kidneys (e.g., cells of the nephrons, proximal tubules, loops of Henle, distal convoluted tubules, and / or collecting ducts) compared to transduction efficiency in the kidneys of the rAAV administered using another route (e.g., IV).

[0266] In some embodiments, the rAAV has at least 3500-fold higher transduction efficiency in the kidneys (e.g., cells of the nephrons, proximal tubules, loops of Henle, distal convoluted tubules, and / or collecting ducts) compared to AAV9 (e.g., administered using the retrograde route as described herein). In some embodiments, the rAAV has at least 100-fold higher transduction efficiency in the kidneys (e.g., nephrons, proximal tubules) compared to AAV9. In some embodiments, the rAAV has at least 800-fold higher transduction efficiency in the kidneys (e.g., cells of the nephrons, proximal tubules, loops of Henle, distal convoluted tubules, and / or collecting ducts) compared to AAV9. In some embodiments, the rAAV has at least 2-fold, at least 5 -fold, at least 10-fold, at least 25 -fold, at least 50-fold, at least 75 -fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 600-fold, at least 700-fold, at least 800-fold, at least 900-fold, at least 1000-fold, at least 1100-fold, at least 1200-fold, at least 1300-fold, at least 1400-fold, at least 1500-fold, at least 1600-fold, at least 1700-fold, at least 1800-fold, at least 1900-fold, at least 2000-fold, at least 2100-fold, at least 2200-fold, at least 2300-fold, at least 2400-fold, at least 2500-fold, at least 2600-fold, at least 2700-fold, at least 2800-fold, at least 2900-fold, at least 3000-fold, at least 3100-fold, at least 3200-fold, at least 3300-fold, at least 3400-fold, or at least 3500-fold higher transduction efficiency in the kidneys (e.g., cells of the nephrons, proximal tubules, loops of Henle, distal convoluted tubules, and / or collecting ducts) compared to AAV9.

[0267] In some embodiments, the rAAV comprises a rational polyploid. As used herein, the term “rational polyploid” refers to AAV vectors which are composed of capsids from two or more AAV734903-3015-35943Attorney Docket No: 046192-000134WOPTserotypes, which can take advantages from individual serotypes for an altered behavior such as tropism, transduction or antigenicity. Some of these polyploid viruses have the ability to change the tropism and transduction efficiency, as well as escape the neutralization by neutralizing antibodies (Nabs). Previously described methodology permits the rational design and production of virions. Such virions are sometimes referred to as “rational polyploid” virions to refer to the fact that the capsid proteins VP1, VP2, and VP3 come from at least two different serotypes, but not all the same serotype. The term “haploid” is sometimes used to refer to a virion where the capsid proteins VP1, VP2 and VP3 are from at least two different serotypes, and the term “triploid” is used to commonly refer to a virion where the capsid proteins VP1, VP2 and VP3 are from three different serotypes. In particular, such rational polyploid, e.g., rational haploid virions and their method of production are disclosed in US Patent No. 10,550,405, which is incorporated herein in its entirety by reference.

[0268] In some embodiments, the rAAV comprises a capsid protein from serotype AAV2G9 or variants thereof. The AAV2G9 capsid comprises amino acids substitutions that introduce a new glycan binding site into the AAV capsid protein. The AAV2G9 capsid protein comprises the Gal binding footprint from AAV9 onto the AAV2 VP3. The AAV2G9 capsid protein was generated by substituting amino acid residues directly involved or flanking the Gal recognition site on the AAV9 VP3 capsid protein subunit onto corresponding residues on the VP3 subunit of AAV2 (e.g., AAV2 VP3 numbering: A266S, Q464V, A467P, D469N, I470M, R471A, D472V, S474G, Y500F, and / or S501A). See e.g., Shen et al. “Engraftment of a Galactose Receptor Footprint onto Adeno-associated Viral Capsids Improves Transduction Efficiency,” The Journal Of Biological Chemistry vol. 288, no.40, pp. 28814-28823, October 4, 2013; Shen, “Understanding And Manipulating AAV-Glycan Interactions,” University of North Carolina at Chapel Hill dissertation (2013) (available on the world wide web at cdr.lib.unc.edu / concem / dissertations / pc289j203); International Patent Publication WO2014144229A1; US Patent 10,077,291 B2; US Patent 11,059,862 B2; US Patent Publication 20210115091 Al; the contents of each of which are incorporated herein by reference in their entireties.

[0269] In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof comprises the A266S variation. In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof does not comprise the A266S variation. In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof comprises the A266S, Q464V, A467P, D469N, I470M, R471A, D472V, S474G, Y500F, and S501A variations. In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof comprises the Q464V, A467P, D469N, I470M, R471A, D472V, S474G, Y500F, and S501A variations. There is an insubstantial difference between 2G9 capsids with or without the A266S variation. 2G9 can also include other variations that do not affect its general properties (e.g., tropism, transduction efficacy in the kidney (e.g., PCT), etc.)744903-3015-35943Attorney Docket No: 046192-000134WOPT

[0270] In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof comprises at least one variation of the AAV9 VP3 capsid protein (see e.g., SEQ ID NO: 2) inserted into the AAV2 VP3 capsid protein (see e.g., SEQ ID NO: 1), inserted at the following position(s): A266S, Q464V, A467P, D469N, I470M, R471A, D472V, S474G, Y500F, and / or S501A (AAV2 VP3 numbering).

[0271] SEQ ID NO: 1, AAV2 VP3 capsid protein (see e g., SEQ ID NO: 65 ofWO2014144229), 735 amino acids (aa) MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDK GEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQA KKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVP DPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTS TRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNW GFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPA DVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQS LDRLMNPLIDQYLYYLSRTNTPSGTTTQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKT SADNNNSEYSWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNV DIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVYL QGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQ VSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL

[0272] SEQ ID NO: 2, AAV9 VP3 capsid protein (see e.g., SEQ ID NO: 75 ofWO2014144229), 736 aa MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGL DKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVF QAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTES VPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITT STRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINN NWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPP FPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHS QSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVST TVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDN VDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDV YLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYST GQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL

[0273] In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof comprises SEQ ID NO: 3, SEQ ID NO: 4, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at754903-3015-35943Attorney Docket No: 046192-000134WOPTleast 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO: 3 or SEQ ID NO: 4, which maintains the same function, or a functional fragment thereof.

[0274] SEQ ID NO: 3, exemplary AAV2G9 VP3 capsid protein, the following variations are noted in bold, underlined text: A266S, Q464V, A467P, D469N, I470M, R471A, D472V, S474G, Y500F, and S501A (AAV2 VP3 numbering).MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDK GEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQA KKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVP DPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTS TRTWALPTYNNHLYKQISSQSGSSNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNW GFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPA DVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQS TDRЛMNPLIDQYLYYLSRTNTPSGTTTQSRLQFSVAGPSNMAVQGRNWLPGPCYRQQRVSKTSADNNNSEFAWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTN VDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVY LQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQ VSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL

[0275] SEQ ID NO: 4, exemplary AAV2G9 VP3 capsid protein, the following variations are noted in bold, underlined text: Q464V, A467P, D469N, I470M, R471A, D472V, S474G, Y500F, and S501A (AAV2 VP3 numbering); see e.g., SEQ ID NO: 24 of US20220354969.MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDK GEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQA KKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVP DPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTS TRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNW GFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPA DVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQS T DR I. MNP! JDOYI Y Yl, S RTNTPSGTTTQS REQFSVAGPSN MA VOG RNWT PGPCYROOR VS l< TSADNNNSEFAWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTN VDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVY LQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQ VSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL

[0276] In some embodiments, the AAV2G9 VP3 capsid protein or variant thereof comprises SVAGPSNMAVQGR (SEQ ID NO: 15) at positions corresponding to amino acids 464-476 of AAV9 VP3 SEQ ID NO: 2. In some embodiments, the AAV2G9 VP3 capsid protein or variant764903-3015-35943Attorney Docket No: 046192-000134WOPTthereof comprises EFAW (SEQ ID NO: 16) at positions corresponding to amino acids 500-503 of AAV9 VP3 SEQ ID NO: 2

[0277] In some embodiments, the rAAV comprises a capsid protein from serotype AAV2.5. AAV2.5 is a chimera composed of AAV 2 with 5 amino acid substitutions from AAV 1 (which uses a-2,3- and a-2,6-N-linked sialic acid as major receptors). AAV2.5 contained four AAV1 substitutions (N705A, Q263A, V708A and T716N, AAV2 numbering) and one insertion of T265 from AAV1. See e.g., Korneyenkov et al., “Next Step in Gene Delivery: Modem Approaches and Further Perspectives of AAV Tropism Modification.” Pharmaceutics 2021 May, 13(5): 750; Hemphill et al. “Adeno-Associated Viral Vectors Show Serotype Specific Transduction of Equine Joint Tissue Explants and Cultured Monolayers,” Scientific Reports volume 4, Article number: 5861 (2014); the contents of each of which are incorporated herein by reference in their entireties.

[0278] In some embodiments, the rAAV comprises a capsid protein from serotype AAVDJ. AAV-DJ is a highly recombinogenic hybrid vector created from experiments involving DNA shuffling of eight AAV serotypes. AAV-DJ is a chimera of AAV type 2 / type 8 / type 9. AAV2 and AAV8 are the closest parental vectors of AAV-DJ. It has been reported that mutations on the 137 / 251 / 503 ubiquitination or phosphorylation sites of the AAV2 or AAV8 capsid lead to dramatic enhancement of gene delivery (K137R / T251A / S503A). See e.g., Grimm et al. “In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses,” J Virol. 2008 Jun; 82(12): 5887-5911; Mao et al. “Single point mutation in adeno-associated viral vectors -DJ capsid leads to improvement for gene delivery in vivo,” BMC Biotechnology volume 16, Article number: 1 (2016); the contents of each of which are incorporated herein by reference in their entireties.

[0279] In some embodiments, the rAAV comprises a capsid protein from serotype AAV2. A molecular clone for AAV2 was isolated in 1983. In some embodiments, the rAAV does not comprise a capsid protein from serotype AAV9. AAV9 was isolated from human DNA in 2004. See e.g., Samulski et al. “Rescue of adeno-associated virus from recombinant plasmids: gene correction within the terminal repeats of AAV,” Cell 1983 May, 33(1): 135-43; Guo et al. “Clades of Adeno-associated viruses are widely disseminated in human tissues,” J Virol. 2004 Jun, 78( 12): 6381 -8; the contents of each of which are incorporated herein by reference in their entireties.

[0280] In some embodiments, the solution comprises rAAV at a concentration that is effective to treat the kidney-associated disorder. In some embodiments, the solution comprises rAAV at a concentration of 108viral genomes per mL (vg / mL) to 1015vg / mL, IxlO13to 5xl013vg / mL, 109vg / mL to 1015vg / mL, 1010vg / mL to 1015vg / mL, 1011vg / mL to 1015vg / mL, 1012vg / mL to 1015vg / mL, 1013vg / mL to 1015vg / mL, 1011vg / mL to 1012vg / mL, 1012vg / mL to 1013vg / mL, 1013vg / mL to 1014vg / mL, 1014vg / mL to 1015vg / mL, 108vg / mL to 1014vg / mL, 108vg / mL to 1013vg / mL, 108vg / mL to 1012vg / mL, 108vg / mL to 1011vg / mL, 108vg / mL to 1010vg / mL, or 108vg / mL to 109774903-3015-35943Attorney Docket No: 046192-000134WOPTvg / mL. In some embodiments, the solution comprises rAAV at a concentration of 108vg / mL to 1013vg / mL. In some embodiments, the solution comprises rAAV at a concentration of at least 108vg / mL, at least 109vg / mL, at least 1010vg / mL, at least 1011vg / mL, at least 1012vg / mL, at least 1013vg / mL, at least 1014vg / mL, at least 1015vg / mL, or more. In some embodiments, the solution comprises rAAV at a concentration of at most 109vg / mL, at most 1010vg / mL, at most 1011vg / mL, at most 1012vg / mL, at most 1013vg / mL, at most 1014vg / mL, or at most 1015vg / mL. In some embodiments, the rAAV is at a concentration of about 5.2xlO10vg / kg, e.g., in a 75 kg subject. In some embodiments, the solution comprises rAAV at a concentration of about IxlO10vg / kg, about 2xlO10vg / kg, about 3xlO10vg / kg, about 4xlO10vg / kg, about 5xlO10vg / kg, about 6xlO10vg / kg, about 7xlO10vg / kg, about 8xlO10vg / kg, about 9xlO10vg / kg, e.g., in a 75 kg subject. It is understood that each of the individual rAAV concentrations described herein can be used to define lower and upper values of an rAAV concentration range.

[0281] In some embodiments, the solution comprises, per 75 kg subject, IxlO11to IxlO14vg total, IxlO14to 2.5xl015vg total, IxlO11to IxlO13vg total, IxlO11to IxlO12vg total, IxlO12to IxlO13vg total, IxlO12to IxlO14vg total, IxlO13to IxlO14vg total, IxlO13to 6xl013vg total, 2xl013to 5xl013vg total, or IxlO13to 2xl013rAAV viral genomes total. In some embodiments, the solution comprises 5xl013to 6xl013rAAV viral genomes total. In some embodiments, the solution comprises at least IxlO13, at least 2xl013, at least 3xl013, at least 4xl013, at least 5xl013, at least 6xl013, at least 7xl013, at least 8xl013, at least 9xl013, or more rAAV viral genomes total. In some embodiments, the solution comprises at most IxlO13, at most 2xl013, at most 3xl013, at most 4xl013, at most 5xl013, at most 6xl013, at most 7xl013, at most 8xl013, at most 9xl013, or more rAAV viral genomes total. In some embodiments, the solution comprises about IxlO11vg total, about 2xlOnvg total, about 3xlOnvg total, about 4xlOnvg total, about 5xlOnvg total, about 6xlOnvg total, about 7xlOnvg total, about 8xlOnvg total, about 9xlOnvg total, about lOxlO11vg total, about IxlO12vg total, about 2xl012vg total, about 3xl012vg total, about 4xl012vg total, about 5xl012vg total, about 6xl012vg total, about 7xl012vg total, about 8xl012vg total, about 9xl012vg total, about lOxlO12vg total, about IxlO13vg total, about 2xl013vg total, about 3xl013vg total, about 4xl013vg total, about 5xl013vg total, about 6xl013vg total, about 7xl013vg total, about 8xl013vg total, about 9xl013vg total, about lOxlO13vg total, or about IxlO14vg total. It is understood that each of the individual rAAV amounts described herein can be used to define lower and upper values of an rAAV amount range.

[0282] In some embodiments, the solution comprises IxlO10viral genomes total. In some embodiments, the solution comprises IxlO10viral genomes total (e.g., 4xl08vg / mL to IxlO9vg / mL).

[0283] In some embodiments, the genome of the rAAV comprises a transgene. As used herein, the term “transgene” refers to a gene or other nucleic acid sequence, which is transduced into the genome of the subject using the rAAV. In order to transduce cells, an rAAV vector enters a cell and784903-3015-35943Attorney Docket No: 046192-000134WOPTdelivers its single-stranded DNA genome to the nucleus, where the genome becomes double-stranded before transcription and integration into the subject’s cell genome.

[0284] In some embodiments, the transgene comprises a reporter protein. Non-limiting examples of such reporter proteins a fluorescent protein (e.g., GPF, mCherry, etc.), luciferase, alkaline phosphatase, beta-galactosidase, beta-lactamase, horseradish peroxidase, a detectable tag (such as c-Myc, HA, VSV-G, HSV, FLAG, V5, HIS, or biotin), and variants thereof. In some embodiments, the transgene comprises a barcode that can be identified by sequencing.

[0285] In some embodiments, the transgene is therapeutic for a kidney-associated disorder. In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is selected from the group consisting of: Alport syndrome; Autosomal dominant polycystic kidney disease (ADPKD); Autosomal dominant tubulointerstitial kidney disease (ADTKD); Autosomal recessive polycystic kidney disease (ARPKD); Apparent mineralocorticoid excess; Autosomal dominant hypocalcemia; Autosomal dominant hypomagnesemia; Bartter Syndrome (e.g., Barttertype 1; Bartter type 2; Barttertype 3; Barttertype 4a; Barttertype 4b; Barttertype 5); Congenital adrenal hyperplasia (e.g., Congenital adrenal hyperplasia type 1; Congenital adrenal hyperplasia type 2; Congenital adrenal hyperplasia type 4; Congenital adrenal hyperplasia type 5); Cystinosis; Cystinuria (e.g., Cystinuria A; Cystinuria B); Dent disease (e.g., Dent disease type 1; Dent disease type 2 / Lowe syndrome); Dicarboxylic aminoaciduria; Distal RTA; EAST / SeSAME syndrome; Fanconi Bickel syndrome; Fanconi renotubular syndrome (e.g., Fanconi renotubular syndrome 1; Fanconi renotubular syndrome 2; Fanconi renotubular syndrome 3; Fanconi renotubular syndrome 4); Gitelman syndrome; Glucocorticoid remediable aldosteronism; Hartnup disorder; Hereditary hypophosphatemic rickets with hypercalciuria; HNF IB-related kidney disease; Hyperphenylalaninemia BH4-deficient;Hypomagnesemia (e.g., Hypomagnesemia type 1 / hypomagnesemia with secondary hypocalcemia; Hypomagnesemia type 2; Hypomagnesemia type 3 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia type 4; Hypomagnesemia type 5 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia, seizures, and mental retardation type 1; Hypomagnesemia, seizures, and mental retardation type 2); Iminoglycinuria; Kenny-Caffey syndrome type 2; Liddle syndrome; Lysinuric protein intolerance; Medullary cystic kidney disease; Neonatal inflammatory skin and bowel disease type 2; Nephrogenic diabetes insipidus; Nephrogenic syndrome of inappropriate antidiuresis; Nephronophthisis; Papillorenal syndrome; Primary hyperoxaluria; Pseudohypoaldosteronism (e.g., Pseudohypoaldosteronism type 1;Pseudohypoaldosteronism type 1A; Pseudohypoaldosteronism type 2b; Pseudohypoaldosteronism type 2c; Pseudohypoaldosteronism type 2d; Pseudohypoaldosteronism type 2e); Renal tubular acidosis type 3; Thin Basement Membrane Nephropathy; Von Hippel-Lindau syndrome; and X-linked hypophosphatemic rickets.794903-3015-35943Attorney Docket No: 046192-000134WOPT

[0286] In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is selected from the group consisting of: autosomal dominant polycystic kidney disease (ADPKD); Alport syndrome; autosomal dominant tubulointerstitial kidney disease (ADTKD); medullary cystic kidney disease; nephronophthisis; Bartter Syndrome; Von Hippel-Lindau syndrome; Gitelman syndrome; congenital nephrotic syndrome; primary hyperoxaluria; Dent disease; Thin Basement Membrane Nephropathy; cystinuria; Liddle syndrome; Papillorenal syndrome; and cystinosis, as described in Table 2A.

[0287] Table 2A: Exemplary kidney-associated disorders (adapted from Rubin et al. 2020, “Improving molecular therapy in the kidney,” Mol Diagn Ther. 24(4): 375-396, the contents of which are incorporated herein by reference in their entirety.cDNA Size Exemplary Gene Therapy Disorder Underlying Genes(bp) StrategyADPKD PKD1 14,138 Gene additionPKD2 5056 Gene addition GANAB 3906 Gene addition ARPKD PKHD1 16,282 Gene addition Alport syndrome COL4A3 8097 Gene addition COL4A4 9895 Gene addition COL4A5 6483 Gene addition ADTKD / Medullary cystic MUC1 (type I) Variable Gene additionkidney disease UMOD 2477 Gene knockdown REN 1462 Gene knockdown HNF1B 2790 Gene addition SEC61A1 1871 Gene addition Nephronophthisis NPHP1 3756 Gene addition Bartter Syndrome SLC12A1 4707 Gene addition KCNJ1 (type II) 4074 Gene addition CLCNKB (type1544 Gene additionIII and IV)BSND (type IV) 3472 Gene addition CLCNKA (type2581 Gene additionIV)MAGED2 (type2066 Gene additionV)Von Hippel-LindauVHP 3737 Gene addition syndromeGitelman syndrome SLC12A3 3119 Gene addition CLCNKB 1544 Gene addition Congenital nephrotic NPHS1 4276 Gene addition syndrome NPHS2 1855 Gene addition Primary hyperoxaluria AGXT (type I) 1865 Gene addition GRHPR (type II) 1280 Gene addition HOGA1 (type III) 2488 Gene additionDent disease CLCN5 (type I) 10,108 Gene additionOCRL (type II) 5138 Gene additionThin Basement Membrane COL4A3 8097 Gene addition Nephropathy COL4A4 9895 Gene additionCOL4A5 6483 Gene addition804903-3015-35943Attorney Docket No: 046192-000134WOPTcDNA Size Exemplary Gene Therapy Disorder Underlying Genes(bp) StrategyCystinuria SLC3A1 1737 Gene addition SLC7A9 1752 Gene additionLiddle syndrome SCNN1A 3481 Gene knockdownSCNN1B 2597 Gene knockdown

[0288] In some embodiments, the transgene comprises a gene that when expressed (e.g., at about a physiological level) in the subject is effective to treat a kidney-associated disorder. In some embodiments, the transgene comprises a gene selected from the group consisting of 4-Hydroxy-2-Oxoglutarate Aldolase 1 (H0GA1; e.g., type III); Alanine-Glyoxylate Aminotransferase (AGXT; e.g., type I); Aquaporin 2 (AQP2); ATPase Na+ / K+ Transporting Subunit Alpha 1 (ATP1A1); Arginine Vasopressin Receptor 2 (AVPR2); ATPase H+ Transporting VO Subunit A4 (ATP6V0A4); ATPase H+ Transporting V1 Subunit B1 (ATP6V1B1); Bartter Syndrome, Infantile, With Sensorineural Deafness (BSND; e.g., type IV); Barttin CLCNK (chloride channel K) Type Accessory Subunit Beta (BSND); Calcium Sensing Receptor (CaSR); Carbonic Anhydrase 2 (CA2); Chloride Voltage-Gated Channel 5 (CLCN5; e.g., type I); Chloride Voltage-Gated Channel Ka (CLCNKA; e.g., type IV); Chloride Voltage-Gated Channel Kb (CLCNKB; e.g., type III and IV); Claudin 16 (CLDN16);Claudin 19 (CLDN19); CLCNKA (Chloride Voltage-Gated Channel Ka); Collagen Type IV Alpha 3 Chain (COL4A3); Collagen Type IV Alpha 4 Chain (COL4A4); Collagen Type IV Alpha 5 Chain (COL4A5); Cullin 3 (CUL3); Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2 (CNNM2); Cytochrome P450 Family 11 Subfamily B Member 1 (CYP11B1); Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2); Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1); Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2); Enoyl-CoA Hydratase And 3-Hydroxyacyl Co A Dehydrogenase (EHHADH); Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); FAM111 (family 111) Trypsin Like Peptidase A (FAM111A); Forkhead Box II (FOXI1); FXYD Domain / Motif Containing Ion Transport Regulator 2 (FXYD2); Glucosidase II Alpha Subunit (GANAB); Glycine Amidinotransferase (GATM);Glyoxylate And Hydroxypyruvate Reductase (GRHPR; e.g., type II); Guanine nucleotide binding protein alpha stimulating (GNAS); Hepatocyte nuclear factor 1 (HNF1) Homeobox B (HNF1B); Hepatocyte Nuclear Factor 4 Alpha (HNF4A); Hydroxy-Delta-5 -Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2); Hydroxysteroid 11-Beta Dehydrogenase 2 (HSD11B2);Inositol Polyphosphate-5-Phosphatase (OCRL; e.g., type II); Kelch Like Family Member 3 (KLHL3); MAGED2 (type V); Mucin 1 (MUC1; e.g., type I); Melanoma Antigen Gene Family Member D2 (MAGED2); Nephrin (NPHS1); Nephrocystin 1 (NPHP1); Nephrosis 2 (NPHS2; Podocin); Nuclear Receptor Subfamily 3 Group C Member 2 (NR3C2); Oculocerebrorenal Syndrome Of Lowe (OCRL) Inositol Polyphosphate-5-Phosphatase; Phosphate Regulating Endopeptidase X-Linked (PHEX); Polycystic Kidney And Hepatic Disease 1 (PKHD1); Polycystin 1 (PKD1); Polycystin 2 (PKD2;814903-3015-35943Attorney Docket No: 046192-000134WOPTPotassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1; e.g., type II); Potassium Inwardly Rectifying Channel Subfamily J Member 10 (KCNJ10); Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1); Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1); Pterin-4 Alpha-Carbinolamine Dehydratase 1 (PCBD1); Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A); Sodium Channel Epithelial 1 Subunit Beta (SCNN1B); Sodium Channel Epithelial 1 Subunit Gamma (SCNN1G); Solute Carrier Family 1 Member 1 (SLC1A1); Solute Carrier Family 2 Member 2 (SLC2A2); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 34 Member 1 (SLC34A1); Solute Carrier Family 34 Member 3 (SLC34A3); Solute Carrier Family 36 Member 2 (SLC36A2); Solute Carrier Family 4 Member 1 (SLC4A1); Solute Carrier Family 6 Member 19 (SLC6A19); Solute Carrier Family 6 Member 20 (SLC6A20); Solute Carrier Family 7 Member 7 (SLC7A7); Solute Carrier Family 7 Member 9 (SLC7A9); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6); Von Hippel-Lindau Tumor Suppressor (VHL); WD Repeat Domain 72 (WDR72); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 1 (WNK1); and With-no-lysine (WNK, Lysine Deficient) Protein Kinase 4 (WNK4).

[0289] In some embodiments, the transgene comprises a gene selected from the group consisting of Alanine-Glyoxylate Aminotransferase (AGXT; e.g., type I); Bartter Syndrome, Infantile, With Sensorineural Deafness (BSND; e.g., type IV); Chloride Voltage-Gated Channel 5 (CLCN5; e.g., type I); Chloride Voltage-Gated Channel Ka (CLCNKA; e.g., type IV); Chloride Voltage-Gated Channel Kb (CLCNKB; e.g., type III and IV); Collagen Type IV Alpha 3 Chain (COL4A3); Collagen Type IV Alpha 4 Chain (COL4A4); Collagen Type IV Alpha 5 Chain (COL4A5); Glucosidase II Alpha Subunit (GANAB); Glyoxylate And Hydroxypyruvate Reductase (GRHPR; e.g., type II); Hepatic Nuclear Factor 1 (HNF1) Homeobox B (HNF1B); 4-Hydroxy-2-Oxoglutarate Aldolase 1 (HOGA1; e.g., type III); Potassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1; e.g., type II); MAGED2 (type V); Mucin 1 (MUC1; e.g., type I); Nephrocystin 1 (NPHP1); Nephrin (NPHS1); Nephrosis 2 (NPHS2; Podocin); Inositol Polyphosphate-5-Phosphatase (OCRL; e.g., type II);Polycystin 1 (PKD1); Polycystin 2 (PKD2); Polycystic Kidney And Hepatic Disease 1 (PKHD1); Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 7 Member 9 (SLC7A9); Von Hippel-Lindau Tumor Suppressor (VHL); and any combination thereof.

[0290] In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is selected from the group consisting of: Apparent mineralocorticoid excess; Autosomal dominant hypocalcemia; Autosomal dominant hypomagnesemia; Bartter type 1; Bartter type 2;Bartter type 3; Bartter type 4a; Bartter type 4b; Bartter type 5; Congenital adrenal hyperplasia type 1; Congenital adrenal hyperplasia type 2; Congenital adrenal hyperplasia type 4; Congenital adrenal824903-3015-35943Attorney Docket No: 046192-000134WOPThyperplasia type 5; Cystinuria A; Cystinuria B; Dent disease type 1; Dent disease type 2 / Lowe syndrome; Dicarboxylic aminoaciduria; Distal RTA; EAST / SeSAME syndrome; Fanconi Bickel syndrome; Fanconi renotubular syndrome 1; Fanconi renotubular syndrome 2; Fanconi renotubular syndrome 3; Fanconi renotubular syndrome 4; Gitelman syndrome; Glucocorticoid remediable aldosteronism; Hartnup disorder; Hereditary hypophosphatemic rickets with hypercalciuria; HNF IB-related kidney disease; Hyperphenylalaninemia BH4-deficient; Hypomagnesemia type 1 / hypomagnesemia with secondary hypocalcemia; Hypomagnesemia type 2; Hypomagnesemia type 3 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia type 4;Hypomagnesemia type 5 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis;Hypomagnesemia, seizures, and mental retardation type 1; Hypomagnesemia, seizures, and mental retardation type 2; Iminoglycinuria; Kenny-Caffey syndrome type 2; Liddle syndrome; Lysinuric protein intolerance; Neonatal inflammatory skin and bowel disease type 2; Nephrogenic diabetes insipidus; Nephrogenic syndrome of inappropriate antidiuresis; Pseudohypoaldosteronism type 1; Pseudohypoaldosteronism type 1A; Pseudohypoaldosteronism type 2b; Pseudohypoaldosteronism type 2c; Pseudohypoaldosteronism type 2d; Pseudohypoaldosteronism type 2e; Renal tubular acidosis type 3; and X-linked hypophosphatemic rickets; as described in Table 2B.

[0291] Table 2B: Exemplary kidney-associated disorders (adapted from Downie et al. 2020, “Inherited tubulopathies of the kidney,” Clin J Am Soc Nephrol. 16(4): 620-630, the contents of which are incorporated herein by reference in their entirety). Listed are exemplary renal tubulopathies grouped by affected nephron segment, the underlying gene(s), and encoded protein(s), as well as their Online Mendelian Inheritance in Man (OMIM) entry number. AD, autosomal dominant; AR, autosomal recessive; XLR, x-linked recessive; RTA, renal tubular acidosis.Inheritan OMI Disorder Gene Proteince M Proximal tubuleL-ARGININE: GLYCINE Fanconi renotubular #1346AD GATM AMIDINOTRANSFERASsyndrome 1 00EFanconi renotubular #1823AR SLC34A1 NaPi2Asyndrome 2 09 Fanconi renotubular #6070AD EHHADH PBFEsyndrome 3 37 Fanconi renotubular #6002AD HNF4A HNF -4syndrome 4 81 Fanconi Bickel #1381AR SLC2A2 GLUT-2syndrome 60#3000 Dent disease type 1 XLR CLCN5 CLC-508 Dent disease type #3005XLR OCRL OCRL2 / Lowe syndrome 35834903-3015-35943Attorney Docket No: 046192-000134WOPTRenal tubular #6114AR CA2 Carbonic anhydrase 2 acidosis type 3 92 Hereditaryhypophosphatemic #2415AR SLC34A3 NaPi2crickets with 30 hypercalciuriaX-linked#3078 hypophosphatemic XLD PHEX PHEX00 rickets#1046 Cystinuria A AD SLC3A1 rBAT14 #6041 Cystinuria B AR SLC7A9 b(0,+)ATl44 Lysinuric protein #2227AR SLC7A7 y(+)LATlintolerance 00#2345 Hartnup disorder AR SLC6A19 B(O)AT100 AR / digen SLC36A2+SLC6A20 / SLC SLC36A2+SLC6A20 / SLC #2426 Iminoglycinuriaic 6A19 6A19 00 Dicarboxylic Excitatory Amino Acid #2227AR SLC1A1aminoaciduria Transporter 3 (EAAT3) 30Thick ascending limb#6008 Barttertype 1 AR SLC12A1 NKCC239 #6003 Bartter type 2 AR KCNJ1 ROMK59 #6020 Bartter type 3 AR CLCNKB CLC-Kb23 #6064 Bartter type 4a AR BSND Barttin12 #6020 Bartter type 4b Digenic CLCNKA+CLCNKB CLC-Ka+CLC-Kb24 #6011 Bartter type 5 XR MAGED2 MAGED299 Hypomagnesemiatype 3 / familial#6039 hypomagnesemia AR CLDN16 Claudinl659 with hypercalciuriaand nephrocalcinosisHypomagnesemiatype 5 / familial#6100 hypomagnesemia AR CLDN19 Claudinl936 with hypercalciuriaand nephrocalcinosisAutosomal dominant #6011AD CaSR Calcium-sensing receptor hypocalcemia 98 Kenny-Caffey #1270AD FAM111A FAM111Asyndrome type 2 00Distal convoluted tubule844903-3015-35943Attorney Docket No: 046192-000134WOPT#6009 Gitelman syndrome AR SLC12A3 NCCT68 EAST / SeSAME #6020AR KCNJ10 Kir4.1syndrome 28 Pseudohypoaldostero #6018AD WNK4 WNK4nism type 2b 44 Pseudohypoaldostero #6052AD WNK1 WNK1nism type 2c 32 Pseudohypoaldostero #6144AD / AR KLHL3 KLHL3nism type 2d 95 Pseudohypoaldostero #6144AD CUL3 CUL3nism type 2e 96 Hypomagnesemiatype #6070 1 / hypomagne semia AR TRPM6 TRPM609 with secondaryhypocalcemiaHypomagnesemia #1540AD FXYD2 Na-K-ATPasetype 2 20 Autosomal dominant #1762AD KCNA1 Kvl.l hypomagnesemia 60 HNFIB-related #1379AD HNF1B HNF1Bkidney disease 20 Hyperphenylalanine #2640AR PCBD1 PCDB1mia BH4-deficient 70 Hypomagnesemia #6117AR EGF EGFtype 4 18 Neonatalinflammatory skin #6160AR EGFR EGFRand bowel disease 69 type 2Hypomagnesemia,#6138 seizures, and mental AD / AR CNNM2 CNNM282 retardation type 1Hypomagnesemia,#6183 seizures, and mental De novo ATP1A1 ATP1A114 retardation type 2Collecting ductPseudohypoaldostero #6002AR SCNN1A ENaC a subunitnism type 1 28 Pseudohypoaldostero #6007AR SCNN1B ENaC P subunitnism type 1 60 Pseudohypoaldostero #6007AR SCNN1G ENaC y subunitnism type 1 61 Pseudohypoaldostero #6009AD NR3C2 MRnism type 1A 83#6007 Liddle syndrome AD SCNN1B ENaC P subunit60854903-3015-35943Attorney Docket No: 046192-000134WOPT#6007 Liddle syndrome AD SCNN1G ENaC y subunit61 Apparent#6142 mineralocorticoid AR HSD11B2 11-P-HSD232 excessGlucocorticoid#6106 remediable AD CYP11B1 / CYP11B2 11-P-hydroxylase / ALDOS13 aldosteronismCongenital adrenal #6138AR CYP21A2 21 -hydroxylase hyperplasia type 1 15 Congenital adrenal #6138AR HSD3B2 3-P-HSD2 hyperplasia type 2 90 Congenital adrenal #6106AR CYP11B1 11-P-hydroxylase hyperplasia type 4 13 Congenital adrenal #6093AR CYP17A1 17-a-hydroxylase hyperplasia type 5 00 Nephrogenic diabetes #3005XLR AVPR2 AVPR2insipidus 38 Nephrogenic diabetes #1077AR / AD AQP2 AQP-2insipidus 77 Nephrogenicsyndrome of #3005XLR AVPR2 V2Rinappropriate 38 antidiuresisNephrogenicsyndrome ofAD GNAS G-a sinappropriateantidiuresis#1092 Distal RTA AD / AR SLC4A1 AE170 #1921 Distal RTA AR ATP6V1B1 V-ATPase subunit Bl32 #6052 Distal RTA AR ATP6V0A4 V-ATPase subunit a439 #6010 Distal RTA AR FOXI1 Forkhead box protein II93 WD repeat-containing #6132 Distal RTA AR WDR72protein 72 14

[0292] In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is associated with the proximal tubule and is selected from the group consisting of:Cystinuria A, Cystinuria B, Dent disease type 1, Dent disease type 2 / Lowe syndrome, Dicarboxylic aminoaciduria, Fanconi Bickel syndrome, Fanconi renotubular syndrome 1, Fanconi renotubular syndrome 2, Fanconi renotubular syndrome 3, Fanconi renotubular syndrome 4, Hartnup disorder, Hereditary hypophosphatemic rickets with hypercalciuria, Iminoglycinuria, Lysinuric protein intolerance, Renal tubular acidosis type 3, and X-linked hypophosphatemic rickets.864903-3015-35943Attorney Docket No: 046192-000134WOPT

[0293] In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is associated with the thick ascending limb of the loop of Henle and is selected from the group consisting of: Autosomal dominant hypocalcemia, Barttertype 1, Barttertype 2, Barttertype 3, Bartter type 4a, Barttertype 4b, Barttertype 5, Hypomagnesemia type 3 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Hypomagnesemia type 5 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis, and Kenny-Caffey syndrome type 2.

[0294] In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is associated with the distal convoluted tubule and is selected from the group consisting of: Autosomal dominant hypomagnesemia; EAST / SeSAME syndrome; Gitelman syndrome; HNF IB-related kidney disease; Hyperphenylalaninemia BH4-deficient; Hypomagnesemia type1 / hypomagnesemia with secondary hypocalcemia; Hypomagnesemia type 2; Hypomagnesemia type 4; Hypomagnesemia, seizures, and mental retardation type 1; Hypomagnesemia, seizures, and mental retardation type 2; Neonatal inflammatory skin and bowel disease type 2; Pseudohypoaldosteronism type 2b; Pseudohypoaldosteronism type 2c; Pseudohypoaldosteronism type 2d; and Pseudohypoaldosteronism type 2e.

[0295] In some embodiments, the kidney-associated disorder, for which the transgene is therapeutic, is associated with the collecting duct and is selected from the group consisting of:Apparent mineralocorticoid excess, Congenital adrenal hyperplasia type 1, Congenital adrenal hyperplasia type 2, Congenital adrenal hyperplasia type 4, Congenital adrenal hyperplasia type 5, Distal RTA, Glucocorticoid remediable aldosteronism, Liddle syndrome, Nephrogenic diabetes insipidus, Nephrogenic syndrome of inappropriate antidiuresis, Pseudohypoaldosteronism type 1, and Pseudohypoaldosteronism type 1A

[0296] In some embodiments, the transgene comprises a gene that when expressed (e.g., at about a physiological level) in the subject is effective to treat a kidney-associated disorder. In some embodiments, the transgene comprises a gene selected from the group consisting of Aquaporin 2 (AQP2); ATPase Na+ / K+ Transporting Subunit Alpha 1 (ATP1A1); ATPase H+ Transporting V0 Subunit A4 (ATP6V0A4); ATPase H+ Transporting V1 Subunit B1 (ATP6V1B1); Arginine Vasopressin Receptor 2 (AVPR2); Barttin CLCNK (chloride channel K) Type Accessory Subunit Beta (BSND); Carbonic Anhydrase 2 (CA2); Calcium Sensing Receptor (CaSR); Chloride Voltage-Gated Channel 5 (CLCN5); CLCNKA (Chloride Voltage-Gated Channel Ka); Chloride Voltage-Gated Channel Kb (CLCNKB); Claudin 16 (CLDN16); Claudin 19 (CLDN19); Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2 (CNNM2); Cullin 3 (CUL3); Cytochrome P450 Family 11 Subfamily B Member 1 (CYP1 IB 1); Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2); Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1); Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2); Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase874903-3015-35943Attorney Docket No: 046192-000134WOPT(EHHADH); FAM111 (family 111) Trypsin Like Peptidase A (FAM111A); Forkhead Box II (FOXI1); FXYD Domain / Motif Containing Ion Transport Regulator 2 (FXYD2); Glycine Amidinotransferase (GATM); guanine nucleotide binding protein, alpha stimulating (GNAS); hepatocyte nuclear factor 1 (HNF1) Homeobox B (HNF1B); Hepatocyte Nuclear Factor 4 Alpha (HNF4A); Hydroxysteroid 11 -Beta Dehydrogenase 2 (HSD11B2); Hydroxy-Delta-5 -Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2); Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1); Potassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1); Potassium Inwardly Rectifying Channel Subfamily J Member 10 (KCNJ10); Kelch Like Family Member 3 (KLHL3); Melanoma Antigen Gene Family Member D2 (MAGED2); Nuclear Receptor Subfamily 3 Group C Member 2 (NR3C2); Oculocerebrorenal Syndrome Of Lowe (OCRL) Inositol Polyphosphate-5-Phosphatase; Pterin-4 Alpha-Carbinolamine Dehydratase 1 (PCBD1); Phosphate Regulating Endopeptidase X-Linked (PHEX); Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A); Sodium Channel Epithelial 1 Subunit Beta (SCNN1B); Sodium Channel Epithelial 1 Subunit Gamma (SCNN1G); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Solute Carrier Family 1 Member 1 (SLC1A1); Solute Carrier Family 2 Member 2 (SLC2A2); Solute Carrier Family 34 Member 1 (SLC34A1); Solute Carrier Family 34 Member 3 (SLC34A3); Solute Carrier Family 36 Member 2 (SLC36A2); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 4 Member 1 (SLC4A1); Solute Carrier Family 6 Member 19 (SLC6A19); Solute Carrier Family 6 Member 20 (SLC6A20); Solute Carrier Family 7 Member 7 (SLC7A7); Solute Carrier Family 7 Member 9 (SLC7A9); Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6); WD Repeat Domain 72 (WDR72); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 1 (WNK1); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 4 (WNK4); and any combination thereof.

[0297] In some embodiments, the transgene comprises a gene encoding a polypeptide that when expressed (e.g., at about a physiological level) in the subject is effective to treat a kidney-associated disorder. In some embodiments, the transgene comprises a gene encoding for a polypeptide selected from the group consisting of ll-[3-HSD2, 1 l-[3-hydroxylase, 17-a-hydroxylase, 21 -hydroxylase, 3-[3-HSD2, AE1, Aldosterone synthase (ALDOS), AQP-2, ATP1A1, AVPR2, B(O)AT1, b(0, +)ATI, Barttin, Calcium-sensing receptor, Carbonic anhydrase 2, Claudinl6, Claudinl9, CLC-5, CLC-Ka+CLC-Kb, CLC-Kb, CNNM2, CUL3, EAAT3, EGF, EGFR, ENaC a subunit, EnaC [3 subunit, EnaC y subunit, FAM111A, Forkhead box protein II, GLUT-2, G-a s, HNF1B, HNF-4, Kir4.1, KLHL3, Kvl.l, L-ARGININE: GLYCINE AMIDINOTRANSFERASE, MAGED2, MR, Na-K-ATPase, NaPi2A, NaPi2c, NCCT, NKCC2, OCRL, PBFE, PCDB1, PHEX, rBAT, ROMK, SLC36A2+SLC6A20 / SLC6A19, TRPM6, V2R, V-ATPase subunit a4, V-ATPase subunit Bl, WD repeat-containing protein 72, WNK1, WNK4, y(+)LATl, and any combination thereof.884903-3015-35943Attorney Docket No: 046192-000134WOPT

[0298] In some embodiments, the kidney-associated disorder is Cystinuria (e.g., Cystinuria A, Cystinuria B). Cystinuria is an inherited autosomal recessive disease characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureters, and bladder. Cystinuria is a type of aminoaciduria. Cystine is a dimer of cysteines. Symptoms of polycystic kidney disease include, but are not limited to crystalluria (crystals in urine); aminoaciduria (urine containing abnormally high levels of amino acids, e.g., cystine); pain in the side or back (e.g., often on one side); pain while urinating; blood in the urine; sharp pain in the side or back; pain near the groin, pelvis, or abdomen; nausea and vomiting; flank pain; loin pain; recurrent abdominal pain; recurrent urinary tract infections; and / or fever.

[0299] In some embodiments, the transgene is SLC3A1 and / or SLC7A9. SLC3A1 and SLC7A9 are subunits of an amino acid transporter (the b0,+ transporter system) that functions to resorb cystine from the urine in the kidney tubules. In some embodiments, the kidney-associated disorder is Cystinuria A, and the transgene is SLC3A1. In some embodiments, the kidney-associated disorder is Cystinuria B, and the transgene is SLC7A9.

[0300] In some embodiments, the transgene comprises SEQ ID NO: 5, SEQ ID NO: 6, or a nucleic acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO: 5, SEQ ID NO: 6, which maintains the same function when expressed as a protein (e.g., cystine transport), or a functional fragment thereof, or a codon-optimized version of the nucleic acid.

[0301] SEQ ID NO: 5, Solute Carrier Family 3 Member 1 (SLC3A1), also known as: ATR1, CSNU1, D2H, NBAT, RBAT; positions 57-2114 ofNCBI ref NM_000341.4, CCDS1819.1, human, 2058 nucleotides (nt) ATGGCTGAAGATAAAAGCAAGAGAGACTCCATCGAGATGAGTATGAAGGGATGCCAGA CAAACAACGGGTTTGTCCATAATGAAGACATTCTGGAGCAGACCCCGGATCCAGGAAGC TCAACAGACAACCTGAAGCACAGCACCAGGGGCATCCTTGGCTCCCAGGAGCCCGACTT CAAGGGCGTCCAGCCCTATGCGGGGATGCCCAAGGAGGTGCTGTTCCAGTTCTCTGGCCA GGCCCGCTACCGCATACCTCGGGAGATCCTCTTCTGGCTCACAGTGGCTTCTGTGCTGGT GCTCATCGCGGCCACCATAGCCATCATTGCCCTCTCTCCAAAGTGCCTAGACTGGTGGCA GGAGGGGCCCATGTACCAGATCTACCCAAGGTCTTTCAAGGACAGTAACAAGGATGGGA ACGGAGATCTGAAAGGTATTCAAGATAAACTGGACTACATCACAGCTTTAAATATAAAA ACTGTTTGGATTACTTCATTTTATAAATCGTCCCTTAAAGATTTCAGATATGGTGTTGAAG ATTTCCGGGAAGTTGATCCCATTTTTGGAACGATGGAAGATTTTGAGAATCTGGTTGCAG CCATACATGATAAAGGTTTAAAATTAATCATCGATTTCATACCAAACCACACGAGTGATA AACATATTTGGTTTCAATTGAGTCGGACACGGACAGGAAAATATACTGATTATTATATCT GGCATGACTGTACCCATGAAAATGGCAAAACCATTCCACCCAACAACTGGTTAAGTGTG894903-3015-35943Attorney Docket No: 046192-000134WOPTTATGGAAACTCCAGTTGGCACTTTGACGAAGTGCGAAACCAATGTTATTTTCATCAGTTT ATGAAAGAGCAACCTGATTTAAATTTCCGCAATCCTGATGTTCAAGAAGAAATAAAAGA AATTTTACGGTTCTGGCTCACAAAGGGTGTTGATGGTTTTAGTTTGGATGCTGTTAAATTC CTCCTAGAAGCAAAGCACCTGAGAGATGAGATCCAAGTAAATAAGACCCAAATCCCGGA CACGGTCACACAATACTCGGAGCTGTACCATGACTTCACCACCACGCAGGTGGGAATGC ACGACATTGTCCGCAGCTTCCGGCAGACCATGGACCAATACAGCACGGAGCCCGGCAGA TACAGGTTCATGGGGACTGAAGCCTATGCAGAGAGTATTGACAGGACCGTGATGTACTA TGGATTGCCATTTATCCAAGAAGCTGATTTTCCCTTCAACAATTACCTCAGCATGCTAGA CACTGTTTCTGGGAACAGCGTGTATGAGGTTATCACATCCTGGATGGAAAACATGCCAGA AGGAAAATGGCCTAACTGGATGATTGGTGGACCAGACAGTTCACGGCTGACTTCGCGTTT GGGGAATCAGTATGTCAACGTGATGAACATGCTTCTTTTCACACTCCCTGGAACTCCTAT AACTTACTATGGAGAAGAAATTGGAATGGGAAATATTGTAGCCGCAAATCTCAATGAAA GCTATGATATTAATACCCTTCGCTCAAAGTCACCAATGCAGTGGGACAATAGTTCAAATG CTGGTTTTTCTGAAGCTAGTAACACCTGGTTACCTACCAATTCAGATTACCACACTGTGA ATGTTGATGTCCAAAAGACTCAGCCCAGATCGGCTTTGAAGTTATATCAAGATTTAAGTC TACTTCATGCCAATGAGCTACTCCTCAACAGGGGCTGGTTTTGCCATTTGAGGAATGACA GCCACTATGTTGTGTACACAAGAGAGCTGGATGGCATCGACAGAATCTTTATCGTGGTTC TGAATTTTGGAGAATCAACACTGTTAAATCTACATAATATGATTTCGGGCCTTCCCGCTA AAATGAGAATAAGGTTAAGTACCAATTCTGCCGACAAAGGCAGTAAAGTTGATACAAGT GGCATTTTTCTGGACAAGGGAGAGGGACTCATCTTTGAACACAACACGAAGAATCTCCTT CATCGCCAAACAGCTTTCAGAGATAGATGCTTTGTTTCCAATCGAGCATGCTATTCCAGT GTACTGAACATACTGTATACCTCGTGTTAG

[0302] SEQ ID NO: 6, Solute Carrier Family 7 Member 9 (SLC7A9), also known as B(0,+)-type amino acid transporter 1, BAT1, or CSNU3; positions 108-1571 of NCBI ref NM_001126335.2, CCDS12425.1, human, 1464 nt ATGGGGGATACTGGCCTGAGAAAGCGGAGAGAGGATGAGAAGTCGATCCAGAGCCAAG AGCCTAAGACCACCAGTCTCCAAAAGGAGCTGGGCCTCATCAGTGGCATCTCCATCATCG TGGGCACCATCATTGGCTCTGGGATCTTCGTTTCCCCCAAGTCTGTGCTCAGCAACACGG AAGCTGTGGGGCCCTGCCTCATCATATGGGCGGCTTGCGGGGTCCTCGCGACGCTGGGTG CCCTGTGCTTTGCGGAGCTTGGCACAATGATCACCAAGTCAGGGGGAGAGTATCCCTACC TGATGGAGGCCTACGGGCCCATCCCCGCCTACCTCTTCTCCTGGGCCAGCCTGATCGTCA TTAAGCCCACGTCCTTCGCCATCATCTGCCTCAGCTTCTCCGAGTATGTGTGTGCGCCCTT CTATGTGGGCTGCAAGCCTCCTCAAATCGTTGTGAAATGCCTGGCCGCCGCCGCCATCTT GTTCATCTCGACAGTGAACTCACTGAGCGTGCGGCTGGGAAGCTACGTCCAGAACATCTT CACCGCGGCCAAGCTGGTGATCGTGGCCATCATCATCATCAGCGGGCTGGTGCTCCTGGC CCAAGGAAACACAAAGAATTTTGATAATTCTTTCGAGGGCGCCCAGCTGTCTGTGGGAG904903-3015-35943Attorney Docket No: 046192-000134WOPTCCATCAGCCTGGCGTTTTACAATGGACTCTGGGCCTATGATGGATGGAATCAACTCAATT ACATCACAGAAGAACTTAGAAACCCTTACAGAAACCTGCCTTTGGCCATTATCATCGGGA TCCCCCTGGTGACGGCGTGCTACATCCTCATGAACGTGTCCTACTTCACCGTGATGACTG CCACCGAACTCCTGCAGTCCCAGGCGGTGGCTGTGACATTTGGTGACCGTGTTCTCTATC CTGCTTCTTGGATCGTTCCACTTTTTGTGGCATTTTCAACCATCGGTGCTGCTAACGGGAC CTGCTTCACAGCGGGCAGACTCATTTACGTGGCGGGCCGGGAGGGTCACATGCTCAAAG TGCTTTCTTACATCAGCGTCAGGCGCCTCACTCCAGCCCCCGCCATCATCTTTTATGGTAT CATAGCAACGATTTATATCATCCCTGGTGACATAAACTCGTTAGTCAATTATTTCAGCTTT GCCGCATGGCTGTTTTATGGCCTGACGATTCTAGGACTCATCGTGATGAGATTTACAAGG AAAGAGCTGGAAAGGCCTATCAAGGTGCCCGTAGTCATTCCCGTCTTGATGACACTCATC TCTGTGTTTTTGGTTCTGGCTCCAATCATCAGCAAGCCCACCTGGGAGTACCTCTACTGTG TGCTGTTTATATTAAGCGGCCTTTTATTTTACTTCCTGTTTGTCCACTACAAGTTTGGATG GGCTCAGAAAATCTCAAAGCCGATTACCATGCACCTTCAGATGCTAATGGAAGTGGTCCC ACCGGAGGAAGACCCTGAGTAA

[0303] In some embodiments, the transgene encodes for a polypeptide comprising SEQ ID NO: 7, SEQ ID NO: 8, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of SEQ ID NO: 7, SEQ ID NO: 8, which maintains the same function (e.g., cystine transport), or a functional fragment thereof.

[0304] SEQ ID NO: 7, Solute Carrier Family 3 Member 1 (SLC3A1), NCBI ref NP_000332.2, human, 685 amino acids (aa) MAEDKSKRDSIEMSMKGCQTNNGFVHNEDILEQTPDPGSSTDNLKHSTRGILGSQEPDFKGV QPYAGMPKEVLFQFSGQARYRIPREILFWLTVASVLVLIAATIAIIALSPKCLDWWQEGPMYQ IYPRSFKDSNKDGNGDLKGIQDKLDYITALNIKTVWITSFYKSSLKDFRYGVEDFREVDPIFGT MEDFENLVAAIHDKGLKLIIDFIPNHTSDKHIWFQLSRTRTGKYTDYYIWHDCTHENGKTIPP NNWLSVYGNSSWHFDEVRNQCYFHQFMKEQPDLNFRNPDVQEEIKEILRFWLTKGVDGFSL DAVKFLLEAKHLRDEIQVNKTQIPDTVTQYSELYHDFTTTQVGMHDIVRSFRQTMDQYSTEP GRYRFMGTEAYAESIDRTVMYYGLPFIQEADFPFNNYLSMLDTVSGNSVYEVITSWMENMP EGKWPNWMIGGPDSSRLTSRLGNQYVNVMNMLLFTLPGTPITYYGEEIGMGNIVAANLNES YDINTLRSKSPMQWDNSSNAGFSEASNTWLPTNSDYHTVNVDVQKTQPRSALKLYQDLSLL HANELLLNRGWFCHLRNDSHYVVYTRELDGIDRIFIVVLNFGESTLLNLHNMISGLPAKMRIR LSTNSADKGSKVDTSGIFLDKGEGLIFEHNTKNLLHRQTAFRDRCFVSNRACYSSVLNILYTSC

[0305] SEQ ID NO: 8, Solute Carrier Family 7 Member 9 (SLC7A9), NCBI refNP_001119807.1, human, 487 aa914903-3015-35943Attorney Docket No: 046192-000134WOPTMGDTGLRKRREDEKSIQSQEPKTTSLQKELGLISGISIIVGTIIGSGIFVSPKSVLSNTEAVGPCLI IWAACGVLATLGALCFAELGTMITKSGGEYPYLMEAYGPIPAYLFSWASLIVIKPTSFAIICLSF SEYVCAPFYVGCKPPQIVVKCLAAAAILFISTVNSLSVRLGSYVQNIFTAAKLVIVAIIIISGLVL LAQGNTKNFDNSFEGAQLSVGAISLAFYNGLWAYDGWNQLNYITEELRNPYRNLPLAIIIGIP LVTACYILMNVSYFTVMTATELLQSQAVAVTFGDRVLYPASWIVPLFVAFSTIGAANGTCFT AGRLIYVAGREGHMLKVLSYISVRRLTPAPAIIFYGIIATIYIIPGDINSLVNYFSFAAWLFYGLT ILGLIVMRFTRKELERPIKVPVVIPVLMTLISVFLVLAPIISKPTWEYLYCVLFILSGLLFYFLFV HYKFGWAQKISKPITMHLQMLMEVVPPEEDPE

[0306] In some embodiments, the kidney-associated disorder is autosomal dominant polycystic kidney disease (ADPKD). ADPKD is an inherited condition that causes small fluid-filled sacs called cysts displacing normal renal tubules in the kidneys. Cysts can develop from any nephron segment, but the cysts most often form in the distal nephron (e.g., distal convoluted tubules) and the collecting duct (CD). Symptoms of polycystic kidney disease include, but are not limited to abdominal pain or tenderness, blood in the urine, excessive urination at night, flank pain on one or both sides, drowsiness, joint pain, nail abnormalities, high blood pressure, back or side pain, a feeling of fullness in the abdomen, enlarged liver, heart murmurs, and / or growths in the kidneys or abdomen. In some embodiments, the transgene is PKD1, PKD2, and / or GANAB. The PKD1 and PKD2 genes encode the proteins polycystin- 1 and polycystin-2, respectively. These two proteins interact to regulate cells in the kidneys and liver, are a part of the process to form tubular structures, and influence growth and fluid secretion function. Mutations of the PKD1 or PKD2 gene creates cells with abnormal functions and ultimately result in the cyst growth that is common in ADPKD. GANAB encodes the alpha subunit of glucosidase II and a member of the glycosyl hydrolase 31 family of proteins. The heterodimeric enzyme glucosidase II plays a role in protein folding and quality control by cleaving glucose residues from immature glycoproteins in the endoplasmic reticulum. Mutations in the GANAB gene can cause autosomal-dominant polycystic kidney and liver disease.

[0307] In some embodiments, the transgene comprises one of SEQ ID NOs: 9-10, or a nucleic acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of one of SEQ ID NOs: 9-10, which maintains the same function when expressed as a protein (e.g., regulate kidney cells, influence formation of kidney tubular structures, and influence kidney fluid secretion function), or a functional fragment thereof, or a codon-optimized version of the nucleic acid.

[0308] SEQ ID NO: 9, polycystin-1 (PKD1), also known as: PBP, PCI, Pc-1, TRPP1; positions 210-13118 of NCBI ref NM_000296.4, CCDS45385.1, human, 12,909 nt ATGCCGCCCGCCGCGCCCGCCCGCCTGGCGCTGGCCCTGGGCCTGGGCCTGTGGCTCGGG GCGCTGGCGGGGGGCCCCGGGCGCGGCTGCGGGCCCTGCGAGCCCCCCTGCCTCTGCGG924903-3015-35943Attorney Docket No: 046192-000134WOPTCCCAGCGCCCGGCGCCGCCTGCCGCGTCAACTGCTCGGGCCGCGGGCTGCGGACGCTCG GTCCCGCGCTGCGCATCCCCGCGGACGCCACAGCGCTAGACGTCTCCCACAACCTGCTCC GGGCGCTGGACGTTGGGCTCCTGGCGAACCTCTCGGCGCTGGCAGAGCTGGATATAAGC AACAACAAGATTTCTACGTTAGAAGAAGGAATATTTGCTAATTTATTTAATTTAAGTGAA ATAAACCTGAGTGGGAACCCGTTTGAGTGTGACTGTGGCCTGGCGTGGCTGCCGCGATG GGCGGAGGAGCAGCAGGTGCGGGTGGTGCAGCCCGAGGCAGCCACGTGTGCTGGGCCTG GCTCCCTGGCTGGCCAGCCTCTGCTTGGCATCCCCTTGCTGGACAGTGGCTGTGGTGAGG AGTATGTCGCCTGCCTCCCTGACAACAGCTCAGGCACCGTGGCAGCAGTGTCCTTTTCAG CTGCCCACGAAGGCCTGCTTCAGCCAGAGGCCTGCAGCGCCTTCTGCTTCTCCACCGGCC AGGGCCTCGCAGCCCTCTCGGAGCAGGGCTGGTGCCTGTGTGGGGCGGCCCAGCCCTCC AGTGCCTCCTTTGCCTGCCTGTCCCTCTGCTCCGGCCCCCCGCCACCTCCTGCCCCCACCT GTAGGGGCCCCACCCTCCTCCAGCACGTCTTCCCTGCCTCCCCAGGGGCCACCCTGGTGG GGCCCCACGGACCTCTGGCCTCTGGCCAGCTAGCAGCCTTCCACATCGCTGCCCCGCTCC CTGTCACTGCCACACGCTGGGACTTCGGAGACGGCTCCGCCGAGGTGGATGCCGCTGGG CCGGCTGCCTCGCATCGCTATGTGCTGCCTGGGCGCTATCACGTGACGGCCGTGCTGGCC CTGGGGGCCGGCTCAGCCCTGCTGGGGACAGACGTGCAGGTGGAAGCGGCACCTGCCGC CCTGGAGCTCGTGTGCCCGTCCTCGGTGCAGAGTGACGAGAGCCTCGACCTCAGCATCCA GAACCGCGGTGGTTCAGGCCTGGAGGCCGCCTACAGCATCGTGGCCCTGGGCGAGGAGC CGGCCCGAGCGGTGCACCCGCTCTGCCCCTCGGACACGGAGATCTTCCCTGGCAACGGG CACTGCTACCGCCTGGTGGTGGAGAAGGCGGCCTGGCTGCAGGCGCAGGAGCAGTGTCA GGCCTGGGCCGGGGCCGCCCTGGCAATGGTGGACAGTCCCGCCGTGCAGCGCTTCCTGG TCTCCCGGGTCACCAGGAGCCTAGACGTGTGGATCGGCTTCTCGACTGTGCAGGGGGTGG AGGTGGGCCCAGCGCCGCAGGGCGAGGCCTTCAGCCTGGAGAGCTGCCAGAACTGGCTG CCCGGGGAGCCACACCCAGCCACAGCCGAGCACTGCGTCCGGCTCGGGCCCACCGGGTG GTGTAACACCGACCTGTGCTCAGCGCCGCACAGCTACGTCTGCGAGCTGCAGCCCGGAG GCCCAGTGCAGGATGCCGAGAACCTCCTCGTGGGAGCGCCCAGTGGGGACCTGCAGGGA CCCCTGACGCCTCTGGCACAGCAGGACGGCCTCTCAGCCCCGCACGAGCCCGTGGAGGT CATGGTATTCCCGGGCCTGCGTCTGAGCCGTGAAGCCTTCCTCACCACGGCCGAATTTGG GACCCAGGAGCTCCGGCGGCCCGCCCAGCTGCGGCTGCAGGTGTACCGGCTCCTCAGCA CAGCAGGGACCCCGGAGAACGGCAGCGAGCCTGAGAGCAGGTCCCCGGACAACAGGAC CCAGCTGGCCCCCGCGTGCATGCCAGGGGGACGCTGGTGCCCTGGAGCCAACATCTGCTT GCCGCTGGACGCCTCCTGCCACCCCCAGGCCTGCGCCAATGGCTGCACGTCAGGGCCAG GGCTACCCGGGGCCCCCTATGCGCTATGGAGAGAGTTCCTCTTCTCCGTTCCCGCGGGGC CCCCCGCGCAGTACTCGGTCACCCTCCACGGCCAGGATGTCCTCATGCTCCCTGGTGACC TCGTTGGCTTGCAGCACGACGCTGGCCCTGGCGCCCTCCTGCACTGCTCGCCGGCTCCCG GCCACCCTGGTCCCCGGGCCCCGTACCTCTCCGCCAACGCCTCGTCATGGCTGCCCCACT934903-3015-35943Attorney Docket No: 046192-000134WOPTTGCCAGCCCAGCTGGAGGGCACTTGGGCCTGCCCTGCCTGTGCCCTGCGGCTGCTTGCAG CCACGGAACAGCTCACCGTGCTGCTGGGCTTGAGGCCCAACCCTGGACTGCGGCTGCCTG GGCGCTATGAGGTCCGGGCAGAGGTGGGCAATGGCGTGTCCAGGCACAACCTCTCCTGC AGCTTTGACGTGGTCTCCCCAGTGGCTGGGCTGCGGGTCATCTACCCTGCCCCCCGCGAC GGCCGCCTCTACGTGCCCACCAACGGCTCAGCCTTGGTGCTCCAGGTGGACTCTGGTGCC AACGCCACGGCCACGGCTCGCTGGCCTGGGGGCAGTGTCAGCGCCCGCTTTGAGAATGT CTGCCCTGCCCTGGTGGCCACCTTCGTGCCCGGCTGCCCCTGGGAGACCAACGATACCCT GTTCTCAGTGGTAGCACTGCCGTGGCTCAGTGAGGGGGAGCACGTGGTGGACGTGGTGG TGGAAAACAGCGCCAGCCGGGCCAACCTCAGCCTGCGGGTGACGGCGGAGGAGCCCATC TGTGGCCTCCGCGCCACGCCCAGCCCCGAGGCCCGTGTACTGCAGGGAGTCCTAGTGAG GTACAGCCCCGTGGTGGAGGCCGGCTCGGACATGGTCTTCCGGTGGACCATCAACGACA AGCAGTCCCTGACCTTCCAGAACGTGGTCTTCAATGTCATTTATCAGAGCGCGGCGGTCT TCAAGCTCTCACTGACGGCCTCCAACCACGTGAGCAACGTCACCGTGAACTACAACGTA ACCGTGGAGCGGATGAACAGGATGCAGGGTCTGCAGGTCTCCACAGTGCCGGCCGTGCT GTCCCCCAATGCCACGCTAGCACTGACGGCGGGCGTGCTGGTGGACTCGGCCGTGGAGG TGGCCTTCCTGTGGACCTTTGGGGATGGGGAGCAGGCCCTCCACCAGTTCCAGCCTCCGT ACAACGAGTCCTTCCCGGTTCCAGACCCCTCGGTGGCCCAGGTGCTGGTGGAGCACAATG TCATGCACACCTACGCTGCCCCAGGTGAGTACCTCCTGACCGTGCTGGCATCTAATGCCT TCGAGAACCTGACGCAGCAGGTGCCTGTGAGCGTGCGCGCCTCCCTGCCCTCCGTGGCTG TGGGTGTGAGTGACGGCGTCCTGGTGGCCGGCCGGCCCGTCACCTTCTACCCGCACCCGC TGCCCTCGCCTGGGGGTGTTCTTTACACGTGGGACTTCGGGGACGGCTCCCCTGTCCTGA CCCAGAGCCAGCCGGCTGCCAACCACACCTATGCCTCGAGGGGCACCTACCACGTGCGC CTGGAGGTCAACAACACGGTGAGCGGTGCGGCGGCCCAGGCGGATGTGCGCGTCTTTGA GGAGCTCCGCGGACTCAGCGTGGACATGAGCCTGGCCGTGGAGCAGGGCGCCCCCGTGG TGGTCAGCGCCGCGGTGCAGACGGGCGACAACATCACGTGGACCTTCGACATGGGGGAC GGCACCGTGCTGTCGGGCCCGGAGGCAACAGTGGAGCATGTGTACCTGCGGGCACAGAA CTGCACAGTGACCGTGGGTGCGGCCAGCCCCGCCGGCCACCTGGCCCGGAGCCTGCACG TGCTGGTCTTCGTCCTGGAGGTGCTGCGCGTTGAACCCGCCGCCTGCATCCCCACGCAGC CTGACGCGCGGCTCACGGCCTACGTCACCGGGAACCCGGCCCACTACCTCTTCGACTGGA CCTTCGGGGATGGCTCCTCCAACACGACCGTGCGGGGGTGCCCGACGGTGACACACAAC TTCACGCGGAGCGGCACGTTCCCCCTGGCGCTGGTGCTGTCCAGCCGCGTGAACAGGGC GCATTACTTCACCAGCATCTGCGTGGAGCCAGAGGTGGGCAACGTCACCCTGCAGCCAG AGAGGCAGTTTGTGCAGCTCGGGGACGAGGCCTGGCTGGTGGCATGTGCCTGGCCCCCG TTCCCCTACCGCTACACCTGGGACTTTGGCACCGAGGAAGCCGCCCCCACCCGTGCCAGG GGCCCTGAGGTGACGTTCATCTACCGAGACCCAGGCTCCTATCTTGTGACAGTCACCGCG TCCAACAACATCTCTGCTGCCAATGACTCAGCCCTGGTGGAGGTGCAGGAGCCCGTGCTG944903-3015-35943Attorney Docket No: 046192-000134WOPTGTCACCAGCATCAAGGTCAATGGCTCCCTTGGGCTGGAGCTGCAGCAGCCGTACCTGTTC TCTGCTGTGGGCCGTGGGCGCCCCGCCAGCTACCTGTGGGATCTGGGGGACGGTGGGTG GCTCGAGGGTCCGGAGGTCACCCACGCTTACAACAGCACAGGTGACTTCACCGTTAGGG TGGCCGGCTGGAATGAGGTGAGCCGCAGCGAGGCCTGGCTCAATGTGACGGTGAAGCGG CGCGTGCGGGGGCTCGTCGTCAATGCAAGCCGCACGGTGGTGCCCCTGAATGGGAGCGT GAGCTTCAGCACGTCGCTGGAGGCCGGCAGTGATGTGCGCTATTCCTGGGTGCTCTGTGA CCGCTGCACGCCCATCCCTGGGGGTCCTACCATCTCTTACACCTTCCGCTCCGTGGGCAC CTTCAATATCATCGTCACGGCTGAGAACGAGGTGGGCTCCGCCCAGGACAGCATCTTCGT CTATGTCCTGCAGCTCATAGAGGGGCTGCAGGTGGTGGGCGGTGGCCGCTACTTCCCCAC CAACCACACGGTACAGCTGCAGGCCGTGGTTAGGGATGGCACCAACGTCTCCTACAGCT GGACTGCCTGGAGGGACAGGGGCCCGGCCCTGGCCGGCAGCGGCAAAGGCTTCTCGCTC ACCGTGCTCGAGGCCGGCACCTACCATGTGCAGCTGCGGGCCACCAACATGCTGGGCAG CGCCTGGGCCGACTGCACCATGGACTTCGTGGAGCCTGTGGGGTGGCTGATGGTGGCCG CCTCCCCGAACCCAGCTGCCGTCAACACAAGCGTCACCCTCAGTGCCGAGCTGGCTGGTG GCAGTGGTGTCGTATACACTTGGTCCTTGGAGGAGGGGCTGAGCTGGGAGACCTCCGAG CCATTTACCACCCATAGCTTCCCCACACCCGGCCTGCACTTGGTCACCATGACGGCAGGG AACCCGCTGGGCTCAGCCAACGCCACCGTGGAAGTGGATGTGCAGGTGCCTGTGAGTGG CCTCAGCATCAGGGCCAGCGAGCCCGGAGGCAGCTTCGTGGCGGCCGGGTCCTCTGTGC CCTTTTGGGGGCAGCTGGCCACGGGCACCAATGTGAGCTGGTGCTGGGCTGTGCCCGGC GGCAGCAGCAAGCGTGGCCCTCATGTCACCATGGTCTTCCCGGATGCTGGCACCTTCTCC ATCCGGCTCAATGCCTCCAACGCAGTCAGCTGGGTCTCAGCCACGTACAACCTCACGGCG GAGGAGCCCATCGTGGGCCTGGTGCTGTGGGCCAGCAGCAAGGTGGTGGCGCCCGGGCA GCTGGTCCATTTTCAGATCCTGCTGGCTGCCGGCTCAGCTGTCACCTTCCGCCTGCAGGTC GGCGGGGCCAACCCCGAGGTGCTCCCCGGGCCCCGTTTCTCCCACAGCTTCCCCCGCGTC GGAGACCACGTGGTGAGCGTGCGGGGCAAAAACCACGTGAGCTGGGCCCAGGCGCAGG TGCGCATCGTGGTGCTGGAGGCCGTGAGTGGGCTGCAGGTGCCCAACTGCTGCGAGCCT GGCATCGCCACGGGCACTGAGAGGAACTTCACAGCCCGCGTGCAGCGCGGCTCTCGGGT CGCCTACGCCTGGTACTTCTCGCTGCAGAAGGTCCAGGGCGACTCGCTGGTCATCCTGTC GGGCCGCGACGTCACCTACACGCCCGTGGCCGCGGGGCTGTTGGAGATCCAGGTGCGCG CCTTCAACGCCCTGGGCAGTGAGAACCGCACGCTGGTGCTGGAGGTTCAGGACGCCGTC CAGTATGTGGCCCTGCAGAGCGGCCCCTGCTTCACCAACCGCTCGGCGCAGTTTGAGGCC GCCACCAGCCCCAGCCCCCGGCGTGTGGCCTACCACTGGGACTTTGGGGATGGGTCGCC AGGGCAGGACACAGATGAGCCCAGGGCCGAGCACTCCTACCTGAGGCCTGGGGACTACC GCGTGCAGGTGAACGCCTCCAACCTGGTGAGCTTCTTCGTGGCGCAGGCCACGGTGACC GTCCAGGTGCTGGCCTGCCGGGAGCCGGAGGTGGACGTGGTCCTGCCCCTGCAGGTGCT GATGCGGCGATCACAGCGCAACTACTTGGAGGCCCACGTTGACCTGCGCGACTGCGTCA954903-3015-35943Attorney Docket No: 046192-000134WOPTCCTACCAGACTGAGTACCGCTGGGAGGTGTATCGCACCGCCAGCTGCCAGCGGCCGGGG CGCCCAGCGCGTGTGGCCCTGCCCGGCGTGGACGTGAGCCGGCCTCGGCTGGTGCTGCC GCGGCTGGCGCTGCCTGTGGGGCACTACTGCTTTGTGTTTGTCGTGTCATTTGGGGACAC GCCACTGACACAGAGCATCCAGGCCAATGTGACGGTGGCCCCCGAGCGCCTGGTGCCCA TCATTGAGGGTGGCTCATACCGCGTGTGGTCAGACACACGGGACCTGGTGCTGGATGGG AGCGAGTCCTACGACCCCAACCTGGAGGACGGCGACCAGACGCCGCTCAGTTTCCACTG GGCCTGTGTGGCTTCGACACAGAGGGAGGCTGGCGGGTGTGCGCTGAACTTTGGGCCCC GCGGGAGCAGCACGGTCACCATTCCACGGGAGCGGCTGGCGGCTGGCGTGGAGTACACC TTCAGCCTGACCGTGTGGAAGGCCGGCCGCAAGGAGGAGGCCACCAACCAGACGGTGCT GATCCGGAGTGGCCGGGTGCCCATTGTGTCCTTGGAGTGTGTGTCCTGCAAGGCACAGGC CGTGTACGAAGTGAGCCGCAGCTCCTACGTGTACTTGGAGGGCCGCTGCCTCAATTGCAG CAGCGGCTCCAAGCGAGGGCGGTGGGCTGCACGTACGTTCAGCAACAAGACGCTGGTGC TGGATGAGACCACCACATCCACGGGCAGTGCAGGCATGCGACTGGTGCTGCGGCGGGGC GTGCTGCGGGACGGCGAGGGATACACCTTCACGCTCACGGTGCTGGGCCGCTCTGGCGA GGAGGAGGGCTGCGCCTCCATCCGCCTGTCCCCCAACCGCCCGCCGCTGGGGGGCTCTTG CCGCCTCTTCCCACTGGGCGCTGTGCACGCCCTCACCACCAAGGTGCACTTCGAATGCAC GGGCTGGCATGACGCGGAGGATGCTGGCGCCCCGCTGGTGTACGCCCTGCTGCTGCGGC GCTGTCGCCAGGGCCACTGCGAGGAGTTCTGTGTCTACAAGGGCAGCCTCTCCAGCTACG GAGCCGTGCTGCCCCCGGGTTTCAGGCCACACTTCGAGGTGGGCCTGGCCGTGGTGGTGC AGGACCAGCTGGGAGCCGCTGTGGTCGCCCTCAACAGGTCTTTGGCCATCACCCTCCCAG AGCCCAACGGCAGCGCAACGGGGCTCACAGTCTGGCTGCACGGGCTCACCGCTAGTGTG CTCCCAGGGCTGCTGCGGCAGGCCGATCCCCAGCACGTCATCGAGTACTCGTTGGCCCTG GTCACCGTGCTGAACGAGTACGAGCGGGCCCTGGACGTGGCGGCAGAGCCCAAGCACGA GCGGCAGCACCGAGCCCAGATACGCAAGAACATCACGGAGACTCTGGTGTCCCTGAGGG TCCACACTGTGGATGACATCCAGCAGATCGCTGCTGCGCTGGCCCAGTGCATGGGGCCCA GCAGGGAGCTCGTATGCCGCTCGTGCCTGAAGCAGACGCTGCACAAGCTGGAGGCCATG ATGCTCATCCTGCAGGCAGAGACCACCGCGGGCACCGTGACGCCCACCGCCATCGGAGA CAGCATCCTCAACATCACAGGAGACCTCATCCACCTGGCCAGCTCGGACGTGCGGGCAC CACAGCCCTCAGAGCTGGGAGCCGAGTCACCATCTCGGATGGTGGCGTCCCAGGCCTAC AACCTGACCTCTGCCCTCATGCGCATCCTCATGCGCTCCCGCGTGCTCAACGAGGAGCCC CTGACGCTGGCGGGCGAGGAGATCGTGGCCCAGGGCAAGCGCTCGGACCCGCGGAGCCT GCTGTGCTATGGCGGCGCCCCAGGGCCTGGCTGCCACTTCTCCATCCCCGAGGCTTTCAG CGGGGCCCTGGCCAACCTCAGTGACGTGGTGCAGCTCATCTTTCTGGTGGACTCCAATCC CTTTCCCTTTGGCTATATCAGCAACTACACCGTCTCCACCAAGGTGGCCTCGATGGCATTC CAGACACAGGCCGGCGCCCAGATCCCCATCGAGCGGCTGGCCTCAGAGCGCGCCATCAC CGTGAAGGTGCCCAACAACTCGGACTGGGCTGCCCGGGGCCACCGCAGCTCCGCCAACT964903-3015-35943Attorney Docket No: 046192-000134WOPTCCGCCAACTCCGTTGTGGTCCAGCCCCAGGCCTCCGTCGGTGCTGTGGTCACCCTGGACA GCAGCAACCCTGCGGCCGGGCTGCATCTGCAGCTCAACTATACGCTGCTGGACGGCCACT ACCTGTCTGAGGAACCTGAGCCCTACCTGGCAGTCTACCTACACTCGGAGCCCCGGCCCA ATGAGCACAACTGCTCGGCTAGCAGGAGGATCCGCCCAGAGTCACTCCAGGGTGCTGAC CACCGGCCCTACACCTTCTTCATTTCCCCGGGGAGCAGAGACCCAGCGGGGAGTTACCAT CTGAACCTCTCCAGCCACTTCCGCTGGTCGGCGCTGCAGGTGTCCGTGGGCCTGTACACG TCCCTGTGCCAGTACTTCAGCGAGGAGGACATGGTGTGGCGGACAGAGGGGCTGCTGCC CCTGGAGGAGACCTCGCCCCGCCAGGCCGTCTGCCTCACCCGCCACCTCACCGCCTTCGG CGCCAGCCTCTTCGTGCCCCCAAGCCATGTCCGCTTTGTGTTTCCTGAGCCGACAGCGGA TGTAAACTACATCGTCATGCTGACATGTGCTGTGTGCCTGGTGACCTACATGGTCATGGC CGCCATCCTGCACAAGCTGGACCAGTTGGATGCCAGCCGGGGCCGCGCCATCCCTTTCTG TGGGCAGCGGGGCCGCTTCAAGTACGAGATCCTCGTCAAGACAGGCTGGGGCCGGGGCT CAGGTACCACGGCCCACGTGGGCATCATGCTGTATGGGGTGGACAGCCGGAGCGGCCAC CGGCACCTGGACGGCGACAGAGCCTTCCACCGCAACAGCCTGGACATCTTCCGGATCGC CACCCCGCACAGCCTGGGTAGCGTGTGGAAGATCCGAGTGTGGCACGACAACAAAGGGC TCAGCCCTGCCTGGTTCCTGCAGCACGTCATCGTCAGGGACCTGCAGACGGCACGCAGCG CCTTCTTCCTGGTCAATGACTGGCTTTCGGTGGAGACGGAGGCCAACGGGGGCCTGGTGG AGAAGGAGGTGCTGGCCGCGAGCGACGCAGCCCTTTTGCGCTTCCGGCGCCTGCTGGTG GCTGAGCTGCAGCGTGGCTTCTTTGACAAGCACATCTGGCTCTCCATATGGGACCGGCCG CCTCGTAGCCGTTTCACTCGCATCCAGAGGGCCACCTGCTGCGTTCTCCTCATCTGCCTCT TCCTGGGCGCCAACGCCGTGTGGTACGGGGCTGTTGGCGACTCTGCCTACAGCACGGGG CATGTGTCCAGGCTGAGCCCGCTGAGCGTCGACACAGTCGCTGTTGGCCTGGTGTCCAGC GTGGTTGTCTATCCCGTCTACCTGGCCATCCTTTTTCTCTTCCGGATGTCCCGGAGCAAGG TGGCTGGGAGCCCGAGCCCCACACCTGCCGGGCAGCAGGTGCTGGACATCGACAGCTGC CTGGACTCGTCCGTGCTGGACAGCTCCTTCCTCACGTTCTCAGGCCTCCACGCTGAGGCC TTTGTTGGACAGATGAAGAGTGACTTGTTTCTGGATGATTCTAAGAGTCTGGTGTGCTGG CCCTCCGGCGAGGGAACGCTCAGTTGGCCGGACCTGCTCAGTGACCCGTCCATTGTGGGT AGCAATCTGCGGCAGCTGGCACGGGGCCAGGCGGGCCATGGGCTGGGCCCAGAGGAGG ACGGCTTCTCCCTGGCCAGCCCCTACTCGCCTGCCAAATCCTTCTCAGCATCAGATGAAG ACCTGATCCAGCAGGTCCTTGCCGAGGGGGTCAGCAGCCCAGCCCCTACCCAAGACACC CACATGGAAACGGACCTGCTCAGCAGCCTGTCCAGCACTCCTGGGGAGAAGACAGAGAC GCTGGCGCTGCAGAGGCTGGGGGAGCTGGGGCCACCCAGCCCAGGCCTGAACTGGGAAC AGCCCCAGGCAGCGAGGCTGTCCAGGACAGGACTGGTGGAGGGTCTGCGGAAGCGCCTG CTGCCGGCCTGGTGTGCCTCCCTGGCCCACGGGCTCAGCCTGCTCCTGGTGGCTGTGGCT GTGGCTGTCTCAGGGTGGGTGGGTGCGAGCTTCCCCCCGGGCGTGAGTGTTGCGTGGCTC CTGTCCAGCAGCGCCAGCTTCCTGGCCTCATTCCTCGGCTGGGAGCCACTGAAGGTCTTG974903-3015-35943Attorney Docket No: 046192-000134WOPTCTGGAAGCCCTGTACTTCTCACTGGTGGCCAAGCGGCTGCACCCGGATGAAGATGACAC CCTGGTAGAGAGCCCGGCTGTGACGCCTGTGAGCGCACGTGTGCCCCGCGTACGGCCAC CCCACGGCTTTGCACTCTTCCTGGCCAAGGAAGAAGCCCGCAAGGTCAAGAGGCTACAT GGCATGCTGCGGAGCCTCCTGGTGTACATGCTTTTTCTGCTGGTGACCCTGCTGGCCAGC TATGGGGATGCCTCATGCCATGGGCACGCCTACCGTCTGCAAAGCGCCATCAAGCAGGA GCTGCACAGCCGGGCCTTCCTGGCCATCACGCGGTCTGAGGAGCTCTGGCCATGGATGGC CCACGTGCTGCTGCCCTACGTCCACGGGAACCAGTCCAGCCCAGAGCTGGGGCCCCCAC GGCTGCGGCAGGTGCGGCTGCAGGAAGCACTCTACCCAGACCCTCCCGGCCCCAGGGTC CACACGTGCTCGGCCGCAGGAGGCTTCAGCACCAGCGATTACGACGTTGGCTGGGAGAG TCCTCACAATGGCTCGGGGACGTGGGCCTATTCAGCGCCGGATCTGCTGGGGGCATGGTC CTGGGGCTCCTGTGCCGTGTATGACAGCGGGGGCTACGTGCAGGAGCTGGGCCTGAGCC TGGAGGAGAGCCGCGACCGGCTGCGCTTCCTGCAGCTGCACAACTGGCTGGACAACAGG AGCCGCGCTGTGTTCCTGGAGCTCACGCGCTACAGCCCGGCCGTGGGGCTGCACGCCGCC GTCACGCTGCGCCTCGAGTTCCCGGCGGCCGGCCGCGCCCTGGCCGCCCTCAGCGTCCGC CCCTTTGCGCTGCGCCGCCTCAGCGCGGGCCTCTCGCTGCCTCTGCTCACCTCGGTGTGCC TGCTGCTGTTCGCCGTGCACTTCGCCGTGGCCGAGGCCCGTACTTGGCACAGGGAAGGGC GCTGGCGCGTGCTGCGGCTCGGAGCCTGGGCGCGGTGGCTGCTGGTGGCGCTGACGGCG GCCACGGCACTGGTACGCCTCGCCCAGCTGGGTGCCGCTGACCGCCAGTGGACCCGTTTC GTGCGCGGCCGCCCGCGCCGCTTCACTAGCTTCGACCAGGTGGCGCAGCTGAGCTCCGCA GCCCGTGGCCTGGCGGCCTCGCTGCTCTTCCTGCTTTTGGTCAAGGCTGCCCAGCAGCTA CGCTTCGTGCGCCAGTGGTCCGTCTTTGGCAAGACATTATGCCGAGCTCTGCCAGAGCTC CTGGGGGTCACCTTGGGCCTGGTGGTGCTCGGGGTAGCCTACGCCCAGCTGGCCATCCTG CTCGTGTCTTCCTGTGTGGACTCCCTCTGGAGCGTGGCCCAGGCCCTGTTGGTGCTGTGCC CTGGGACTGGGCTCTCTACCCTGTGTCCTGCCGAGTCCTGGCACCTGTCACCCCTGCTGTG TGTGGGGCTCTGGGCACTGCGGCTGTGGGGCGCCCTACGGCTGGGGGCTGTTATTCTCCG CTGGCGCTACCACGCCTTGCGTGGAGAGCTGTACCGGCCGGCCTGGGAGCCCCAGGACT ACGAGATGGTGGAGTTGTTCCTGCGCAGGCTGCGCCTCTGGATGGGCCTCAGCAAGGTC AAGGAGTTCCGCCACAAAGTCCGCTTTGAAGGGATGGAGCCGCTGCCCTCTCGCTCCTCC AGGGGCTCCAAGGTATCCCCGGATGTGCCCCCACCCAGCGCTGGCTCCGATGCCTCGCAC CCCTCCACCTCCTCCAGCCAGCTGGATGGGCTGAGCGTGAGCCTGGGCCGGCTGGGGAC AAGGTGTGAGCCTGAGCCCTCCCGCCTCCAAGCCGTGTTCGAGGCCCTGCTCACCCAGTT TGACCGACTCAACCAGGCCACAGAGGACGTCTACCAGCTGGAGCAGCAGCTGCACAGCC TGCAAGGCCGCAGGAGCAGCCGGGCGCCCGCCGGATCTTCCCGTGGCCCATCCCCGGGC CTGCGGCCAGCACTGCCCAGCCGCCTTGCCCGGGCCAGTCGGGGTGTGGACCTGGCCACT GGCCCCAGCAGGACACCCCTTCGGGCCAAGAACAAGGTCCACCCCAGCAGCACTTAG984903-3015-35943Attorney Docket No: 046192-000134WOPT

[0309] SEQ ID NO: 10, polycystin-2 (PKD2), also known as: PC2, PKD4, Pc-2, APKD2, TRPP2; positions 100-3006 of NCBI ref NM_000297.4, CCDS3627.1, human, 2907 nt ATGGTGAACTCCAGTCGCGTGCAGCCTCAGCAGCCCGGGGACGCCAAGCGGCCGCCCGC GCCCCGCGCGCCGGACCCGGGCCGGCTGATGGCTGGCTGCGCGGCCGTGGGCGCCAGCC TCGCCGCCCCGGGCGGCCTCTGCGAGCAGCGGGGCCTGGAGATCGAGATGCAGCGCATC CGGCAGGCGGCCGCGCGGGACCCCCCGGCCGGAGCCGCGGCCTCCCCTTCTCCTCCGCTC TCGTCGTGCTCCCGGCAGGCGTGGAGCCGCGATAACCCCGGCTTCGAGGCCGAGGAGGA GGAGGAGGAGGTGGAAGGGGAAGAAGGCGGAATGGTGGTGGAGATGGACGTAGAGTGG CGCCCGGGCAGCCGGAGGTCGGCCGCCTCCTCGGCCGTGAGCTCCGTGGGCGCGCGGAG CCGGGGGCTTGGGGGCTACCACGGCGCGGGCCACCCGAGCGGGAGGCGGCGCCGGCGA GAGGACCAGGGCCCGCCGTGCCCCAGCCCAGTCGGCGGCGGGGACCCGCTGCATCGCCA CCTCCCCCTGGAAGGGCAGCCGCCCCGAGTGGCCTGGGCGGAGAGGCTGGTTCGCGGGC TGCGAGGTCTCTGGGGAACAAGACTCATGGAGGAAAGCAGCACTAACCGAGAGAAATA CCTTAAAAGTGTTTTACGGGAACTGGTCACATACCTCCTTTTTCTCATAGTCTTGTGCATC TTGACCTACGGCATGATGAGCTCCAATGTGTACTACTACACCCGGATGATGTCACAGCTC TTCCTAGACACCCCCGTGTCCAAAACGGAGAAAACTAACTTTAAAACTCTGTCTTCCATG GAAGACTTCTGGAAGTTCACAGAAGGCTCCTTATTGGATGGGCTGTACTGGAAGATGCA GCCCAGCAACCAGACTGAAGCTGACAACCGAAGTTTCATCTTCTATGAGAACCTGCTGTT AGGGGTTCCACGAATACGGCAACTCCGAGTCAGAAATGGATCCTGCTCTATCCCCCAGG ACTTGAGAGATGAAATTAAAGAGTGCTATGATGTCTACTCTGTCAGTAGTGAAGATAGG GCTCCCTTTGGGCCCCGAAATGGAACCGCTTGGATCTACACAAGTGAAAAAGACTTGAA TGGTAGTAGCCACTGGGGAATCATTGCAACTTATAGTGGAGCTGGCTATTATCTGGATTT GTCAAGAACAAGAGAGGAAACAGCTGCACAAGTTGCTAGCCTCAAGAAAAATGTCTGGC TGGACCGAGGAACCAGGGCAACTTTTATTGACTTCTCAGTGTACAACGCCAACATTAACC TGTTCTGTGTGGTCAGGTTATTGGTTGAATTCCCAGCAACAGGTGGTGTGATTCCATCTTG GCAATTTCAGCCTTTAAAGCTGATCCGATATGTCACAACTTTTGATTTCTTCCTGGCAGCC TGTGAGATTATCTTTTGTTTCTTTATCTTTTACTATGTGGTGGAAGAGATATTGGAAATTC GCATTCACAAACTACACTATTTCAGGAGTTTCTGGAATTGTCTGGATGTTGTGATCGTTGT GCTGTCAGTGGTAGCTATAGGAATTAACATATACAGAACATCAAATGTGGAGGTGCTAC TACAGTTTCTGGAAGATCAAAATACTTTCCCCAACTTTGAGCATCTGGCATATTGGCAGA TACAGTTCAACAATATAGCTGCTGTCACAGTATTTTTTGTCTGGATTAAGCTCTTCAAATT CATCAATTTTAACAGGACCATGAGCCAGCTCTCGACAACCATGTCTCGATGTGCCAAAGA CCTGTTTGGCTTTGCTATTATGTTCTTCATTATTTTCCTAGCGTATGCTCAGTTGGCATACC TTGTCTTTGGCACTCAGGTCGATGACTTCAGTACTTTCCAAGAGTGTATCTTCACTCAATT CCGTATCATTTTGGGCGATATCAACTTTGCAGAGATTGAGGAAGCTAATCGAGTTTTGGG ACCAATTTATTTCACTACATTTGTGTTCTTTATGTTCTTCATTCTTTTGAATATGTTTTTGG994903-3015-35943Attorney Docket No: 046192-000134WOPTCTATCATCAATGATACTTACTCTGAAGTGAAATCTGACTTGGCACAGCAGAAAGCTGAAA TGGAACTCTCAGATCTTATCAGAAAGGGCTACCATAAAGCTTTGGTCAAACTAAAACTGA AAAAAAATACCGTGGATGACATTTCAGAGAGTCTGCGGCAAGGAGGAGGCAAGTTAAAC TTTGACGAACTTCGACAAGATCTCAAAGGGAAGGGCCATACTGATGCAGAGATTGAGGC AATATTCACAAAGTACGACCAAGATGGAGACCAAGAACTGACCGAACATGAACATCAGC AGATGAGAGACGACTTGGAGAAAGAGAGGGAGGACCTGGATTTGGATCACAGTTCTTTA CCACGTCCCATGAGCAGCCGAAGTTTCCCTCGAAGCCTGGATGACTCTGAGGAGGATGA CGATGAAGATAGCGGACATAGCTCCAGAAGGAGGGGAAGCATTTCTAGTGGCGTTTCTT ACGAAGAGTTTCAAGTCCTGGTGAGACGAGTGGACCGGATGGAGCATTCCATCGGCAGC ATAGTGTCCAAGATTGACGCCGTGATCGTGAAGCTAGAGATTATGGAGCGAGCCAAACT GAAGAGGAGGGAGGTGCTGGGAAGGCTGTTGGATGGGGTGGCCGAGGATGAAAGGCTG GGTCGTGACAGTGAAATCCATAGGGAACAGATGGAACGGCTAGTACGTGAAGAGTTGGA ACGCTGGGAATCCGATGATGCAGCTTCCCAGATCAGTCATGGTTTAGGCACGCCAGTGG GACTAAATGGTCAACCTCGCCCCAGAAGCTCCCGCCCATCTTCCTCCCAATCTACAGAAG GCATGGAAGGTGCAGGTGGAAATGGGAGTTCTAATGTCCACGTATGA

[0310] In some embodiments, the transgene encodes for a polypeptide comprising one of SEQ ID NOs: 11-12, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the sequence of one of SEQ ID NOs: 11-12, which maintains the same function (e.g., regulate kidney cells, influence formation of kidney tubular structures, and influence kidney fluid secretion function), or a functional fragment thereof.

[0311] SEQ ID NO: 11, polycystin-1 (PKD1), NCBI ref NP_000287.4, human, 4302 aa MPPAAPARLALALGLGLWLGALAGGPGRGCGPCEPPCLCGPAPGAACRVNCSGRGLRTLGP ALRIPADATALDVSHNLLRALDVGLLANLSALAELDISNNKISTLEEGIFANLFNLSEINLSGNP FECDCGLAWLPRWAEEQQVRVVQPEAATCAGPGSLAGQPLLGIPLLDSGCGEEYVACLPDN SSGTVAAVSFSAAHEGLLQPEACSAFCFSTGQGLAALSEQGWCLCGAAQPSSASFACLSLCS GPPPPPAPTCRGPTLLQHVFPASPGATLVGPHGPLASGQLAAFHIAAPLPVTATRWDFGDGSA EVDAAGPAASHRYVLPGRYHVTAVLALGAGSALLGTDVQVEAAPAALELVCPSSVQSDESL DLSIQNRGGSGLEAAYSIVALGEEPARAVHPLCPSDTEIFPGNGHCYRLVVEKAAWLQAQEQ CQAWAGAALAMVDSPAVQRFLVSRVTRSLDVWIGFSTVQGVEVGPAPQGEAFSLESCQNW LPGEPHPATAEHCVRLGPTGWCNTDLCSAPHSYVCELQPGGPVQDAENLLVGAPSGDLQGP LTPLAQQDGLSAPHEPVEVMVFPGLRLSREAFLTTAEFGTQELRRPAQLRLQVYRLLSTAGTP ENGSEPESRSPDNRTQLAPACMPGGRWCPGANICLPLDASCHPQACANGCTSGPGLPGAPYA LWREFLFSVPAGPPAQYSVTLHGQDVLMLPGDLVGLQHDAGPGALLHCSPAPGHPGPRAPY LSANASSWLPHLPAQLEGTWACPACALRLLAATEQLTVLLGLRPNPGLRLPGRYEVRAEVG1004903-3015-35943Attorney Docket No: 046192-000134WOPTNGVSRHNLSCSFD...

Claims

1. Attorney Docket No: 046192-000134WOPT2.CLAIMS3.What is claimed herein is:

1. A method of transducing nephrons in a kidney of a subject with a recombinant adeno- associated virus (rAAV), the method comprising:5.guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, wherein nephrons of the kidney are transduced at a therapeutically effective level, wherein none of the renal artery, renal vein, and ureter are occluded during administration of the solution comprising the rAAV.

2. A method of transducing nephrons in a kidney of a subject with a recombinant adeno- associated virus (rAAV), the method comprising:7.guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject, wherein nephrons of the kidney are transduced at a therapeutically effective level.

3. The method of claim 1 or 2, wherein the delivery device is 0 mm to about 10 mm away from the at least one renal papilla while administering the rAAV.

4. The method of claim 1 or 2, wherein the solution comprising the rAAV is selectively administered to the at least one renal papilla for about 1 minute to about 2 minutes per renal papilla.

5. The method of claim 1 or 2, wherein about 1 mL to about 5 mL of the solution comprising the rAAV is selectively administered to each targeted renal papilla of the kidney.

6. The method of claim 1 or 2, further comprising maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O while the rAAV is being administered.

7. The method of claim 1 or 2, wherein the method results in the transduction of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or more of the nephrons in the kidney with the rAAV.

8. The method of claim 1 or 2, wherein the transduction efficiency of the rAAV of the nephrons in the kidney is at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-13.17414.4903-3015-35943 Attorney Docket No: 046192-000134WOPT15.fold, at least 400-fold, at least 1000-fold, or at least 3500-fold increased compared to a corresponding transduction efficiency of corresponding nephrons in another kidney treated by intravenous administration of the solution comprising the rAAV.

9. The method of claim 1 or 2, wherein the rAAV does not comprise an AAV9 capsid, and the transduction efficiency of the rAAV of the nephrons in the kidney is at least 2-fold, at least 5- fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 400-fold, at least 1000-fold, or at least 3500-fold increased compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

10. The method of claim 1 or 2, wherein the rAAV does not comprise an AAV9 capsid, and the transduction efficiency of the rAAV in proximal tubule cells of the nephrons in the kidney is at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 400- fold, at least 1000-fold, or at least 3500-fold increased compared to a corresponding transduction efficiency in proximal tubule cells achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

11. The method of claim 2, further comprising a step of occluding at least one of the following: a renal artery, a renal vein, and / or a ureter of the kidney, prior to administering the solution comprising the rAAV.

12. The method of claim 11, further comprising a step of un-occluding the renal artery, the renal vein, and / or the ureter after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV.

13. The method of claim 2, further comprising a step of occluding a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof, prior to administering the solution comprising the rAAV.

14. The method of claim 13, further comprising a step of un-occluding the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV.

15. The method of claim 1 or 2, wherein the kidney is not isolated from systemic circulation.

16. The method of claim 2, wherein a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney is not occluded during performance of the method.

17. The method of claim 2, wherein none of the renal artery, renal vein, and ureter are occluded during administration of the solution comprising the rAAV.

18. The method of claim 1 or 2, wherein the solution comprising the rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 27 cm H2O to about 80 cm H2O.24.17525.4903-3015-35943 Attorney Docket No: 046192-000134WOPT19. The method of claim 1 or 2, wherein the subject is a human, a non-human primate, a horse, a dog, or a pig.

20. The method of claim 1 or 2, wherein at least about 30% of the nephrons of the kidney are transduced with the rAAV.

21. The method of claim 1 or 2, wherein the volume of the solution comprising the rAAV administered to the subject is from about 0.13 mL / kg to about 0.33 mL / kg.

22. The method of claim 1 or 2, wherein the volume of the solution comprising the rAAV administered to the subject is from about 0.27 mL / kg to about 0.33 mL / mg.

23. The method of claim 1 or 2, wherein the volume of the solution comprising the rAAV administered to the subject is from about 0.20 mL / kg to about 1.25 mL / mg.

24. The method of claim 1 or 2, wherein the solution comprising the rAAV is administered using a balloon catheter.

25. The method of claim 11 or 13, wherein the renal blood vessel and / or the ureter is occluded using a balloon catheter.

26. The method of claim 11 or 13, wherein the renal blood vessel and / or the ureter is occluded using a clamp.

27. The method of claim 11 or 13, wherein only one of the renal artery or renal vein is occluded.

28. The method of claim 2, wherein the renal vein of the kidney is not occluded.

29. The method of claim 1 or 2, wherein the method does not comprise a continuous perfusion of an isolated kidney.

30. The method of claim 1 or 2, wherein the method does not comprise a closed circuit comprising the kidney.

31. The method of claim 1 or 2, wherein the method does not comprise a substantially closed system comprising the kidney.

32. The method of claim 1 or 2, wherein the method does not comprise diverting circulation from the kidney.

33. The method of claim 1 or 2, wherein the method does not comprise bypassing the kidney.

34. The method of claim 1 or 2, wherein the method is performed in vivo.

35. The method of claim 1 or 2, wherein the method is not performed ex vivo.

36. The method of claim 12 or 14, wherein the period of time for occluding the at least one renal blood vessel and / or the ureter is 15-45 minutes subsequent to the occluding.

37. The method of claim 12 or 14, wherein the period of time for occluding the at least one renal blood vessel and / or the ureter is 20-40 minutes subsequent to the occluding.

38. The method of claim 12 or 14, wherein the period of time for occluding the at least one renal blood vessel and / or the ureter is about 15-30 minutes subsequent to the occluding.45.17646.4903-3015-35943 Attorney Docket No: 046192-000134WOPT39. The method of claim 12 or 14, wherein the volume of the solution comprising the rAAV is from about 0.13 mL / kg to about 0.33 mL / kg, and wherein the period of time for occluding the renal blood vessel and / or ureter is about 15-30 minutes subsequent to the occluding.

40. The method of claim 1 or 2, wherein the rAAV comprises an AAV capsid protein selected from Table 1.

41. The method of claim 1 or 2, wherein the rAAV comprises a capsid protein selected from the group consisting of AAV2G9, AAV2.5, AAVDJ, and AAV2.

42. The method of claim 40, wherein the capsid protein is AAV2G9.

43. The method of claim 1 or 2, wherein the rAAV comprises a rational polyploid.

44. The method of claim 1 or 2, wherein the solution comprises the rAAV at a concentration of 108viral genomes per mL (vg / mL) to 1015vg / mL.

45. The method of claim 1 or 2, wherein the solution comprises the rAAV at a concentration of 108vg / mL to 1013vg / mL.

46. The method of claim 1 or 2, wherein the solution comprises the rAAV at a concentration of lxl013to 5xl013vg / mL.

47. The method of claim 1 or 2, wherein the solution comprises IxlO14to 2.5xl015rAAV viral genomes total.

48. The method of claim 1 or 2, wherein the solution comprises IxlO13to 2xl013rAAV viral genomes total.

49. The method of claim 1 or 2, wherein the solution comprises 5xl013to 6xl013rAAV viral genomes total.

50. The method of claim 1 or 2, wherein the solution comprises IxlO10viral genomes total.

51. The method of claim 1 or 2, wherein the rAAV comprises a transgene.

52. The method of claim 51, wherein the transgene is selected from the group consisting of 4- Hydroxy-2-Oxoglutarate Aldolase 1 (HOGA1; e.g., type III); Alanine-Glyoxylate Aminotransferase (AGXT; e.g., type I); Aquaporin 2 (AQP2); ATPase Na+ / K+ Transporting Subunit Alpha 1 (ATP1A1); Arginine Vasopressin Receptor 2 (AVPR2); ATPase H+ Transporting V0 Subunit A4 (ATP6V0A4); ATPase H+ Transporting V1 Subunit B1 (ATP6V1B1); Bartter Syndrome, Infantile, With Sensorineural Deafness (BSND; e.g., type IV); Barttin CLCNK (chloride channel K) Type Accessory Subunit Beta (BSND); Calcium Sensing Receptor (CaSR); Carbonic Anhydrase 2 (CA2); Chloride Voltage-Gated Channel 5 (CLCN5; e.g., type I); Chloride Voltage-Gated Channel Ka (CLCNKA; e.g., type IV);60.Chloride Voltage-Gated Channel Kb (CLCNKB; e.g., type III and IV); Claudin 16 (CLDN16); Claudin 19 (CLDN19); CLCNKA (Chloride Voltage-Gated Channel Ka);61.Collagen Type IV Alpha 3 Chain (COL4A3); Collagen Type IV Alpha 4 Chain (COL4A4); Collagen Type IV Alpha 5 Chain (COL4A5); Cullin 3 (CUL3); Cyclin And CBS Domain62.17763.4903-3015-35943 Attorney Docket No: 046192-000134WOPT64.Divalent Metal Cation Transport Mediator 2 (CNNM2); Cytochrome P450 Family 11 Subfamily B Member 1 (CYP11B1); Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2); Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1); Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2); Enoyl-CoA Hydratase And 3-Hydroxyacyl Co A Dehydrogenase (EHHADH); Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); FAM111 (family 111) Trypsin Like Peptidase A (FAM111A); Forkhead Box I1 (FOXI1); FXYD Domain / Motif Containing Ion Transport Regulator 2 (FXYD2); Glucosidase II Alpha Subunit (GANAB); Glycine Amidinotransferase (GATM); Glyoxylate And Hydroxypyruvate Reductase (GRHPR; e.g., type II); Guanine nucleotide binding protein alpha stimulating (GNAS); Hepatocyte nuclear factor 1 (HNF1) Homeobox B (HNF1B); Hepatocyte Nuclear Factor 4 Alpha (HNF4A); Hydroxy-Delta-5 -Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2); Hydroxysteroid 11-Beta Dehydrogenase 2 (HSD11B2); Inositol Polyphosphate-5 -Phosphatase (OCRL; e.g., type II); Kelch Like Family Member 3 (KLHL3); MAGED2 (type V); Mucin 1 (MUC1; e.g., type I); Melanoma Antigen Gene Family Member D2 (MAGED2); Nephrin (NPHS1);65.Nephrocystin 1 (NPHP1); Nephrosis 2 (NPHS2; Podocin); Nuclear Receptor Subfamily 3 Group C Member 2 (NR3C2); Oculocerebrorenal Syndrome Of Lowe (OCRL) Inositol Polyphosphate-5-Phosphatase; Phosphate Regulating Endopeptidase X-Linked (PHEX); Polycystic Kidney And Hepatic Disease 1 (PKHD1); Poly cystin 1 (PKD1); Poly cystin 2 (PKD2; Potassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1; e.g., type II); Potassium Inwardly Rectifying Channel Subfamily J Member 10 (KCNJ10); Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1); Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1); Pterin-4 Alpha-Carbinolamine Dehydratase 1 (PCBD1); Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A); Sodium Channel Epithelial 1 Subunit Beta (SCNN1B); Sodium Channel Epithelial 1 Subunit Gamma (SCNN1G); Solute Carrier Family 1 Member 1 (SLC1A1); Solute Carrier Family 2 Member 2 (SLC2A2); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 34 Member 1 (SLC34A1); Solute Carrier Family 34 Member 3 (SLC34A3); Solute Carrier Family 36 Member 2 (SLC36A2); Solute Carrier Family 4 Member 1 (SLC4A1); Solute Carrier Family 6 Member 19 (SLC6A19); Solute Carrier Family 6 Member 20 (SLC6A20); Solute Carrier Family 7 Member 7 (SLC7A7); Solute Carrier Family 7 Member 9 (SLC7A9); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6); Von Hippel-Lindau Tumor Suppressor (VHL); WD Repeat Domain 72 (WDR72); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 1 (WNK1); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 4 (WNK4)and combinations thereof.66.17867.4903-3015-35943 Attorney Docket No: 046192-000134WOPT53. The method of claim 51, wherein the transgene comprises an inhibitor of a gene or protein selected from the group consisting of: Renin (REN), Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A), Sodium Channel Epithelial 1 Subunit Beta (SCNN1B), and Uromodulin (UMOD).

54. The method of claim 1 or 2, wherein circulating serum of the subject does not neutralize the rAAV upon administration.

55. The method of claim 1 or 2, wherein the subject has antibodies that neutralize the rAAV to be administered in the circulating serum, and the antibodies do not neutralize the rAAV in the kidney upon administration.

56. The method of claim 1 or 2, wherein a subsequent administration of the rAAV of claim 1 is performed without resulting in a substantial inflammatory response in the kidney.

57. The method of claim 56, wherein the subsequent administration is at least one day later.

58. The method of claim 56, wherein the subsequent administration is at least one month later.

59. The method of claim 1 or 2, wherein the method transduces proximal tubules of the kidney with the rAAV.

60. The method of claim 1 or 2, wherein the method transduces at least one cell population of a glomerulus, a glomerular capsule, a proximal convoluted tubule, the loop of Henle, a distal convoluted tubule, or a collecting duct of the kidney with the rAAV.

61. The method of claim 1 or 2, wherein the rAAV comprises a kidney-specific promoter.

62. The method of claim 61, wherein the kidney-specific promoter is selected from the group consisting of: kidney-specific cadherin (KSPC) gene promoter; Na+ / glucose co-transporter (SGLT2) gene promoter; sodium potassium, 2 chloride co-transporter (NKCC2) gene promoter; and E-cadherin (ECAD) gene promoter.

63. The method of claim 61, wherein the kidney-specific promoter is a synthetic promoter.

64. The method of claim 1 or 2, wherein the rAAV has a genome comprising a promoter specific to proximal convoluted tubules and / or collecting ducts.

65. A method of treating a kidney-associated disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a recombinant adeno- associated virus (rAAV) to the subject by performing the method according to claim 1 or 2.

66. The method of claim 65, wherein the kidney-associated disorder is selected from the group consisting of: Alport syndrome; Autosomal dominant polycystic kidney disease (ADPKD); Autosomal dominant tubulointerstitial kidney disease (ADTKD); Autosomal recessive polycystic kidney disease (ARPKD); Apparent mineralocorticoid excess; Autosomal dominant hypocalcemia; Autosomal dominant hypomagnesemia; Bartter Syndrome (e.g., Barttertype 1; Bartter type 2; Bartter type 3; Bartter type 4a; Bartter type 4b; Bartter type 5); Congenital adrenal hyperplasia (e.g., Congenital adrenal hyperplasia type 1; Congenital80.17981.4903-3015-35943 Attorney Docket No: 046192-000134WOPT82.adrenal hyperplasia type 2; Congenital adrenal hyperplasia type 4; Congenital adrenal hyperplasia type 5); Cystinosis; Cystinuria (e.g., Cystinuria A; Cystinuria B); Dent disease (e.g., Dent disease type 1; Dent disease type 2 / Lowe syndrome); Dicarboxylic aminoaciduria; Distal RTA; EAST / SeSAME syndrome; Fanconi Bickel syndrome; Fanconi renotubular syndrome (e.g., Fanconi renotubular syndrome 1; Fanconi renotubular syndrome 2; Fanconi renotubular syndrome 3; Fanconi renotubular syndrome 4); Gitelman syndrome;83.Glucocorticoid remediable aldosteronism; Hartnup disorder; Hereditary hypophosphatemic rickets with hypercalciuria; HNF IB-related kidney disease; Hyperphenylalaninemia BH4- deficient; Hypomagnesemia (e.g., Hypomagnesemia type 1 / hypomagnesemia with secondary hypocalcemia; Hypomagnesemia type 2; Hypomagnesemia type 3 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia type 4; Hypomagnesemia type 5 / familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Hypomagnesemia, seizures, and mental retardation type 1; Hypomagnesemia, seizures, and mental retardation type 2); Iminoglycinuria; Kenny-Caffey syndrome type 2; Liddle syndrome; Lysinuric protein intolerance; Medullary cystic kidney disease; Neonatal inflammatory skin and bowel disease type 2; Nephrogenic diabetes insipidus; Nephrogenic syndrome of inappropriate antidiuresis; Nephronophthisis; Papillorenal syndrome; Primary hyperoxaluria;84.Pseudohypoaldosteronism (e.g., Pseudohypoaldosteronism type 1; Pseudohypoaldosteronism type 1A; Pseudohypoaldosteronism type 2b; Pseudohypoaldosteronism type 2c;85.Pseudohypoaldosteronism type 2d; Pseudohypoaldosteronism type 2e); Renal tubular acidosis type 3; Thin Basement Membrane Nephropathy; Von Hippel-Lindau syndrome; and X-linked hypophosphatemic rickets.

67. The method of claim 65, wherein the kidney-associated disorder is Cystinuria, and the transgene is SLC3A1 and / or SLC7A9.

68. The method of claim 65, wherein the kidney-associated disorder is autosomal dominant polycystic kidney disease (ADPKD), and the transgene is PKD1, PKD2, and / or GANAB.

69. A method of transducing at least about 10% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising:88.e) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof;89.f) guiding a delivery device through the subject’s urethra, bladder, and ureter;90.g) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and91.18092.4903-3015-35943 Attorney Docket No: 046192-000134WOPT93.h) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 10% of the nephrons in the kidney with the rAAV.

70. A method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising:95.e) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof;96.f) guiding a delivery device through the subject’s urethra, bladder, and ureter;97.g) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and98.h) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

71. A method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising:100.e) blocking a renal artery of the kidney and not blocking a renal vein of the kidney; f) guiding a delivery device through the subject’s urethra, bladder, and ureter; g) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device; and h) unblocking the renal artery after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

72. A method of transducing nephrons in a kidney of a subject, the method comprising:102.e) blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney;103.f) guiding a delivery device through the subject’s urethra, bladder, and ureter; g) selectively administering at least a portion of a solution comprising rAAV to at least one targeted renal papilla of the kidney through the delivery device, the rAAV not being rAAV9; and104.h) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV,105.181106.4903-3015-35943 Attorney Docket No: 046192-000134WOPT107.wherein the method results in a transduction efficiency that is at least 2-fold higher compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

73. The method of claim 72, wherein the rAAV comprises a capsid protein selected from Table 1.

74. The method of claim 72, wherein the rAAV has at least 2-fold higher transduction efficiency in the kidney compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

75. The method of claim 72, wherein the rAAV has 400-fold higher transduction efficiency in the kidney compared to a corresponding transduction efficiency achieved by administering rAAV comprising an AAV9 capsid to another kidney by the same method.

76. A method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising:112.e) isolating the kidney from systemic circulation;113.f) guiding a delivery device through the subject’s urethra, bladder, and ureter;114.g) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and115.h) re-establishing the kidney into systemic circulation after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV,116.wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

77. A method of treating a kidney disorder in a subject in need thereof, the method comprising:118.administering to a kidney of the subject a therapeutically effective amount of a first recombinant adeno-associated virus (rAAV) encoding a transgene that is therapeutic toward the kidney disorder; and119.subsequent to administering the first rAAV, administering to the kidney or a different kidney of the subject a therapeutically effective amount of a second rAAV encoding the transgene or a different transgene that is therapeutic toward to the kidney disorder, wherein the first rAAV and the second rAAV are cross seroreactive, and wherein the subject does not elicit a significant immune response to the second rAAV in the kidney.

78. The method of claim 77, wherein at least one solution comprising the first and / or second rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O.121.182122.4903-3015-35943 Attorney Docket No: 046192-000134WOPT79. The method of claim 77, wherein a solution comprising the second rAAV is administered after about a week.

80. The method of claim 77, wherein the first and / or second rAAVs are administered by an administration method comprising:125.guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the first or second rAAV through the delivery device to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject.

81. The method of claim 77, wherein the first and / or second rAAVs are administered by an administration method comprising:127.e) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof;128.f) guiding a delivery device through the subject’s urethra, bladder, and ureter; g) selectively administering at least a portion of a solution comprising the first or second rAAV through the delivery device to at least one targeted renal papilla of the kidney or a different kidney, the solution having a total volume of volume is from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and129.h) unblocking renal blood vessel after a period of time of from about 10 minutes to about 60 minutes administering the solution comprising the first or second rAAV.

82. The method of claim 77, wherein the administration method results in at least about 25% of the nephrons in the kidney being transduced with the rAAV.

83. The method of claim 77, wherein the subject has neutralizing antibodies toward the first rAAV therapeutic prior to the administering.

84. The method of claim 77, wherein the capsid protein of the first rAAV is the same serotype as the capsid protein of the second rAAV.

85. The method of claim 77, wherein the capsid protein of the first rAAV is a different serotype as the capsid protein of the second rAAV.

86. The method of claim 77, wherein the time period for subsequent administration of the second rAAV is determined based on the efficacy or longevity of the administration of the first rAAV.

87. The method of claim 77, wherein the first rAAV is administered to a first kidney of the subject, and the second rAAV is administered to a second kidney of the subject.

88. The method of claim 77, wherein the first rAAV is administered to a first kidney of the subject, and the second rAAV is administered to the first kidney of the subject.137.183138.4903-3015-35943 Attorney Docket No: 046192-000134WOPT89. The method of claim 77, wherein the first rAAV is administered to both kidneys of the subject, and the second rAAV is administered to both kidneys of the subject.

90. A method of treating a kidney disorder in a subject in need thereof, the subject being seropositive for a recombinant adeno-associated virus (rAAV) therapeutic, the method comprising:141.selectively administering to at least one targeted renal papilla of a kidney of the subject the rAAV therapeutic encoding a transgene that is therapeutic toward the kidney disorder,142.wherein the subject does not elicit a significant immune response to the rAAV therapeutic in the kidney.

91. The method of claim 90, wherein the subject has neutralizing antibodies toward the rAAV therapeutic prior to the administering.

92. The method of claim 90, wherein the rAAV is administered by an administration method comprising:145.guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the first or second rAAV through the delivery device to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject.

93. The method of claim 90, wherein the rAAV is administered by an administration method comprising:147.e) blocking a renal blood vessel of the kidney selected from the group consisting of a renal artery, a renal vein, and a combination thereof;148.f) guiding a delivery device through the subject’s urethra, bladder, and ureter; g) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject; and149.h) unblocking renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV, wherein the administration method results in at least about 25% of the nephrons in the kidney being transduced with the rAAV.

94. A method of transducing at least about 25% of the nephrons in a kidney of a subject with a recombinant adeno-associated virus (rAAV), the method comprising:151.e) blocking a renal blood vessel selected from the group consisting of a renal artery, a renal vein, and a combination thereof of the kidney;152.184153.4903-3015-35943 Attorney Docket No: 046192-000134WOPT154.f) guiding a delivery device through the subject’s urethra, bladder, and ureter; g) selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney through the delivery device, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject, wherein the rAAV comprises a capsid protein selected from Table 1; and155.h) unblocking the renal blood vessel after a period of time of from about 10 minutes to about 60 minutes after administering the solution comprising the rAAV, wherein the method results in the transduction of at least about 25% of the nephrons in the kidney with the rAAV.

95. A method of treating a kidney-associated disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the rAAV to the subject by performing the method according to claim 94.

96. The method of claim 95, wherein the rAAV is administered to the kidney while maintaining an intra-renal pressure of from about 25 cm H2O to about 55 cm H2O.

97. The method of claim 95, wherein the volume of the solution is 0.27 mL / kg to 0.33 mL / kg.

98. The method of claim 95, wherein the volume of the solution is 0.20 mL / kg to 1.25 mL / kg.

99. The method of claim 95, wherein the period of time is 30-60 minutes after administering the solution comprising the rAAV.

100. The method of claim 95, wherein the subject is seropositive for the rAAV prior to the administration of the solution comprising the rAAV.

101. The method of any one of claims 1, 2, 65, 69-72, 76, 77, 90, 94, or 95, wherein the rAAV is administered in liposomes, nanocapsules, microparticles, microspheres, lipid particles, lipid nanoparticles, or vesicles.

102. The method of any one of claims 1, 2, 65, 69-72, 76, 77, 90, 94, or 95, wherein the subject the rAAV is administered in lipid nanoparticles (LNPs).

103. A pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) comprising:165.d) an AAV capsid protein selected from Table 1;166.e) a transgene comprising:167.i) a gene selected from the group consisting of 4-Hydroxy-2-Oxoglutarate Aldolase 1 (HOGA1; e.g., type III); Alanine-Glyoxylate Aminotransferase (AGXT; e.g., type I); Aquaporin 2 (AQP2); ATPase Na+ / K+ Transporting Subunit Alpha 1 (ATP1A1); Arginine Vasopressin Receptor 2 (AVPR2); ATPase H+ Transporting V0 Subunit A4 (ATP6V0A4); ATPase H+ Transporting V1 Subunit B1 (ATP6V1B1); Bartter Syndrome, Infantile, With168.185169.4903-3015-35943 Attorney Docket No: 046192-000134WOPT170.Sensorineural Deafness (BSND; e.g., type IV); Barttin CLCNK (chloride channel K) Type Accessory Subunit Beta (BSND); Calcium Sensing Receptor (CaSR); Carbonic Anhydrase 2 (CA2); Chloride Voltage-Gated Channel 5 (CLCN5; e.g., type I); Chloride Voltage-Gated Channel Ka (CLCNKA; e.g., type IV); Chloride Voltage-Gated Channel Kb (CLCNKB; e.g., type III and IV); Claudin 16 (CLDN16); Claudin 19 (CLDN19);171.CLCNKA (Chloride Voltage-Gated Channel Ka); Collagen Type IV Alpha 3 Chain (COL4A3); Collagen Type IV Alpha 4 Chain (COL4A4); Collagen Type IV Alpha 5 Chain (COL4A5); Cullin 3 (CUL3); Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 2 (CNNM2); Cytochrome P450 Family 11 Subfamily B Member 1 (CYP11B1); Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2); Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1); Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2); Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (EHHADH); Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); FAM111 (family 111) Trypsin Like Peptidase A (FAM111A); Forkhead Box I1 (FOXI1); FXYD Domain / Motif Containing Ion Transport Regulator 2 (FXYD2); Glucosidase II Alpha Subunit (GAN AB); Glycine Amidinotransferase (GATM); Glyoxylate And Hydroxypyruvate Reductase (GRHPR; e.g., type II); Guanine nucleotide binding protein alpha stimulating (GNAS); Hepatocyte nuclear factor 1 (HNF1) Homeobox B (HNF1B); Hepatocyte Nuclear Factor 4 Alpha (HNF4A); Hydroxy-Delta-5 -Steroid Dehydrogenase, 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2); Hydroxysteroid 11 -Beta Dehydrogenase 2 (HSD11B2); Inositol Polyphosphate-5 -Phosphatase (OCRL; e.g., type II); Kelch Like Family Member 3 (KLHL3); MAGED2 (type V); Mucin 1 (MUC1; e.g., type I); Melanoma Antigen Gene Family Member D2 (MAGED2); Nephrin (NPHS1); Nephrocystin 1 (NPHP1); Nephrosis 2 (NPHS2; Podocin); Nuclear Receptor Subfamily 3 Group C Member 2 (NR3C2); Oculocerebrorenal Syndrome Of Lowe (OCRL) Inositol Polyphosphate-5-Phosphatase; Phosphate Regulating Endopeptidase X-Linked (PHEX); Polycystic Kidney And Hepatic Disease 1 (PKHD1);172.Polycystin 1 (PKD1); Polycystin 2 (PKD2; Potassium Inwardly Rectifying Channel Subfamily J Member 1 (KCNJ1; e.g., type II); Potassium Inwardly Rectifying Channel Subfamily J Member 10 (KCNJ10); Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1); Protein transport protein173.186174.4903-3015-35943 Attorney Docket No: 046192-000134WOPT175.Sec61 subunit alpha isoform 1 (SEC61A1); Pterin-4 Alpha-Carbinolamine Dehydratase 1 (PCBD1); Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A); Sodium Channel Epithelial 1 Subunit Beta (SCNN1B); Sodium Channel Epithelial 1 Subunit Gamma (SCNN1G); Solute Carrier Family 1 Member 1 (SLC1A1); Solute Carrier Family 2 Member 2 (SLC2A2); Solute Carrier Family 3 Member 1 (SLC3A1); Solute Carrier Family 34 Member 1 (SLC34A1); Solute Carrier Family 34 Member 3 (SLC34A3); Solute Carrier Family 36 Member 2 (SLC36A2); Solute Carrier Family 4 Member 1 (SLC4A1); Solute Carrier Family 6 Member 19 (SLC6A19); Solute Carrier Family 6 Member 20 (SLC6A20); Solute Carrier Family 7 Member 7 (SLC7A7); Solute Carrier Family 7 Member 9 (SLC7A9); Solute Carrier Family 12 Member 1 (SLC12A1); Solute Carrier Family 12 Member 3 (SLC12A3); Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6); Von Hippel-Lindau Tumor Suppressor (VHL); WD Repeat Domain 72 (WDR72); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 1 (WNK1); With-no-lysine (WNK, Lysine Deficient) Protein Kinase 4 (WNK4); and combinations thereof; or176.ii) an inhibitor of a gene or protein selected from the group consisting of: Renin (REN), Sodium Channel Epithelial 1 Subunit Alpha (SCNN1 A), Sodium Channel Epithelial 1 Subunit Beta (SCNN1B), and Uromodulin (UMOD); and177.f) a pharmaceutically acceptable carrier.

104. The pharmaceutical composition of claim 103, wherein the pharmaceutically acceptable carrier comprises mannitol.

105. The pharmaceutical composition of claim 103, wherein the AAV comprises a capsid protein of AAV2G9.

106. The pharmaceutical composition of claim 103, wherein the solution that comprises the rAAV is at a concentration of 108viral genomes per mL (vg / mL) to 1015vg / mL.

107. The pharmaceutical composition of claim 103, wherein solution that comprises the rAAV is at a concentration of 108vg / mL to 1013vg / mL.

108. The pharmaceutical composition of claim 103, wherein the solution that comprises the rAAV is at a concentration of IxlO13to 5xl013vg / mL.

109. The pharmaceutical composition of claim 103, wherein the pharmaceutical composition comprises IxlO14to 2.5xl015rAAV viral genomes total.

110. The pharmaceutical composition of claim 103, wherein the pharmaceutical composition comprises IxlO13to 2xl013rAAV viral genomes total.185.187186.4903-3015-35943 Attorney Docket No: 046192-000134WOPT111. The pharmaceutical composition of claim 103, wherein the pharmaceutical composition comprises 5xl013to 6xl013rAAV viral genomes total.

112. The pharmaceutical composition of claim 103, wherein the pharmaceutical composition is in a unit dose of from about 0.13 mL / kg to about 0.33 mL / kg, the kg being the weight of the subject.

113. The pharmaceutical composition of claim 103, wherein the pharmaceutical composition is in a unit dose of from about 0.27 mL / kg to about 0.33 mL / kg.

114. The pharmaceutical composition of claim 103, wherein the pharmaceutical composition is in a unit dose of from about 0.27 mL / kg to about 1.25 mL / kg.

115. The pharmaceutical composition of claim 103, wherein the transgene comprises a reporter protein.

116. The pharmaceutical composition of claim 103, wherein the genome of the rAAV comprises a kidney-specific promoter.

117. The pharmaceutical composition of claim 116, wherein the kidney-specific promoter is selected from the group consisting of: kidney-specific cadherin (KSPC) gene promoter; Na+ / glucose co-transporter (SGLT2) gene promoter; sodium potassium, 2 chloride cotransporter (NKCC2) gene promoter; and E-cadherin (ECAD) gene promoter.

118. The pharmaceutical composition of claim 112, wherein the kidney-specific promoter is a synthetic promoter.

119. The pharmaceutical composition of claim 103, wherein the genome of the rAAV comprises a promoter specific to proximal convoluted tubules and / or collecting ducts.

120. The pharmaceutical composition of claim 103, wherein the rAAV is formulated for delivery to at least one renal papilla.

121. The pharmaceutical composition of claim 103, wherein the rAAV is formulated for delivery in liposomes, nanocapsules, microparticles, microspheres, lipid particles, lipid nanoparticles, or vesicles.

122. The pharmaceutical composition of claim 103, wherein the rAAV is formulated for delivery in lipid nanoparticles (LNPs).

123. A method of transducing nephrons in a kidney of a subject with a recombinant adeno- associated virus (rAAV), the method comprising: guiding a delivery device through the subject’s urethra, bladder, and ureter; and selectively administering at least a portion of a solution comprising the rAAV to at least one targeted renal papilla of the kidney, the solution having a total volume of from about 0.13 mL / kg to about 1.25 mL / kg, the kg being the weight of the subject, wherein the rAAV comprises AAV2G9, and wherein nephrons of the kidney are transduced with the rAAV at a therapeutically effective level.200.188201.4903-3015-35943

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