Compositions and methods for regulating mapt

Abstract

The disclosure relates to small interfering RNA (siRNA) molecules targeting MAPT and adeno-associated viral (AAV) particles encoding the same for treating tauopathies.

Description

Invention title: Compositions and Methods for Regulating MAPT. This disclosure relates to small interfering RNA (siRNA) molecules targeting MAPT and adeno-associated viral (AAV) particles encoding the same for treating tau pathologies.

Claims

We claim:

1. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant comprises an amino acid sequence having the following formula: [N1]-[N2]-[N3], wherein: (i) [N1] comprises X1, X2, and X3, wherein at least one of X1, X2, or X3 is G; (ii) [N2] comprises the amino acid sequence of SPH; and (iii) [N3] comprises X4, X5, and X6, wherein at least one of X4, X5, or X6 is a basic amino acid, e.g., a K or R; wherein [N1]-[N2]-[N3] is present in hypervariable loop IV; and wherein the AAV capsid variant comprises an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:

138.

2. The AAV particle of claim 1, wherein [N3] comprises SKA, KSG, ARM, VKS, ASR, VKI, KKN, VRM, RKA, KTS, KFG, KIG, KLG, KTT, KTY, KYG, SKD, SKP, TRG, VRG, KRG, GAR, KSA, KSR, SKL, SRA, SKR, SLR, SRG, SSR, FLR, SKW, SKS, WKA, VRR, SKV, SKT, SKG, GKA, TKA, NKA, SKL, SKN, AKA, KTG, KSL, KSE, KSV, KSW, KSN, KHG, KSQ, KSK, KLW, WKG, KMG, KMA, or RSG.

3. The AAV particle of claim 1 or 2, wherein [N2]-[N3] comprises SPHSKA (SEQ ID NO: 941), SPHKSG (SEQ ID NO: 946), SPHARM (SEQ ID NO: 947), SPHVKS (SEQ ID NO: 948), SPHASR (SEQ ID NO: 949), SPHVKI (SEQ ID NO: 950), SPHKKN (SEQ ID NO: 954), SPHVRM (SEQ ID NO: 955), SPHRKA (SEQ ID NO: 956), SPHKFG (SEQ ID NO: 957), SPHKIG (SEQ ID NO: 958), SPHKLG (SEQ ID NO: 959), SPHKTS (SEQ ID NO: 963), SPHKTT (SEQ ID NO: 964), SPHKTY (SEQ ID NO: 965), SPHKYG (SEQ ID NO: 966), SPHSKD (SEQ ID NO: 967), SPHSKP (SEQ ID NO: 968), SPHTRG (SEQ ID NO: 972), SPHVRG (SEQ ID NO: 973), SPHKRG (SEQ ID NO: 974), SPHGAR (SEQ ID NO: 975), SPHKSA (SEQ ID NO: 94), SPHKSR (SEQ ID NO: 951), SPHSKL (SEQ ID NO: 960), SPHSRA (SEQ ID NO: 969), SPHSKR (SEQ ID NO: 978), SPHSLR (SEQ ID NO: 952), SPHSRG (SEQ ID NO: 961), SPHSSR (SEQ ID NO: 970), SPHFLR (SEQ ID NO: 979), SPHSKW (SEQ ID NO: 953), SPHSKS (SEQ ID NO: 962) SPHWKA (SEQ ID NO: 971), SPHVRR (SEQ ID NO: 980), SPHSKT (SEQ ID NO: 95), SPHSKG (SEQ ID NO: 96), SPHGKA (SEQ ID NO: 97), SPHNKA (SEQ ID NO: 98), SPHSKN (SEQ ID NO: 99), SPHAKA (SEQ ID NO: 100), SPHSKV (SEQ ID NO: 101), SPHKTG (SEQ ID NO: 102), SPHTKA (SEQ ID NO: 103), SPHKSL (SEQ ID NO: 104), SPHKSE (SEQ ID NO: 105), SPHKSV (SEQ ID NO: 106), SPHKSW (SEQ ID NO: 107), SPHKSN (SEQ ID NO: 108), SPHKHG (SEQ ID NO: 109), SPHKSQ (SEQ ID NO: 110), SPHKSK (SEQ ID NO: 111), SPHKLW (SEQ ID NO: 112), SPHWKG (SEQ ID NO: 113), SPHKMG (SEQ ID NO: 114), SPHKMA (SEQ ID NO: 115), or SPHRSG (SEQ ID NO: 976).

4. The AAV particle of any one of claims 1-3, wherein [N1] comprises GSG, GHD, VSG, GQD, CSG, GRG, CSH, GQS, GSH, RVG, GSC, GLL, GDD, GHE, GNY, MSG, RNG, TSG, ISG, GPG, ESG, SSG, GNG, ASG, NSG, LSG, GGG, KSG, HSG, GTG, PSG, GSV, RSG, GIG, WSG, DSG, IDG, GLG, DAG, DGG, MEG, ENG, GSA, KNG, KEG, AIG, GYD, GHG, GRD, GND, GPD, GMG, GQV, GHN, GHP, or GHS.

5. The AAV particle of any one of claims 1-4, wherein [N1]-[N2]-[N3] comprises: (i) GSGSPHSKA (SEQ ID NO: 60), GHDSPHKSG (SEQ ID NO: 62), VSGSPHSKA (SEQ ID NO: 1083), GSGSPHARM (SEQ ID NO: 1076), GSGSPHVKS (SEQ ID NO: 1077), GQDSPHKSG (SEQ ID NO: 1078), GSGSPHASR (SEQ ID NO: 1079), GSGSPHVKI (SEQ ID NO: 1080), GSGSPHKKN (SEQ ID NO: 1081), GSGSPHVRM (SEQ ID NO: 1082), CSGSPHSKA (SEQ ID NO: 1084), GSGSPHRKA (SEQ ID NO: 1085), CSGSPHKTS (SEQ ID NO: 1086), CSHSPHKSG (SEQ ID NO: 1087), GQSSPHRSG (SEQ ID NO: 1088), GRGSPHASR (SEQ ID NO: 1089), GRGSPHSKA (SEQ ID NO: 1090), GSGSPHKFG (SEQ ID NO: 1091), GSGSPHKIG (SEQ ID NO: 1092), GSGSPHKLG (SEQ ID NO: 1093), GSGSPHKTS (SEQ ID NO: 1094), GSGSPHKTT (SEQ ID NO: 1095), GSGSPHKTY (SEQ ID NO: 1096), GSGSPHKYG (SEQ ID NO: 1097), GSGSPHSKD (SEQ ID NO: 1098), GSGSPHSKP (SEQ ID NO: 1099), GSGSPHTRG (SEQ ID NO: 1100), GSGSPHVRG (SEQ ID NO: 1101), GSHSPHKRG (SEQ ID NO: 1102), GSHSPHKSG (SEQ ID NO: 1103), VSGSPHASR (SEQ ID NO: 1104), VSGSPHGAR (SEQ ID NO: 1105), VSGSPHKFG (SEQ ID NO: 1106), GHDSPHKRG (SEQ ID NO: 1107), GDDSPHKSG (SEQ ID NO: 1108), GHESPHKSA (SEQ ID NO: 1109), GHDSPHKSA (SEQ ID NO: 1110), GNYSPHKIG (SEQ ID NO: 1111), GHDSPHKSR (SEQ ID NO: 1112), GSGSPHSKL (SEQ ID NO: 1113), GSGSPHSRA (SEQ ID NO: 1114), GSGSPHSKR (SEQ ID NO: 1115), GSGSPHSLR (SEQ ID NO: 1116), GSGSPHSRG (SEQ ID NO: 1117), GSGSPHSSR (SEQ ID NO: 1118), RVGSPHSKA (SEQ ID NO: 1119), GSCSPHRKA (SEQ ID NO: 1120), GSGSPHFLR (SEQ ID NO: 1121), GSGSPHSKW (SEQ ID NO: 1122), GSGSPHSKS (SEQ ID NO: 1123), GLLSPHWKA (SEQ ID NO: 1124), GSGSPHVRR (SEQ ID NO: 1125), GSGSPHSKV (SEQ ID NO: 1126), MSGSPHSKA (SEQ ID NO: 1127), RNGSPHSKA (SEQ ID NO: 1128), TSGSPHSKA (SEQ ID NO: 1129), ISGSPHSKA (SEQ ID NO: 1130), GPGSPHSKA (SEQ ID NO: 1131), GSGSPHSKT (SEQ ID NO: 1132), ESGSPHSKA (SEQ ID NO: 1133), SSGSPHSKA (SEQ ID NO: 1134), GNGSPHSKA (SEQ ID NO: 1135), ASGSPHSKA (SEQ ID NO: 1136), NSGSPHSKA (SEQ ID NO: 1137), LSGSPHSKA (SEQ ID NO: 1138), GGGSPHSKA (SEQ ID NO: 1139), KSGSPHSKA (SEQ ID NO: 1140), GGGSPHSKS (SEQ ID NO: 1141), GSGSPHSKG (SEQ ID NO: 1142), HSGSPHSKA (SEQ ID NO: 1143), GTGSPHSKA (SEQ ID NO: 1144), PSGSPHSKA (SEQ ID NO: 1145), GSVSPHGKA (SEQ ID NO: 1146), RSGSPHSKA (SEQ ID NO: 1147), GSGSPHTKA (SEQ ID NO: 1148), GIGSPHSKA (SEQ ID NO: 1149), WSGSPHSKA (SEQ ID NO: 1150), DSGSPHSKA (SEQ ID NO: 1151), IDGSPHSKA (SEQ ID NO: 1152), GSGSPHNKA (SEQ ID NO: 1153), GLGSPHSKS (SEQ ID NO: 1154), DAGSPHSKA (SEQ ID NO: 1155), DGGSPHSKA (SEQ ID NO: 1156), MEGSPHSKA (SEQ ID NO:1157), ENGSPHSKA (SEQ ID NO: 1158), GSASPHSKA (SEQ ID NO: 1159), GNGSPHSKS (SEQ ID NO: 1160), KNGSPHSKA (SEQ ID NO: 1161), KEGSPHSKA (SEQ ID NO: 1162), AIGSPHSKA (SEQ ID NO: 1163), GSGSPHSKN (SEQ ID NO: 1164), GSGSPHAKA (SEQ ID NO: 1165), GHDSPHKIG (SEQ ID NO: 1166), GYDSPHKSG (SEQ ID NO: 1167), GHESPHKSG (SEQ ID NO: 1168), GHDSPHKTG (SEQ ID NO: 1169), GRGSPHKRG (SEQ ID NO: 1170), GQDSPHKSG (SEQ ID NO: 1078), GHDSPHKSL (SEQ ID NO: 1171), GHGSPHSKA (SEQ ID NO: 1172), GHDSPHKSE (SEQ ID NO: 1173), VSGSPHSKA (SEQ ID NO: 1083), GRDSPHKSG (SEQ ID NO: 1174), GNDSPHKSV (SEQ ID NO: 1175), GQDSPHKIG (SEQ ID NO: 1176), GHDSPHKSV (SEQ ID NO: 1177), GPDSPHKIG (SEQ ID NO: 1178), GPDSPHKSG (SEQ ID NO: 1179), GHDSPHKSW (SEQ ID NO: 1180), GHDSPHKSN (SEQ ID NO: 1181), GMGSPHSKT (SEQ ID NO: 1182), GHDSPHKHG (SEQ ID NO: 1183), GQVSPHKSG (SEQ ID NO: 1184), GDDSPHKSV (SEQ ID NO: 1185), GHNSPHKSG (SEQ ID NO: 1186), GNGSPHKRG (SEQ ID NO: 1187), GHDSPHKYG (SEQ ID NO: 1188), GHDSPHKSQ (SEQ ID NO: 1189), GNDSPHKIG (SEQ ID NO: 1190), GHDSPHKSK (SEQ ID NO: 1191), GHDSPHKLW (SEQ ID NO: 1192), GHPSPHWKG (SEQ ID NO: 1193), GHDSPHKMG (SEQ ID NO: 1194), GHDSPHKMA (SEQ ID NO: 1195), or GHSSPHRSG (SEQ ID NO: 1196); or (ii) GSGSPHSKA (SEQ ID NO: 60), GHDSPHKSG (SEQ ID NO: 62), or VSGSPHSKA (SEQ ID NO: 1083).

6. The AAV particle of any one of claims 1-5, which further comprises: (i) [N0], wherein [N0] comprises TIN, TEN, TER, SMN, TIM, YLS, GLS, MPE, MEG, MEY, AEW, CEW, ANN, IPE, ADM, IEY, ADY, IET, MEW, CEY, RIN, MEI, LEY, ADW, IEI, DIM, FEQ, MEF, CDQ, LPE, IEN, MES, AEI, VEY, IIN, TSN, IEV, MEM, AEV, MDA, VEW, AEQ, LEW, MEL, MET, MEA, IES, MEV, CEI, ATN, MDG, QEV, ADQ, NMN, IEM, ISN, TGN, QQQ, HDW, IEG, TII, TFP, TEK, EIN, TVN, TFN, SIN, TSY, ELH, AIN, SVN, TDN, TFH, TVH, TSS, TID, TCN, NIN, TEH, AEM, AIK, TDK, TFK, SDQ, TEI, NTN, TET, SIK, TEL, TEA, TAN, TIY, TFS, TES, TTN, TED, TNN, EVH, TIS, TVR, TDR, TIK, NHI, TIP, ESD, TDL, TVP, TVI, AEH, NCL, TVK, NAD, TIT, NCV, TIR, NAL, VIN, TIQ, TEF, TRE, QGE, SEK, NVN, GGE, EFV, SDK, TEQ, EVQ, TEY, NCW, TDV, SDI, NSI, NSL, EVV, TEP, SEL, TWQ, TEV, AVN, GVL, TLN, TEG, TRD, NAI, AEN, AET, ETA, or NNL; and / or (ii) [N4], wherein [N4] comprises QNQQ (SEQ ID NO: 1198), WNQQ (SEQ ID NO: 1199), QYYV (SEQ ID NO: 1200), RRQQ (SEQ ID NO: 1201), GCGQ (SEQ ID NO: 1202), LRQQ (SEQ ID NO: 1203), RNQQ (SEQ ID NO: 1204), VNQQ (SEQ ID NO: 1205), FRLQ (SEQ ID NO: 1206), FNQQ (SEQ ID NO: 1207), LLQQ (SEQ ID NO: 1208), SNQQ (SEQ ID NO: 1209), RLQQ (SEQ ID NO: 1210), LNQQ (SEQ ID NO: 1211), QRKL (SEQ ID NO: 1212), LRRQ (SEQ ID NO: 1213), QRLR (SEQ ID NO: 1214), QRRL (SEQ ID NO: 1215), RRLQ (SEQ ID NO: 1216), RLRQ (SEQ ID NO: 1217), SKRQ (SEQ ID NO: 1218), QLYR (SEQ ID NO: 1219), QLTV (SEQ ID NO: 1220), QNKQ (SEQ ID NO: 1221), KNQQ (SEQ ID NO: 1222),QKQQ (SEQ ID NO: 1223), QTQQ (SEQ ID NO: 1224), QNHQ (SEQ ID NO: 1225), QHQQ (SEQ ID NO: 1226), QNQH (SEQ ID NO: 1227), QHRQ (SEQ ID NO: 1228), LTQQ (SEQ ID NO: 1229), QNQW (SEQ ID NO: 1230), QNTH (SEQ ID NO: 1231), RRRQ (SEQ ID NO: 1232), QYQQ (SEQ ID NO: 1233), QNDQ (SEQ ID NO: 1234), QNRH (SEQ ID NO: 1235), RDQQ (SEQ ID NO: 1236), PNLQ (SEQ ID NO: 1237), HVRQ (SEQ ID NO: 1238), PNQH (SEQ ID NO: 1239), HNQQ (SEQ ID NO: 1240), QSQQ (SEQ ID NO: 1241), QPAK (SEQ ID NO: 1242), QNLA (SEQ ID NO: 1243), QNQL (SEQ ID NO: 1244), QGQQ (SEQ ID NO: 1245), LNRQ (SEQ ID NO: 1246), QNPP (SEQ ID NO: 1247), QNLQ (SEQ ID NO: 1248), QDQE (SEQ ID NO: 1249), QDQQ (SEQ ID NO: 1250), HWQQ (SEQ ID NO: 1251), PNQQ (SEQ ID NO: 1252), PEQQ (SEQ ID NO: 1253), QRTM (SEQ ID NO: 1254), LHQH (SEQ ID NO: 1255), QHRI (SEQ ID NO: 1256), QYIH (SEQ ID NO: 1257), QKFE (SEQ ID NO: 1258), QFPS (SEQ ID NO: 1259), QNPL (SEQ ID NO: 1260), QAIK (SEQ ID NO: 1261), QNRQ (SEQ ID NO: 1263), QYQH (SEQ ID NO: 1264), QNPQ (SEQ ID NO: 1265), QHQL (SEQ ID NO: 1266), QSPP (SEQ ID NO: 1267), QAKL (SEQ ID NO: 1268), KSQQ (SEQ ID NO: 1269), QDRP (SEQ ID NO: 1270), QNLG (SEQ ID NO: 1271), QAFH (SEQ ID NO: 1272), QNAQ (SEQ ID NO: 1273), HNQL (SEQ ID NO: 1274), QKLN (SEQ ID NO: 1275), QNVQ (SEQ ID NO: 1276), QAQQ (SEQ ID NO: 1277), QTPP (SEQ ID NO: 1278), QPPA (SEQ ID NO: 1279), QERP (SEQ ID NO: 1280), QDLQ (SEQ ID NO: 1281), QAMH (SEQ ID NO: 1282), QHPS (SEQ ID NO: 1283), PGLQ (SEQ ID NO: 1284), QGIR (SEQ ID NO: 1285), QAPA (SEQ ID NO: 1286), QIPP (SEQ ID NO: 1287), QTQL (SEQ ID NO: 1288), QAPS (SEQ ID NO: 1289), QNTY (SEQ ID NO: 1290), QDKQ (SEQ ID NO: 1291), QNHL (SEQ ID NO: 1292), QIGM (SEQ ID NO: 1293), LNKQ (SEQ ID NO: 1294), PNQL (SEQ ID NO: 1295), QLQQ (SEQ ID NO: 1296), QRMS (SEQ ID NO: 1297), QGIL (SEQ ID NO: 1298), QDRQ (SEQ ID NO: 1299), RDWQ (SEQ ID NO: 1300), QERS (SEQ ID NO: 1301), QNYQ (SEQ ID NO: 1302), QRTC (SEQ ID NO: 1303), QIGH (SEQ ID NO: 1304), QGAI (SEQ ID NO: 1305), QVPP (SEQ ID NO: 1306), QVQQ (SEQ ID NO: 1307), LMRQ (SEQ ID NO: 1308), QYSV (SEQ ID NO: 1309), QAIT (SEQ ID NO: 1310), QKTL (SEQ ID NO: 1311), QLHH (SEQ ID NO: 1312), QNII (SEQ ID NO: 1313), QGHH (SEQ ID NO: 1314), QSKV (SEQ ID NO: 1315), QLPS (SEQ ID NO: 1316), IGKQ (SEQ ID NO: 1317), QAIH (SEQ ID NO: 1318), QHGL (SEQ ID NO: 1319), QFMC (SEQ ID NO: 1320), QNQM (SEQ ID NO: 1321), QHLQ (SEQ ID NO: 1322), QPAR (SEQ ID NO: 1323), QSLQ (SEQ ID NO: 1324), QSQL (SEQ ID NO: 1325), HSQQ (SEQ ID NO: 1326), QMPS (SEQ ID NO: 1327), QGSL (SEQ ID NO: 1328), QVPA (SEQ ID NO: 1329), HYQQ (SEQ ID NO: 1330), QVPS (SEQ ID NO: 1331), RGEQ (SEQ ID NO: 1332), PGQQ (SEQ ID NO: 1333), LEQQ (SEQ ID NO: 1334), QNQS (SEQ ID NO: 1335), QKVI (SEQ ID NO: 1336), QNND (SEQ ID NO: 1337), QSVH (SEQ ID NO: 1338), QPLG (SEQ ID NO: 1339), HNQE (SEQ ID NO: 1340), QIQQ (SEQ ID NO: 1341), QVRN (SEQ ID NO: 1342), PSNQ (SEQ ID NO: 1343), QVGH (SEQ ID NO: 1344), QRDI (SEQ ID NO: 1345), QMPN (SEQ ID NO: 1346), RGLQ (SEQ ID NO: 1347), PSLQ (SEQ ID NO: 1348), QRDQ (SEQ ID NO: 1349), QAKG (SEQ ID NO: 1350), QSAH (SEQ ID NO: 1351), QSTM (SEQ ID NO: 1352), QREM (SEQ IDNO: 1353), QYRA (SEQ ID NO: 1354), QRQQ (SEQ ID NO: 1355), QWQQ (SEQ ID NO: 1356), QRMN (SEQ ID NO: 1357), GDSQ (SEQ ID NO: 1358), QKIS (SEQ ID NO: 1359), PSMQ (SEQ ID NO: 1360), SPRQ (SEQ ID NO: 1361), MEQQ (SEQ ID NO: 1362), QYQN (SEQ ID NO: 1363), QIRQ (SEQ ID NO: 1364), QSVQ (SEQ ID NO: 1365), RSQQ (SEQ ID NO: 1366), QNKL (SEQ ID NO: 1367), QIQH (SEQ ID NO: 1368), PRQQ (SEQ ID NO: 1369), HTQQ (SEQ ID NO: 1370), QRQH (SEQ ID NO: 1371), RNQE (SEQ ID NO: 1372), QSKQ (SEQ ID NO: 1373), QNQP (SEQ ID NO: 1374), QSPQ (SEQ ID NO: 1375), QTRQ (SEQ ID NO: 1376), QNLH (SEQ ID NO: 1377), QNQE (SEQ ID NO: 1378), LNQP (SEQ ID NO: 1379), QNQD (SEQ ID NO: 1380), QNLL (SEQ ID NO: 1381), QLVI (SEQ ID NO: 1382), RTQE (SEQ ID NO: 1383), QTHQ (SEQ ID NO: 1384), QDQH (SEQ ID NO: 1385), QSQH (SEQ ID NO: 1386), VRQQ (SEQ ID NO: 1387), AWQQ (SEQ ID NO: 1388), QSVP (SEQ ID NO: 1389), QNIQ (SEQ ID NO: 1390), LDQQ (SEQ ID NO: 1391), PDQQ (SEQ ID NO: 1392), ESQQ (SEQ ID NO: 1393), QRQL (SEQ ID NO: 1394), QIIV (SEQ ID NO: 1395), QKQS (SEQ ID NO: 1396), QSHQ (SEQ ID NO: 1397), QFVV (SEQ ID NO: 1398), QSQP (SEQ ID NO: 1399), QNEQ (SEQ ID NO: 1400), INQQ (SEQ ID NO: 1401), RNRQ (SEQ ID NO: 1402), RDQK (SEQ ID NO: 1403), QWKR (SEQ ID NO: 1404), ENRQ (SEQ ID NO: 1405), QTQP (SEQ ID NO: 1406), QKQL (SEQ ID NO: 1407), RNQL (SEQ ID NO: 1408), ISIQ (SEQ ID NO: 1409), QTVC (SEQ ID NO: 1410), QQIM (SEQ ID NO: 1411), LNHQ (SEQ ID NO: 1412), QNQA (SEQ ID NO: 1413), QMIH (SEQ ID NO: 1414), RNHQ (SEQ ID NO: 1415), or QKMN (SEQ ID NO: 1416).

7. The AAV particle of claim 6, wherein [N0]-[N1]-[N2]-[N3]-[N4] comprises: (i) the amino acid sequence of any one of SEQ ID NOs: 2242-2886; or (ii) TENVSGSPHSKAQNQQ (SEQ ID NO: 2283), TERVSGSPHSKAQNQQ (SEQ ID NO: 2272), TINGSGSPHSKAQNQQ (SEQ ID NO: 2242), or TINGHDSPHKSGQNQQ (SEQ ID NO: 2243).

8. The AAV particle of claim 6 or 7, wherein: (i) [N0] is present at amino acids 450-452, numbered according to SEQ ID NO: 981, 982, or 138; (ii) [N1] is present at amino acids 453-455, numbered according to SEQ ID NO: 981, 982, or 138; (iii) [N2] is present at amino acids 456-458, numbered according to SEQ ID NO: 981 or 982; (iv) [N3] is present at amino acids 459-461, numbered according to SEQ ID NO: 981 or 982; (v) [N4] is present at amino acids 462-465, numbered according to SEQ ID NO: 981 or 982; and / or (vi) [N0]-[N1]-[N2]-[N3]-[N4] is present at amino acids 450-465, numbered according to SEQ ID NO: 981 or 982.

9. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant comprises: (i) the amino acid sequence of SPHSKA (SEQ ID NO: 941) in hypervariable loop IV; and (ii) an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:

138.

10. The AAV particle of claim 9, wherein the amino acid sequence of SPHSKA (SEQ ID NO: 941) is present immediately subsequent to amino acid 455, numbered according to SEQ ID NO:

981.

11. The AAV particle of claim 9 or 10, wherein the AAV capsid variant further comprises the amino acid E at position 451, numbered according to SEQ ID NO:

981.

12. The AAV particle of any one of claims 9-11, wherein the AAV capsid variant comprises the amino acid V at position 453, numbered according to SEQ ID NO:

981.

13. The AAV particle of any one of claims 9-12, wherein the AAV capsid variant comprises the amino acid R at position 452, numbered according to SEQ ID NO:

981.

14. The AAV particle of any one of claims 1-13, wherein the AAV capsid variant comprises: (i) an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 3904, 36, or 981; (ii) an amino acid sequence at least 95% or at least 98% identical to amino acids 138-742 of SEQ ID NO: 3904, 36, or 981; and / or (iii) an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 3904, 36, or 981.

15. The AAV particle of any one of claims 1-14, wherein the AAV capsid variant comprises: (i) the amino acid sequence of amino acids 203-742 of SEQ ID NO: 3904, 36, or 981; (ii) the amino acid sequence of amino acids 138-742 of SEQ ID NO: 3904, 36, or 981; and / or (iii) the amino acid sequence of SEQ ID NO: 3904, 36, or 981.

16. An AAV particle comprising an AAV capsid variant and a nucleic acid encoding a polynucleotide for inhibiting expression of human microtubule-associated protein tau (MAPT), wherein the AAV capsid variant comprises: (i) the amino acid sequence of HDSPHK (SEQ ID NO: 2) in hypervariable loop IV; and (ii) an amino acid sequence at least 95% identical to the amino acid sequence of positions 203-736 of SEQ ID NO:

138.

17. The AAV particle of claim 16, wherein the amino acid sequence of HDSPHK (SEQ ID NO: 2) is present immediately subsequent to amino acid 453, numbered according to SEQ ID NO:

982.

18. The AAV particle of any one of claims 1-9, 16, or 17, wherein the AAV capsid variant comprises: (i) an amino acid sequence at least 95% or at least 98% identical to amino acids 203-742 of SEQ ID NO: 982, 37, or 6; (ii) an amino acid sequence at least 95% or at least 98% identical to amino acids138-742 of SEQ ID NO: 982, 37, or 6; and / or (iii) an amino acid sequence at least 95% or at least 98% identical to the amino acid sequence of SEQ ID NO: 982, 37, or 6.

19. The AAV particle of any one of claims 1-9 or 16-18, wherein the AAV capsid variant comprises: (i) the amino acid sequence of amino acids 203-742 of SEQ ID NO: 982, 37, or 6; (ii) the amino acid sequence of amino acids 138-742 of SEQ ID NO: 982, 37, or 6; and / or (iii) the amino acid sequence of SEQ ID NO: 982, 37, or 6.

20. The AAV particle of any one of claims 1-19, wherein hypervariable loop IV comprises amino acids 449- 460, numbered according to SEQ ID NO:

138.

21. The AAV particle of any one of claims 1-20, wherein the AAV capsid variant: (i) has an increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138; (ii) transduces a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)), optionally wherein the level of transduction is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65-fold greater as compared to a reference sequence of SEQ ID NO: 138, e.g., whenmeasured by an assay, e.g., an immunohistochemistry assay or a qPCR assay, e.g., as described in Example 3 or 7; (iii) is enriched at least about 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or 210-fold, in the brain compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1 or 4; (iv) has increased tropism for a CNS cell or tissue, e.g., a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, of at least two to three species, e.g., a non-human primate and rodent (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 outbred mice), relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138; (v) is enriched at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100-fold, in the brain of at least two to three species, e.g., a non-human primate and rodent (e.g., Macaca fascicularis, Chlorocebus sabaeus, Callithrix jacchus, and / or mouse (e.g., BALB / c mice, C57Bl / 6 mice, and / or CD-1 outbred mice), compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 2, 5, or 8; (vi) delivers an increased level of a payload to a brain region, optionally wherein the level of the payload is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2 or 8), optionally wherein the brain region is a midbrain region (e.g., the hippocampus or thalamus), frontal cortex, temporal cortex, motor cortex, cerebral cortex, caudate, putamen, dentate nucleus, substantia nigra, or the brainstem; (vii) delivers an increased level of viral genomes to a brain region, optionally wherein the level of viral genomes is increased by at least 5, 10, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50-fold, as compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay, e.g., a qRT-PCR or a qPCR assay (e.g., as described in Example 2 or 8), optionally wherein the brain region is a putamen, caudate, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)); (viii) is enriched at least about 5, 10, 15, 20, 25, 30, or 35-fold, in the spinal cord compared to a reference sequence of SEQ ID NO: 138, e.g., when measured by an assay as described in Example 1 or 8, optionally wherein the region of the spinal cord is a thoracic spinal cord region, cervical spinal cord region, C5 ventral horn region, lumbar spinal cord region, or L5 ventral horn region; (ix) shows preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG) and / or the liver; (x) is capable of transducing neuronal cells and / or non-neuronal cells (e.g., astrocytes);(xi) is capable of transducing at least 20%, 25%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85, 90%, or 95% of cells in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, cerebellar cortex, cerebellum, dentate nucleus, and / or Lateral Geniculate Nucleus (LGN)) , e.g., when measured by an assay as described in Example 11; (xii) is capable of transducing at least 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% of astrocytes (e.g., Sox9+ astrocytes) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 11; (xiii) is capable of transducing at least 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, or 70% of neurons (e.g., NeuN+ neurons) in a brain region (e.g., a putamen, caudate, entorhinal cortex, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, or temporal cortex), e.g., when measured by an assay as described in Example 11; and / or (xiv) is capable of transducing at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, or 95%, 96%, or 97% of astrocytes (e.g., Sox9+ astrocytes) in the spinal cord (e.g., the cervical spinal cord, the thoracic spinal cord, or the lumbar spinal cord), e.g., when measured by an assay as described in Example 11.

22. The AAV particle of any one of claims 1-21, wherein nucleic acid encodes a siRNA comprising a sense strand and an antisense strand , wherein the antisense strand sequence is fully or partially complementary to human MAPT.

23. The AAV particle of claim 22, wherein: (i) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 4A, 5A, 9A, or 9B; and / or (ii) the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Tables 4A, 5A, 9A, or 9B; wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

24. The AAV particle of claim 22 or 23, wherein: (i) the antisense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sensestrand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) the antisense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998; (iv) the antisense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (v) the antisense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4694 and the sense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4492; (vi) the antisense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (viii) the antisense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (ix) the antisense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4477; (x) the antisense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and the sense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4521;(xi) the antisense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4494; or (xii) the antisense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4718 and the sense strand sequence comprises at least 18 or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4527.

25. The AAV particle of any one of claims 22-24, wherein: (i) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4906; (ii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4918; (iii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4922; (iv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4966; (v) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4970; (vi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4978; (vii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4982; (viii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4910;(ix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4914; (x) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5054; (xi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4926; (xii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4930; (xiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4934; (xiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4938; (xv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4942; (xvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5060; (xvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4946; (xviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4950; (xix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4954;(xx) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958; (xxi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4962; (xxii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5064; (xxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4974; (xxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5066; (xxv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4986; (xxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4990; (xxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4994; (xxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4998; (xxix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5002; (xxx) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5070;(xxxi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5006; (xxxii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5010; (xxxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5014; (xxxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958; (xxxv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5022; (xxxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5074; (xxxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5077; (xxxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5084; (xxxix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5088; (xl) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5092; (xli) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5096;(xlii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5098; (xliii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5101; (xliv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5108; (xlv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5112; (xlvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5116; (xlvii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5120; (xlviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5122; (xlix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5125; (l) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5132; (li) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5136; (lii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5140;(liii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or (liv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5146.

26. The AAV particle of any one of claims 22-25, wherein: (i) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4906; (ii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918; (iii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4922; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4966; (v) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4970; (vi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4978; (vii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4982; (viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4910; (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914; (x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5054; (xi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4926; (xii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4930; (xiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4934;(xiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4938; (xv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4942; (xvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5060; (xvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946; (xviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4950; (xix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954; (xx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4962; (xxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5064; (xxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4974; (xxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5066; (xxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4986; (xxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4990; (xxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994; (xxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4998; (xxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5002; (xxx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5070;(xxxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5006; (xxxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5010; (xxxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5014; (xxxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xxxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5022; (xxxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5074; (xxxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077; (xxxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5084; (xxxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5088; (xl) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5092; (xli) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5096; (xlii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; (xliii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5101; (xliv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5108; (xlv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5112; (xlvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116; (xlvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5120;(xlviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5122; (xlix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5125; (l) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5132; (li) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5136; (lii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5140; (liii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5144; or (liv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146.

27. The AAV particle of any one of claims 22-26, wherein: (i) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905; (ii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4917; (iii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921; (iv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4965; (v) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4969; (vi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977; or(vii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981.

28. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein: (a) the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978, and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918, and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

29. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein: (a) the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978, and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918, and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

30. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT, wherein the encoded polynucleotide comprises a siRNA comprising a sense strand sequence and an antisense strand sequence, wherein:(a) the encoded sense strand sequence comprises SEQ ID NO: 4906, and the encoded antisense strand sequence comprises SEQ ID NO: 4908; (b) the encoded sense strand sequence comprises SEQ ID NO: 4978, and the encoded antisense strand sequence comprises SEQ ID NO: 4920; or (c) the encoded sense strand sequence comprises SEQ ID NO: 4918, and the encoded antisense strand sequence comprises SEQ ID NO: 4920.

31. The AAV particle of any one of claims 22-30, wherein: (i) the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence comprise at least 15-30, 19-21, or 25-30 nucleotides in length, e.g., 17, 18, 20, 21, 22, 25, or 30 nucleotides in length; (ii) the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence comprise an overhang, e.g., an overhang at the 5’ end of the sense strand sequence and / or at the 3’ end of the antisense strand sequence, of 1 or 2 nucleotides; (iii) the sense strand and the antisense strand comprise one mismatch; and / or (iv) the antisense strand and the target sequence comprise one mismatch.

32. The AAV particle of any one of claims 1-31, wherein the polynucleotide for inhibiting MAPT (e.g., human MAPT) further comprises a modulatory polynucleotide, wherein the modulatory polynucleotide comprises the siRNA.

33. The AAV particle of claim 32, wherein the modulatory polynucleotide further comprises one, two, three or all of: (i) a 5’ flanking region; (ii) a loop region; and (iii) a 3’ flanking region.

34. The AAV particle of claim 33, wherein: (A) (i) the 5’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4878- 4886; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886;(ii) the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4887-4896; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; and / or (iii) the 3’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4897- 4904; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; and / or (B) (i) the nucleotide sequence encoding the 5’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 5387, 4354, 4355 or 5390-5395; (ii) the nucleotide sequence encoding the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4362-4371; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4362-4371; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4362-4371; and / or (iii) the nucleotide sequence encoding the 3’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 4372-4379; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4372-4379; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4372-4379.

35. The AAV particle of any one of claims 32-34, wherein the modulatory polynucleotide comprises:(A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; (B) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprisingone, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; (C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4887; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4899; or (D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4891, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; and (iii) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4900, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotidesrelative to the nucleotide sequence of SEQ ID NO: 4900, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.

36. The AAV particle of any one of claims 32-35, wherein the modulatory polynucleotide comprises in 5’ to 3’ order: (i) the 5’ flanking region, sense strand sequence, loop region, antisense strand sequence, and 3’ flanking region; or (ii) the 5’ flanking region, antisense strand sequence, loop region, sense strand sequence, and 3’ flanking region.

37. The AAV particle of any one of claims 32-36, wherein the modulatory polynucleotide comprises in 5’ to 3’ order: (A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4906; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4908; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900; (B) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three,four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4918; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4920; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900; (C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4922; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4924; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900; (D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotidesequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4966; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; (E) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4970; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898;(F) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4978; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898; or (G) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4982; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and (v) a 3’ flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO:4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898.

38. The AAV particle of any one of claims 32-37, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises in 5’ to 3’ order: (A) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4905; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4907; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (B) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4917; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4919; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (C) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4921; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4923; and (v) a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375; (D) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4965;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; (E) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4969; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; (F) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two,three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4977; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373; or (G) (i) a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4981; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923; and (v) a 3’ flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373.

39. The AAV particle of any one of claims 32-38, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, 4409, 4390, 4391, 4393, 4394, 4380-4389, 4392, 4395-4404, 4406, or 4407, or nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.

40. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

41. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

42. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a nucleic acid encoding a polynucleotide targeting human MAPT comprising the nucleotide sequence of any one of SEQ ID NOs: 4405, 4408, or 4393.

43. The AAV particle of any one of claims 1-42, which comprises a viral genome comprising a promoter operably linked to the nucleic acid encoding the polynucleotide for inhibiting human MAPT.

44. The AAV particle of claim 43, wherein the promoter: (i) is a ubiquitous promoter; (ii) is a cell or tissue specific promoter; (iii) is chosen from human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) immediate- early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC,cTnT, and CMV-MLC2k), a liver promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512) or a functional fragment, e.g., a truncation, or a functional variant thereof; (iii) is a CBA promoter or variant thereof; (iv) a synapsin promoter or variant thereof; (v) comprises the nucleotide sequence of any one of the nucleotide sequences provided in Table 2; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to any one of the nucleotide sequences provided in Table 2; or a nucleotide sequence with at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the nucleotide sequences provided in Table 2; (vi) comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5199; or (vii) comprises the nucleotide sequence of SEQ ID NO: 3883; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3883.

45. The AAV particle of claim 43 or 44, wherein the viral genome further comprises: (i) at least one or two inverted terminal repeat (ITR) sequences, optionally wherein the AAV viral genome comprises an ITR sequence positioned 5’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA and / or an ITR sequence positioned 3’ relative to the nucleic acid encoding the modulatory polynucleotide or siRNA; (ii) a polyadenylation (polyA) signal sequence; (iii) an enhancer, a Kozak sequence, an intron region, and / or an exon region; and / or (iv) a nucleotide sequence encoding a microRNA (miR) binding site, e.g., a miR binding site that modulates, e.g., reduces expression of payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed; optionally wherein the encoded miR binding site modulates, e.g., reduces expression of the payload encoded by the viral genome in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof.

46. The AAV particle of claim 45, wherein: (i) the ITR positioned 5’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 5503; a nucleotide sequence comprising at leastone, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197 or 5503; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197 or 5503; (ii) the ITR positioned 3’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 5504; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200 or 5504; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5200 or 5504; (iii) the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 4476; (iv) the enhancer comprises a CMVie enhancer or variant thereof; (v) the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471 or 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471 or 4472; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471 or 4472; and / or (vi) the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4475.

47. The AAV particle of any one of claims 43-46, wherein the viral genome is self-complementary or single stranded.

48. The AAV particle of any one of claims 43-47, wherein the viral genome comprises in 5’ to 3’ order: (A) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (B) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 3883; at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3883; (iii) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(iv) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (v) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vi) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; or (C) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4469; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4472; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4472; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or anucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4470.

49. The AAV particle of any one of claims 43-48, which comprises in 5’ to 3’ order: (A) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or anucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (B) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 3883; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 3883; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3883; (iii) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (iv) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (v) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vi) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (C) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;(iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4408, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (D) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than tenmodifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4409, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (E) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;(vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (F) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4391, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and(vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; (G) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200; or (H) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or anucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4394, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.

50. The AAV particle of any one of claims 43-49, which comprises the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194, 3886-3893, or 5473-5502, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194 or 5473- 5502.

51. An AAV particle comprising:(i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 3904; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, or 5184.

52. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 36; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, or 5184.

53. An AAV particle comprising: (i) an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 982; and (ii) a viral genome comprising the nucleotide sequence of SEQ ID NO: 5173, 3886, 5195, or 5184.

54. A cell comprising the AAV particle of any one of claims 1-53, optionally wherein, the cell is: (a) a mammalian cell or an insect cell; (b) a cell of a brain region or a spinal cord region (e.g., a CNS cell); (c) a cell of the brain or the spinal cord (e.g., a cell of a putamen, caudate, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, Lateral Geniculate Nucleus (LGN), cervical spinal cord, lumbar spinal cord, and / or thoracic spinal cord); or (d) a neuron or an astrocyte.

55. A method of making the AAV particle of any one of claims 1-53, comprising: (i) providing a host cell comprising a AAV viral genome; (ii) incubating the host cell under conditions suitable to enclose the viral genome in an AAV capsid protein; thereby making the AAV particle.

56. A pharmaceutical composition comprising the AAV particle of any one of claims 1-53, and a pharmaceutically acceptable excipient.

57. A method of delivering an siRNA for inhibiting MAPT expression to a cell, comprising administering to the cell an effective amount of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, thereby delivering the siRNA for inhibiting MAPT expression to the cell.

58. The method of claim 57, wherein the cell is: (a) a mammalian cell or an insect cell;(b) a cell of a brain region or a spinal cord region (e.g., a CNS cell); (c) a cell of the brain or the spinal cord (e.g., a cell of a putamen, caudate, hippocampus, thalamus, substantia nigra, motor cortex, frontal cortex, temporal cortex, cerebral cortex, dentate nucleus, Lateral Geniculate Nucleus (LGN), cervical spinal cord, lumbar spinal cord, and / or thoracic spinal cord); (d) a neuron or an astrocyte; and / or (e) in a subject.

59. The method of claim 58, wherein the subject has or has been diagnosed with having a genetic disorder (e.g., a monogenic disorder or a polygenic disorder); a neurological disorder (e.g., a neurodegenerative disorder); a disorder associated with tau expression, e.g., aberrant tau expression; and / or a tauopathy.

60. A method of treating a subject having or diagnosed with having a genetic disorder (e.g., a monogenic disorder or a polygenic disorder); a neurological disorder (e.g., a neurodegenerative disorder); a disorder associated with tau expression, e.g., aberrant tau expression; and / or a tauopathy, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53.

61. The method of claim 59 or 60, wherein the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy is Alzheimer’s disease (AD), Frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down’s syndrome, Pick’s disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), Prion diseases, CJD, Multiple system atrophy, mild cognitive impairment, Tangle-only dementia, or Progressive subcortical gliosis.

62. The method of claim 60 or 61, wherein treating comprises prevention of progression of the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy in the subject in the subject.

63. The method of any one of claims 60-62, further comprising performing a blood test, an imaging test (e.g., a PET scan or a PET scan in combination with biomarker, e.g., serum biomarker staining), a CNS biopsy sample, or an aqueous cerebral spinal fluid biopsy, optionally wherein the blood test, imaging test, biopsysample, or aqueous cerebral spinal fluid biopsy is performed prior to, during, or after treatment with the AAV particle, modulatory polynucleotide, siRNA, or pharmaceutical composition.

64. The method of any one of claims 60-63, wherein the pharmaceutical composition or AAV particle are administered to the subject: (i) intravenously, via intra-cisterna magna injection (ICM), intracerebrally, intrathecally, intracerebroventricularly, via intraparenchymal administration, or intramuscularly; (ii) via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration; (iii) intravenously.

65. The pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, for use in a method of delivering an siRNA for inhibiting MAPT expression to a cell.

66. The pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, for use in the treatment of a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy.

67. Use of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, in the manufacture of a medicament for delivering an siRNA for inhibiting MAPT expression to a cell.

68. Use of the pharmaceutical composition of claim 56 or the AAV particle of any one of claims 1-53, in the manufacture of a medicament for treating a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and / or tauopathy.

Images