Methods and compositions for prevention or treatment of RSV infection
View Patent ↗Methods and compositions are provided for the prevention or treatment of RSV infection in a human. The methods include administering one or more doses of a composition comprising an siRNA. The dose can be formulated for topical or parenteral administration. Topical administration includes administration as a nasal spray, or by inhalation of respirable particles or droplets.
1. A method of reducing the risk of Respiratory Syncytial Virus (RSV) associated bronchiolitis obliterans syndrome (BOS) in a subject, comprising administering to said subject a composition comprising a therapeutically effective amount of a dsRNA that targets a P, N, or L gene of RSV wherein the dsRNA comprises a sense strand and an antisense strand and each strand is 15-30 nucleotides in length, wherein the antisense strand of the dsRNA targeting the N gene is complementary to at least 15 contiguous nucleotides of SEQ ID NOS: 277-284.
2. The method of claim 1 , wherein the sense strand is selected from SEQ ID NOs: 3-116, 231-249, and 269-276, and the antisense strand is selected from SEQ ID NOs: 117-230, 250-268, and 277-284.
3. The method of claim 1 , wherein said subject is a human lung transplant recipient.
4. The method of claim 1 , wherein said subject is receiving bronchodilator therapy.
5. The method of claim 1 , wherein ribavarin is administered to said subject.
6. The method of claim 1 , wherein said administration is intranasal or intrapulmonary.
7. The method of claim 6 , wherein said intrapulmonary administration is by inhalation of said composition.
8. The method of claim 1 , wherein said composition is administered as an aerosol.
9. The method of claim 8 , wherein said aerosol is a nasal spray.
10. The method of claim 8 , wherein said aerosol is produced by a nebulizer.
11. The method of claim 10 , wherein said nebulizer is a PARI eFlow® 30L nebulizer.
12. The method of claim 1 , comprising administering a plurality of doses of said composition.
13. The method of claim 12 , wherein one of said plurality of doses is administered daily.
14. The method of claim 12 , wherein said plurality of doses is two or three doses.
15. The method of claim 12 , wherein said subject is presently infected with RSV when the first of said plurality of doses is administered.
16. The method of claim 12 , wherein said administering of said plurality of doses is by inhalation and delivers a total dose of between 0.1 and 0.6 mg/kg of anhydrous oligonucleotide to said subject.
17. The method of claim 1 , further comprising determining a characteristic of RSV infection, wherein said characteristic is selected from RSV mRNA, RSV peak viral load, time to peak RSV viral load, duration of RSV viral shedding, RSV viral AUC, or RSV titer.
18. The method of claim 1 , wherein said administering reduces RSV protein, RSV mRNA, RSV peak viral load, time to peak RSV viral load, duration of RSV viral shedding, RSV viral AUC, or RSV titer in a cell of the respiratory tract of said subject.
19. The method of claim 1 , wherein said administration of said composition to said subject is started within seven days of onset of symptoms of RSV infection, wherein said symptoms comprise a decrease in FEV1, fever, new onset rhinorrhea, sore throat, nasal congestion, cough, wheezing, headache, myalgia, chills, or shortness of breath.
20. The method of claim 1 , wherein said administration of said composition improves FEV1 or causes a reduction in one or more symptoms of RSV infection in said subject relative to a placebo, wherein said symptoms are selected from the group consisting of fever, new onset rhinorrhea, sore throat, nasal congestion, cough, wheezing, headache, myalgia, chills, or shortness of breath or prevents a reduction in lung function for at least 90 days as determined by measurement of a FEV1 in said subject.
21. The method of claim 17 , wherein said characteristic of RSV infection is determined by quantitative RT-PCR (qRT-PCR) analysis of a nasal swab sample and/or a sputum sample from said subject.
22. The method of claim 4 , wherein said human lung transplant recipient is administered said composition within one hour of receiving bronchodilator therapy.
23. The method of claim 5 , wherein said subject is administered said composition one to two hours before administration of ribavirin.
24. The method of claim 1 , wherein the method prevents a reduction in lung function for at least 90 days as determined by measurement of a FEV1 in the lung transplant recipient.
25. The method of claim 1 , wherein the dsRNA comprises one of the following sense strand and antisense strand pairs:
SEQ ID
SEQ ID
NO.
Sense
NO.
Antisense
3
GGAUCCCAUUAUUAAUGGAdTdT
117
UCCAUUAAUAAUGGGAUCCdTdT
4
GAUCCCAUUAUUAAUGGAAdTdT
118
UUCCAUUAAUAAUGGGAUCdTdT
5
AGUUAUUUAAAAGGUGUUAdTdT
119
UAACACCUUUUAAAUAACUdTdT
6
GUUAUUUAAAAGGUGUUAUdTdT
120
AUAACACCUUUUAAAUAACdTdT
7
AUUUAAAAGGUGUUAUCUCdTdT
121
GAGAUAACACCUUUUAAAUdTdT
8
UUAAAAGGUGUUAUCUCUUdTdT
122
AAGAGAUAACACCUUUUAAdTdT
9
AAGUCCACUACUAGAGCAUdTdT
123
AUGCUCUAGUAGUGGACUUdTdT
10
AGUCCACUACUAGAGCAUAdTdT
124
UAUGCUCUAGUAGUGGACUdTdT
11
GUCCACUACUAGAGCAUAUdTdT
125
AUAUGCUCUAGUAGUGGACdTdT
12
UCCACUACUAGAGCAUAUGdTdT
126
CAUAUGCUCUAGUAGUGGAdTdT
13
GAAGAGCUAUAGAAAUAAGdTdT
127
CUUAUUUCUAUAGCUCUUCdTdT
14
GAGCUAUAGAAAUAAGUGAdTdT
128
UCACUUAUUUCUAUAGCUCdTdT
15
CUAUAGAAAUAAGUGAUGUdTdT
129
ACAUCACUUAUUUCUAUAGdTdT
16
UCAAAACAACACUCUUGAAdTdT
130
UUCAAGAGUGUUGUUUUGAdTdT
17
UAGAGGGAUUUAUUAUGUCdTdT
131
GACAUAAUAAAUCCCUCUAdTdT
18
AUAAAAGGGUUUGUAAAUAdTdT
132
UAUUUACAAACCCUUUUAUdTdT
19
CUCAGUGUAGGUAGAAUGUdTdT
133
ACAUUCUACCUACACUGAGdTdT
20
UCAGUGUAGGUAGAAUGUUdTdT
134
AACAUUCUACCUACACUGAdTdT
21
CAGUGUAGGUAGAAUGUUUdTdT
135
AAACAUUCUACCUACACUGdTdT
22
AGUGUAGGUAGAAUGUUUGdTdT
136
CAAACAUUCUACCUACACUdTdT
23
GUGUAGGUAGAAUGUUUGCdTdT
137
GCAAACAUUCUACCUACACdTdT
24
ACAAGAUAUGGUGAUCUAGdTdT
138
CUAGAUCACCAUAUCUUGUdTdT
25
AGCAAAUUCAAUCAAGCAUdTdT
139
AUGCUUGAUUGAAUUUGCUdTdT
26
GCAAAUUCAAUCAAGCAUUdTdT
140
AAUGCUUGAUUGAAUUUGCdTdT
27
GAUGAACAAAGUGGAUUAUdTdT
141
AUAAUCCACUUUGUUCAUCdTdT
28
UAAUAUCUCUCAAAGGGAAdTdT
142
UUCCCUUUGAGAGAUAUUAdTdT
29
AUAUCUCUCAAAGGGAAAUdTdT
143
AUUUCCCUUUGAGAGAUAUdTdT
30
UAUCUCUCAAAGGGAAAUUdTdT
144
AAUUUCCCUUUGAGAGAUAdTdT
31
CAUGCUCAAGCAGAUUAUUdTdT
145
AAUAAUCUGCUUGAGCAUGdTdT
32
UGCUCAAGCAGAUUAUUUGdTdT
146
CAAAUAAUCUGCUUGAGCAdTdT
33
UAGCAUUAAAUAGCCUUAAdTdT
147
UUAAGGCUAUUUAAUGCUAdTdT
34
AGCAUUAAAUAGCCUUAAAdTdT
148
UUUAAGGCUAUUUAAUGCUdTdT
35
GCAUUAAAUAGCCUUAAAUdTdT
149
AUUUAAGGCUAUUUAAUGCdTdT
36
CAUUAAAUAGCCUUAAAUUdTdT
150
AAUUUAAGGCUAUUUAAUGdTdT
37
UAUUAUGCAGUUUAAUAUUdTdT
151
AAUAUUAAACUGCAUAAUAdTdT
38
UUAUGCAGUUUAAUAUUUAdTdT
152
UAAAUAUUAAACUGCAUAAdTdT
39
AAAAGUGCACAACAUUAUAdTdT
153
UAUAAUGUUGUGCACUUUUdTdT
40
AAAGUGCACAACAUUAUACdTdT
154
GUAUAAUGUUGUGCACUUUdTdT
41
AUAUAGAACCUACAUAUCCdTdT
155
GGAUAUGUAGGUUCUAUAUdTdT
42
UAUAGAACCUACAUAUCCUdTdT
156
AGGAUAUGUAGGUUCUAUAdTdT
43
UAAGAGUUGUUUAUGAAAGdTdT
157
CUUUCAUAAACAACUCUUAdTdT
44
ACAGUCAGUAGUAGACCAUdTdT
158
AUGGUCUACUACUGACUGUdTdT
45
CAGUCAGUAGUAGACCAUGdTdT
159
CAUGGUCUACUACUGACUGdTdT
46
AGUCAGUAGUAGACCAUGUdTdT
160
ACAUGGUCUACUACUGACUdTdT
47
GUCAGUAGUAGACCAUGUGdTdT
161
CACAUGGUCUACUACUGACdTdT
48
UCAGUAGUAGACCAUGUGAdTdT
162
UCACAUGGUCUACUACUGAdTdT
49
CAUGUGAAUUCCCUGCAUCdTdT
163
GAUGCAGGGAAUUCACAUGdTdT
50
AUGUGAAUUCCCUGCAUCAdTdT
164
UGAUGCAGGGAAUUCACAUdTdT
51
UGUGAAUUCCCUGCAUCAAdTdT
165
UUGAUGCAGGGAAUUCACAdTdT
52
GUGAAUUCCCUGCAUCAAUdTdT
166
AUUGAUGCAGGGAAUUCACdTdT
53
AAUUCCCUGCAUCAAUACCdTdT
167
GGUAUUGAUGCAGGGAAUUdTdT
54
GCAUCAAUACCAGCUUAUAdTdT
168
UAUAAGCUGGUAUUGAUGCdTdT
55
CAUCAAUACCAGCUUAUAGdTdT
169
CUAUAAGCUGGUAUUGAUGdTdT
56
AUACCAGCUUAUAGAACAAdTdT
170
UUGUUCUAUAAGCUGGUAUdTdT
57
UACCAGCUUAUAGAACAACdTdT
171
GUUGUUCUAUAAGCUGGUAdTdT
58
ACCAGCUUAUAGAACAACAdTdT
172
UGUUGUUCUAUAAGCUGGUdTdT
59
CCAGCUUAUAGAACAACAAdTdT
173
UUGUUGUUCUAUAAGCUGGdTdT
60
CAGCUUAUAGAACAACAAAdTdT
174
UUUGUUGUUCUAUAAGCUGdTdT
61
AUAGAACAACAAAUUAUCAdTdT
175
UGAUAAUUUGUUGUUCUAUdTdT
62
UAUUAACAGAAAAGUAUGGdTdT
176
CCAUACUUUUCUGUUAAUAdTdT
63
UGAGAUACAUUUGAUGAAAdTdT
177
UUUCAUCAAAUGUAUCUCAdTdT
64
GAGAUACAUUUGAUGAAACdTdT
178
GUUUCAUCAAAUGUAUCUCdTdT
65
GAUACAUUUGAUGAAACCUdTdT
179
AGGUUUCAUCAAAUGUAUCdTdT
66
AUACAUUUGAUGAAACCUCdTdT
180
GAGGUUUCAUCAAAUGUAUdTdT
67
UACAUUUGAUGAAACCUCCdTdT
181
GGAGGUUUCAUCAAAUGUAdTdT
68
AAGUGAUACAAAAACAGCAdTdT
182
UGCUGUUUUUGUAUCACUUdTdT
69
AGUGAUACAAAAACAGCAUdTdT
183
AUGCUGUUUUUGUAUCACUdTdT
70
UGAUACAAAAACAGCAUAUdTdT
184
AUAUGCUGUUUUUGUAUCAdTdT
71
UUUAAGUACUAAUUUAGCUdTdT
185
AGCUAAAUUAGUACUUAAAdTdT
72
UUAAGUACUAAUUUAGCUGdTdT
186
CAGCUAAAUUAGUACUUAAdTdT
73
UAAGUACUAAUUUAGCUGGdTdT
187
CCAGCUAAAUUAGUACUUAdTdT
74
AAGUACUAAUUUAGCUGGAdTdT
188
UCCAGCUAAAUUAGUACUUdTdT
75
AGUACUAAUUUAGCUGGACdTdT
189
GUCCAGCUAAAUUAGUACUdTdT
76
GUACUAAUUUAGCUGGACAdTdT
190
UGUCCAGCUAAAUUAGUACdTdT
77
ACUAAUUUAGCUGGACAUUdTdT
191
AAUGUCCAGCUAAAUUAGUdTdT
78
AAUUUAGCUGGACAUUGGAdTdT
192
UCCAAUGUCCAGCUAAAUUdTdT
79
AUUUAGCUGGACAUUGGAUdTdT
193
AUCCAAUGUCCAGCUAAAUdTdT
80
UUAGCUGGACAUUGGAUUCdTdT
194
GAAUCCAAUGUCCAGCUAAdTdT
81
UUUUGAAAAAGAUUGGGGAdTdT
195
UCCCCAAUCUUUUUCAAAAdTdT
82
UUUGAAAAAGAUUGGGGAGdTdT
196
CUCCCCAAUCUUUUUCAAAdTdT
83
UGAAAAAGAUUGGGGAGAGdTdT
197
CUCUCCCCAAUCUUUUUCAdTdT
84
GAAAAAGAUUGGGGAGAGGdTdT
198
CCUCUCCCCAAUCUUUUUCdTdT
85
UAUGAACACUUCAGAUCUUdTdT
199
AAGAUCUGAAGUGUUCAUAdTdT
86
AUGAACACUUCAGAUCUUCdTdT
200
GAAGAUCUGAAGUGUUCAUdTdT
87
UGCCCUUGGGUUGUUAACAdTdT
201
UGUUAACAACCCAAGGGCAdTdT
88
GCCCUUGGGUUGUUAACAUdTdT
202
AUGUUAACAACCCAAGGGCdTdT
89
UAUAGCAUUCAUAGGUGAAdTdT
203
UUCACCUAUGAAUGCUAUAdTdT
90
AUAGCAUUCAUAGGUGAAGdTdT
204
CUUCACCUAUGAAUGCUAUdTdT
91
UAGCAUUCAUAGGUGAAGGdTdT
205
CCUUCACCUAUGAAUGCUAdTdT
92
AUUCAUAGGUGAAGGAGCAdTdT
206
UGCUCCUUCACCUAUGAAUdTdT
93
UUGCAAUGAUCAUAGUUUAdTdT
207
UAAACUAUGAUCAUUGCAAdTdT
94
UGCAAUGAUCAUAGUUUACdTdT
208
GUAAACUAUGAUCAUUGCAdTdT
95
GCAAUGAUCAUAGUUUACCdTdT
209
GGUAAACUAUGAUCAUUGCdTdT
96
CAAUGAUCAUAGUUUACCUdTdT
210
AGGUAAACUAUGAUCAUUGdTdT
97
AAUGAUCAUAGUUUACCUAdTdT
211
UAGGUAAACUAUGAUCAUUdTdT
98
AUGAUCAUAGUUUACCUAUdTdT
212
AUAGGUAAACUAUGAUCAUdTdT
99
GAUCAUAGUUUACCUAUUGdTdT
213
CAAUAGGUAAACUAUGAUCdTdT
100
AUCAUAGUUUACCUAUUGAdTdT
214
UCAAUAGGUAAACUAUGAUdTdT
101
UCAUAGUUUACCUAUUGAGdTdT
215
CUCAAUAGGUAAACUAUGAdTdT
102
CAUAGUUUACCUAUUGAGUdTdT
216
ACUCAAUAGGUAAACUAUGdTdT
103
AUAGUUUACCUAUUGAGUUdTdT
217
AACUCAAUAGGUAAACUAUdTdT
104
CAUUGGUCUUAUUUACAUAdTdT
218
UAUGUAAAUAAGACCAAUGdTdT
105
UUGGUCUUAUUUACAUAUAdTdT
219
UAUAUGUAAAUAAGACCAAdTdT
106
UGGUCUUAUUUACAUAUAAdTdT
220
UUAUAUGUAAAUAAGACCAdTdT
107
GGUCUUAUUUACAUAUAAAdTdT
221
UUUAUAUGUAAAUAAGACCdTdT
108
AUAUCAUGCUCAAGAUGAUdTdT
222
AUCAUCUUGAGCAUGAUAUdTdT
109
UAUCAUGCUCAAGAUGAUAdTdT
223
UAUCAUCUUGAGCAUGAUAdTdT
110
UGAUAUUGAUUUCAAAUUAdTdT
224
UAAUUUGAAAUCAAUAUCAdTdT
111
UACUUAGUCCUUACAAUAGdTdT
225
CUAUUGUAAGGACUAAGUAdTdT
112
UUAGUCCUUACAAUAGGUCdTdT
226
GACCUAUUGUAAGGACUAAdTdT
113
UAGUCCUUACAAUAGGUCCdTdT
227
GGACCUAUUGUAAGGACUAdTdT
114
AUAUUCUAUAGCUGGACGUdTdT
228
ACGUCCAGCUAUAGAAUAUdTdT
115
UAUUCUAUAGCUGGACGUAdTdT
229
UACGUCCAGCUAUAGAAUAdTdT
116
AUUCUAUAGCUGGACGUAAdTdT
230
UUACGUCCAGCUAUAGAAUdTdT
231
AAAUUCCUAGAAUCAAUAAdTdT
250
UUAUUGAUUCUAGGAAUUUdTdT
232
AAUUCCUAGAAUCAAUAAAdTdT
251
UUUAUUGAUUCUAGGAAUUdTdT
233
UUCCUAGAAUCAAUAAAGGdTdT
252
CCUUUAUUGAUUCUAGGAAdTdT
234
UCCUAGAAUCAAUAAAGGGdTdT
253
CCCUUUAUUGAUUCUAGGAdTdT
235
CUAGAAUCAAUAAAGGGCAdTdT
254
UGCCCUUUAUUGAUUCUAGdTdT
236
ACAUUUGAUAACAAUGAAGdTdT
255
CUUCAUUGUUAUCAAAUGUdTdT
237
CAUUUGAUAACAAUGAAGAdTdT
256
UCUUCAUUGUUAUCAAAUGdTdT
238
AUUUGAUAACAAUGAAGAAdTdT
257
UUCUUCAUUGUUAUCAAAUdTdT
239
UUUGAUAACAAUGAAGAAGdTdT
258
CUUCUUCAUUGUUAUCAAAdTdT
240
AAGUGAAAUACUAGGAAUGdTdT
259
CAUUCCUAGUAUUUCACUUdTdT
241
AGUGAAAUACUAGGAAUGCdTdT
260
GCAUUCCUAGUAUUUCACUdTdT
242
GUGAAAUACUAGGAAUGCUdTdT
261
AGCAUUCCUAGUAUUUCACdTdT
243
UGAAAUACUAGGAAUGCUUdTdT
262
AAGCAUUCCUAGUAUUUCAdTdT
244
GAAAUACUAGGAAUGCUUCdTdT
263
GAAGCAUUCCUAGUAUUUCdTdT
245
AAAUACUAGGAAUGCUUCAdTdT
264
UGAAGCAUUCCUAGUAUUUdTdT
246
GAAGCAUUAAUGACCAAUGdTdT
265
CAUUGGUCAUUAAUGCUUCdTdT
247
AAGCAUUAAUGACCAAUGAdTdT
266
UCAUUGGUCAUUAAUGCUUdTdT
248
CGAUAAUAUAACAGCAAGAdTsdT
267
UCUUGCUGUUAUAUUAUCGdTsdT
249
CGAUUAUAUUACAGGAUGAdTsdT
268
UCAUCCUGUAAUAUAAUCGdTsdT
1
GGCUCUUAGCAAAGUCAAGdTdT
2
CUUGACUUUGCUAAGAGCCdTdT
269
CUCUUAGCAAAGUCAAGUUdTdT
277
AACUUGACUUUGCUAAGAGdTdT
270
CUGUCAUCCAGCAAAUACAdTdT
278
UGUAUUUGCUGGAUGACAGdTdT
271
UGUCAUCCAGCAAAUACACdTdT
279
GUGUAUUUGCUGGAUGACAdTdT
272
UAAUAGGUAUGUUAUAUGCdTdT
280
GCAUAUAACAUACCUAUUAdTdT
273
AUUGAGAUAGAAUCUAGAAdTdT
281
UUCUAGAUUCUAUCUCAAUdTdT
274
AUUCUACCAUAUAUUGAACdTdT
282
GUUCAAUAUAUGGUAGAAUdTdT
275
UUCUACCAUAUAUUGAACAdTdT
283
UGUUCAAUAUAUGGUAGAAdTdT
276
UCUACCAUAUAUUGAACAAdTdT
284
UUGUUCAAUAUAUGGUAGAdTdT.
26. A method of reducing the risk of Respiratory Syncytial Virus (RSV) associated bronchiolitis obliterans syndrome (BOS) in a human lung transplant recipient, comprising administering to said subject a composition comprising a therapeutically effective amount of a dsRNA that targets a P, N, or L gene of RSV wherein the dsRNA comprises a sense strand and an antisense strand and each strand is 15-30 nucleotides in length, wherein the antisense strand of the dsRNA targeting the N gene is complementary to at least 15 contiguous nucleotides of SEQ ID NOS: 277-284, wherein ribavirin is administered to said human lung transplant recipient, and wherein the composition is administered daily as an aerosol produced by a PARI eFlow® 30L nebulizer.
27. A method of reducing the risk of Respiratory Syncytial Virus (RSV) associated bronchiolitis obliterans syndrome (BOS) in a human lung transplant recipient, comprising administering to said subject a composition comprising a therapeutically effective amount of a dsRNA that targets a P, N, or L gene of RSV wherein the dsRNA comprises a sense strand and an antisense strand and each strand is 15-30 nucleotides in length, wherein ribavirin is administered to said human lung transplant recipient, wherein the composition is administered daily as an aerosol produced by a PARI eFlow® 30L nebulizer, and wherein the dsRNA comprises one of the following sense strand and antisense strand pairs:
SEQ ID
SEQ ID
NO.
Sense
NO.
Antisense
3
GGAUCCCAUUAUUAAUGGAdTdT
117
UCCAUUAAUAAUGGGAUCCdTdT
4
GAUCCCAUUAUUAAUGGAAdTdT
118
UUCCAUUAAUAAUGGGAUCdTdT
5
AGUUAUUUAAAAGGUGUUAdTdT
119
UAACACCUUUUAAAUAACUdTdT
6
GUUAUUUAAAAGGUGUUAUdTdT
120
AUAACACCUUUUAAAUAACdTdT
7
AUUUAAAAGGUGUUAUCUCdTdT
121
GAGAUAACACCUUUUAAAUdTdT
8
UUAAAAGGUGUUAUCUCUUdTdT
122
AAGAGAUAACACCUUUUAAdTdT
9
AAGUCCACUACUAGAGCAUdTdT
123
AUGCUCUAGUAGUGGACUUdTdT
10
AGUCCACUACUAGAGCAUAdTdT
124
UAUGCUCUAGUAGUGGACUdTdT
11
GUCCACUACUAGAGCAUAUdTdT
125
AUAUGCUCUAGUAGUGGACdTdT
12
UCCACUACUAGAGCAUAUGdTdT
126
CAUAUGCUCUAGUAGUGGAdTdT
13
GAAGAGCUAUAGAAAUAAGdTdT
127
CUUAUUUCUAUAGCUCUUCdTdT
14
GAGCUAUAGAAAUAAGUGAdTdT
128
UCACUUAUUUCUAUAGCUCdTdT
15
CUAUAGAAAUAAGUGAUGUdTdT
129
ACAUCACUUAUUUCUAUAGdTdT
16
UCAAAACAACACUCUUGAAdTdT
130
UUCAAGAGUGUUGUUUUGAdTdT
17
UAGAGGGAUUUAUUAUGUCdTdT
131
GACAUAAUAAAUCCCUCUAdTdT
18
AUAAAAGGGUUUGUAAAUAdTdT
132
UAUUUACAAACCCUUUUAUdTdT
19
CUCAGUGUAGGUAGAAUGUdTdT
133
ACAUUCUACCUACACUGAGdTdT
20
UCAGUGUAGGUAGAAUGUUdTdT
134
AACAUUCUACCUACACUGAdTdT
21
CAGUGUAGGUAGAAUGUUUdTdT
135
AAACAUUCUACCUACACUGdTdT
22
AGUGUAGGUAGAAUGUUUGdTdT
136
CAAACAUUCUACCUACACUdTdT
23
GUGUAGGUAGAAUGUUUGCdTdT
137
GCAAACAUUCUACCUACACdTdT
24
ACAAGAUAUGGUGAUCUAGdTdT
138
CUAGAUCACCAUAUCUUGUdTdT
25
AGCAAAUUCAAUCAAGCAUdTdT
139
AUGCUUGAUUGAAUUUGCUdTdT
26
GCAAAUUCAAUCAAGCAUUdTdT
140
AAUGCUUGAUUGAAUUUGCdTdT
27
GAUGAACAAAGUGGAUUAUdTdT
141
AUAAUCCACUUUGUUCAUCdTdT
28
UAAUAUCUCUCAAAGGGAAdTdT
142
UUCCCUUUGAGAGAUAUUAdTdT
29
AUAUCUCUCAAAGGGAAAUdTdT
143
AUUUCCCUUUGAGAGAUAUdTdT
30
UAUCUCUCAAAGGGAAAUUdTdT
144
AAUUUCCCUUUGAGAGAUAdTdT
31
CAUGCUCAAGCAGAUUAUUdTdT
145
AAUAAUCUGCUUGAGCAUGdTdT
32
UGCUCAAGCAGAUUAUUUGdTdT
146
CAAAUAAUCUGCUUGAGCAdTdT
33
UAGCAUUAAAUAGCCUUAAdTdT
147
UUAAGGCUAUUUAAUGCUAdTdT
34
AGCAUUAAAUAGCCUUAAAdTdT
148
UUUAAGGCUAUUUAAUGCUdTdT
35
GCAUUAAAUAGCCUUAAAUdTdT
149
AUUUAAGGCUAUUUAAUGCdTdT
36
CAUUAAAUAGCCUUAAAUUdTdT
150
AAUUUAAGGCUAUUUAAUGdTdT
37
UAUUAUGCAGUUUAAUAUUdTdT
151
AAUAUUAAACUGCAUAAUAdTdT
38
UUAUGCAGUUUAAUAUUUAdTdT
152
UAAAUAUUAAACUGCAUAAdTdT
39
AAAAGUGCACAACAUUAUAdTdT
153
UAUAAUGUUGUGCACUUUUdTdT
40
AAAGUGCACAACAUUAUACdTdT
154
GUAUAAUGUUGUGCACUUUdTdT
41
AUAUAGAACCUACAUAUCCdTdT
155
GGAUAUGUAGGUUCUAUAUdTdT
42
UAUAGAACCUACAUAUCCUdTdT
156
AGGAUAUGUAGGUUCUAUAdTdT
43
UAAGAGUUGUUUAUGAAAGdTdT
157
CUUUCAUAAACAACUCUUAdTdT
44
ACAGUCAGUAGUAGACCAUdTdT
158
AUGGUCUACUACUGACUGUdTdT
45
CAGUCAGUAGUAGACCAUGdTdT
159
CAUGGUCUACUACUGACUGdTdT
46
AGUCAGUAGUAGACCAUGUdTdT
160
ACAUGGUCUACUACUGACUdTdT
47
GUCAGUAGUAGACCAUGUGdTdT
161
CACAUGGUCUACUACUGACdTdT
48
UCAGUAGUAGACCAUGUGAdTdT
162
UCACAUGGUCUACUACUGAdTdT
49
CAUGUGAAUUCCCUGCAUCdTdT
163
GAUGCAGGGAAUUCACAUGdTdT
50
AUGUGAAUUCCCUGCAUCAdTdT
164
UGAUGCAGGGAAUUCACAUdTdT
51
UGUGAAUUCCCUGCAUCAAdTdT
165
UUGAUGCAGGGAAUUCACAdTdT
52
GUGAAUUCCCUGCAUCAAUdTdT
166
AUUGAUGCAGGGAAUUCACdTdT
53
AAUUCCCUGCAUCAAUACCdTdT
167
GGUAUUGAUGCAGGGAAUUdTdT
54
GCAUCAAUACCAGCUUAUAdTdT
168
UAUAAGCUGGUAUUGAUGCdTdT
55
CAUCAAUACCAGCUUAUAGdTdT
169
CUAUAAGCUGGUAUUGAUGdTdT
56
AUACCAGCUUAUAGAACAAdTdT
170
UUGUUCUAUAAGCUGGUAUdTdT
57
UACCAGCUUAUAGAACAACdTdT
171
GUUGUUCUAUAAGCUGGUAdTdT
58
ACCAGCUUAUAGAACAACAdTdT
172
UGUUGUUCUAUAAGCUGGUdTdT
59
CCAGCUUAUAGAACAACAAdTdT
173
UUGUUGUUCUAUAAGCUGGdTdT
60
CAGCUUAUAGAACAACAAAdTdT
174
UUUGUUGUUCUAUAAGCUGdTdT
61
AUAGAACAACAAAUUAUCAdTdT
175
UGAUAAUUUGUUGUUCUAUdTdT
62
UAUUAACAGAAAAGUAUGGdTdT
176
CCAUACUUUUCUGUUAAUAdTdT
63
UGAGAUACAUUUGAUGAAAdTdT
177
UUUCAUCAAAUGUAUCUCAdTdT
64
GAGAUACAUUUGAUGAAACdTdT
178
GUUUCAUCAAAUGUAUCUCdTdT
65
GAUACAUUUGAUGAAACCUdTdT
179
AGGUUUCAUCAAAUGUAUCdTdT
66
AUACAUUUGAUGAAACCUCdTdT
180
GAGGUUUCAUCAAAUGUAUdTdT
67
UACAUUUGAUGAAACCUCCdTdT
181
GGAGGUUUCAUCAAAUGUAdTdT
68
AAGUGAUACAAAAACAGCAdTdT
182
UGCUGUUUUUGUAUCACUUdTdT
69
AGUGAUACAAAAACAGCAUdTdT
183
AUGCUGUUUUUGUAUCACUdTdT
70
UGAUACAAAAACAGCAUAUdTdT
184
AUAUGCUGUUUUUGUAUCAdTdT
71
UUUAAGUACUAAUUUAGCUdTdT
185
AGCUAAAUUAGUACUUAAAdTdT
72
UUAAGUACUAAUUUAGCUGdTdT
186
CAGCUAAAUUAGUACUUAAdTdT
73
UAAGUACUAAUUUAGCUGGdTdT
187
CCAGCUAAAUUAGUACUUAdTdT
74
AAGUACUAAUUUAGCUGGAdTdT
188
UCCAGCUAAAUUAGUACUUdTdT
75
AGUACUAAUUUAGCUGGACdTdT
189
GUCCAGCUAAAUUAGUACUdTdT
76
GUACUAAUUUAGCUGGACAdTdT
190
UGUCCAGCUAAAUUAGUACdTdT
77
ACUAAUUUAGCUGGACAUUdTdT
191
AAUGUCCAGCUAAAUUAGUdTdT
78
AAUUUAGCUGGACAUUGGAdTdT
192
UCCAAUGUCCAGCUAAAUUdTdT
79
AUUUAGCUGGACAUUGGAUdTdT
193
AUCCAAUGUCCAGCUAAAUdTdT
80
UUAGCUGGACAUUGGAUUCdTdT
194
GAAUCCAAUGUCCAGCUAAdTdT
81
UUUUGAAAAAGAUUGGGGAdTdT
195
UCCCCAAUCUUUUUCAAAAdTdT
82
UUUGAAAAAGAUUGGGGAGdTdT
196
CUCCCCAAUCUUUUUCAAAdTdT
83
UGAAAAAGAUUGGGGAGAGdTdT
197
CUCUCCCCAAUCUUUUUCAdTdT
84
GAAAAAGAUUGGGGAGAGGdTdT
198
CCUCUCCCCAAUCUUUUUCdTdT
85
UAUGAACACUUCAGAUCUUdTdT
199
AAGAUCUGAAGUGUUCAUAdTdT
86
AUGAACACUUCAGAUCUUCdTdT
200
GAAGAUCUGAAGUGUUCAUdTdT
87
UGCCCUUGGGUUGUUAACAdTdT
201
UGUUAACAACCCAAGGGCAdTdT
88
GCCCUUGGGUUGUUAACAUdTdT
202
AUGUUAACAACCCAAGGGCdTdT
89
UAUAGCAUUCAUAGGUGAAdTdT
203
UUCACCUAUGAAUGCUAUAdTdT
90
AUAGCAUUCAUAGGUGAAGdTdT
204
CUUCACCUAUGAAUGCUAUdTdT
91
UAGCAUUCAUAGGUGAAGGdTdT
205
CCUUCACCUAUGAAUGCUAdTdT
92
AUUCAUAGGUGAAGGAGCAdTdT
206
UGCUCCUUCACCUAUGAAUdTdT
93
UUGCAAUGAUCAUAGUUUAdTdT
207
UAAACUAUGAUCAUUGCAAdTdT
94
UGCAAUGAUCAUAGUUUACdTdT
208
GUAAACUAUGAUCAUUGCAdTdT
95
GCAAUGAUCAUAGUUUACCdTdT
209
GGUAAACUAUGAUCAUUGCdTdT
96
CAAUGAUCAUAGUUUACCUdTdT
210
AGGUAAACUAUGAUCAUUGdTdT
97
AAUGAUCAUAGUUUACCUAdTdT
211
UAGGUAAACUAUGAUCAUUdTdT
98
AUGAUCAUAGUUUACCUAUdTdT
212
AUAGGUAAACUAUGAUCAUdTdT
99
GAUCAUAGUUUACCUAUUGdTdT
213
CAAUAGGUAAACUAUGAUCdTdT
100
AUCAUAGUUUACCUAUUGAdTdT
214
UCAAUAGGUAAACUAUGAUdTdT
101
UCAUAGUUUACCUAUUGAGdTdT
215
CUCAAUAGGUAAACUAUGAdTdT
102
CAUAGUUUACCUAUUGAGUdTdT
216
ACUCAAUAGGUAAACUAUGdTdT
103
AUAGUUUACCUAUUGAGUUdTdT
217
AACUCAAUAGGUAAACUAUdTdT
104
CAUUGGUCUUAUUUACAUAdTdT
218
UAUGUAAAUAAGACCAAUGdTdT
105
UUGGUCUUAUUUACAUAUAdTdT
219
UAUAUGUAAAUAAGACCAAdTdT
106
UGGUCUUAUUUACAUAUAAdTdT
220
UUAUAUGUAAAUAAGACCAdTdT
107
GGUCUUAUUUACAUAUAAAdTdT
221
UUUAUAUGUAAAUAAGACCdTdT
108
AUAUCAUGCUCAAGAUGAUdTdT
222
AUCAUCUUGAGCAUGAUAUdTdT
109
UAUCAUGCUCAAGAUGAUAdTdT
223
UAUCAUCUUGAGCAUGAUAdTdT
110
UGAUAUUGAUUUCAAAUUAdTdT
224
UAAUUUGAAAUCAAUAUCAdTdT
111
UACUUAGUCCUUACAAUAGdTdT
225
CUAUUGUAAGGACUAAGUAdTdT
112
UUAGUCCUUACAAUAGGUCdTdT
226
GACCUAUUGUAAGGACUAAdTdT
113
UAGUCCUUACAAUAGGUCCdTdT
227
GGACCUAUUGUAAGGACUAdTdT
114
AUAUUCUAUAGCUGGACGUdTdT
228
ACGUCCAGCUAUAGAAUAUdTdT
115
UAUUCUAUAGCUGGACGUAdTdT
229
UACGUCCAGCUAUAGAAUAdTdT
116
AUUCUAUAGCUGGACGUAAdTdT
230
UUACGUCCAGCUAUAGAAUdTdT
231
AAAUUCCUAGAAUCAAUAAdTdT
250
UUAUUGAUUCUAGGAAUUUdTdT
232
AAUUCCUAGAAUCAAUAAAdTdT
251
UUUAUUGAUUCUAGGAAUUdTdT
233
UUCCUAGAAUCAAUAAAGGdTdT
252
CCUUUAUUGAUUCUAGGAAdTdT
234
UCCUAGAAUCAAUAAAGGGdTdT
253
CCCUUUAUUGAUUCUAGGAdTdT
235
CUAGAAUCAAUAAAGGGCAdTdT
254
UGCCCUUUAUUGAUUCUAGdTdT
236
ACAUUUGAUAACAAUGAAGdTdT
255
CUUCAUUGUUAUCAAAUGUdTdT
237
CAUUUGAUAACAAUGAAGAdTdT
256
UCUUCAUUGUUAUCAAAUGdTdT
238
AUUUGAUAACAAUGAAGAAdTdT
257
UUCUUCAUUGUUAUCAAAUdTdT
239
UUUGAUAACAAUGAAGAAGdTdT
258
CUUCUUCAUUGUUAUCAAAdTdT
240
AAGUGAAAUACUAGGAAUGdTdT
259
CAUUCCUAGUAUUUCACUUdTdT
241
AGUGAAAUACUAGGAAUGCdTdT
260
GCAUUCCUAGUAUUUCACUdTdT
242
GUGAAAUACUAGGAAUGCUdTdT
261
AGCAUUCCUAGUAUUUCACdTdT
243
UGAAAUACUAGGAAUGCUUdTdT
262
AAGCAUUCCUAGUAUUUCAdTdT
244
GAAAUACUAGGAAUGCUUCdTdT
263
GAAGCAUUCCUAGUAUUUCdTdT
245
AAAUACUAGGAAUGCUUCAdTdT
264
UGAAGCAUUCCUAGUAUUUdTdT
246
GAAGCAUUAAUGACCAAUGdTdT
265
CAUUGGUCAUUAAUGCUUCdTdT
247
AAGCAUUAAUGACCAAUGAdTdT
266
UCAUUGGUCAUUAAUGCUUdTdT
248
CGAUAAUAUAACAGCAAGAdTsdT
267
UCUUGCUGUUAUAUUAUCGdTsdT
249
CGAUUAUAUUACAGGAUGAdTsdT
268
UCAUCCUGUAAUAUAAUCGdTsdT
1
GGCUCUUAGCAAAGUCAAGdTdT
2
CUUGACUUUGCUAAGAGCCdTdT
269
CUCUUAGCAAAGUCAAGUUdTdT
277
AACUUGACUUUGCUAAGAGdTdT
270
CUGUCAUCCAGCAAAUACAdTdT
278
UGUAUUUGCUGGAUGACAGdTdT
271
UGUCAUCCAGCAAAUACACdTdT
279
GUGUAUUUGCUGGAUGACAdTdT
272
UAAUAGGUAUGUUAUAUGCdTdT
280
GCAUAUAACAUACCUAUUAdTdT
273
AUUGAGAUAGAAUCUAGAAdTdT
281
UUCUAGAUUCUAUCUCAAUdTdT
274
AUUCUACCAUAUAUUGAACdTdT
282
GUUCAAUAUAUGGUAGAAUdTdT
275
UUCUACCAUAUAUUGAACAdTdT
283
UGUUCAAUAUAUGGUAGAAdTdT
276
UCUACCAUAUAUUGAACAAdTdT
284
UUGUUCAAUAUAUGGUAGAdTdT.