US2020248180A1PendingUtilityA1
Compositions and Methods for TTR Gene Editing and Treating ATTR Amyloidosis
Est. expirySep 29, 2037(~11.2 yrs left)· nominal 20-yr term from priority
Inventors:Arti Mahendra Prakash KanjoliaShobu OdateJessica Lynn SeitzerReynald Michael LescarbeauWalter Strapps
C12N 2310/20A61P 25/28A61K 48/005C12N 15/88C12N 15/102C12N 15/113C12N 15/111A61K 48/0091A61K 48/0041A61K 48/00C12N 2800/80C12N 2310/321C12N 9/22C07K 14/47
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Claims
Abstract
Compositions and methods for editing, e.g., introducing double-stranded breaks, within the TTR gene are provided. Compositions and methods for treating subjects having amyloidosis associated with transthyretin (ATTR), are provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of inducing a double-stranded break (DSB) within the TTR gene, comprising delivering a composition to a cell, wherein the composition comprises
a. a guide RNA comprising a guide sequence selected from SEQ ID NOs: 5-82;
b. a guide RNA comprising at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide RNA comprising a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82.
2 . A method of modifying the TTR gene comprising delivering a composition to a cell, wherein the composition comprises (i) an RNA-guided DNA binding agent or a nucleic acid encoding an RNA-guided DNA binding agent and (ii) a guide RNA comprising:
a. a guide sequence selected from SEQ ID NOs: 5-82;
b. at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82.
3 . A method of treating amyloidosis associated with TTR (ATTR), comprising administering a composition to a subject in need thereof, wherein the composition comprises (i) an RNA-guided DNA binding agent or a nucleic acid encoding an RNA-guided DNA binding agent and (ii) a guide RNA comprising:
a. a guide sequence selected from SEQ ID NOs: 5-82;
b. at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82, thereby treating ATTR.
4 . A method of reducing TTR serum concentration, comprising administering a composition to a subject in need thereof, wherein the composition comprises (i) an RNA-guided DNA binding agent or a nucleic acid encoding an RNA-guided DNA binding agent and (ii) a guide RNA comprising:
a. a guide sequence selected from SEQ ID NOs: 5-82;
b. at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82, thereby reducing TTR serum concentration.
5 . A method for reducing or preventing the accumulation of amyloids or amyloid fibrils comprising TTR in a subject, comprising administering a composition to a subject in need thereof, wherein the composition comprises (i) an RNA-guided DNA binding agent or a nucleic acid encoding an RNA-guided DNA binding agent and (ii) a guide RNA comprising:
a. a guide sequence selected from SEQ ID NOs: 5-82;
b. at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82, thereby reducing accumulation of amyloids or amyloid fibrils.
6 . A composition comprising a guide RNA comprising:
a. a guide sequence selected from SEQ ID NOs: 5-82;
b. at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82.
7 . A composition comprising a vector encoding a guide RNA, wherein the guide RNA comprises:
a. a guide sequence selected from SEQ ID NOs: 5-82;
b. at least 17, 18, 19, or 20 contiguous nucleotides of a sequence selected from SEQ ID NOs: 5-82; or
c. a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID NOs: 5-82.
8 . The composition of claim 6 or 7 , for use in inducing a double-stranded break (DSB) within the TTR gene in a cell or subject.
9 . The composition of claim 6 or 7 , for use in modifying the TTR gene in a cell or subject.
10 . The composition of claim 6 or 7 , for use in treating amyloidosis associated with TTR (ATTR) in a subject.
11 . The composition of claim 6 or 7 , for use in reducing TTR serum concentration in a subject.
12 . The composition of claim 6 or 7 , for use in reducing or preventing the accumulation of amyloids or amyloid fibrils in a subject.
13 . The method of any one of claims 1 - 5 or the composition for use of any one of claims 8 - 12 , wherein the composition reduces serum TTR levels.
14 . The method or composition for use of claim 13 , wherein the serum TTR levels are reduced by at least 50% as compared to serum TTR levels before administration of the composition.
15 . The method or composition for use of claim 13 , wherein the serum TTR levels are reduced by 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, 95-98%, 98-99%, or 99-100% as compared to serum TTR levels before administration of the composition.
16 . The method or composition for use of any one of claim 1 - 5 or 8 - 15 , wherein the composition results in editing of the TTR gene.
17 . The method or composition for use of claim 16 , wherein the editing is calculated as a percentage of the population that is edited (percent editing).
18 . The method or composition for use of claim 17 , wherein the percent editing is between 30 and 99% of the population.
19 . The method or composition for use of claim 17 , wherein the percent editing is between 30 and 35%, 35 and 40%, 40 and 45%, 45 and 50%, 50 and 55%, 55 and 60%, 60 and 65%, 65 and 70%, 70 and 75%, 75 and 80%, 80 and 85%, 85 and 90%, 90 and 95%, or 95 and 99% of the population.
20 . The method of any one of claims 1 - 5 or the composition for use of any one of claims 8 - 19 , wherein the composition reduces amyloid deposition in at least one tissue.
21 . The method or composition for use of claim 20 , wherein the at least one tissue comprises one or more of stomach, colon, sciatic nerve, or dorsal root ganglion.
22 . The method or composition for use of claim 20 or 21 , wherein amyloid deposition is measured 8 weeks after administration of the composition.
23 . The method or composition for use of any one of claims 20 - 22 , wherein amyloid deposition is compared to a negative control or a level measured before administration of the composition.
24 . The method or composition for use of any one of claims 20 - 23 , wherein amyloid deposition is measured in a biopsy sample and/or by immunostaining.
25 . The method or composition for use of any one of claims 20 - 24 , wherein amyloid deposition is reduced by between 30 and 35%, 35 and 40%, 40 and 45%, 45 and 50%, 50 and 55%, 55 and 60%, 60 and 65%, 65 and 70%, 70 and 75%, 75 and 80%, 80 and 85%, 85 and 90%, 90 and 95%, or 95 and 99% of the amyloid deposition seen in a negative control.
26 . The method or composition for use of any one of claims 20 - 25 , wherein amyloid deposition is reduced by between 30 and 35%, 35 and 40%, 40 and 45%, 45 and 50%, 50 and 55%, 55 and 60%, 60 and 65%, 65 and 70%, 70 and 75%, 75 and 80%, 80 and 85%, 85 and 90%, 90 and 95%, or 95 and 99% of the amyloid deposition seen before administration of the composition.
27 . The method or composition for use of any one of claim 1 - 5 or 8 - 26 , wherein the composition is administered or delivered at least two times.
28 . The method or composition for use of claim 27 , wherein the composition is administered or delivered at least three times.
29 . The method or composition for use of claim 27 , wherein the composition is administered or delivered at least four times.
30 . The method or composition for use of claim 27 , wherein the composition is administered or delivered up to five, six, seven, eight, nine, or ten times.
31 . The method or composition for use of any one of claims 27 - 30 , wherein the administration or delivery occurs at an interval of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days.
32 . The method or composition for use of any one of claims 27 - 30 , wherein the administration or delivery occurs at an interval of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks.
33 . The method or composition for use of any one of claims 27 - 30 , wherein the administration or delivery occurs at an interval of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 months.
34 . The method or composition of any one of the preceding claims, wherein the guide sequence is selected from SEQ ID NOs: 5-82.
35 . The method or composition of any one of the preceding claims, wherein the guide RNA is at least partially complementary to a target sequence present in the human TTR gene.
36 . The method or composition of claim 35 , wherein the target sequence is in exon 1, 2, 3, or 4 of the human TTR gene.
37 . The method or composition of claim 35 , wherein the target sequence is in exon 1 of the human TTR gene.
38 . The method or composition of claim 35 , wherein the target sequence is in exon 2 of the human TTR gene.
39 . The method or composition of claim 35 , wherein the target sequence is in exon 3 of the human TTR gene.
40 . The method or composition of claim 35 , wherein the target sequence is in exon 4 of the human TTR gene.
41 . The method or composition of any one of claims 1 - 40 , wherein the guide sequence is complementary to a target sequence in the positive strand of TTR.
42 . The method or composition of any one of claims 1 - 40 , wherein the guide sequence is complementary to a target sequence in the negative strand of TTR.
43 . The method or composition of any one of claims 1 - 40 , wherein the first guide sequence is complementary to a first target sequence in the positive strand of the TTR gene, and wherein the composition further comprises a second guide sequence that is complementary to a second target sequence in the negative strand of the TTR gene.
44 . The method or composition of any one of the preceding claims, wherein the guide RNA comprises a crRNA that comprises the guide sequence and further comprises a nucleotide sequence of SEQ ID NO: 126, wherein the nucleotides of SEQ ID NO: 126 follow the guide sequence at its 3′ end.
45 . The method or composition of any one of the preceding claims, wherein the guide RNA is a dual guide (dgRNA).
46 . The method or composition of claim 45 , wherein the dual guide RNA comprises a crRNA comprising a nucleotide sequence of SEQ ID NO: 126, wherein the nucleotides of SEQ ID NO: 126 follow the guide sequence at its 3′ end, and a trRNA.
47 . The method or composition of any one of claims 1 - 43 , wherein the guide RNA is a single guide (sgRNA).
48 . The method or composition of claim 47 , wherein the sgRNA comprises a guide sequence that has the pattern of SEQ ID NO: 3.
49 . The method or composition of claim 47 , wherein the sgRNA comprises the sequence of SEQ ID NO: 3.
50 . The method or composition of claim 48 or 49 , wherein each N in SEQ ID NO: 3 is any natural or non-natural nucleotide, wherein the N's form the guide sequence, and the guide sequence targets Cas9 to the TTR gene.
51 . The method or composition of any one of claims 47 - 50 , wherein the sgRNA comprises any one of the guide sequences of SEQ ID NOs: 5-82 and the nucleotides of SEQ ID NO: 126.
52 . The method or composition of any one of claims 47 - 51 , wherein the sgRNA comprises a guide sequence that is at least 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% identical to a sequence selected from SEQ ID Nos: 87-124.
53 . The method or composition of claim 47 , wherein the sgRNA comprises a sequence selected from SEQ ID Nos: 87-124.
54 . The method or composition of any one of the preceding claims, wherein the guide RNA comprises at least one modification.
55 . The method or composition of claim 54 , wherein the at least one modification includes a 2′-O-methyl (2′-O-Me) modified nucleotide.
56 . The method or composition of claim 54 or 55 , wherein the at least one modification includes a phosphorothioate (PS) bond between nucleotides.
57 . The method or composition of any one of claims 54 - 56 , wherein the at least one modification includes a 2′-fluoro (2′-F) modified nucleotide.
58 . The method or composition of any one of claims 54 - 57 , wherein the at least one modification includes a modification at one or more of the first five nucleotides at the 5′ end.
59 . The method or composition of any one of claims 54 - 58 , wherein the at least one modification includes a modification at one or more of the last five nucleotides at the 3′ end.
60 . The method or composition of any one of claims 54 - 59 , wherein the at least one modification includes PS bonds between the first four nucleotides.
61 . The method or composition of any one of claims 54 - 60 , wherein the at least one modification includes PS bonds between the last four nucleotides.
62 . The method or composition of any one of claims 54 - 61 , wherein the at least one modification includes 2′-O-Me modified nucleotides at the first three nucleotides at the 5′ end.
63 . The method or composition of any one of claims 54 - 62 , wherein the at least one modification includes 2′-O-Me modified nucleotides at the last three nucleotides at the 3′ end.
64 . The method or composition of any one of claims 54 - 63 , wherein the guide RNA comprises the modified nucleotides of SEQ ID NO: 3.
65 . The method or composition of any one of claims 1 - 64 , wherein the composition further comprises a pharmaceutically acceptable excipient.
66 . The method or composition of any one of claims 1 - 65 , wherein the guide RNA is associated with a lipid nanoparticle (LNP).
67 . The method or composition of claim 66 , wherein the LNP comprises a CCD lipid.
68 . The method or composition of claim 67 , wherein the CCD lipid is Lipid A or Lipid B.
69 . The method or composition of claim 66 - 68 , wherein the LNP comprises a neutral lipid.
70 . The method or composition of claim 69 , wherein the neutral lipid is DSPC
71 . The method or composition of any one of claims 66 - 70 , wherein the LNP comprises a helper lipid.
72 . The method or composition of claim 71 , wherein the helper lipid is cholesterol.
73 . The method or composition of any one of claims 66 - 72 , wherein the LNP comprises a stealth lipid.
74 . The method or composition of claim 73 , wherein the stealth lipid is PEG2k-DMG.
75 . The method or composition of any one of the preceding claims, wherein the composition further comprises an RNA-guided DNA binding agent.
76 . The method or composition of any one of the preceding claims, wherein the composition further comprises an mRNA that encodes an RNA-guided DNA binding agent.
77 . The method or composition of claim 75 or 76 , wherein the RNA-guided DNA binding agent is a Cas cleavase.
78 . The method or composition of claim 77 , wherein the RNA-guided DNA binding agent is Cas9.
79 . The method or composition of any one of claims 75 - 78 , wherein the RNA-guided DNA binding agent is modified.
80 . The method or composition of any one of claims 75 - 79 , wherein the RNA-guided DNA binding agent is a nickase.
81 . The method or composition of claim 79 or 80 , wherein the modified RNA-guided DNA binding agent comprises a nuclear localization signal (NLS).
82 . The method or composition of any one of claims 75 - 81 , wherein the RNA-guided DNA binding agent is a Cas from a Type-II CRISPR/Cas system.
83 . The method or composition of any one of the preceding claims, wherein the composition is a pharmaceutical formulation and further comprises a pharmaceutically acceptable carrier.
84 . The method or composition for use of any one of claim 1 - 5 or 8 - 83 , wherein the composition reduces or prevents amyloids or amyloid fibrils comprising TTR.
85 . The method or composition for use of claim 84 , wherein the amyloids or amyloid fibrils are in the nerves, heart, or gastrointestinal track.
86 . The method or composition for use of any one of claim 1 - 5 or 8 - 83 , wherein non-homologous ending joining (NHEJ) leads to a mutation during repair of a DSB in the TTR gene.
87 . The method or composition for use of claim 86 , wherein NHEJ leads to a deletion or insertion of a nucleotide(s) during repair of a DSB in the TTR gene.
88 . The method or composition for use of claim 87 , wherein the deletion or insertion of a nucleotide(s) induces a frame shift or nonsense mutation in the TTR gene.
89 . The method or composition for use of claim 87 , wherein a frame shift or nonsense mutation is induced in the TTR gene of at least 50% of liver cells.
90 . The method or composition for use of claim 89 , wherein a frame shift or nonsense mutation is induced in the TTR gene of 50%-60%, 60%-70%, 70% or 80%, 80%-90%, 90-95%, 95%-99%, or 99%-100% of liver cells.
91 . The method or composition for use of any one of claims 87 - 90 , wherein a deletion or insertion of a nucleotide(s) occurs in the TTR gene at least 50-fold or more than in off-target sites.
92 . The method or composition for use of claim 91 , wherein the deletion or insertion of a nucleotide(s) occurs in the TTR gene 50-fold to 150-fold, 150-fold to 500-fold, 500-fold to 1500-fold, 1500-fold to 5000-fold, 5000-fold to 15000-fold, 15000-fold to 30000-fold, or 30000-fold to 60000-fold more than in off-target sites.
93 . The method or composition for use of any one of claims 87 - 92 , wherein the deletion or insertion of a nucleotide(s) occurs at less than or equal to 3, 2, 1, or 0 off-target site(s) in primary human hepatocytes, optionally wherein the off-target site(s) does (do) not occur in a protein coding region in the genome of the primary human hepatocytes.
94 . The method or composition for use of claim 93 , wherein the deletion or insertion of a nucleotide(s) occurs at a number of off-target sites in primary human hepatocytes that is less than the number of off-target sites at which a deletion or insertion of a nucleotide(s) occurs in Cas9-overexpressing cells, optionally wherein the off-target site(s) does (do) not occur in a protein coding region in the genome of the primary human hepatocytes.
95 . The method or composition for use of claim 94 , wherein the Cas9-overexpressing cells are HEK293 cells stably expressing Cas9.
96 . The method or composition for use of any one of claims 93 - 95 , wherein the number of off-target sites in primary human hepatocytes is determined by analyzing genomic DNA from primary human hepatocytes transfected in vitro with Cas9 mRNA and the guide RNA, optionally wherein the off-target site(s) does (do) not occur in a protein coding region in the genome of the primary human hepatocytes.
97 . The method or composition for use of any one of claims 93 - 95 , wherein the number of off-target sites in primary human hepatocytes is determined by an oligonucleotide insertion assay comprising analyzing genomic DNA from primary human hepatocytes transfected in vitro with Cas9 mRNA, the guide RNA, and a donor oligonucleotide, optionally wherein the off-target site(s) does (do) not occur in a protein coding region in the genome of the primary human hepatocytes.
98 . The method or composition of any one of claim 1 - 43 or 47 - 97 , wherein the sequence of the guide RNA is:
a) SEQ ID NO: 92 or 104;
b) SEQ ID NO: 87, 89, 96, or 113;
c) SEQ ID NO: 100, 102, 106, 111, or 112; or
d) SEQ ID NO: 88, 90, 91, 93, 94, 95, 97, 101, 103, 108, or 109,
optionally wherein the guide RNA does not produce indels at off-target site(s) that occur in a protein coding region in the genome of primary human hepatocytes.
99 . The method or composition for use of any one of claim 1 - 5 or 8 - 98 , wherein administering the composition reduces levels of TTR in the subject.
100 . The method or composition for use of claim 99 , wherein the levels of TTR are reduced by at least 50%.
101 . The method or composition for use of claim 100 , wherein the levels of TTR are reduced by 50%-60%, 60%-70%, 70% or 80%, 80%-90%, 90-95%, 95%-99%, or 99%-100%.
102 . The method or composition for use of claim 100 or 101 , wherein the levels of TTR are measured in serum, plasma, blood, cerebral spinal fluid, or sputum.
103 . The method or composition for use of claim 100 or 101 , wherein the levels of TTR are measured in liver, choroid plexus, and/or retina.
104 . The method or composition for use of any one of claims 99 - 103 , wherein the levels of TTR are measured via enzyme-linked immunosorbent assay (ELISA).
105 . The method or composition for use of any one of claim 1 - 5 or 8 - 104 , wherein the subject has ATTR.
106 . The method or composition for use of any one of claim 1 - 5 or 8 - 105 , wherein the subject is human.
107 . The method or composition for use of claim 105 or 106 , wherein the subject has ATTRwt.
108 . The method or composition for use of claim 105 or 106 , wherein the subject has hereditary ATTR.
109 . The method or composition for use of any one of claim 1 - 5 , 8 - 106 , or 108 , wherein the subject has a family history of ATTR.
110 . The method or composition for use of any one of claim 1 - 5 , 8 - 106 , or 108 - 109 , wherein the subject has familial amyloid polyneuropathy.
111 . The method or composition for use of any one of claim 1 - 5 or 8 - 110 , wherein the subject has only or predominantly nerve symptoms of ATTR.
112 . The method or composition for use of any one of claim 1 - 5 or 8 - 110 , wherein the subject has familial amyloid cardiomyopathy.
113 . The method or composition for use of any one of claim 1 - 5 , 8 - 109 , or 112 , wherein the subject has only or predominantly cardiac symptoms of ATTR.
114 . The method or composition for use of any one of claim 1 - 5 or 8 - 113 , wherein the subject expresses TTR having a V30 mutation.
115 . The method or composition for use of claim 114 , wherein the V30 mutation is V30A, V30G, V30L, or V30M.
116 . The method or composition for use of claim any one of claim 1 - 5 or 8 - 113 , wherein the subject expresses TTR having a T60 mutation.
117 . The method or composition for use of claim 116 , wherein the T60 mutation is T60A.
118 . The method or composition for use of claim any one of claim 1 - 5 or 8 - 113 , wherein the subject expresses TTR having a V122 mutation.
119 . The method or composition for use of claim 118 , wherein the V122 mutation is V122A, V122I, or V122(−).
120 . The method or composition for use of any one of claim 1 - 5 or 8 - 119 , wherein the subject expresses wild-type TTR.
121 . The method or composition for use of any one of claim 1 - 5 , 8 - 107 , or 120 , wherein the subject does not express TTR having a V30, T60, or V122 mutation.
122 . The method or composition for use of any one of claim 1 - 5 , 8 - 107 , or 120 - 121 , wherein the subject does not express TTR having a pathological mutation.
123 . The method or composition for use of claim 121 , wherein the subject is homozygous for wild-type TTR.
124 . The method or composition for use of any one of claim 1 - 5 or 8 - 123 , wherein after administration the subject has an improvement, stabilization, or slowing of change in symptoms of sensorimotor neuropathy.
125 . The method or composition for use of claim 124 , wherein the improvement, stabilization, or slowing of change in sensory neuropathy is measured using electromyogram, nerve conduction tests, or patient-reported outcomes.
126 . The method or composition for use of any one of claim 1 - 5 or 8 - 125 , wherein the subject has an improvement, stabilization, or slowing of change in symptoms of congestive heart failure.
127 . The method or composition for use of claim 126 , wherein the improvement, stabilization, or slowing of change in congestive heart failure is measured using cardiac biomarker tests, lung function tests, chest x-rays, or electrocardiography.
128 . The method or composition for use of any one of claim 1 - 5 or 8 - 127 , wherein the composition or pharmaceutical formulation is administered via a viral vector.
129 . The method or composition for use of any one of claim 1 - 5 or 8 - 127 , wherein the composition or pharmaceutical formulation is administered via lipid nanoparticles.
130 . The method or composition for use of any one of claim 1 - 5 or 8 - 129 , wherein the subject is tested for specific mutations in the TTR gene before administering the composition or formulation.
131 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 5.
132 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 6.
133 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 7.
134 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 8.
135 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 9.
136 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 10.
137 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 11.
138 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 12.
139 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 13.
140 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 14.
141 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 15.
142 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 16.
143 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 17.
144 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 18.
145 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 19.
146 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 20.
147 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 21.
148 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 22.
149 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 23.
150 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 24.
151 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 25.
152 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 26.
153 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 27.
154 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 28.
155 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 29.
156 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 30.
157 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 31.
158 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 32.
159 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 33.
160 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 34.
161 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 35.
162 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 36.
163 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 37.
164 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 38.
165 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 39.
166 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 40.
167 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 41.
168 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 42.
169 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 43.
170 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 44.
171 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 45.
172 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 46.
173 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 47.
174 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 48.
175 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 49.
176 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 50.
177 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 51.
178 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 52.
179 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 53.
180 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 54.
181 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 55.
182 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 56.
183 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 57.
184 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 58.
185 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 59.
186 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 60.
187 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 61.
188 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 62.
189 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 63.
190 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 64.
191 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 65.
192 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 66.
193 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 67.
194 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 68.
195 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 69.
196 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 70.
197 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 71.
198 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 72.
199 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 73.
200 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 74.
201 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 75.
202 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 76.
203 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 77.
204 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 78.
205 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 79.
206 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 80.
207 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 81.
208 . The method or composition of any one of claims 1 - 130 , wherein the sequence selected from SEQ ID NOs: 5-82 is SEQ ID NO: 82.
209 . Use of a composition or formulation of any of claims 6 - 208 for the preparation of a medicament for treating a human subject having ATTR.Cited by (0)
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