US2011294868A1PendingUtilityA1

Modulation of transthyretin expression

59
Assignee: MONIA BRETT PPriority: Apr 29, 2010Filed: Apr 29, 2011Published: Dec 1, 2011
Est. expiryApr 29, 2030(~3.8 yrs left)· nominal 20-yr term from priority
Inventors:Brett P. MoniaSusan M. FreierAndrew M. Siwkowski
A61P 7/00A61P 7/04A61P 9/04A61P 7/10A61P 9/00A61P 3/10A61P 9/06A61P 25/20A61P 25/28A61P 3/00A61P 25/22A61P 25/08A61P 25/02A61P 27/02A61P 27/06A61P 25/24A61P 25/18A61P 15/10A61P 1/08C12N 15/113C12N 2310/52A61P 1/10A61P 25/00A61K 31/712C07H 21/04A61P 21/00A61P 1/12A61K 48/00C12N 2310/321A61P 13/00C12N 2310/315C12N 2310/14C12N 2310/341C12N 2320/30A61P 1/16C12N 2310/11A61P 11/00A61P 15/00C12N 15/11A61P 19/10C12N 2310/3341
59
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of transthyretin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate transthyretin amyloidosis, or a symptom thereof.

Claims

exact text as granted — not AI-modified
1 . A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides, wherein the linked nucleosides consist of the sequence recited in SEQ ID No: 80. 
     
     
         2 - 10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         12 . The compound of  claim 11 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         13 . The compound of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         14 . The compound of  claim 13 , wherein the at least one modified sugar is a bicyclic sugar. 
     
     
         15 . The compound of  claim 14 , wherein each of the at least one bicyclic sugar comprises a 4′-CH 2 —N(R)—O-2′ bridge wherein R is, independently, H, C1-C12 alkyl, or a protecting group. 
     
     
         16 . The compound of  claim 14 , wherein each of the at least one bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         17 . The compound of  claim 13 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group. 
     
     
         18 . The compound of  claim 1 , comprising at least one tetrahydropyran modified nucleoside wherein a tetrahydropyran ring replaces the furanose ring. 
     
     
         19 . The compound of  claim 18 , wherein each of the at least one tetrahydropyran modified nucleoside has the structure: 
       
         
           
           
               
               
           
         
         wherein Bx is an optionally protected heterocyclic base moiety. 
       
     
     
         20 . The compound of  claim 1 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         21 . The compound of  claim 20 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         22 . The compound of  claim 1 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         23 . The compound of  claim 22 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.   
     
     
         24 . The compound of  claim 22 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of eight linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.   
     
     
         25 . The compound of  claim 22 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of eight linked deoxynucleosides;   a 5′ wing segment consisting of six linked nucleosides; and   a 3′ wing segment consisting of six linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.   
     
     
         26 . (canceled) 
     
     
         27 . A composition comprising the compound of  claim 1  or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. 
     
     
         28 . A method comprising administering to an animal the compound of  claim 1 . 
     
     
         29 . The method of  claim 28 , wherein the animal is a human. 
     
     
         30 . The method of  claim 28 , wherein administering the compound prevents, treats, ameliorates, or slows progression of transthyretin amyloidosis. 
     
     
         31 . The method of  claim 28 , comprising co-administering the compound and a second agent. 
     
     
         32 . The method of  claim 31 , wherein the compound and the second agent are administered concomitantly. 
     
     
         33 . The method of  claim 28 , wherein the administering is to the choroid plexus. 
     
     
         34 . A method to reduce transthyretin mRNA or protein expression in an animal comprising administering to the animal the compound of  claim 1  to reduce transthyretin mRNA or protein expression in the animal. 
     
     
         35 . The method of  claim 34 , wherein the animal is a human. 
     
     
         36 . The method of  claim 34 , wherein reducing transthyretin mRNA or protein expression prevents, treats, ameliorates, or slows progression of transthyretin amyloidosis. 
     
     
         37 . The method of  claim 34 , comprising co-administering the compound or composition and a second agent. 
     
     
         38 . The method of  claim 37 , wherein the compound or composition and the second agent are administered concomitantly. 
     
     
         39 . The method of  claim 34 , wherein the administering is to the choroid plexus. 
     
     
         40 . A method for treating a human with transthyretin amyloidosis comprising identifying the human with the transthyretin amyloidosis and administering to the human a therapeutically effective amount of the compound of  claim 1  so as to treat the human for transthyretin amyloidosis. 
     
     
         41 . The method of  claim 40 , wherein the treatment reduces at least one of restlessness, lack of coordination, nystagmus, spastic paraparesis, lack of muscle coordination, impaired vision, insomnia, unusual sensations, myoclonus, blindness, loss of speech, Carpal tunnel syndrome, seizures, subarachnoid hemorrhages, stroke and bleeding in the brain, hydrocephalus, ataxia, and spastic paralysis, coma, sensory neuropathy, parathesia, hypesthesia, motor neuropathy, autonomic neuropathy, orthostatic hypotension, cyclic constipation, cyclic diarrhea, nausea, vomiting, reduced sweating, impotence, delayed gastric emptying, urinary retention, urinary incontinence, progressive cardiopathy, fatigue, shortness of breath, weight loss, lack of appetite, numbness, tingling, weakness, enlarged tongue, nephrotic syndrome, congestive heart failure, dyspnea on exertion, peripheral edema, arrhythmias, palpitations, light-headedness, syncope, postural hypotension, peripheral nerve problems, sensory motor impairment, lower limb neuropathy, upper limb neuropathy, hyperalgesia, altered temperature sensation, lower extremity weakness, cachexia, peripheral edema, hepatomegaly, purpura, diastolic dysfunction, premature ventricular contractions, cranial neuropathy, diminished deep tendon reflexes, amyloid deposits in the corpus vitreum, vitreous opacity, dry eyes, glaucoma, scalloped appearance in the pupils, or swelling of the feet due to water retention in the human. 
     
     
         42 . The method of  claim 40 , comprising co-administering the compound or composition and a second agent. 
     
     
         43 . The method of  claim 42 , wherein the compound or composition and the second agent are administered concomitantly. 
     
     
         44 . The method of  claim 40 , wherein the administering is to the choroid plexus. 
     
     
         45 . A method for reducing or preventing transthyretin amyloidosis comprising administering to a human a therapeutically effective amount of a compound of  claim 1 , thereby reducing or preventing transthyretin amyloidosis. 
     
     
         46 . The method of  claim 45 , comprising co-administering the compound or composition and a second agent. 
     
     
         47 . The method of  claim 46 , wherein the compound or composition and the second agent are administered concomitantly. 
     
     
         48 . The method of  claim 45 , wherein the administering is to the choroid plexus. 
     
     
         49 - 62 . (canceled)

Cited by (0)

No later patents cite this yet.

References (0)

No backward citations on record.