US2021324387A1PendingUtilityA1

Aav vectors for treatment of dominant retinitis pigmentosa

63
Assignee: UNIV FLORIDAPriority: Mar 1, 2016Filed: May 21, 2021Published: Oct 21, 2021
Est. expiryMar 1, 2036(~9.6 yrs left)· nominal 20-yr term from priority
Inventors:Alfred S. LewinWilliam W. HauswirthMichael T. MassengillWilliam A. BeltranGustavo D. AguirreArtur CideciyanSamuel G. Jacobson
C12N 15/113C12N 2330/51C12N 2310/141A61P 27/02C12N 2750/14143C12N 15/86C12N 2310/14C12N 2310/531C12N 7/00C12N 15/1138C12N 2310/122
63
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

Aspects of the disclosure relate to methods and compositions for treating retinitis pigmentosa. In some aspects, the disclosure provides compositions and methods for delivering an interfering nucleic acid (for example an interfering RNA) to a subject in order to reduce expression of one or both alleles of an endogenous rho gene (for example a mutant rho allele associated with retinitis pigmentosa) in the subject. In some embodiments, a replacement rho gene that is resistant to the interfering nucleic acid also is delivered to the subject.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A synthetic ribonucleic acid (RNA) molecule comprising:
 a) a sense strand of sequence CUGCCUACAUGUUUCUGCU (SEQ ID NO: 1) and an antisense strand of sequence AGCAGAAACAUGUAGGCAG (SEQ ID NO: 2);   b) a sense strand of sequence CCUACAUGUUUCUGCUGAU (SEQ ID NO: 3) and an antisense strand of sequence AUCAGCAGAAACAUGUAGG (SEQ ID NO: 4);   c) a sense strand of sequence GCAUGGUCAUCAUCAUGGU (SEQ ID NO: 5) and an antisense strand of sequence ACCAUGAUGAUGACCAUGC (SEQ ID NO: 6); or   d) a sense strand of sequence GUGGCAUUCUACAUCUUCA (SEQ ID NO: 7) and an antisense strand of sequence UGAAGAUGUAGAAUGCCAC (SEQ ID NO: 8).   
     
     
         2 . The synthetic RNA molecule of  claim 1 , wherein the RNA is a small interfering RNA (siRNA). 
     
     
         3 . The synthetic RNA molecule of  claim 1 , wherein the RNA is a small hairpin RNA (shRNA). 
     
     
         4 . The shRNA of  claim 3 , having a loop that comprises RNA of sequence UCAAGAG (SEQ ID NO: 9) or RNA of sequence UGUGCUU (SEQ ID NO: 10). 
     
     
         5 . The synthetic RNA molecule of  claim 1 , wherein the RNA is an artificial micro RNA (miRNA). 
     
     
         6 . The artificial miRNA of  claim 5 , wherein the artificial miRNA comprises RNA of sequence UGCUGUUGACAGUGAGCGA(X) n UAGUGAAGCCACAGAUGUA(Y) n CUGCCUACUGC CUCGGA (SEQ ID NO: 19), and wherein:
 a) (X) n  comprises SEQ ID NO: 1 and (Y) n  comprises SEQ ID NO: 2;   b) (X) n  comprises SEQ ID NO: 3 and (Y) n  comprises SEQ ID NO: 4;   c) (X) n  comprises SEQ ID NO: 5 and (Y) n  comprises SEQ ID NO: 6; or   d) (X) n  comprises SEQ ID NO: 7 and (Y) n  comprises SEQ ID NO: 8.   
     
     
         7 . The synthetic RNA of any one of  claims 1 - 6 , further comprising an unpaired overhang sequence at the 5′ and/or 3′ end. 
     
     
         8 . The synthetic RNA of  claim 7 , wherein the unpaired overhang sequence comprises a sequence of repeating bases. 
     
     
         9 . The synthetic RNA of  claim 8 , wherein the sequence of repeating bases comprises repeating uracil (U) bases. 
     
     
         10 . The synthetic RNA of  claim 9 , wherein the unpaired overhang sequence is UU. 
     
     
         11 . A composition comprising the synthetic RNA of any one of  claims 1 - 10 . 
     
     
         12 . The composition of  claim 11 , further comprising one or more physiologically acceptable carriers and/or one or more physiologically acceptable adjuvants. 
     
     
         13 . A vector encoding:
 a) the shRNA of  claim 3  or  4 ; or   b) the artificial miRNA of  claim 5  or  6 .   
     
     
         14 . The vector of  claim 13 , wherein the shRNA is selected from any one of SEQ ID NOs: 11-18. 
     
     
         15 . The vector of any one of  claims 13 - 14 , wherein the vector is an expression plasmid. 
     
     
         16 . The vector of any one of  claims 13 - 15 , wherein the vector is a viral vector. 
     
     
         17 . The viral vector of  claim 16 , wherein the viral vector comprises an adeno-associated viral vector. 
     
     
         18 . A method of decreasing RHO expression in a subject, the method comprising administering to the subject the composition of  claims 11 - 12  or the vector of  claims 13 - 17 . 
     
     
         19 . A method of treating retinitis pigmentosa (RP) in a subject, the method comprising administering to the subject both:
 a) the composition of  claims 11 - 12  or the vector of  claims 13 - 17 ; and   b) a recombinant RHO gene that does not contain a sequence targeted by an interfering RNA of the composition or the vector of a).   
     
     
         20 . The method of  claim 19 , wherein the recombinant RHO gene is delivered using an rAAV. 
     
     
         21 . The method of  claim 20 , wherein the interfering RNA and the recombinant RHO gene are delivered using the same rAAV. 
     
     
         22 . The method of  claim 21 , wherein the interfering RNA and the recombinant RHO gene are both under expression control of a single promoter sequence. 
     
     
         23 . The method of  claim 22 , wherein the interfering RNA and the recombinant RHO gene are each under expression control of independent promoter sequences. 
     
     
         24 . The method of  claim 23 , wherein the interfering RNA is shRNA, and wherein the shRNA is under expression control of an RNA polymerase III promoter. 
     
     
         25 . The method of  claim 23 , wherein the interfering RNA is an artificial miRNA, and wherein the artificial miRNA is under expression control of an RNA polymerase II promoter. 
     
     
         26 . The method of  claim 24  or  25 , wherein the recombinant RHO gene is under expression control of a constitutive or inducible promoter. 
     
     
         27 . The method of any one of  claims 19 - 26 , wherein the subject is a mammal. 
     
     
         28 . The method of  claim 27 , wherein the mammal is a rodent or a dog. 
     
     
         29 . The method of  claim 27 , wherein the mammal is a human.

Cited by (0)

No later patents cite this yet.

References (0)

No backward citations on record.