Compositions and methods for treating cep290-associated disease

Abstract

Compositions and methods for treatment of CEP290 related diseases are disclosed.

1 - 568 . (canceled) 
     
     
         569 . A method of altering a cell in an eye of a subject comprising administering to the eye of the subject:
 an adeno-associated virus (AAV) vector comprising a nucleotide sequence encoding a first guide RNA (gRNA) molecule comprising a first targeting domain complementary with a first target domain from a CEP290 gene and a nucleotide sequence encoding a Cas9 molecule; and   a corticosteroid administered daily at a first dose for at least 4 weeks and beginning no more than fourteen days prior to administering the AAV vector.   
     
     
         570 . The method of  claim 569 , wherein the AAV vector further comprises a nucleotide sequence encoding a second gRNA molecule comprising a second targeting domain complementary with a second target domain from the CEP290 gene. 
     
     
         571 . The method of  claim 570 , wherein the first targeting domain comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:530 (CEP290-323), SEQ ID NO:555 (CEP290-485), SEQ ID NO:468 (CEP290-490), and SEQ ID NO:538 (CEP290-492). 
     
     
         572 . The method of  claim 571 , wherein the second targeting domain comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:558 (CEP290-64), SEQ ID NO:2321 (CEP290-11), SEQ ID NO:2312 (CEP290-230), SEQ ID NO:460 (CEP290-496), SEQ ID NO:586 (CEP290-502), and SEQ ID NO:568 (CEP290-504). 
     
     
         573 . The method of  claim 572 , wherein the corticosteroid is administered at the first dose beginning one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen days prior to administering the AAV vector. 
     
     
         574 . The method of  claim 573 , wherein the corticosteroid is administered for four weeks, for five weeks, for six weeks, for seven weeks, for eight weeks, for nine weeks, or for ten weeks. 
     
     
         575 . The method of  claim 574 , wherein the corticosteroid is an oral corticosteroid. 
     
     
         576 . The method of  claim 575 , wherein the oral corticosteroid is prednisone. 
     
     
         577 . The method of  claim 576 , wherein the first dose of the corticosteroid is 0.1 mg/kg/per day to 1 mg/kg/day. 
     
     
         578 . The method of  claim 577 , wherein the first dose of the corticosteroid is 0.5 mg/kg/per day. 
     
     
         579 . The method of  claim 577 , wherein the first dose of the corticosteroid is 1.0 mg/kg/per day. 
     
     
         580 . The method of  claim 578 , wherein the AAV vector is administered to the subretinal space of the eye. 
     
     
         581 . The method of  claim 580 , wherein the corticosteroid is administered at a first dose of at least four weeks and the corticosteroid is then administered at a tapered dose. 
     
     
         582 . A method of altering a cell in an eye of a subject comprising administering to the eye of the subject:
 a recombinant viral particle comprising a nucleotide sequence encoding a first guide RNA (gRNA) molecule comprising a first targeting domain complementary with a first target domain from a CEP290 gene and a nucleotide sequence encoding a Cas9 molecule; and   a corticosteroid administered daily at a first dose for at least 4 weeks and beginning no more than fourteen days prior to administering recombinant viral particle.   
     
     
         583 . The method of  claim 582 , wherein the recombinant viral particle further comprises a nucleotide sequence encoding a second gRNA molecule comprising a second targeting domain complementary with a second target domain from the CEP290 gene. 
     
     
         584 . The method of  claim 583 , wherein the first targeting domain comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:530 (CEP290-323), SEQ ID NO:555 (CEP290-485), SEQ ID NO:468 (CEP290-490), and SEQ ID NO:538 (CEP290-492). 
     
     
         585 . The method of  claim 584 , wherein the second targeting domain comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:558 (CEP290-64), SEQ ID NO:2321 (CEP290-11), SEQ ID NO:2312 (CEP290-230), SEQ ID NO:460 (CEP290-496), SEQ ID NO:586 (CEP290-502), and SEQ ID NO:568 (CEP290-504). 
     
     
         586 . The method of  claim 585 , wherein the corticosteroid is administered at the first dose beginning one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen days prior to administering the recombinant viral particle. 
     
     
         587 . The method of  claim 586 , wherein the corticosteroid is administered for four weeks, for five weeks, for six weeks, for seven weeks, for eight weeks, for nine weeks, or for ten weeks. 
     
     
         588 . The method of  claim 587 , wherein the corticosteroid is an oral corticosteroid. 
     
     
         589 . The method of  claim 588 , wherein the oral corticosteroid is prednisone. 
     
     
         590 . The method of  claim 589 , wherein the first dose of the corticosteroid is 0.1 mg/kg/per day to 1 mg/kg/day. 
     
     
         591 . The method of  claim 590 , wherein the first dose of the corticosteroid is 0.5 mg/kg/per day. 
     
     
         592 . The method of  claim 590 , wherein the first dose of the corticosteroid is 1.0 mg/kg/per day. 
     
     
         593 . The method of  claim 591 , wherein the AAV vector is administered to the subretinal space of the eye. 
     
     
         594 . The method of  claim 593 , wherein the corticosteroid is administered at a first dose of at least four weeks and the corticosteroid is then administered at a tapered dose.