Compositions and methods for treating leber's hereditary optic neuropathy

Abstract

Disclosed herein is a recombinant nucleic acid, comprising: a mitochondrial targeting sequence; a mitochondrial protein coding sequence, wherein said mitochondrial protein coding sequence encodes a polypeptide comprising a mitochondrial protein; and a 3′UTR nucleic acid sequence. Also disclosed is a pharmaceutical composition comprising the recombinant nucleic acid and a method of treating Leber's hereditary optic neuropathy (LHON) using the pharmaceutical composition.

1 - 139 . (canceled) 
     
     
         140 . A pharmaceutical composition, comprising:
 an adeno-associated virus (AAV) comprising a recombinant nucleic acid comprising a sequence that is at least 90% identical to a sequence as set forth in SEQ ID NO: 15; and   a pharmaceutically acceptable excipient comprising phosphate-buffered saline (PBS), α,α-trehalose dehydrate, L-histidine monohydrochloride monohydrate, polysorbate 20, poloxamer 188, or any combination thereof.   
     
     
         141 . The pharmaceutical composition of  claim 140 , wherein said pharmaceutically acceptable excipient comprises poloxamer 188. 
     
     
         142 . The pharmaceutical composition of  claim 141 , wherein said pharmaceutically acceptable excipient comprises 0.0001%-0.01% poloxamer 188. 
     
     
         143 . The pharmaceutical composition of  claim 142 , wherein said pharmaceutically acceptable excipient comprises 0.001% poloxamer 188. 
     
     
         144 . The pharmaceutical composition of  claim 140 , wherein said pharmaceutically acceptable excipient further comprises one or more salts. 
     
     
         145 . The pharmaceutical composition of  claim 144 , wherein said one or more salts comprises NaCl, NaH 2 PO 4 , Na 2 HPO 4 , or KH 2 PO 4 . 
     
     
         146 . The pharmaceutical composition of  claim 145 , wherein said one or more salts comprises NaCl, NaH 2 PO 4 , Na 2 HPO 4 , and KH 2 PO 4 . 
     
     
         147 . The pharmaceutical composition of  claim 146 , wherein said one or more salts comprises 80 mM NaCl, 5 mM NaH 2 PO 4 , 40 mM Na 2 HPO 4 , and 5 mM KH 2 PO 4 . 
     
     
         148 . The pharmaceutical composition of  claim 140 , wherein said pharmaceutical composition has a pH of 6-8. 
     
     
         149 . The pharmaceutical composition of  claim 148 , wherein said pharmaceutical composition has a pH of 7.2-7.4. 
     
     
         150 . The pharmaceutical composition of  claim 149 , wherein said pharmaceutical composition has a pH of 7.3. 
     
     
         151 . The pharmaceutical composition of  claim 140 , wherein said pharmaceutical composition has a viral titer of at least 1.0×10 10  vg/mL. 
     
     
         152 . The pharmaceutical composition of  claim 151 , wherein said pharmaceutical composition has a viral titer of at least 5.0×10 10  vg/mL. 
     
     
         153 . The pharmaceutical composition of  claim 140 , when said pharmaceutical composition is subject to five freeze/thaw cycles, said pharmaceutical composition retains at least 60% of a viral titer as compared to the viral titer prior to the five freeze/thaw cycles. 
     
     
         154 . The pharmaceutical composition of  claim 140 , wherein said pharmaceutical composition, when administered to a patient with Leber's hereditary optic neuropathy, generates a higher average recovery of vision than a comparable pharmaceutical composition without said recombinant nucleic acid. 
     
     
         155 . A method of treating Leber's hereditary optic neuropathy (LHON), comprising administering the pharmaceutical composition of  claim 140  to a patient in need thereof. 
     
     
         156 . The method of  claim 155 , wherein said pharmaceutical composition is administered via intravitreal injection. 
     
     
         157 . The method of  claim 156 , wherein about 0.01-0.1 mL of said pharmaceutical composition is administered via intravitreal injection. 
     
     
         158 . The method of  claim 157 , wherein about 0.05 mL of said pharmaceutical composition is administered via intravitreal injection. 
     
     
         159 . The method of  claim 155 , further comprising administering methylprednisolone to said patient. 
     
     
         160 . The method of  claim 159 , wherein said methylprednisolone is administered intravenously or orally. 
     
     
         161 . The method of  claim 160 , comprising administering methylprednisolone intravenously for at least one day, which is followed by administering methylprednisolone orally for at least a week. 
     
     
         162 . The method of  claim 161 , comprising administering methylprednisolone intravenously for about 3 days, which is followed by administering methylprednisolone orally for at least about 6 weeks. 
     
     
         163 . The method of  claim 159 , wherein said methylprednisolone is administered daily for at least 2 days prior to said intravitreal injection of said pharmaceutical composition. 
     
     
         164 . The method of  claim 159 , wherein said methylprednisolone is administered intravenously at a daily dose of about 80 mg/60 kg. 
     
     
         165 . The method of  claim 155 , further comprising administering creatine phosphate sodium to said patient. 
     
     
         166 . The method of  claim 165 , wherein said creatine phosphate sodium is administered intravenously. 
     
     
         167 . The method of  claim 155 , wherein said administering said pharmaceutical composition generates a higher average recovery of vision than a comparable pharmaceutical composition without said recombinant nucleic acid.