Methods of treating ATPase-mediated diseases with a nucleic acid encoding ATP1A3 and a neuron-specific promoter
The present disclosure provides nucleic acid expression cassettes, vectors, compositions and methods for the treatment of ATPase-mediated diseases in a subject.
1 . A method for treating an ATPase-mediated disease comprising: administering to a subject in need thereof a therapeutically effective amount of a vector comprising a nucleic acid sequence encoding ATP1A3 and a neuron-specific promoter, wherein following administration of the vector, one or more symptoms of the ATPase-mediated disease are decreased and/or ameliorated; wherein the one or more symptoms of the ATPase-mediated disease comprise abnormalities affecting the subject's balance, gait, memory, and impulsivity and wherein the ATPase-mediated disease is alternating hemiplegia of childhood (AHC); wherein the nucleic acid sequence encoding ATP1A3 has at least 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO:01, SEQ ID NO:02, or SEQ ID NO:07.
2 . The method of claim 1 , wherein the vector comprises an adeno associated vector (AAV) vector, and wherein the AAV comprises AAV1, AAV8, or AAV9.
3 . The method of claim 1 , wherein the encoded ATP1A3 has at least 90% identity to the sequence set forth in SEQ ID NO:03 or SEQ ID NO:06.
4 . The method of claim 1 , wherein the nucleic acid sequence further comprises a first inverted repeat and a second inverted terminal repeat.
5 . The method of claim 1 , wherein the neuron-specific promoter comprises a synapsin 1 promoter, a calcium/calmodulin-dependent protein kinase II promoter, a tubulin α1 promoter, a neuron-specific enolase promoter, or a platelet-derived growth factor beta chain promoter.
6 . The method of claim 1 , wherein the neuron-specific promoter comprises a human synapsin promoter, and wherein the human synapsin promoter comprises the nucleic acid sequence set forth in SEQ ID NO:04, SEQ ID NO:05, or SEQ ID NO:09.
7 . The method of claim 1 , wherein the nucleic acid sequence further comprises a bovine growth hormone polyadenylation signal (BGHpA), a Simian virus 40 polyadenylation signal (SV40pA), and/or a synthetic polyadenylation signal.
8 . The method of claim 1 , wherein the nucleic acid sequence further comprises one or more linker sequences, and wherein the one or more linker sequences comprise the sequence set forth in SEQ ID NO:11, SEQ ID NO:13, or SEQ ID NO: 15.
9 . The method of claim 1 , wherein administering comprises intracerebroventricular administration, intra-cistern a magna administration, intrahippocampal administration, or intrathecal administration.
10 . The method of claim 1 , wherein the subject has an ATP1A3 protein mutation.
11 . The method of claim 10 , wherein the ATP1A3 protein mutation comprises a E815K mutation, a D801N mutation, an 1180N mutation, a R756C mutation, or a V589F mutation, as compared to a wild-type ATP1A3 protein having the sequence set forth in SEQ ID NO:03 or SEQ ID NO:06.
12 . The method of claim 1 , wherein the therapeutically effective amount of the vector comprises about 1×10 10 vg/kg, about 1×10 11 vg/kg, about 1×10 12 vg/kg, about 1×10 13 vg/kg, about 1×10 14 vg/kg, or about 1×10 15 vg/kg.
13 . A method for treating an ATPase-mediated disease comprising: administering to a subject in need thereof a therapeutically effective amount of a vector comprising a nucleic acid sequence encoding ATP1A3 operably linked to a human synapsin promoter, wherein the nucleic acid sequence encoding ATP1A3 has at least 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO:07, wherein following administration of the vector, one or more symptoms of the ATPase-mediated disease are decreased and/or ameliorated; wherein the one or more symptoms of the ATPase-mediated disease comprise abnormalities affecting the subject's balance, gait, memory, and impulsivity and wherein the ATPase-mediated disease is alternating hemiplegia of childhood (AHC).
14 . The method of claim 13 , wherein the encoded ATP1A3 comprises the sequence set forth in SEQ ID NO:06.
15 . The method of claim 13 , wherein the human synapsin promoter comprises the nucleotide sequence set forth in SEQ ID NO:05.