Agents that reduce neuronal overexcitation
Agents that reduce the level of a tau gene product in a cell, e.g., in a neuron, include antisense nucleic acids. For example, antisense nucleic acids can be used to down-regulate expression of a tau gene in a cell (e.g., in a neuron). The antisense sequence is complementary to the mRNA of the targeted gene (e.g., tau), and inhibits expression of the targeted gene products. Suitable oligonucleotides can be chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. A number of such modifications have been described in the literature, which modifications alter the chemistry of the backbone, sugars, or heterocyclic bases.
1. A pharmaceutical composition comprising:
a) a modified nucleic acid agent that specifically reduces the level of a tau gene product in a cell, and that targets a region of a tau gene selected from:
(SEQ ID NO: 13)
(i) 5′-gat cttagcaacg tccagtccaa gtgtggctca
aaggataata tcaaacacgt cccgggaggc ggcagtgtgc
aaatagtcta caaaccagtt-3′;
(SEQ ID NO: 14)
(ii) 5′-gacctgagca aggtgacctc caagtgtggc
tcattaggca
acatccatca taaaccagga ggtggccagg tggaagtaaa
atctgagaag ctt-3′;
(SEQ ID NO: 15)
(iii) 5′-gacttca aggacagagt ccagtcgaag attgggtccc
tggacaatat cacccacgtc cctggcggag gaaataaaaa
gattgaaacc cacaagctg-3′;
(SEQ ID NO: 16)
(iv) 5′-aagtcgccgt cttccgccaa gagccgcctg-3′;
(SEQ ID NO: 17)
(v) 5′-gccaagacag accacggggc ggagatcgtg-3′;
and
b) a pharmaceutically acceptable excipient.
2. The composition of claim 1 , wherein the pharmaceutically acceptable excipient comprises an agent that provides for crossing the blood-brain barrier.
3. The composition of claim 1 , wherein the tau gene product is encoded by a wild-type tau allele.
4. The composition of claim 1 , wherein the nucleic acid agent comprises at least one modification that increases stability and/or biological activity of the agent.
5. The composition of claim 1 , wherein the composition further comprises a lipid.
6. The composition of claim 1 , wherein the composition further comprises a biodegradable polymer.
7. The composition of claim 1 , wherein the nucleic acid agent is encapsulated in a liposome.
8. The composition of claim 1 , wherein the nucleic acid agent is formulated for crossing the blood-brain barrier.
9. The composition of claim 1 , wherein the nucleic acid agent is an antisense nucleic acid.
10. The composition of claim 1 , wherein the nucleic acid agent comprises a backbone modification.
11. The composition of claim 1 , wherein the composition comprises polyethyleneimine, polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine, or polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine.
12. The composition of claim 1 , wherein the nucleic acid agent is complexed with a membrane disruptive agent.
13. The composition of claim 1 , wherein the modified nucleic acid comprises a modified sugar.
14. The composition of claim 1 , wherein the modified nucleic acid comprises at least one modified base.
15. The composition of claim 1 , wherein the nucleic acid agent is encoded by a recombinant expression vector.
16. The composition of claim 15 , wherein the nucleic acid agent is expressed by an adeno-associated virus or a retrovirus.