Increased and sustained in vivo gene expression using a nucleic acid, histone and amphipathic compound composition
The invention features a non-transgenic model of Alzheimer's Disease, method for inducing prolonged in vivo gene expression in a mammal, and methods of inhibiting Alzheimer's Disease-associated neuronal cell death.
1. A method for inducing increasing and sustained levels of in vivo gene expression of an exogenous nucleic acid in a mammal over a prolonged period of time, comprising contacting a non-muscular tissue of said mammal with a composition comprising said exogenous nucleic acid, a histone, and an amphipathic compound, wherein increasing and sustained levels of gene expression of said exogenous nucleic acid is detected in said mammal for at least one week after contacting said tissue with said composition.
2. The method of claim 1 , wherein said tissue is neuronal tissue.
3. The method of claim 1 , wherein said tissue is a central nervous system (CNS) tissue.
4. The method of claim 1 , wherein said tissue comprises a post-mitotic neuronal cell.
5. The method of claim 1 , wherein said tissue comprises a cortical neuronal cell.
6. The method of claim 1 , wherein said tissue comprises a hippocampal neuronal cell, a glial cell, or a vascular endothelial cell.
7. The method of claim 1 , wherein increasing and sustained levels of gene expression in said tissue is detected in vivo for at least two weeks after contacting said tissue with said composition.
8. The method of claim 1 , wherein increasing and sustained levels of gene expression in said tissue is detected in vivo for at least four weeks after contacting said tissue with said composition.
9. The method of claim 1 , wherein increasing and sustained levels of gene expression in said tissue is detected in vivo for at least eight weeks after contacting said tissue with said composition.
10. The method of claim 1 , wherein said composition is in the form of a liposome.
11. The method of claim 10 , wherein said liposome is neutral or cationic.
12. The method of claim 10 , wherein said lipsome is anionic.
13. The method of claim 1 , wherein said histone is selected from the group consisting of H1, H2A, H2B, H3, and H4.
14. The method of claim 1 , wherein said composition further comprises a nuclear localizing signal.
15. The method of claim 1 wherein the amphipathic compound is a non-natural polyamine having a hydrophobic moiety, wherein said hydrophobic moiety is selected from the group consisting of a C6-C24 alkane, C6-C24 alkene, sterol, steroid, lipid, fatty acid, and hydrophobic hormone.
16. The method of claim 1 , wherein said nucleic acid is an AD7c-NTP antisense molecule or a nitric oxide synthase III antisense molecule.
17. The method of claim 16 , wherein said nucleic acid comprises a sequence complementary to the nucleotide sequence of SEQ ID NO:1.