Method of inducing neuronal production in the brain and spinal cord
The present invention relates to methods of inducing neuronal production in the brain, recruiting neurons to the brain, and treating a neurodegenerative condition by providing a nucleic acid construct encoding a neurotrophic factor, and injecting the nucleic acid construct intraventricularly into a subject's brain.
1. A method of inducing addition of medium spiny neurons in a post-natal or adult mammalian subject's brain comprising:
providing a nucleic acid construct encoding a neurotrophic factor selected from the group consisting of neurotrophin-4 (NT-4) and brain-derived neurotrophic factor, and a nucleic acid construct encoding a bone morphogenetic protein inhibitor, wherein the nucleic acid constructs are in viral vectors, and
injecting said viral vectors into the post-natal or adult mammalian subject's lateral ventricles to infect the mammalian subject's ventricular wall under conditions effective to express the neurotrophic factor and bone morphogenetic protein inhibitor and to induce addition of medium spiny neurons in any one or all of the caudate nucleus and the putamen of the mammalian subject.
2. The method according to claim 1 , wherein the neurotrophic factor is NT-4.
3. The method according to claim 1 , wherein the neurotrophic factor is brain-derived neurotrophic factor.
4. The method according to claim 1 , wherein the viral vectors are selected from the group consisting of an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, and a combination thereof.
5. The method according to claim 1 , wherein the nucleic acid construct encoding the neurotrophic factor further comprises a constitutive promoter for controlling expression of the neurotrophic factor.
6. The method according to claim 1 , wherein the nucleic acid construct encoding the neurotrophic factor further comprises a cell-specific promoter for controlling expression of the neurotrophic factor.
7. The method according to claim 1 , wherein the nucleic acid construct encoding the neurotrophic factor further comprises an inducible or conditional promoter for controlling expression of the neurotrophic factor.
8. A method of inducing addition of medium spiny neurons in a mammalian subject having Huntington's disease comprising:
providing a nucleic acid construct encoding a neurotrophic factor selected from the group consisting of neurotrophin-4 (NT-4) and brain-derived neurotrophic factor, and a nucleic acid construct encoding a bone morphogenetic protein inhibitor, wherein the nucleic acid constructs are in viral vectors, and
injecting said viral vectors into the mammalian subject's lateral ventricles to infect the mammalian subject's ventricular wall under conditions effective to express the neurotrophic factor and bone morphogenetic protein inhibitor and to induce addition of medium spiny neurons in any one or all of the caudate nucleus and the putamen of the mammalian subject.
9. The method according to claim 8 , wherein the neurotrophic factor is NT-4.
10. The method according to claim 8 , wherein the neurotrophic factor is brain-derived neurotrophic factor.
11. The method according to claim 8 , wherein the viral vectors are selected from the group consisting of an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, and a combination thereof.
12. The method according to claim 8 , wherein the nucleic acid construct encoding the neurotrophic factor further comprises a constitutive promoter for controlling expression of the neurotrophic factor.
13. The method according to claim 8 , wherein the nucleic acid construct encoding the neurotrophic factor further comprises a cell-specific promoter for controlling expression of the neurotrophic factor.
14. The method according to claim 8 , wherein the nucleic acid construct encoding the neurotrophic factor further comprises an inducible or conditional promoter for controlling expression of the neurotrophic factor.