Methods for inhibiting starvation of a cell
The present invention is directed to methods for the treatment or prevention of starvation in a cell, e.g., a neuronal cell, and methods for the treatment and prevention of disorders associated therewith by the administration of an agent, e.g., a nucleic acid molecule, which enhances the intracellular generation and/or uptake of glucose, pyruvate, lactate, and/or NADPH.
1. A method for inhibiting starvation of a photoreceptor cell compromised by retinitis pigmentosa, comprising contacting said cell with at least one isolated nucleic acid molecule which enhances the intracellular generation and/or uptake of glucose in said photoreceptor cell, wherein the at least one isolated nucleic acid molecule encodes an enzyme selected from the group consisting of glucose-6-phosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, 6-phosphogluconolactonase, phosphogluconate dehydrogenase, ribulose-5-phosphate isomerase, ribulose-5-phosphate epimerase, transketolase, transaldolase, GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14,
thereby inhibiting starvation of said photoreceptor cell.
2. A method for treating or preventing retinitis pigmentosa in a subject comprising administering to said subject at least one isolated nucleic acid molecule which enhances the intracellular generation and/or uptake of glucose such that starvation of a photoreceptor cell in the subject is inhibited, wherein the at least one isolated nucleic acid molecule encodes an enzyme selected from the group consisting of glucose-6-phosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, 6-phosphogluconolactonase, phosphogluconate dehydrogenase, ribulose-5-phosphate isomerase, ribulose-5-phosphate epimerase, transketolase, transaldolase, GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14,
thereby treating or preventing retinitis pigmentosa in said subject.
3. A method for prolonging the viability of a cone cell compromised by retinitis pigmentosa, comprising contacting said cell with at least one isolated nucleic acid molecule which enhances the intracellular generation and/or uptake of glucose such that starvation of the cone cell is inhibited, wherein the at least one isolated nucleic acid molecule encodes an enzyme selected from the group consisting of glucose-6-phosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, 6-phosphogluconolactonase, phosphogluconate dehydrogenase, ribulose-5-phosphate isomerase, ribulose-5-phosphate epimerase, transketolase, transaldolase, GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14,
thereby prolonging the viability of said cone cell.
4. A method for prolonging the viability of a rod cell compromised by retinitis pigmentosa, comprising contacting said cell with at least one isolated nucleic acid molecules which enhances the intracellular generation and/or uptake of glucose such that starvation of the rod cell is inhibited, wherein the at least one isolated nucleic acid molecule encodes an enzyme selected from the group consisting of glucose-6-phosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, 6-phosphogluconolactonase, phosphogluconate dehydrogenase, ribulose-5-phosphate isomerase, ribulose-5-phosphate epimerase, transketolase, transaldolase, GLUT1, GLUT2, GLUT3, GLUT4, GLUT5, GLUT6, GLUT7, GLUT8, GLUT9, GLUT10, GLUT11, GLUT12, GLUT13, and GLUT14,
thereby prolonging the viability of said rod cell.
5. The method of any one of claims 1 and 2 - 4 , wherein the at least one isolated nucleic acid molecule enhances an activity selected from the group consisting of the intracellular generation of glucose, the uptake of glucose into a cell, the intracellular generation of NADPH, metabolic flux through gluconeogenesis, metabolic flux through the pentose phosphate pathway, the ability of a cell to generate phospholipids, and the ability of a cell to detoxify free oxygen radicals.
6. The method of any one of claims 1 and 2 - 4 , wherein the at least one isolated nucleic acid molecule reduces metabolic flux through glycolysis.
7. The method of any one of claims 1 and 2 - 4 , wherein the at least one isolated nucleic acid molecule encodes an enzyme selected from the group consisting of glucose-6-phosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and fructose 1,6-bisphosphatase.
8. The method of any one of claims 1 and 2 - 4 , wherein the at least one isolated nucleic acid molecule encodes an enzyme involved in the pentose phosphate pathway.
9. The method of claim 5 , wherein the at least one isolated nucleic acid molecule encodes an enzyme selected from the group consisting of pyruvate carboxylase, phosphoenolpyruvate carboxykinase and fructose 1,6-bisphosphatase.
10. The method of any one of claims 1 and 2 - 4 , wherein the at least one nucleic acid molecule is contained within a vector.
11. The method of claim 10 , wherein the vector is a retrovirus, an adenovirus, an adenoviral/retroviral chimera, an adeno-associated virus (AAV), a herpes simplex virus I or II, a parvovirus, a reticuloendotheliosis virus, a poliovirus, a papillomavirus, a vaccinia virus and a lentivirus.
12. The method of claim 2 , wherein the administration is intraocular administration.
13. The method of claim 12 , wherein the intraocular administration is selected from the group consisting of intravitreal, subconjuctival, sub-tenon, periocular, retrobulbar, suprachoroidal, and intrascleral administration.
14. The method of any one of claim 1 , 3 , or 4 , wherein the cell is contacted with at least two isolated nucleic acid molecules which enhance the intracellular generation and/or uptake of glucose such that starvation of the rod cell is inhibited.
15. The method of claim 2 , wherein the subject is administered at least two isolated nucleic acid molecules which enhance the intracellular generation and/or uptake of glucose such that starvation of the rod cell is inhibited.
16. The method of claim 14 , wherein the nucleic acid molecules are contained in a single vector.
17. The method of claim 14 , wherein the nucleic acid molecules are contained in different vectors.