INTRATHECAL DELIVERY OF RECOMBINANT ADENO-ASSOCIATED VIRUS 9
The present invention relates to Adeno-associated virus type 9 methods and materials useful for intrathecal delivery of polynucleotides. Use of the methods and materials is indicated, for example, for treatment of lower motor neuron diseases such as SMA and ALS as well as Pompe disease and lysosomal storage disorders. It is disclosed that administration of a non-ionic, low-osmolar contrast agent, together with a rAA9 vector for the expression of Survival Motor Neuron protein, improves the survival of SMN mutant mice as compared to the administration of the expression vector alone.
1 - 23 . (canceled)
24 . A composition comprising: (a) a recombinant AAV9 (rAAV9) comprising an rAAV9 genome comprising a gene for treating a CLN disease selected from the group consisting of a CLN1 gene, a CLN2 gene, a CLN3 gene, a CLN4 gene, a CLN5 gene, a CLN6 gene, and a CLN8 gene; and (b) contrast agent.
25 . The composition of claim 24 , wherein the contrast agent is a non-ionic, low-osmolar contrast agent.
26 . The composition of claim 25 , wherein the non-ionic, low-osmolar contrast agent is selected from the group consisting of iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, and combinations thereof.
27 . The composition of claim 25 , wherein the non-ionic, low-osmolar contrast agent is iohexol.
28 . The composition of claim 24 , wherein the rAAV9 genome is a single-stranded genome.
29 . The composition of claim 24 , wherein the rAAV9 genome is a self-complementary genome.
30 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN1 gene.
31 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN2 gene.
32 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN3 gene.
33 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN4 gene.
34 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN5 gene.
35 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN6 gene.
36 . The composition of claim 24 , wherein the gene for treating the CLN disease is a CLN8 gene.
37 . A method of treating a CLN disease in a patient in need thereof comprising, delivering a composition of claim 1 to a brain or spinal cord of a patient in need thereof, wherein the CLN disease is a CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, or CLN8 disease.
38 . The method of claim 37 , wherein the composition is delivered by intrathecal injection, intracisternal, or intracerebroventricular injection.
39 . The method of claim 38 , further comprising placing the patient in the Trendelenberg position after intrathecal injection of the composition.
40 . The method of claim 37 , wherein the contrast agent is a non-ionic, low-osmolar contrast agent.
41 . The method of claim 40 , wherein the non-ionic, low-osmolar contrast agent is selected from the group consisting of iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, and combinations thereof.
42 . The method of claim 40 , wherein the non-ionic, low-osmolar contrast agent is iohexol.
43 . The method of claim 37 , wherein the CLN disease is a CLN1 disease, and the gene for treating the CLN disease is a CLN1 gene.
44 . The method of claim 37 , wherein the CLN disease is a CLN2 disease, and the gene for treating the CLN disease is a CLN2 gene.
45 . The method of claim 37 , wherein the CLN disease is a CLN3 disease, and the gene for treating the CLN disease is a CLN3 gene.
46 . The method of claim 37 , wherein the CLN disease is a CLN4 disease, and the gene for treating a CLN disease is a CLN4 gene.
47 . The method of claim 37 , wherein the CLN disease is a CLN5 disease, and the gene for treating the CLN disease is a CLN5 gene.
48 . The method of claim 37 , wherein the CLN disease is a CLN6 disease, and the gene for treating the CLN disease is a CLN6 gene.
49 . The method of claim 37 , wherein the CLN disease is a CLN8 disease, and the gene for treating the CLN disease is a CLN8 gene.
50 . The method of claim 37 , wherein the delivering to the brain or spinal cord comprises delivery to a brain stem.
51 . The method of claim 37 , wherein the delivering to the brain or spinal cord comprises delivery to a motor cortex.
52 . The method of claim 37 , wherein the delivering to the brain or spinal cord comprises delivery to a nerve cell, a glial cell, or both.
53 . The method of claim 37 , wherein the delivering to the brain or spinal cord comprises delivery to a neuron, a lower motor neuron, a microglial cell, an oligodendrocyte, an astrocyte, a Schwann cell or combination thereof.