Intrathecal delivery of recombinant adeno-associated virus 9

Abstract

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 . A method of delivering a polynucleotide to the central nervous system of a patient in need thereof comprising intrathecal delivery of a rAAV9 and a non-ionic, low-osmolar contrast agent to the patient, wherein the rAAV9 comprises a self-complementary genome including the polynucleotide. 
     
     
         2 . The method of  claim 1  wherein the polynucleotide is delivered to the brain. 
     
     
         3 . The method of  claim 1  wherein the polynucleotide is delivered to the spinal cord. 
     
     
         4 . The method of  claim 1  wherein the polynucleotide is delivered to a glial cell. 
     
     
         5 . The method of  claim 4  wherein the glial cell is an astrocyte. 
     
     
         6 . The method of  claim 1  wherein the polynucleotide is delivered to a lower motor neuron. 
     
     
         7 . The method of  claim 1  wherein the non-ionic, low-osmolar contrast agent is iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol or ioxilan. 
     
     
         8 . The method of  claim 7  wherein the non-ionic, low-osmolar contrast agent is iohexol. 
     
     
         9 . The method of  claim 1  wherein the polynucleotide is a survival motor neuron (SMN) polynucleotide. 
     
     
         10 . A method of treating a neurological disease in a patient in need thereof comprising intrathecal delivery of a rAAV9 and a non-ionic, low-osmolar contrast agent to the patient, wherein the rAAV9 comprises a self-complementary genome including a therapeutic polynucleotide. 
     
     
         11 . The method of  claim 10  wherein the neurological disease is Rett Syndrome. 
     
     
         12 . The method of  claim 10  wherein the neurological disease is a neurodegenerative disease. 
     
     
         13 . The method of  claim 12  wherein the therapeutic polynucleotide is a survival motor neuron (SMN) polynucleotide. 
     
     
         14 . The method of  claim 12  wherein the neurodegenerative disease is spinal muscular atrophy. 
     
     
         15 . The method of  claim 12  wherein the neurodegenerative disease is amyotrophic lateral sclerosis. 
     
     
         16 . The method of  claim 10  wherein the polynucleotide is delivered to the brain. 
     
     
         17 . The method of  claim 10  wherein the polynucleotide is delivered to the spinal cord. 
     
     
         18 . The method of  claim 10  wherein the polynucleotide is delivered to a glial cell. 
     
     
         19 . The method of  claim 18  wherein the glial cell is an astrocyte. 
     
     
         20 . The method of  claim 10  wherein the polynucleotide is delivered to a lower motor neuron. 
     
     
         21 . The method of  claim 10  wherein the non-ionic, low-osmolar contrast agent is iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol or ioxilan. 
     
     
         22 . The method of  claim 21  wherein the non-ionic, low-osmolar contrast agent is iohexol. 
     
     
         23 . The method of any one of  claims 1 - 22  wherein the patient is put in the Trendelenberg position after intrathecal delivery of the rAAV9.