Gene therapy for neurometabolic disorders

Abstract

The disclosure pertains to methods and compositions for treating disorders affecting the central nervous system (CNS). These disorders include neurometabolic disorders such as lysosomal storage diseases that affect the central nervous system, e.g., Niemann-Pick A disease. They also include disorders such as Alzheimer's disease. The disclosed methods involve contacting an axonal ending of a neuron with a composition containing high titer AAV carrying a therapeutic transgene so that the AAV vector is axonally transported in a retrograde fashion and transgene product is expressed distally to the administration site.

1 - 38 . (Cancelled)  
     
     
         39 . A method comprising: 
 administering a composition comprising an AAV vector encoding for a biologically active molecule to a site in the disease-compromised central nervous system of a mammal, under conditions whereby said injected AAV vectors transduce cells located at a distal site in the central nervous system and said encoded biologically active molecule is translated.    
     
     
         40 . The method of  claim 39 , wherein the translated biologically active molecule is then expressed.  
     
     
         41 . The method of  claim 39 , wherein the mammal has a lysosomal storage disease.  
     
     
         42 . The method of  claim 41 , wherein the lysosomal storage disease is Niemann Pick A disease.  
     
     
         43 . The method of  claim 39 , wherein the mammal is human.  
     
     
         44 . The method of  claim 39 , wherein the distal site is contralateral to the administration site.  
     
     
         45 . The method of  claim 39 , where the administration site is in a region of the CNS selected from the group consisting of the spinal cord, the brainstem, the hippocampus, the striatum, the medulla, the pons, the mesencephalon, the cerebellum, the thalamus, the hypothalamus, the cerebral cortex, the occipital lobe, the temporal lobe, the parietal lobe, and the frontal lobe.  
     
     
         46 . The method of  claim 39 , wherein the administration site is in the hippocampus and the distal site is in a region of the brain selected from the group consisting of the contralateral dentate gyrus and the contralateral CA3, and the medial septum, and the entorhinal cortex.  
     
     
         47 . The method of  claim 39 , wherein the administration site is in a region of the brain selected from the group consisting of the striatum and the cerebellum, and the distal site is in a region of the brain selected from the group consisting of the substantia nigra and the medulla oblongata.  
     
     
         48 . The method of  claim 39 , further comprising administration of a composition to a second site in the CNS of the mammal, wherein the composition comprises an AAV vector comprising a polynucleotide encoding a biologically active molecule product.  
     
     
         49 . The method of  claim 48 , wherein the second administration site is contralateral to the first administration site.  
     
     
         50 . The method of  claim 40 , wherein the biologically active molecule is a lysosomal hydrolase.  
     
     
         51 . The method of  claim 50 , wherein the lysosomal hydrolase is any one of lysosomal hydrolases listed in Table 1.  
     
     
         52 . The method of  claim 50 , wherein the lysosomal hydrolase is acid sphingomyelinase.  
     
     
         53 . The method of  claim 39 , wherein the administration site is in the deep cerebellar nuclei and the distal site is the spinal cord.  
     
     
         54 . The method of  claim 39 , wherein the distance between the administration site and distal site is at least 2 mm.  
     
     
         55 . The method of  claim 39 , wherein the concentration of the AAV vector in the composition is at least 5×1012 gp/ml.  
     
     
         56 . A method comprising: 
 administering a composition comprising an AAV vector encoding for a metalloendopeptidase molecule to a site in the central nervous system of a mammal with Alzheimer's disease, under conditions whereby said injected AAV vectors transduce cells located at a distal site in the central nervous system and said encoded metalloendopeptidase is expressed.    
     
     
         57 . The method of  claim 56 , wherein the metalloendopeptidase is selected from the group consisting of neprilysin, insulysin, and thimet oligopeptidase.  
     
     
         58 . The method of  claim 39  or 56, wherein the AAV vector is selected from the group consisting of AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8.  
     
     
         59 . The method of  claim 56 , wherein the distance between the administration site and the distal site is at least 2 mm.  
     
     
         60 . The method of  claim 56 , wherein the concentration of the AAV vector in the composition is at least 5×1012 gp/ml.