Methods for therapy of neurodegenerative disease of the brain

Abstract

A specific clinical protocol for use toward therapy of defective, diseased and damaged neurons in the mammalian brain, of particular usefulness for treatment of neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease. The protocol is practiced by delivering a definite concentration of recombinant neurotrophin, such as glial cell-derived neurotrophic factor), into a targeted region of the brain (such as the substantia nigra) using a lentiviral expression vector. The neurotrophin is delivered to, or within close proximity of, identified defective, diseased or damaged brain cells. The concentration of neurotrophin delivered as part of a neurotrophic composition varies from 10 10 to 10 15 neurotrophin encoding viral particles/ml of composition fluid. Each delivery site receives from 2.5 μl to 25 μl of neurotrophic composition, delivered slowly, as in over a period of time ranging upwards of 10 minutes/delivery site. Each delivery site is at, or within 500 μm of, a targeted cell, and no more than about 10 mm from another delivery site. The method stimulates growth of targeted neurons, and reversal of functional deficits associated with the neurodegenerative disease being treated.

1 . A method for delivery of a therapeutic neurotrophin to targeted defective, diseased or damaged neurons in the mammalian brain, the method comprising delivering a neurotrophic composition, comprising a neurotrophin encoding lentiviral expression vector, into one or more delivery sites within a region of the brain containing targeted neurons; wherein the neurotrophin is expressed in, or within 500 μm from, a targeted cell, and no more than about 10 mm from another delivery site; and wherein further contact with the neurotrophin ameliorates the defect, disease or damage.  
     
     
         2 . The method according to  claim 1 , wherein the region of the brain containing the targeted neurons is the substantia nigra.  
     
     
         3 . The method according to  claim 2 , wherein the targeted neurons are dopaminergic neurons.  
     
     
         4 . The method according to  claim 1 , wherein the viral expression vector is HIV-1.  
     
     
         5 . The method according to  claim 1 , wherein the neurotrophic composition is a fluid having a concentration of neurotrophin encoding lentiviral particles in the range from 10 10  to 10 10  particles per ml of neurotrophic composition.  
     
     
         6 . The method according to  claim 5 , wherein from 2.5 μl to 25 μl of the neurotrophic composition is delivered to each delivery site.  
     
     
         7 . The method according to  claim 1 , wherein the treated mammal is a human and the transgene encodes a human neurotrophin.  
     
     
         8 . The method according to  claim 7 , wherein the neurotrophin is human glial cell-derived neurotrophic factor (GDNF).  
     
     
         9 . The method according to  claim 7 , wherein the human is suffering from Parkinson's disease, and the disease is ameliorated by stimulation of growth of dopaminergic neurons.  
     
     
         10 . The method according to  claim 9 , wherein the disease is ameliorated by reversal of deficits in motor function associated with the Parkinson's disease.  
     
     
         11 . The method according to  claim 7 , wherein the human is suffering from Alzheimer's disease, and the disease is ameliorated by stimulation of growth of cholinergic neurons.  
     
     
         12 . The method according to  claim 11 , wherein the disease is ameliorated by improvement of cognitive function whose impairment was associated with Alzheimer's disease.