Generation of neurons by reprogramming of oligodendrocytes and oligodendrocyte precursor cells

Abstract

The invention relates to products and methods for transdifferentiating oligodendrocytes and/or oligodendrocyte precursor cells to neurons. The invention further relates to methods of treating central nervous system disorders and conditions.

1 . A viral particle comprising an expression cassette comprising a promoter active in both oligodendrocytes and neurons operably linked to a polynucleotide encoding an interfering RNA that binds to a polynucleotide encoding a mammalian polypyrimidine tract binding protein 1 (PTBP1) and inhibits PTBP1 expression:
 wherein the interfering PIA comprises the nucleotide sequence of SEQ ID NO: 3 and the complement thereof or a nucleotide sequence at least 90% identical thereto or SEQ ID NO: 4 and the complement thereof or a nucleotide sequence at least 90% thereto; and   wherein the virus particle has a tropism for oligodendrocytes and/or oligodendrocyte precursor cells.   
     
     
         2 . (canceled) 
     
     
         3 . The viral particle of  claim 1 , wherein the viral particle is an adeno-associated virus (AAV) vector. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The viral particle of  claim 1 , wherein the interfering RNA is a shRNA, a siRNA, and/or a miRNA. 
     
     
         7 - 11 . (canceled) 
     
     
         12 . A composition comprising the viral particle of  claim 1  and a carrier. 
     
     
         13 . A pharmaceutical composition comprising the viral particle of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method of attenuating expression of PTBP1 in a cell, comprising contacting the cell with the viral particle of  claim 1 , wherein the expression of PTBP1 is attenuated. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A method of transdifferentiating an oligodendrocyte or a oligodendrocyte precursor cell to a neuron, comprising contacting the oligodendrocyte or oligodendrocyte precursor cell with the viral particle of  claim 1 , thereby transdifferentiating the oligodendrocyte or oligodendrocyte precursor cell to a neuron. 
     
     
         19 . The method of  claim 18 , wherein the oligodendrocyte or oligodendrocyte precursor cell is in vitro or ex vivo. 
     
     
         20 . The method of  claim 18 , wherein the oligodendrocyte or oligodendrocyte precursor cell is in a mammalian subject. 
     
     
         21 . A method of increasing the number of neurons in the brain of a mammalian subject, comprising delivering to the brain the viral particle of  claim 1 , thereby increasing the number of neurons in the brain of the mammalian subject relative to the number of neurons prior to the delivery. 
     
     
         22 . A method of transdifferentiating an oligodendrocyte or an oligodendrocyte precursor cell to a neuron in the brain of a mammalian subject, comprising delivering to the brain the viral particle of  claim 1 , thereby transdifferentiating an oligodendrocyte or an oligodendrocyte precursor cell to a neuron in the brain of the mammalian subject. 
     
     
         23 .- 25 . (canceled) 
     
     
         26 . A method of treating a central nervous system disorder or condition responsive to an increase in the number of neurons in a mammalian subject in need thereof, the method comprising delivering to the brain the viral particle of  claim 1 , thereby treating the central nervous system disorder or condition. 
     
     
         27 . The method of  claim 26 , wherein the disorder or condition is a neurodegenerative disorder. 
     
     
         28 . The method of  claim 27 , wherein the neurodegenerative disorder is Parkinson's disease, Alzheimer's disease, Huntington's chorea, and/or amyotrophic lateral sclerosis. 
     
     
         29 . The method of  claim 26 , wherein the disorder or condition is a traumatic brain injury and/or spinal cord injury and/or stroke. 
     
     
         30 . The method of  claim 26 , wherein the disorder or condition is aging. 
     
     
         31 . The method of  claim 26 , further comprising delivering to the oligodendrocyte or oligodendrocyte precursor cell or the brain a differentiation factor. 
     
     
         32 . The method of  claim 31 , wherein the differentiation factor is selected from the group consisting of NeuroD1, Asc11, Brn2a, Myt11, SOX2, and any combination thereof. 
     
     
         33 . The method of  claim 26 , further comprising delivering to the oligodendrocyte or oligodendrocyte precursor cell or the brain a neurotrophic factor. 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 26 , further comprising delivering to the oligodendrocyte or oligodendrocyte precursor cell or the brain an inhibitor of expression of a REI silencing transcription factor complex. 
     
     
         36 . (canceled)