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 . An expression cassette comprising a polynucleotide encoding an antisense RNA or an interfering RNA targeted to a polynucleotide encoding a mammalian polypyrimidine tract binding protein 1 (PTBP1). 
     
     
         2 . The expression cassette of  claim 1 , wherein the expression cassette is in a viral vector. 
     
     
         3 . The expression cassette of  claim 2 , wherein the viral vector is an adeno-associated virus (AAV) vector. 
     
     
         4 . The expression cassette of  claim 1 , wherein the polynucleotide encodes an antisense RNA targeted to a mammalian PTBP1 protein. 
     
     
         5 . The expression cassette of  claim 1 , wherein the polynucleotide encodes an interfering RNA targeted to a mammalian PTBP1 protein. 
     
     
         6 . The expression cassette of  claim 5 , wherein the interfering RNA is a shRNA, a siRNA, and/or a miRNA. 
     
     
         7 . The expression cassette of  claim 6 , wherein the interfering RNA is a siRNA comprising the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 2 or a nucleotide sequence at least 90% identical thereto. 
     
     
         8 . The expression cassette of  claim 1 , wherein the polynucleotide is operably linked to a promoter. 
     
     
         9 . The expression cassette of  claim 8 , wherein the promoter is a constitutive promoter. 
     
     
         10 . A virus particle comprising the expression cassette of  claim 1 . 
     
     
         11 . The virus particle of  claim 10 , wherein the virus particle has a tropism for oligodendrocytes and/or oligodendrocyte precursor cells. 
     
     
         12 . A composition comprising the expression cassette of  claim 1 . 
     
     
         13 . A pharmaceutical composition comprising the expression cassette 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 expression cassette 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 expression cassette 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 expression cassette 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 expression cassette 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 expression cassette of  claim 1 , thereby treating the central nervous system disorder or condition. 
     
     
         27 - 36 . (canceled)