Regenerating functional neurons for treatment of disease and injury in the nervous system
Methods for producing new neurons in the brain in vivo are provided according to aspects of the present invention which include introducing NeuroD1 into a glial cell, particularly into a reactive astrocyte or NG2 cell, thereby “converting” the reactive glial cell to a neuron. Methods of producing a neuronal phenotype in a glial cell are provided according to aspects of the present invention which include expressing exogenous NeuroD1 in the glial cell, wherein expressing exogenous NeuroD1 includes delivering an expression vector, such as a viral expression vector, including a nucleic acid encoding the exogenous NeuroD1 to the glial cell.
1. A method of treating a neurological condition in a subject in need thereof, wherein the neurological condition is characterized by loss of neurons and presence of reactive astrocytes, comprising:
administering a therapeutically effective dose of transcription factor NeuroD1 to a reactive astrocyte of the subject, wherein administering the therapeutically effective dose of NeuroD1 comprises administering an expression vector comprising a nucleic acid sequence encoding NeuroD1 protein, wherein no transcription factor other than NeuroD1 is required to be exogenously expressed in the reactive astrocytes, thereby producing a neuronal phenotype in the reactive astrocytes to ameliorate the neurological condition of the subject.
2. The method of treating a neurological condition in a subject in need thereof,-according to claim 1 , wherein the nucleic acid sequence encoding NeuroD1 protein comprises a nucleic acid sequence selected from the group consisting of: a nucleic acid sequence encoding SEQ ID NO:2 or a functional fragment thereof; a nucleic acid sequence encoding SEQ ID NO:4 or a functional fragment thereof; SEQ ID NO:1 or a functional fragment thereof; SEQ ID NO:3 or a functional fragment thereof; and a nucleic acid sequence encoding a protein which has 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater, identity to SEQ ID NO: 2 or SEQ ID NO: 4, or a functional fragment thereof.
3. The method of treating a neurological condition in a subject in need thereof, according to claim 1 , wherein the reactive glial cells are present in the subject due to a neurological condition selected from the group consisting of: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), epilepsy, an injury to the central or peripheral nervous system, and stroke.
4. The method of treating a neurological condition in a subject in need thereof, according to claim 1 , wherein administering a therapeutically effective dose of NeuroD1 comprises local administration or systemic administration.