Glucocerebrosidase gene therapy for Parkinson's disease
The present invention is directed, in part, to the treatment of a subject having a neurodegenerative disorder, such as Parkinson's disease (PD), by providing glucocerebrosidase enzyme. The enzyme may be provided, e.g., through gene therapy or by administration of a glucocerebrosidase protein. Accordingly, the present invention encompasses glucocerebrosidase nucleic acids or proteins for use in the treatment of PD or other neurodegenerative disorders.
1. A method of treating Parkinson's disease (PD), the method comprising delivering to the central nervous system (CNS) of a subject in need thereof a vector comprising a nucleic acid encoding a glucocerebrosidase protein, wherein the nucleic acid encoding the glucocerebrosidase protein is operably linked to a synapsin promoter, wherein the vector is an AAV2/5 vector, wherein the vector is administered by injection, and wherein the method decreases the size or amount of insoluble α-synuclein aggregates in one or more brain tissues relative to a control.
2. The method of claim 1 , wherein the sequence of the nucleic acid has at least 90% identity to SEQ ID NO.: 1 or SEQ ID NO.: 2.
3. The method of claim 1 , wherein the glucocerebrosidase protein comprises an amino acid sequence having at least 90% identity to SEQ ID NO.: 3, SEQ ID NO.: 4, or SEQ ID NO.: 5.
4. The method of claim 1 , wherein the method increases the amount and/or activity of glucocerebrosidase protein in one or more brain tissues relative to a control.
5. The method of claim 1 , wherein the method increases the amount of LC3-II in one or more brain tissues relative to a control.
6. The method of claim 1 , wherein the method increases, relative to a control, the amount of any of one or more of beclin-1, LAMP-2A, and ceramide in one or more brain tissues.
7. The method of claim 1 , wherein the method increases the amount or concentration of ubiquitin-like protein p62 in one or more brain tissues relative to a control.
8. The method of claim 1 , wherein the method treats degeneration of neurons.
9. The method of claim 8 , wherein the degeneration of neurons is degeneration of dopaminergic neurons.
10. The method of claim 8 , wherein the treatment of the degeneration comprises a decrease, relative to a control, in the number or severity of one or more of swollen axons, bulging axons, and axons that are both swollen and bulging.
11. The method of claim 1 , wherein the administration of the nucleic acid increases macroautophagy relative to a control.
12. A gene therapy vector for the treatment of Parkinson's disease, the gene therapy vector comprising a nucleic acid encoding a glucocerebrosidase protein operably linked to a synapsin promoter, wherein the vector is an AAV2/5 vector, characterized in that delivery of the vector to the central nervous system (CNS) of a subject suffering from Parkinson's disease (PD), wherein the vector is administered by injection, decreases the size or amount of insoluble α-synuclein aggregates in one or more brain tissues relative to a control.
13. The gene therapy vector of claim 12 , wherein the nucleic acid comprises a nucleotide sequence having at least 90% identity to SEQ ID NO.: 1 or SEQ ID NO.: 2.
14. The gene therapy vector of claim 12 , wherein the glucocerebrosidase protein comprises an amino acid sequence having at least 90% identity to SEQ ID NO.: 3, SEQ ID NO.: 4, or SEQ ID NO.: 5.