Methods of treating lysosomal disorders

Abstract

Provided herein are methods for treating a lysosomal transmembrane protein disease or disorder through ex vivo introduction of a nucleic acid molecule into hematopoietic stem and progenitor cells (HSPCs) followed by transplantation of the HSPCs into a subject in need of treatment. Also provided are vectors containing the nucleic acid molecule.

What is claimed is: 
     
         1 . A method of treating a lysosomal transmembrane protein disease or disorder in a subject comprising:
 introducing a corresponding functional human lysosomal transmembrane protein into hematopoietic stem and progenitor cells (HSPCs) of the subject; and   transplanting the HSPCs into the subject,   
       thereby treating the lysosomal transmembrane protein disease or disorder. 
     
     
         2 . The method of  claim 1 , wherein when:
 (a) the lysosomal transmembrane protein disease or disorder is mucopolysaccharidosis type IIIC, the corresponding functional human lysosomal transmembrane protein is HGSNAT; and   (b) the lysosomal transmembrane protein disease or disorder is Neiman-Pick Type C, the corresponding functional human lysosomal transmembrane protein is NPC-1.   
     
     
         3 . The method of  claim 1 , wherein the step of introducing comprises contacting a vector comprising a polynucleotide encoding functional human lysosomal transmembrane protein and a functional promoter with the HSPCs and allowing expression of the functional human lysosomal transmembrane protein. 
     
     
         4 . The method of  claim 1 , wherein the subject is human. 
     
     
         5 . The method of  claim 1 , wherein the vector is a viral vector selected from the group consisting of a lentiviral, adenoviral, and AAV vector. 
     
     
         6 . The method of  claim 1 , wherein the step of introducing is performed ex vivo. 
     
     
         7 . The method of  claim 1 , wherein the HSPCs are isolated from the bone marrow of the subject. 
     
     
         8 . A method of treating or ameliorating a lysosomal protein disease or disorder in a subject comprising:
 isolating hematopoietic stem and progenitor cells (HSPCs) from bone marrow from the subject;   introducing a functional human lysosomal transmembrane gene into the HSPCs, wherein the gene encodes a protein corresponding to the lysosomal protein disease or disorder; and   transplanting the HSPCs back into the subject,   
       thereby treating or ameliorating the lysosomal protein disease or disorder. 
     
     
         9 . The method of  claim 8 , wherein when:
 (a) the lysosomal transmembrane protein disease or disorder is mucopolysaccharidosis type IIIC, the functional human lysosomal transmembrane gene is HGSNAT; and   (b) the lysosomal transmembrane protein disease or disorder is Neiman-Pick Type C, the functional human lysosomal transmembrane gene is NPC1.   
     
     
         10 . The method of  claim 8 , wherein the HSPCs are CD34+ cells. 
     
     
         11 . The method of  claim 8 , wherein administration is intravenous. 
     
     
         12 . A method of treating or ameliorating a lysosomal protein disease or disorder in a subject comprising: producing a functional human lysosomal transmembrane gene in the subject using gene editing. 
     
     
         13 . The method of  claim 12 , wherein when:
 (a) the lysosomal transmembrane protein disease or disorder is mucopolysaccharidosis type IIIC, the functional human lysosomal transmembrane gene is HGSNAT; and   (b) the lysosomal transmembrane protein disease or disorder is Neiman-Pick Type C, the functional human lysosomal transmembrane gene is NPC1.   
     
     
         14 . The method of  claim 12 , wherein producing a functional human lysosomal gene un the subject comprises contacting cells expressing a defective lysosomal transmembrane protein from the subject with a vector encoding a gene editing system that, when transfected into the cells, removes a trinucleotide extension mutation of an endogenous gene encoding the lysosomal transmembrane protein, thereby treating the lysosomal protein disease or disorder. 
     
     
         15 . The method of  claim 14 , wherein the gene editing system is selected from the group consisting of CRISPR/Cas, zinc finger nucleases, and transcription activator-life effector nucleases. 
     
     
         16 . The method of  claim 14 , wherein the step of contacting comprises administering to the subject an effective amount of the vector. 
     
     
         17 . The method of  claim 14 , wherein the step of contacting comprises obtaining a sample of cells from the subject, transfecting the gene editing system into the sample of cells, and thereafter, transplanting the transfected cells into the subject. 
     
     
         18 . The method of  claim 17 , wherein the sample of cells is selected from the group consisting of blood cells and HSPCs.