Methods for the Use of Low-Dose Immune Modulators Transiently for Treating Patients Undergoing Protein Replacement Therapy

Abstract

The present disclosure provides compositions and methods for inducing immune tolerance in subjects suffering from metabolic diseases.

1 - 23 . (canceled) 
     
     
         24 . A method of inducing immune tolerance to gene therapy in a subject suffering from a metabolic disorder, the method comprising administering to the subject a therapeutically effective amount of an immune modulator and a therapeutic agent such that immune tolerance is induced in the subject. 
     
     
         25 . The method of  claim 24 , wherein the therapeutic agent is a nucleic acid encoding a protein that is deficient or absent in the subject. 
     
     
         26 . The method of  claim 25 , wherein the nucleic acid is present in a vector. 
     
     
         27 . The method of  claim 26 , wherein the vector is a liposome, a lipid nanoparticle, or a stable nucleic acid lipid particle. 
     
     
         28 . The method of  claim 25 , wherein the immune tolerance is induced to the nucleic acid or to the vector. 
     
     
         29 . The method of  claim 25 , wherein the protein is acid alpha-glucosidase (GAA). 
     
     
         30 . The method of  claim 29 , wherein the GAA is recombinant human GAA (rhGAA). 
     
     
         31 . The method of  claim 24 , wherein the metabolic disorder is Fabry Disease, Gaucher disease, GSDs types I-VII, IX, XI, XII and XIII, cardiac glycogenesis due to AMP-activated protein kinase gamma subunit 2 deficiency, MPS diseases including MPS I (Hurler, Hurler-Scheie, or Scheie syndrome), MPS II (Hunter disease), and MPS VI (Maroteaux-Lamy syndrome), Pompe disease, or Wolman disease. 
     
     
         32 . The method of  claim 24 , wherein in the metabolic disease is Pompe disease. 
     
     
         33 . The method of  claim 24 , wherein the subject is a treatment-naive cross-reactive immunological material (CRIM)-positive or a treatment-naive CRIM-negative lysosomal storage disease patient. 
     
     
         34 . The method of  claim 24 , wherein the immune modulator is methotrexate, rituximab, prednisone, or bortezomib. 
     
     
         35 . The method of  claim 24 , wherein the immune modulator is a combination of methotrexate and prednisone. 
     
     
         36 . The method of  claim 24 , wherein the immune modulator is administered at a transient low-dose. 
     
     
         37 . The method of  claim 24 , wherein the immune modulator is administered at a dose of about 0.1 mg/kg body weight to about 0.6 mg/kg body weight. 
     
     
         38 . The method of  claim 24 , wherein the immune modulator is administered concurrently with the therapeutic agent. 
     
     
         39 . The method of  claim 24 , wherein the immune modulator is administered at about a daily dose of 0.4 mg/kg body weight for a minimum of 3 cycles, with three days per cycle. 
     
     
         40 . The method of  claim 24 , wherein the immune modulator is administered orally about one day to about one minute before the therapeutic agent is administered. 
     
     
         41 . The method of  claim 24 , wherein the immune modulator is administered subcutaneously about 15 minutes before the therapeutic agent. 
     
     
         42 . A method of treating or preventing Pompe disease in a patient, the method comprising:
 i) administering to the patient a therapeutically effective amount of a nucleic acid encoding acid alpha-glucosidase (GAA), and   ii) administering to the patient a therapeutically effective amount of one or more immune modulators.   
     
     
         43 . The method of  claim 42 , wherein the one or more immune modulators are methotrexate, rituximab, prednisone, or bortezomib.