Pharmaceutical compositions containing proteases and methods for the treatment of lysosomal storage diseases

Abstract

The invention provides a method and compositions for treating a subject with a lysosomal storage disease such as gaucher disease, by administering to a subject with a lysosomal storage disease a therapeutically effective amount of composition comprising at least one of a protease or peptidase in an amount sufficient to ameliorate, reduce or improve at least one symptom of the disease. The invention also provides dietary supplements for subjects having lysosomal storage diseases.

1 - 27 . (canceled) 
     
     
         28 . A method for ameloriating, reducing or improving at least one symptom or sign or surrogate marker of Gaucher disease, which method comprises orally administering to an individual in need thereof an effective amount of a pharmaceutically acceptable composition comprising a blend of proteolytic enzymes having dipeptidyl peptidase IV activity and endo and exopeptidase activity to cleave terminal proline containing dipeptides in proteins such as gluten and casein in an amount sufficient to ameliorate, reduce or improve at least one symptom, sign, or marker of the disease; wherein said enzyme blend has 54,000 hemoglobin units on a tyrosine basis, 130 units of aminopeptidase activity and 50 spectrophotometric acid protease units. 
     
     
         29 . The method of  claim 28 , wherein the symptom or sign that is ameliorated, reduced or improved is selected from the group consisting of: loss of bone density (osteopenia), bone pain and bone fractures; enlarged liver (hepatomegaly); enlarged spleen (splenomegaly); anemia; pulmonary hypertension; excessive fatigue; a low number of blood platelets (thrombocytopenia); yellow spots in the eyes (pingueculae); delayed puberty; ataxia; spasticity; seizures; auditory impairment; nosebleeds; cognitive impairment; intention tremors; rigidity; bradykinesis; expressionless facies; slurred or monotonous speech; myoclonic jerks; olfactory loss; avascular osteonecrosis; and dementia. 
     
     
         30 . The method of  claim 28 , wherein the disease marker that is ameliorated, reduced or improved is selected from the group consisting of: lysosomal acid β-glucosidase activity; the presence of lipid-laden macrophages (“Gaucher macrophages”); levels of chitotriosidase; levels of liver enzymes; levels of pulmonary chemokine PARC/CCL 18; levels of angiotensin converting enzyme (ACE), total acid phosphatase and bone-specific acid phosphatase; immunological defects such as anemia, thrombocytopenia, leukopenia, hypergamma-globulinemia, decreased amount of T-lymphocytes in the spleen, systemic B cell hyperproliferation, plasmacytosis, plasma α-synuclein; levels of inflammatory cytokines, the presence of inflammatory foci in tissues or organs comprising macrophages, lymphocytes, and neutrophils, and impaired neutrophil chemotaxis; skeletal defects such as infiltration of Gaucher cells in the bone marrow, reduced levels of triglycerides; bone density and other abnormal radiographic findings; neurological symptoms such as neuronal loss, neurodegeneration, horizontal gaze abnormalities, myoclonic movements, corneal opacity, pulmonary infiltration of Gaucher macrophages; aberrant trafficking of acid β-glucosidase in cells from Gaucher patients from the ER to the lysosome; aberrant trafficking of cellular lipids though the endosomal pathway; the presence of increased amounts of mis-folded acid β-glucosidase in the ER or cytosol; the presence of ER and/or stress resulting from toxic accumulation of GCase (as determined by gene and/or protein expression of stress-related markers); aberrant endosomal pH levels; the presence of increased plasma membrane expression of MHCII and/or CD1d on monocytes; aberrant cell morphology; suppression of the ubiquitin/proteasome pathway; an increase in the amount of ubiquitinated proteins; and a change in a biochemical marker in serum or urine. 
     
     
         31 . The method of according to  claim 28 , wherein the enzyme blend is derived from a fermented food or beverage. 
     
     
         32 . The method according to  claim 28 , wherein the enzyme blend is derived from a food-grade microorganism, yeast, algae, seaweed, plant, vertebrate animal, invertebrate animal, annelid, insect, or arthropod. 
     
     
         33 . The method according to  claim 28 , wherein the enzyme blend is derived from a species of  Aspergillus.    
     
     
         34 . The method according to  claim 28 , wherein the pharmaceutically acceptable composition is labeled as a dietary supplement. 
     
     
         35 . The method according to  claim 34 , wherein the pharmaceutically acceptable composition is formulated as a dried powder, a tablet, a hard gelatin capsule or a soft gelatin capsule. 
     
     
         36 . The method according to  claim 34 , wherein the pharmaceutically acceptable composition is provided within an ingestible carrier material suitable for human consumption. 
     
     
         37 . The method of  claim 36 , wherein the carrier material is selected from the group consisting of a cereal based product, rice cake, soy cake, food bar product, cold formed food bar product, custard, pudding, gelatin, rice milk, soy milk, mashed fruit product, candy, candy bar, applesauce, yogurt, beverage, and fermented beverage. 
     
     
         38 . The method according to  claims 37  wherein the pharmaceutically acceptable composition further contains one or more of the following ingredients selected from the group consisting of: vitamins, minerals, herb or herbal extracts, probiotics or prebiotics, antioxidants, bioflavonoids, papain, lactase, amylase, protease, lipase, and plant and animal concentrates. 
     
     
         39 . The method according to  claim 28 , wherein the pharmaceutically acceptable composition contains one or more proteases. 
     
     
         40 . The method according to  claim 28 , wherein the pharmaceutically acceptable composition is administered in combination or in conjunction with a separate, FDA-approved pharmaceutical composition. 
     
     
         41 . The method according to  claim 28 , wherein the pharmaceutically acceptable composition further contains a therapeutically-active small molecule. 
     
     
         42 . The method according to  claim 40 , wherein the FDA-approved pharmaceutical composition is a therapeutically-active small molecule. 
     
     
         43 . The method according to  claim 29 , wherein the sign that is ameliorated, reduced or improved in an individual having Gaucher disease is an enlarged spleen (splenomegaly). 
     
     
         44 . A method of screening for proteases and peptidases suitable for treating Gaucher's disease, said method comprising: (a) quantifying a symptom or a marker of Gaucher disease in an individual(s) having Gaucher disease; (b) orally administering to said individual(s) a physiologically acceptable a blend of proteolytic enzymes having dipeptidyl peptidase IV activity and endo and exopeptidase activity to cleave terminal proline containing dipeptides in proteins such as gluten and casein in a pharmaceutically acceptable carrier, in a known amount for a known period of time; and (c) quantifying the aforementioned symptom or surrogate marker to assess whether there is a quantitative change in the symptom or marker as a result of the administration of the protease or peptidase composition. 
     
     
         45 . A method of treating a subject with a lysosomal storage disease selected from the group consisting of glycogen storage disease type II, mucopolysaccharidoses, mucolipidosis II, mucolipidosis III, mucosulfatidosis, GM2 activator protein deficiency variant AB, Danon disease, Salla disease, Tay-Sachs disease, Sandhoff disease, Schindler disease, Kanzaki disease, a-mannosidosis, b-mannosidosis, fucosidosis, siali-dosis, aspartylglucosaminuria, carbohydrate-deficient glycoprotein syndrome, Wolman disease, Farber disease, Niemann-Pick disease types A, B, and C, Krabbe disease, Fabry disease, multiple sulfatase deficiency, GM1 gangliosidosis, GM2 gangliosidosis, GM3 gangliosidosis, galacto-sialidosis, cystinosis, sialic acid storage disease, pyknodysostosis, metachromatic leuko-dystrophy, galactosialidosis, lactosylceramidosis, Pompe disease, and cobalamin deficiency type F, the method comprising orally administering to a subject with a lysosomal storage disease a therapeutically effective amount of composition comprising a blend of proteolytic enzymes having dipeptidyl peptidase IV activity and endo and exopeptidase activity to cleave terminal proline containing dipeptides in proteins such as gluten and casein in an amount sufficient to ameliorate, reduce or improve at least one symptom of the disease; wherein said enzyme blend has 54,000 hemoglobin units on a tyrosine basis, 130 units of aminopeptidase activity and 50 spectrophotometric acid protease units. 
     
     
         46 . The method of  claim 45  wherein the subject is a human. 
     
     
         47 . A method for providing dietary supplementation to a subject with a lysosomal storage disease selected from the group consisting of glycogen storage disease type II, mucopolysaccharidoses, mucolipidosis II, mucolipidosis III, mucosulfatidosis, GM2 activator protein deficiency variant AB, Danon disease, Salla disease, Tay-Sachs disease, Sandhoff disease, Schindler disease, Kanzaki disease, a-mannosidosis, b-mannosidosis, fucosidosis, sialidosis, aspartylglucosaminuria, carbohydrate-deficient glycoprotein syndrome, Wolman disease, Farber disease, Niemann-Pick disease types A, B, and C, Krabbe disease, Fabry disease, multiple sulfatase deficiency, GM1 gangliosidosis, GM2 gangliosidosis, GM3 gangliosidosis, galactosialidosis, cystinosis, sialic acid storage disease, pyknodysostosis, metachromatic leukodystrophy, galactosialidosis, lactosylceramidosis, Pompe disease, and cobalamin deficiency type F, the method comprising orally administering to a subject with a lysosomal storage disease an effective amount of a dietary supplement comprising a blend of proteolytic enzymes having dipeptidyl peptidase IV activity and endo and exopeptidase activity to cleave terminal proline containing dipeptides in proteins such as gluten and casein and wherein said enzyme blend has 54,000 hemoglobin units on a tyrosine basis, 130 units of aminopeptidase activity and 50 spectrophotometric acid protease units. 
     
     
         48 . A method for ameloriating, reducing or improving at least one sign or symptom or surrogate marker of Parkinson's disease in an individual having one or more Gaucher disease gene mutations, which method comprises orally administering to an individual in need thereof an effective amount of a pharmaceutically acceptable composition comprising a blend of proteolytic enzymes having dipeptidyl peptidase IV activity and endo and exopeptidase activity to cleave terminal proline containing dipeptides in proteins such as gluten and casein in an amount sufficient to ameliorate, reduce or improve at least one sign, symptom, or marker of Parkinson's disease; and wherein said enzyme blend has 54,000 hemoglobin units on a tyrosine basis, 130 units of aminopeptidase activity and 50 spectrophotometric acid protease units. 
     
     
         49 . The method of  claim 48 , wherein the symptom or sign that is ameliorated, reduced or improved is selected from the group consisting of: intention tremors, rigidity and bradykinesis, expressionless facies, slurred or monotonous speech, myoclonic jerks, olfactory loss, avascular osteonecrosis, and dementia.