Methods for treating lysosomal acid lipase deficiency in patients

Abstract

The present invention provides methods of treating LAL deficiency comprising administering to a mammal a therapeutically effective amount of lysosomal acid lipase with an effective dosage frequency. Methods of improving growth and liver function, increasing LAL tissue concentration, and increasing LAL activity in a human patient suffering from LAL deficiency are also provided.

What is claimed is: 
     
         1 . A method of treating a human patient with a lysosomal acid lipase (LAL) deficiency comprising administering recombinant human LAL to the patient, wherein the administration is sufficient to improve liver function. 
     
     
         2 . The method of  claim 1 , wherein the administration is sufficient to normalize liver tests. 
     
     
         3 . The method of  claim 1  or  2 , wherein the administration minimizes hepatomegaly. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the administration is sufficient to decrease liver size. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the administration is sufficient to decrease serum levels of liver transaminases. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the administration is sufficient to reduce lipid levels. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the administration is sufficient to reduce triglyceride levels. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the administration is sufficient to reduce cholesteryl esters. 
     
     
         9 . A method of increasing LAL activity in a human patient with a LAL deficiency comprising administering recombinant human LAL to the patient, wherein the administration results in increased LAL activity in the patient. 
     
     
         10 . The method of  claim 9 , wherein the administration is sufficient to increase LAL activity in the patient by at least about 35 pmol/mg/min. 
     
     
         11 . A method of treating a condition associated with LAL deficiency in a patient in need thereof comprising administering an effective amount of exogenous LAL protein to the patient one time every 5 days to one time every 30 days. 
     
     
         12 . A method of treating a condition associated with LAL deficiency in a patient in need thereof comprising administering to the patient a dose of 0.1 mg to 50 mg per kilogram of exogenous LAL, administered one time every 7 days to one time every 14 days. 
     
     
         13 . A method of treating a condition associated with LAL deficiency in a patient in need thereof comprising administering to the patient a dose of about 0.1 mg to 5.0 mg per kilogram of exogenous LAL. 
     
     
         14 . A method of treating Wolman Disease or CESD in a human patient in need thereof comprising administering to the patient a dose of about 0.1 mg to 50 mg per kilogram of exogenous LAL, administered one time every 5 days to one time every 30 days. 
     
     
         15 . The method of any one of  claims 11 - 14 , wherein the exogenous LAL is a recombinant human LAL. 
     
     
         16 . The method of any one of  claims 11 - 15  wherein the exogenous LAL comprises at least one mannose or mannose-6-phosphate. 
     
     
         17 . The method of any one of  claim 1 - 12  or  14 - 16 , wherein the LAL is administered in amount of about 0.10 to about 5.0 mg/kg. 
     
     
         18 . The method of  claim 17 , wherein the amount is about 0.30 mg/kg. 
     
     
         19 . The method of  claim 17 , wherein the amount is about 0.35 mg/kg. 
     
     
         20 . The method of  claim 17 , wherein the amount is about 1.0 mg/kg. 
     
     
         21 . The method of  claim 17 , wherein the amount is about 3.0 mg/kg. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein the administration is about weekly. 
     
     
         23 . The method of any one of  claims 1 - 21 , wherein the administration is about hi-weekly. 
     
     
         24 . The method of any one of  claims 1 - 23 , wherein the administration is sufficient to reduce levels of serum aspartate transaminase (AST) by at least 50% from pre-treatment levels. 
     
     
         25 . The method of any one of  claims 1 - 24 , wherein the administration is sufficient to reduce levels of serum alanine transaminase (ALT) by at least 50% from pretreatment levels. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein the administration is sufficient to achieve a LAL half-life (t 1/2 ) less than about 17 minutes. 
     
     
         27 . The method of any one of  claims 1 - 26 , wherein the administration is sufficient to achieve a LAL half-life (t 1/2 ) of about 6, 7, 8, 9, 10, 11, 12 13, 14, 15, 16 or 17 minutes. 
     
     
         28 . The method of any one of  claims 1 - 27 , wherein the administration is sufficient to achieve a C max  at least about 200 ng per mL of serum. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the administration is sufficient to achieve a C max  between about 200 ng per mL of serum and 800 ng per mL of serum. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the LAL is internalized by fibroblasts. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein the LAL is internalized by macrophages. 
     
     
         32 . The method of any one of  claims 1 - 31 , wherein the LAL is produced by a transgenic avian. 
     
     
         33 . The method of any one of  claims 1 - 31 , wherein the LAL is produced by a mammalian cell line. 
     
     
         34 . The method of  claim 33 , wherein the mammalian cell line is a human cell line. 
     
     
         35 . The method of any one of  claims 1 - 34 , wherein the administration is intravenous. 
     
     
         36 . The method of  claim 35 , wherein the administration is by infusion. 
     
     
         37 . The method of  claim 36 , wherein the infusion is about two to about four hours. 
     
     
         38 . The method of  claim 36  or  37 , wherein the infusion is at a rate of about 0.1 mg/kg/hr to about 4 mg/kg/hr. 
     
     
         39 . The method of any one of  claims 1 - 38 , wherein the administration minimizes immune responses to the recombinant human LAL. 
     
     
         40 . The method of any one of  claims 1 - 39 , wherein the administration reduces lymphadenopathy. 
     
     
         41 . The method of any one of  claims 1 - 40 , wherein the administration is sufficient to decrease serum ferritin levels. 
     
     
         42 . The method of any one of  claims 1 - 41 , wherein the administration is sufficient to increase serum hemoglobin levels. 
     
     
         43 . The method of any one of  claims 1 - 42 , wherein the administration is sufficient to increase growth in a child patient. 
     
     
         44 . The method of any one of  claims 1 - 43 , wherein the administration is sufficient to increase the rate of body weight increase. 
     
     
         45 . The method of any one of  claims 1 - 44 , wherein the growth rate of the patient after administration is at least about 2 times the growth rate of the patient prior to the administration. 
     
     
         46 . The method of any one of  claims 1 - 45 , wherein the administration is sufficient to increase adipose tissue. 
     
     
         47 . The method of any one of  claims 1 - 46 , wherein the patient is less than one year old. 
     
     
         48 . The method of any one of  claims 1 - 46 , wherein the patient is at least one year old. 
     
     
         49 . The method of any one of  claims 1 - 48 , wherein the patient has been diagnosed with Wolman's disease. 
     
     
         50 . The method of any one of  claims 1 - 49 , wherein the patient has been diagnosed with Cholesteryl Ester Storage Disease (CESD). 
     
     
         51 . The method of  claim 50 , wherein the CESD was diagnosed before 10 years of age. 
     
     
         52 . The method of any one of  claims 1 - 51 , further comprising administering a second therapeutic. 
     
     
         53 . The method of  claim 52 , wherein the second therapeutic is a cholesterol-reducing drug. 
     
     
         54 . The method of  claim 53 , wherein the second therapeutic is a statin. 
     
     
         55 . The method of  claim 53 , wherein the second therapeutic is ezetimibe. 
     
     
         56 . The method of  claim 52 , wherein the second therapeutic decreases the immunogenicity of LAL. 
     
     
         57 . The method of  claim 52 , wherein the second therapeutic is an antihistamine. 
     
     
         58 . The method of  claim 52 , wherein the second therapeutic is an immunosuppressant. 
     
     
         59 . The method of  claim 57 , wherein the antihistamine is a pharmaceutically effective dose of diphenhydramine that is administered before the LAL is administered. 
     
     
         60 . The method of  claim 59 , wherein the dose of diphenhydramine is about 1 to about 5 mg per kilogram. 
     
     
         61 . The method of  claim 59  or  60 , wherein the diphenhydramine is administered about 20 to about 90 minutes prior to administration of LAL. 
     
     
         62 . The method of any one of  claims 1 - 61 , wherein the method further comprises completion of an assessment to monitor clinical and pathological presentation in the patient. 
     
     
         63 . The method of  claim 62 , wherein the assessment is: lipid analysis, chest x-ray, liver function test, stool chart, plasma mevalonic acid analysis, immunogenicity testing, plasma lysosomal acid lipase analysis, chitotriosidase analysis, portal hypertension analysis, anthropometry, characterization of the liver or spleen, imaging of the gastrointestinal tract, or a combination thereof. 
     
     
         64 . The method of  claim 63 , wherein the imaging technology is ultrasound, magnetic resonance imaging, or nuclear magnetic resonance spectroscopy. 
     
     
         65 . A composition for administering LAL according to the method of any of  claims 1 - 64 .