Cyclodextrin for the treatment of lysosomal storage diseases

Abstract

The invention provides for methods of treating lysosomal storage disorders and/or reduction of non-cholesterol lipids, using cyclodextrin compounds, including in combination with other therapeutics, including vitamin E.

1 . A method of treating a lysosomal storage disorder in a subject, comprising:
 determining that the subject is in need of non-cholesterol lipid reduction or reduction of non-cholesterol dominant lipid and macromolecule accumulation, and   administering to the subject in need thereof; an effective amount of a cyclodextrin compound, or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof.   
     
     
         2 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the non-cholesterol lipid is lipopigments, globotriaosylceramide, ceramide, sphingomyelin, heparan sulfate, partially degraded heparan sulfate, GM2 ganglioside, triglycerides, or cholesterol esters. 
     
     
         6 . The method of  claim 1 , wherein the lysosomal storage disorder is Tay-Sachs disease, Sphingolipidoses, Gaucher disease, Mucolipidosis, Galactosialidosis, Salla disorder, Cystinosis, Danon disease, Fabry disease, Farber disease, Lipofuscinoses, Pompe disease, Gangliodisosis, ISSD, Krabbe disease, leukodystrophy, Hurler disease, Scheie disease, Hunter disease, San Filippo disease, Sandhoff disease, Schinder disease, Batten disorder, or Wolman disease. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the cyclodextrin compound is of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof, wherein,
 each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or —C(0)OR B , —OC(0)R B , C(0)R B , or —C(0)NR A R B ; 
 each R 1  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR B , —SR B , —SOR B , —SO 2 R B , —N(R B )S(0 2 )—R B , —(R B )S(O 2 )NR A R B , —NR A R B , —C(0)OR B , —0C(0)R B , —C(0)R B , —C(0)NR A R B , or —N(R B )C(0)R B ; each of which is optionally substituted; 
 each R A  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 each R B  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 
 each m is independently 0, 1, 2, 3, 4, or 5. 
 
     
     
         9 . The method of  claim 8 , wherein each R is independently H, optionally substituted alkyl, —C(0)OR B , -0C(0)R B , —C(0)R B , or —C(0)NR A R B . 
     
     
         10 . The method of  claim 9 , wherein each R is independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; wherein each is straight chain or branched. 
     
     
         11 . The method of  claim 8 , wherein n is 1,2, or 3. 
     
     
         12 . The method of  claim 1 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin (2HPβCD), hydroxypropyl-β-cyclodextrin (HPβCD), methyl-β-cyclodextrin (MβCD), α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof. 
     
     
         13 . The method of  claim 1 , further comprising the step of administering an additional therapeutic agent distinct from the cyclodextrin compound. 
     
     
         14 . The method of  claim 13  wherein the additional therapeutic agent is administered in combination or otherwise in conjunction with the cyclodextrin compound. 
     
     
         15 . The method of  claim 13  wherein the additional therapeutic agent is a vitamin. 
     
     
         16 . The method of  claim 15  wherein the additional therapeutic agent is vitamin E. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The method of  claim 1  wherein the step of administering the cyclodextrin comprises administering the compound in a dosage of between about 0.01 μg/kg and 100 mg/kg. 
     
     
         20 - 35 . (canceled) 
     
     
         36 . A method of reducing non-cholesterol lipids or reduction of non-cholesterol dominant lipid and macromolecule accumulation in a subject, the method comprising administering to the subject a cyclodextrin compound, or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof; and detecting the amount of lipid reduction. 
     
     
         37 . The method of  claim 36  wherein the subject is identified as being in need of lipid reduction. 
     
     
         38 . The method of  claim 1  further comprising the step of synthesizing or obtaining the cyclodextrin compound. 
     
     
         39 . The method of  claim 1 , wherein the subject is a human. 
     
     
         40 . The method of  claim 1  wherein the cyclodextrin compound and/or any additional distinct therapeutic agents are administered intracranially to the subject. 
     
     
         41 . A pharmaceutical composition comprising a cyclodextrin compound, or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof, and vitamin E, together with a pharmaceutically-acceptable carrier or excipient. 
     
     
         42 - 44 . (canceled) 
     
     
         45 . A kit comprising an effective amount of a cyclodextrin compound, or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof, in unit dosage form, together with instructions for administering the compound to a subject suffering from a lysosomal storage disorder. 
     
     
         46 - 48 . (canceled)