Cyclodextrin for the treatment of lysosomal storage diseases
Inventors
McKew, John • Zheng, Wei • Xu, Miao • Swaroop, Manju • Marugan, Juan J.
Assignees
US Department of Health and Human Services
Publication Number
US-11020422-B2
Publication Date
2021-06-01
Expiration Date
2033-08-03
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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.
Core Innovation
The invention provides methods of treating lysosomal storage disorders and reducing non-cholesterol lipids or non-cholesterol dominant lipid and macromolecule accumulation by administering cyclodextrin compounds or their pharmaceutically acceptable salts, esters, solvates, or hydrates. The invention includes methods of treatment using cyclodextrin compounds alone or in combination with additional therapeutic agents, such as vitamin E, including delta-tocopherol, to achieve enhanced therapeutic effects. Administration may be performed by various routes, including intracranial administration, and dosages range from about 0.01 mg/kg/day to 100 mg/kg/day depending on the compound and therapeutic method.
The problem being solved relates to lysosomal storage diseases caused by genetic mutations leading to accumulation of lipids, glycoproteins, and other macromolecules in lysosomes, resulting in enlarged lysosomes, cell malfunction, and potentially cell death. While cyclodextrins have been known to reduce cholesterol accumulation in some lysosomal storage diseases like Niemann Pick Type C, the invention addresses the broader need to reduce non-cholesterol lipid accumulation and treat a wide range of lysosomal storage diseases, including about 40 to 50 different inherited metabolic disorders. Combining cyclodextrins with vitamin E compounds provides a synergistic or additive therapeutic effect, reduces the required dosages, and minimizes side effects, thereby making treatments more feasible.
Claims Coverage
The patent contains one independent claim focused on methods for treating specific lysosomal storage diseases using hydroxypropyl-β-cyclodextrin compounds administered intracranially.
Method of treating specific lysosomal storage diseases using intracranial administration of hydroxypropyl-β-cyclodextrin
A method of treating Batten disease, Farber disease, mucolipidosis types III and IV, mucopolysaccharidosis types I and VI in a human by administering an effective amount of a hydroxypropyl-β-cyclodextrin compound or its pharmaceutically acceptable salt, solvate, or hydrate intracranially.
Use of hydroxypropyl-β-cyclodextrin compounds with defined hydroxypropyl substitution
Administration of hydroxypropyl-β-cyclodextrin compounds comprising from one to ten hydroxypropyl groups, including an embodiment with an average of four hydroxypropyl groups.
Administration routes for hydroxypropyl-β-cyclodextrin compounds targeting central nervous system
Administration of hydroxypropyl-β-cyclodextrin compounds via intrathecal, intraventricular, intracerebral, or epidural routes, with a preferred embodiment of intrathecal administration.
Combination with pharmaceutically acceptable carriers or excipients
Administering hydroxypropyl-β-cyclodextrin compounds in combination with pharmaceutically acceptable carriers or excipients to facilitate treatment.
The claim covers the use of hydroxypropyl-β-cyclodextrin compounds with specific hydroxypropyl substitution patterns administered via various intracranial routes for treating several lysosomal storage diseases in humans, including the possibility of combining the compound with pharmaceutically acceptable carriers or excipients.
Stated Advantages
Treatment of all lysosomal storage diseases with cyclodextrins, including hydroxypropyl-beta-cyclodextrin, except for Niemann Pick Type C disease in certain aspects.
Use of cyclodextrins in combination with vitamin E for synergistic or additive therapeutic effects, allowing reduction of cyclodextrin dosage, making treatment more practical and reducing side effects by lowering doses of both drugs.
Combination of different forms of cyclodextrins and modified vitamin E analogs for improved efficacy and reduced side effects.
Cyclodextrins increase lysosomal exocytosis, leading to reduction of lipid accumulation in lysosomal storage diseases.
Combination therapy allows significant reduction in cyclodextrin doses, facilitating clinical use by lowering side effects and overcoming challenges in drug solubility and brain penetration.
Documented Applications
Treatment of lysosomal storage disorders including approximately 40 to 50 inherited metabolic disorders characterized by accumulation of lipids, glycoproteins, and macromolecules in lysosomes.
Treatment of specific diseases including Batten disease, Farber disease, mucolipidosis types III and IV, mucopolysaccharidosis types I and VI, Tay-Sachs disease, Niemann Pick diseases, Wolman disease, Fabry disease, Sanfilippo disease, and Gaucher disease, among others.
Reduction of non-cholesterol lipids and non-cholesterol dominant lipids such as lipopigments, globotriaosylceramide, ceramide, sphingomyelin, heparan sulfate, GM2 ganglioside, triglycerides, and cholesterol esters in subjects suffering from lysosomal storage diseases.
Use of cyclodextrin compounds in combination with vitamin E (including delta-tocopherol) as therapeutics to synergistically reduce lipid accumulation and treat lysosomal storage disorders.
Intracranial administration of hydroxypropyl-β-cyclodextrin compounds to humans for treatment of specific lysosomal diseases.
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