Use of delta tocopherol for the treatment of lysosomal storage disorders
Inventors
Zheng, Wei • Marugan, Juan Jose • Liu, Ke • Southall, Noel Terrence • Austin, Christopher P.
Assignees
US Department of Health and Human Services
Publication Number
US-10039741-B2
Publication Date
2018-08-07
Expiration Date
2031-07-19
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Abstract
This disclosure relates generally to the treatment of lysosomal storage disorders. Specifically, the disclosure relates to a novel use of δ tocopherol in the treatment of diseases and conditions related to lysosomal storage disorders. Included in the present disclosure is a method for the modulation of cholesterol recycling. Further, the disclosure relates to conditions such as Niemann-Pick type C disease, Farber disease, Niemann-Pick type A disease, Wolman disease and Tay Sachs disease. Further included in the present disclosure is a method for treating lysosomal storage disorders comprising the administration of δ tocopherol. Further included in the present disclosure is a method for treating lysosomal storage disorders comprising the administration of δ tocopherol in combination with cyclodextrin to a patient in need thereof.
Core Innovation
This invention relates generally to the treatment of lysosomal storage disorders (LSDs) using delta tocopherol (δ-tocopherol). The disclosure identifies a novel use of δ-tocopherol to reduce free cholesterol accumulation and decrease the size of enlarged lysosomes, which are characteristic features of lysosomal storage disorders such as Niemann-Pick type C disease, Farber disease, Niemann-Pick type A disease, Wolman disease, and Tay Sachs disease. The method includes administering δ-tocopherol alone or in combination with cyclodextrin to modulate cholesterol recycling and ameliorate disease symptoms.
The problem being addressed is the lack of effective treatments for LSDs, particularly Niemann-Pick type C disease (NPCD), which involves lysosomal accumulation of unesterified cholesterol due to impaired retrograde transport from late endosomes and lysosomes. Current therapies, such as Miglustat and cyclodextrin, have limited efficacy and require high doses that may cause adverse effects. There is a critical need for novel therapeutic agents that can reduce lysosomal cholesterol accumulation and improve lysosomal function with greater potency and safety.
The invention reveals that δ-tocopherol is uniquely potent among vitamin E isoforms in reducing free cholesterol accumulation in NPCD fibroblasts, with a potency 6 to 8 times higher than α-, β-, and γ-tocopherols. δ-tocopherol facilitates cholesterol efflux via an alternative NPC1/NPC2-independent pathway by inserting into cellular membranes and enhancing lipid movement. This results in decreased lysosome size and reduced accumulation of lipids in multiple LSDs. Furthermore, combination therapy of δ-tocopherol and cyclodextrin at reduced concentrations provides synergistic or additive benefits, decreasing required dosages and adverse effects while improving therapeutic efficacy.
Claims Coverage
The patent discloses two independent claims directed to methods involving δ-tocopherol for treating lysosomal storage disorders and reducing cholesterol accumulation.
Combination therapy of δ-tocopherol and cyclodextrin for lysosomal storage disorders
A method for treating lysosomal storage disorders by administering therapeutically and synergistically effective amounts of δ-tocopherol and cyclodextrin, with cyclodextrin optionally being 2-hydroxypropyl-beta-cyclodextrin. Dosages of δ-tocopherol may result in plasma concentrations between 10 μM and 50 μM and be less than 1000 IU/kg per day. Administration routes include oral, topical, suppository, intravenous, intradermic, intragaster, intramuscular, intraperitoneal, intrathecal, and intracerebroventricular. The method may further include administering CYP4F2 inhibitors such as ketoconazole, sesame seeds, lignan sesamin, or lignan sesaminol.
Method for reducing cholesterol accumulation in cells using δ-tocopherol and cyclodextrin
A method for reducing cholesterol accumulation, including free cholesterol accumulation in lysosomes of cells, by administering therapeutically and synergistically effective amounts of δ-tocopherol and cyclodextrin, with similar dosage ranges and administration routes as described above. This method may also include CYP4F2 inhibitors as adjuncts.
The independent claims cover methods for treating lysosomal storage disorders and reducing cellular cholesterol accumulation by administering δ-tocopherol in combination with cyclodextrin. The claims specify effective dosage ranges, administration methods, and optionally include CYP4F2 inhibitors, thus encompassing innovative therapeutic strategies leveraging δ-tocopherol's potency and synergistic combination with cyclodextrin.
Stated Advantages
δ-tocopherol has significantly higher potency in reducing cholesterol accumulation and lysosome size in lysosomal storage disorder cells compared to other vitamin E isoforms.
Combination therapy with δ-tocopherol and cyclodextrin allows for reduced dosages of both drugs, potentially minimizing adverse effects while enhancing therapeutic efficacy.
δ-tocopherol facilitates an alternative cholesterol recycling pathway independent of NPC1/NPC2 proteins, addressing a central pathogenic mechanism in LSDs.
Documented Applications
Treatment of lysosomal storage disorders including Niemann-Pick type C disease, Farber disease, Niemann-Pick type A disease, Wolman disease, and Tay Sachs disease.
Reduction of free cholesterol accumulation in cells affected by lysosomal storage disorders.
Use in human patients requiring modulation of cholesterol recycling and reduction of lysosomal lipid storage.
Combination therapy with cyclodextrin to enhance treatment of lysosomal storage disorders.
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