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-9044451-B2
Publication Date
2015-06-02
Expiration Date
2031-07-19
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
This disclosure relates generally to the treatment of lysosomal storage disorders. Specifically, the disclosure relates to a novel use of delta 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 delta tocopherol. Further included in the present disclosure is a method for treating lysosomal storage disorders comprising the administration of delta 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) by a novel use of delta tocopherol (δ-tocopherol). The disclosure includes methods for modulating cholesterol recycling and treating diseases such as Niemann-Pick type C disease, Farber disease, Niemann-Pick type A disease, Wolman disease, and Tay Sachs disease, by administering δ-tocopherol alone or in combination with cyclodextrin.
The problem solved addresses the lack of effective treatments for lysosomal storage disorders, particularly Niemann-Pick type C disease (NPCD), which is characterized by the accumulation of unesterified cholesterol and other lipids in lysosomes due to trafficking defects. Current therapies provide only symptom relief with limited efficacy. The invention seeks to overcome the challenges of existing therapies, including drug toxicity and inefficacy in human applications, by identifying δ-tocopherol as a potent compound to reduce cholesterol accumulation and lysosome enlargement in LSD cells.
The invention further discloses that δ-tocopherol is uniquely effective among vitamin E isoforms in reducing free cholesterol levels and lysosome size by facilitating lipid movement in membranes through an NPC1/NPC2-independent pathway. This approach enhances cholesterol efflux and alternative cholesterol recycling, providing a new therapeutic strategy. The invention also includes combination therapy with cyclodextrin to achieve synergistic effects at reduced dosages, minimizing potential toxicity.
Claims Coverage
The patent contains two independent claims focused on the therapeutic use of δ-tocopherol in treating lysosomal storage disorders and reducing cholesterol accumulation in cells.
Use of δ-tocopherol for treating lysosomal storage disorders without α-tocopherol
A method of treating lysosomal storage disorders by administering a pharmaceutically effective composition comprising δ-tocopherol, wherein the composition excludes α-tocopherol. The treatment covers diseases such as Niemann-Pick Type C disease, Niemann-Pick Type A disease, Wolman disease, Farber disease, and Tay Sachs disease. The composition may further comprise cyclodextrin, with dosages resulting in plasma concentrations of 10 μM to 50 μM of δ-tocopherol or dosages less than 1000 IU/kg per day. Administration routes include oral, topical, suppository, intravenous, intradermic, intragastric, intramuscular, and intraperitoneal.
Use of δ-tocopherol for reducing cholesterol accumulation in cells excluding other tocopherols
A method for reducing intracellular cholesterol accumulation, particularly free cholesterol in lysosomes, by administering a composition comprising δ-tocopherol that does not contain other tocopherols. This method applies to hosts including humans and uses similar dosage ranges and administration routes as the treatment of lysosomal storage disorders. The composition can also include cyclodextrin.
The independent claims focus on the novel therapeutic use of purified δ-tocopherol alone or in combination with cyclodextrin to treat lysosomal storage disorders and reduce cholesterol accumulation, specifically excluding α-tocopherol or other tocopherol isoforms, with defined dosages and administration methods.
Stated Advantages
δ-tocopherol is significantly more potent than other vitamin E isoforms in reducing cholesterol accumulation and lysosomal enlargement in lysosomal storage disorder cells.
Combination therapy of δ-tocopherol with cyclodextrin allows reduced dosages of both agents, minimizing potential adverse effects while enhancing therapeutic efficacy due to different mechanisms of action.
δ-tocopherol treatment does not cause significant cytotoxicity at effective concentrations, supporting safety in therapeutic use.
Documented Applications
Treatment of lysosomal storage disorders including Niemann-Pick Type C disease, Niemann-Pick Type A disease, Wolman disease, Farber disease, and Tay Sachs disease.
Modulation of cholesterol recycling and reduction of free cholesterol accumulation in cells, particularly in lysosomes of cells affected by lysosomal storage disorders.
Combination therapy involving δ-tocopherol and cyclodextrin for enhanced treatment efficacy of lysosomal storage diseases.
Interested in licensing this patent?