Substrate reduction therapy
Inventors
Platt, Frances Mary • Lloyd-Evans, Emyr • Porter, Forbes Dennison
Assignees
University of Oxford • US Department of Health and Human Services
Publication Number
US-9428541-B2
Publication Date
2016-08-30
Expiration Date
2028-06-26
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Abstract
The present invention provides a compound which is an inhibitor of sphingolipid biosynthesis for use in the treatment of a disease which has a secondary Niemann-Pick type C disease like cellular phenotype.
Core Innovation
The invention provides a compound which is an inhibitor of sphingolipid biosynthesis for use in the treatment of diseases exhibiting a secondary Niemann-Pick type C disease like cellular phenotype. Specifically, the invention addresses diseases such as Smith-Lemli-Opitz Syndrome (SLOS) characterized by abnormal intracellular cholesterol transport and sphingolipid storage in late endosome/lysosome systems. It posits that treating cells with inhibitors of sphingolipid biosynthesis can correct abnormalities in sphingolipid storage and transport, thereby ameliorating intracellular cholesterol transport defects.
SLOS results from a deficiency in 3β-hydroxysterol Δ7-reductase, causing an accumulation of the cholesterol precursor 7-dehydrocholesterol (7-DHC), decreased cholesterol levels, and storage of cholesterol in late endosomes/lysosomes, which impairs cholesterol utilization despite dietary cholesterol supplementation. The invention highlights the limitation of current therapies that increase exogenous cholesterol without addressing the intracellular storage and transport defects. It presents substrate reduction therapy, via inhibition of sphingolipid biosynthesis, as an approach to mitigate the intracellular cholesterol transport defects associated with SLOS and similar disorders characterized by secondary Niemann-Pick type C cellular phenotype.
The invention further provides detailed chemical definitions of compounds acting as inhibitors of sphingolipid biosynthesis, including formulae (I), (II), (III), (IV), (V), (IX), and (XII), and describes RNA as an alternative inhibitor of sphingolipid biosynthesis. It also excludes certain lysosomal storage disorders such as mucopolysaccharidosis and mucolipidosis IV from the therapeutic scope. The therapeutic approach can be used alone or in combination with cholesterol supplementation or inhibitors of de novo cholesterol biosynthesis, such as statins, to improve treatment efficacy.
Claims Coverage
The claims define a method of treating diseases with a secondary Niemann-Pick type C disease like cellular phenotype by administering inhibitors of sphingolipid biosynthesis. Key inventive features focus on the use of specific inhibitors and their application in treating defined diseases.
Use of sphingolipid biosynthesis inhibitors in treatment
The therapeutic method involves administering an effective amount of compounds that inhibit sphingolipid biosynthesis to subjects suffering from diseases with secondary Niemann-Pick type C disease like cellular phenotype.
Selection of specific chemical inhibitors
The method uses specific compounds such as N-butyldeoxynojirimycin, N-nonyldeoxynojirimycin, N-butyldeoxygalactonojirimycin, N-5-adamantane-1-yl-methoxypentyl-deoxynojirimycin, alpha-homogalactonojirimycin, nojirimycin, deoxynojirimycin, N7-oxadecyl-deoxynojirimycin, deoxygalactonojirimycin, N-butyl-deoxygalactonojirimycin, N-nonyl-6deoxy-DGJ, alpha-homoallonojirimycin, and beta-1C-butyl-deoxygalactonojirimycin for treatment.
Application to specific diseases with secondary NPC phenotype
The method applies to treating select diseases including inborn errors of cholesterol synthesis, Tangier disease, Pelizaeus-Merzbacher disease, Mucolipidosis II (cell), and variant late infantile-Neuronal Ceroid Lipofuscinosis.
The claims cover therapeutic methods employing selected inhibitors of sphingolipid biosynthesis for treating specific diseases characterized by a secondary Niemann-Pick type C disease like cellular phenotype, highlighting the targeted chemical compounds and diseases treated.
Stated Advantages
Inhibitors of sphingolipid biosynthesis can ameliorate intracellular cholesterol transport defects associated with diseases having a secondary Niemann-Pick type C disease like cellular phenotype.
The treatment can improve cellular utilization of exogenously delivered cholesterol, especially in disorders like Smith-Lemli-Opitz Syndrome where dietary cholesterol supplementation is insufficient.
The use of known inhibitors such as NB-DNJ and NB-DGJ is advantageous due to their ability to cross the blood-brain barrier and their established safety profiles.
Combination therapies including inhibitors of sphingolipid biosynthesis with cholesterol supplementation or statins may enhance treatment efficacy.
Documented Applications
Treatment of diseases characterized by a secondary Niemann-Pick type C disease like cellular phenotype, including Smith-Lemli-Opitz Syndrome and other inborn errors of cholesterol synthesis.
Use in treating specific diseases such as Tangier disease, Pelizaeus-Merzbacher disease, Mucolipidosis II (cell), and variant late infantile-Neuronal Ceroid Lipofuscinosis.
Treatment of disorders involving abnormal sphingolipid storage and intracellular cholesterol transport defects.
Therapy in combination with cholesterol supplementation and/or inhibitors of de novo cholesterol biosynthesis like statins.
Administration via various pharmaceutical formulations including oral tablets, injectable solutions, liposomal delivery, syrups, and others.
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