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-8557844-B2
Publication Date
2013-10-15
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 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. The invention demonstrates that accumulation in Smith-Lemli-Opitz Syndrome (SLOS) cells of the class II amphiphile 7-dehydrocholesterol (7-DHC) causes abnormal sphingolipid storage and transport in the late endosome/lysosome (LE/Lys) system, resembling a Niemann-Pick type C (NPC) disease like cellular phenotype. Treatment of such cells with an inhibitor of sphingolipid biosynthesis was found to correct these abnormalities, supporting the potential therapeutic benefit of these inhibitors for SLOS and other diseases with a similar secondary NPC phenotype.
The invention addresses the problem that current therapies for diseases like SLOS, such as dietary cholesterol supplementation and inhibition of de novo sterol synthesis (e.g., using simvastatin), have limited clinical benefit. This limitation is attributed to intracellular accumulation of sterol precursors like 7-DHC, which impairs cholesterol transport by causing abnormal storage and defective endocytosis reminiscent of NPC disease. The invention offers treatment with sphingolipid biosynthesis inhibitors that can ameliorate intracellular cholesterol transport defects associated with these diseases, thereby improving the utilization of exogenously delivered cholesterol and potentially offering enhanced therapeutic efficacy compared to existing treatments.
Claims Coverage
The patent includes one independent claim presenting a method of treating diseases with a secondary Niemann-Pick type C disease like cellular phenotype using specific inhibitors of sphingolipid biosynthesis.
Method of treating diseases with secondary Niemann-Pick type C phenotype using inhibitors of sphingolipid biosynthesis
A method of treating a subject having a disease with a secondary Niemann-Pick type C disease like cellular phenotype, including Smith-Lemli-Opitz Syndrome (SLOS), CHILD syndrome, XLD chondrodysplasia punctata type 2, Conradi-Hünnermann-Happle syndrome, or HEM dysplasia, by selecting the subject and administering an effective amount of an inhibitor of sphingolipid biosynthesis from a specified list including N-butyldeoxynojirimycin, N-nonyldeoxynojirimycin, N-butyldeoxygalactonojirimycin, and several related iminosugar compounds.
Use of inhibitors targeting glycosyltransferase or sulfotransferase enzymes
The use of an inhibitor that specifically targets glycosyltransferase or sulfotransferase enzymes to inhibit sphingolipid biosynthesis in the treatment method.
Glycosyltransferase subclass specificity in inhibition
The inhibitor can be selected from glycosyltransferases including glucosyltransferase, sialyltransferase, galactosyltransferase, ceramide galactosyltransferase, fucosyltransferase, or N-acetylhexosaminetransferase.
Inhibition of glucosylceramide synthase
The inhibitor specifically inhibits glucosylceramide synthase, a key enzyme in sphingolipid biosynthesis.
Inhibitors of ceramide biosynthesis used for treatment
Employing inhibitors of ceramide biosynthesis including serine palmitoyltransferase or dihydroceramide synthase inhibitors in the therapeutic method.
Inhibition of ceramide degradation enzymes
The method may use inhibitors of ceramide degradation, for example, inhibitors of acid ceramidase enzyme activity.
Targeting diseases with accumulation of class II amphiphiles
The treatment method applies to diseases characterized by accumulation of class II amphiphiles, which induce a Niemann-Pick type C like phenotype.
Class II amphiphiles as cholesterol precursors or analogues
The class II amphiphile that accumulates is typically a precursor or analogue of cholesterol, such as 7-dehydrocholesterol.
Combination therapy with cholesterol and inhibitors
Combining the administration of sphingolipid biosynthesis inhibitors with cholesterol and/or inhibitors of de novo cholesterol biosynthesis for treating Smith-Lemli-Opitz Syndrome (SLOS).
Use of N-butyldeoxynojirimycin as inhibitor for SLOS
Specific administration of N-butyldeoxynojirimycin as the sphingolipid biosynthesis inhibitor in treating SLOS.
Treatment specifically targeted to Smith-Lemli-Opitz Syndrome
The method specifically addresses treatment of patients diagnosed with Smith-Lemli-Opitz Syndrome (SLOS).
The claims cover a method of treating diseases exhibiting a secondary Niemann-Pick type C phenotype by administering selected inhibitors of sphingolipid biosynthesis, with emphasis on diseases such as SLOS and related disorders. The inventive features include the use of specific classes of inhibitors, targeting of particular enzymes in the biosynthesis and degradation pathways, application to diseases with class II amphiphile accumulation, and the possibility of combination therapies including cholesterol and de novo cholesterol biosynthesis inhibitors.
Stated Advantages
Inhibitors of sphingolipid biosynthesis can correct abnormal intracellular cholesterol transport defects associated with SLOS and other diseases with a secondary Niemann-Pick type C phenotype.
Treatment with sphingolipid biosynthesis inhibitors can lead to improved utilization of exogenously delivered cholesterol in SLOS patients, overcoming limitations of dietary cholesterol supplementation alone.
Reduction of glycosphingolipid storage by these inhibitors can correct defective endocytosis and abnormal lipid trafficking in affected cells.
The use of inhibitors such as NB-DNJ and NB-DGJ is supported by their clinical use in other glycolipid storage disorders and their ability to penetrate the central nervous system without significant neurological side effects.
Documented Applications
Treatment of Smith-Lemli-Opitz Syndrome (SLOS).
Treatment of CHILD syndrome.
Treatment of XLD chondrodysplasia punctata type 2.
Treatment of Conradi-Hünnermann-Happle syndrome.
Treatment of HEM dysplasia.
Treatment of diseases characterized by secondary Niemann-Pick type C disease like cellular phenotype involving accumulation of class II amphiphiles such as 7-DHC.
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