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Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease

Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of pa...

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Autores principales: Cabrera-Salazar, Mario A., DeRiso, Matthew, Bercury, Scott D., Li, Lingyun, Lydon, John T., Weber, William, Pande, Nilesh, Cromwell, Mandy A., Copeland, Diane, Leonard, John, Cheng, Seng H., Scheule, Ronald K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422338/
https://www.ncbi.nlm.nih.gov/pubmed/22912851
http://dx.doi.org/10.1371/journal.pone.0043310
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author Cabrera-Salazar, Mario A.
DeRiso, Matthew
Bercury, Scott D.
Li, Lingyun
Lydon, John T.
Weber, William
Pande, Nilesh
Cromwell, Mandy A.
Copeland, Diane
Leonard, John
Cheng, Seng H.
Scheule, Ronald K.
author_facet Cabrera-Salazar, Mario A.
DeRiso, Matthew
Bercury, Scott D.
Li, Lingyun
Lydon, John T.
Weber, William
Pande, Nilesh
Cromwell, Mandy A.
Copeland, Diane
Leonard, John
Cheng, Seng H.
Scheule, Ronald K.
author_sort Cabrera-Salazar, Mario A.
collection PubMed
description Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.
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spelling pubmed-34223382012-08-21 Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease Cabrera-Salazar, Mario A. DeRiso, Matthew Bercury, Scott D. Li, Lingyun Lydon, John T. Weber, William Pande, Nilesh Cromwell, Mandy A. Copeland, Diane Leonard, John Cheng, Seng H. Scheule, Ronald K. PLoS One Research Article Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases. Public Library of Science 2012-08-17 /pmc/articles/PMC3422338/ /pubmed/22912851 http://dx.doi.org/10.1371/journal.pone.0043310 Text en © 2012 Cabrera-Salazar et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cabrera-Salazar, Mario A.
DeRiso, Matthew
Bercury, Scott D.
Li, Lingyun
Lydon, John T.
Weber, William
Pande, Nilesh
Cromwell, Mandy A.
Copeland, Diane
Leonard, John
Cheng, Seng H.
Scheule, Ronald K.
Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease
title Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease
title_full Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease
title_fullStr Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease
title_full_unstemmed Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease
title_short Systemic Delivery of a Glucosylceramide Synthase Inhibitor Reduces CNS Substrates and Increases Lifespan in a Mouse Model of Type 2 Gaucher Disease
title_sort systemic delivery of a glucosylceramide synthase inhibitor reduces cns substrates and increases lifespan in a mouse model of type 2 gaucher disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422338/
https://www.ncbi.nlm.nih.gov/pubmed/22912851
http://dx.doi.org/10.1371/journal.pone.0043310
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