Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease
Identifieur interne : 000054 ( France/Analysis ); précédent : 000053; suivant : 000055Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease
Auteurs : C. H. Vite [États-Unis] ; J. H. Bagel [États-Unis] ; G. P. Swain [États-Unis] ; M. Prociuk [États-Unis] ; T. U. Sikora [États-Unis] ; V. M. Stein [États-Unis] ; P. O Onnell [États-Unis] ; T. Ruane [États-Unis] ; S. Ward [États-Unis] ; A. Crooks [États-Unis] ; S. Li [États-Unis] ; E. Mauldin [États-Unis] ; S. Stellar [États-Unis] ; M. De Meulder [Belgique] ; M. L. Kao [États-Unis] ; D. S. Ory [États-Unis] ; C. Davidson [États-Unis] ; M. T. Vanier [France] ; S. U. Walkley [États-Unis]Source :
- Science translational medicine [ 1946-6234 ] ; 2015.
Abstract
Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. Whereas subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-beta-cyclodextrin (HPβCD) ameliorated hepatic disease, doses sufficient to reduce neurological disease resulted in pulmonary toxicity. In contrast, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. Together, these studies in the feline animal model have provided critical data on efficacy and safety of drug administration directly into the CNS that will be important for advancing HPβCD into clinical trials.
Url:
DOI: 10.1126/scitranslmed.3010101
PubMed: 25717099
PubMed Central: 4415615
Affiliations:
- Belgique, France, États-Unis
- Auvergne-Rhône-Alpes, Missouri (État), New Jersey, Pennsylvanie, Rhône-Alpes, État de New York
- Lyon
- Université Claude Bernard Lyon 1
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PMC:4415615Le document en format XML
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H." last="Vite">C. H. Vite</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Bagel, J H" sort="Bagel, J H" uniqKey="Bagel J" first="J. H." last="Bagel">J. H. Bagel</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Swain, G P" sort="Swain, G P" uniqKey="Swain G" first="G. P." last="Swain">G. P. Swain</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Prociuk, M" sort="Prociuk, M" uniqKey="Prociuk M" first="M." last="Prociuk">M. Prociuk</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Sikora, T U" sort="Sikora, T U" uniqKey="Sikora T" first="T. U." last="Sikora">T. U. Sikora</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Stein, V M" sort="Stein, V M" uniqKey="Stein V" first="V. M." last="Stein">V. M. Stein</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="O Onnell, P" sort="O Onnell, P" uniqKey="O Onnell P" first="P." last="O Onnell">P. O Onnell</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Ruane, T" sort="Ruane, T" uniqKey="Ruane T" first="T." last="Ruane">T. Ruane</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Ward, S" sort="Ward, S" uniqKey="Ward S" first="S." last="Ward">S. Ward</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Crooks, A" sort="Crooks, A" uniqKey="Crooks A" first="A." last="Crooks">A. Crooks</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Li, S" sort="Li, S" uniqKey="Li S" first="S." last="Li">S. Li</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Mauldin, E" sort="Mauldin, E" uniqKey="Mauldin E" first="E." last="Mauldin">E. Mauldin</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia</wicri:cityArea></affiliation></author><author><name sortKey="Stellar, S" sort="Stellar, S" uniqKey="Stellar S" first="S." last="Stellar">S. Stellar</name><affiliation wicri:level="2"><nlm:aff id="A3">Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville</wicri:cityArea></affiliation></author><author><name sortKey="De Meulder, M" sort="De Meulder, M" uniqKey="De Meulder M" first="M." last="De Meulder">M. De Meulder</name><affiliation wicri:level="1"><nlm:aff id="A4">Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse</wicri:regionArea><wicri:noRegion>Beerse</wicri:noRegion></affiliation></author><author><name sortKey="Kao, M L" sort="Kao, M L" uniqKey="Kao M" first="M. L." last="Kao">M. L. Kao</name><affiliation wicri:level="2"><nlm:aff id="A3">Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville</wicri:cityArea></affiliation></author><author><name sortKey="Ory, D S" sort="Ory, D S" uniqKey="Ory D" first="D. S." last="Ory">D. S. Ory</name><affiliation wicri:level="2"><nlm:aff id="A5">Diabetic Cardiovascular Disease Center, School of Medicine, Washington University School of Medicine, St Louis, Missouri</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>Diabetic Cardiovascular Disease Center, School of Medicine, Washington University School of Medicine, St Louis</wicri:cityArea></affiliation></author><author><name sortKey="Davidson, C" sort="Davidson, C" uniqKey="Davidson C" first="C." last="Davidson">C. Davidson</name><affiliation wicri:level="2"><nlm:aff id="A6">Dominick P Purpura Department of Neuroscience, Rose F Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Dominick P Purpura Department of Neuroscience, Rose F Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx</wicri:cityArea></affiliation></author><author><name sortKey="Vanier, M T" sort="Vanier, M T" uniqKey="Vanier M" first="M. T." last="Vanier">M. T. Vanier</name><affiliation wicri:level="4"><nlm:aff id="A7">Institut National de la Santé et de la Recherche Médicale (INSERM U820); EA4611, Université Claude Bernard Lyon1, Lyon, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale (INSERM U820); EA4611, Université Claude Bernard Lyon1, Lyon</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName><orgName type="university">Université Claude Bernard Lyon 1</orgName></affiliation></author><author><name sortKey="Walkley, S U" sort="Walkley, S U" uniqKey="Walkley S" first="S. U." last="Walkley">S. U. Walkley</name><affiliation wicri:level="2"><nlm:aff id="A6">Dominick P Purpura Department of Neuroscience, Rose F Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Dominick P Purpura Department of Neuroscience, Rose F Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx</wicri:cityArea></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="ISSN">1946-6234</idno><idno type="eISSN">1946-6242</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. Whereas subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-beta-cyclodextrin (HPβCD) ameliorated hepatic disease, doses sufficient to reduce neurological disease resulted in pulmonary toxicity. In contrast, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. Together, these studies in the feline animal model have provided critical data on efficacy and safety of drug administration directly into the CNS that will be important for advancing HPβCD into clinical trials.</p></div></front></TEI><affiliations><list><country><li>Belgique</li><li>France</li><li>États-Unis</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Missouri (État)</li><li>New Jersey</li><li>Pennsylvanie</li><li>Rhône-Alpes</li><li>État de New York</li></region><settlement><li>Lyon</li></settlement><orgName><li>Université Claude Bernard Lyon 1</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Vite, C H" sort="Vite, C H" uniqKey="Vite C" first="C. H." last="Vite">C. H. Vite</name></region><name sortKey="Bagel, J H" sort="Bagel, J H" uniqKey="Bagel J" first="J. H." last="Bagel">J. H. Bagel</name><name sortKey="Crooks, A" sort="Crooks, A" uniqKey="Crooks A" first="A." last="Crooks">A. Crooks</name><name sortKey="Davidson, C" sort="Davidson, C" uniqKey="Davidson C" first="C." last="Davidson">C. Davidson</name><name sortKey="Kao, M L" sort="Kao, M L" uniqKey="Kao M" first="M. L." last="Kao">M. L. Kao</name><name sortKey="Li, S" sort="Li, S" uniqKey="Li S" first="S." last="Li">S. Li</name><name sortKey="Mauldin, E" sort="Mauldin, E" uniqKey="Mauldin E" first="E." last="Mauldin">E. Mauldin</name><name sortKey="O Onnell, P" sort="O Onnell, P" uniqKey="O Onnell P" first="P." last="O Onnell">P. O Onnell</name><name sortKey="Ory, D S" sort="Ory, D S" uniqKey="Ory D" first="D. S." last="Ory">D. S. Ory</name><name sortKey="Prociuk, M" sort="Prociuk, M" uniqKey="Prociuk M" first="M." last="Prociuk">M. Prociuk</name><name sortKey="Ruane, T" sort="Ruane, T" uniqKey="Ruane T" first="T." last="Ruane">T. Ruane</name><name sortKey="Sikora, T U" sort="Sikora, T U" uniqKey="Sikora T" first="T. U." last="Sikora">T. U. Sikora</name><name sortKey="Stein, V M" sort="Stein, V M" uniqKey="Stein V" first="V. M." last="Stein">V. M. Stein</name><name sortKey="Stellar, S" sort="Stellar, S" uniqKey="Stellar S" first="S." last="Stellar">S. Stellar</name><name sortKey="Swain, G P" sort="Swain, G P" uniqKey="Swain G" first="G. P." last="Swain">G. P. Swain</name><name sortKey="Walkley, S U" sort="Walkley, S U" uniqKey="Walkley S" first="S. U." last="Walkley">S. U. Walkley</name><name sortKey="Ward, S" sort="Ward, S" uniqKey="Ward S" first="S." last="Ward">S. Ward</name></country><country name="Belgique"><noRegion><name sortKey="De Meulder, M" sort="De Meulder, M" uniqKey="De Meulder M" first="M." last="De Meulder">M. De Meulder</name></noRegion></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Vanier, M T" sort="Vanier, M T" uniqKey="Vanier M" first="M. T." last="Vanier">M. T. 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