Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease
Identifieur interne : 000508 ( Pmc/Corpus ); précédent : 000507; suivant : 000509Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease
Auteurs : C. H. Vite ; J. H. Bagel ; G. P. Swain ; M. Prociuk ; T. U. Sikora ; V. M. Stein ; P. O Onnell ; T. Ruane ; S. Ward ; A. Crooks ; S. Li ; E. Mauldin ; S. Stellar ; M. De Meulder ; M. L. Kao ; D. S. Ory ; C. Davidson ; M. T. Vanier ; S. U. WalkleySource :
- 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
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease</title><author><name sortKey="Vite, C H" sort="Vite, C H" uniqKey="Vite C" first="C. H." last="Vite">C. H. Vite</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Prociuk, M" sort="Prociuk, M" uniqKey="Prociuk M" first="M." last="Prociuk">M. Prociuk</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Ruane, T" sort="Ruane, T" uniqKey="Ruane T" first="T." last="Ruane">T. Ruane</name><affiliation><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Ward, S" sort="Ward, S" uniqKey="Ward S" first="S." last="Ward">S. Ward</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Crooks, A" sort="Crooks, A" uniqKey="Crooks A" first="A." last="Crooks">A. Crooks</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Li, S" sort="Li, S" uniqKey="Li S" first="S." last="Li">S. Li</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Mauldin, E" sort="Mauldin, E" uniqKey="Mauldin E" first="E." last="Mauldin">E. Mauldin</name><affiliation><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Stellar, S" sort="Stellar, S" uniqKey="Stellar S" first="S." last="Stellar">S. Stellar</name><affiliation><nlm:aff id="A3">Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</nlm:aff></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><nlm:aff id="A4">Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium</nlm:aff></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><nlm:aff id="A3">Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</nlm:aff></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><nlm:aff id="A5">Diabetic Cardiovascular Disease Center, School of Medicine, Washington University School of Medicine, St Louis, Missouri</nlm:aff></affiliation></author><author><name sortKey="Davidson, C" sort="Davidson, C" uniqKey="Davidson C" first="C." last="Davidson">C. Davidson</name><affiliation><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></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><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></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><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></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25717099</idno><idno type="pmc">4415615</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415615</idno><idno type="RBID">PMC:4415615</idno><idno type="doi">10.1126/scitranslmed.3010101</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000508</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000508</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease</title><author><name sortKey="Vite, C H" sort="Vite, C H" uniqKey="Vite C" first="C. H." last="Vite">C. H. Vite</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Prociuk, M" sort="Prociuk, M" uniqKey="Prociuk M" first="M." last="Prociuk">M. Prociuk</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></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><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Ruane, T" sort="Ruane, T" uniqKey="Ruane T" first="T." last="Ruane">T. Ruane</name><affiliation><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Ward, S" sort="Ward, S" uniqKey="Ward S" first="S." last="Ward">S. Ward</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Crooks, A" sort="Crooks, A" uniqKey="Crooks A" first="A." last="Crooks">A. Crooks</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Li, S" sort="Li, S" uniqKey="Li S" first="S." last="Li">S. Li</name><affiliation><nlm:aff id="A1">Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Mauldin, E" sort="Mauldin, E" uniqKey="Mauldin E" first="E." last="Mauldin">E. Mauldin</name><affiliation><nlm:aff id="A2">Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</nlm:aff></affiliation></author><author><name sortKey="Stellar, S" sort="Stellar, S" uniqKey="Stellar S" first="S." last="Stellar">S. Stellar</name><affiliation><nlm:aff id="A3">Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</nlm:aff></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><nlm:aff id="A4">Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium</nlm:aff></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><nlm:aff id="A3">Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</nlm:aff></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><nlm:aff id="A5">Diabetic Cardiovascular Disease Center, School of Medicine, Washington University School of Medicine, St Louis, Missouri</nlm:aff></affiliation></author><author><name sortKey="Davidson, C" sort="Davidson, C" uniqKey="Davidson C" first="C." last="Davidson">C. Davidson</name><affiliation><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></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><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></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><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></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><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101505086</journal-id><journal-id journal-id-type="pubmed-jr-id">36963</journal-id><journal-id journal-id-type="nlm-ta">Sci Transl Med</journal-id><journal-id journal-id-type="iso-abbrev">Sci Transl Med</journal-id><journal-title-group><journal-title>Science translational medicine</journal-title></journal-title-group><issn pub-type="ppub">1946-6234</issn><issn pub-type="epub">1946-6242</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25717099</article-id><article-id pub-id-type="pmc">4415615</article-id><article-id pub-id-type="doi">10.1126/scitranslmed.3010101</article-id><article-id pub-id-type="manuscript">NIHMS679887</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Intracisternal Cyclodextrin Prevents Cerebellar Dysfunction and Purkinje Cell Death in Feline Niemann-Pick type C1 disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Vite</surname><given-names>C. H.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Bagel</surname><given-names>J. H.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Swain</surname><given-names>G. P.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Prociuk</surname><given-names>M.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sikora</surname><given-names>T. U.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Stein</surname><given-names>V. M.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN2" ref-type="author-notes">†</xref></contrib><contrib contrib-type="author"><name><surname>O’Donnell</surname><given-names>P.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ruane</surname><given-names>T.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ward</surname><given-names>S.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Crooks</surname><given-names>A.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>S.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN3" ref-type="author-notes">‡</xref></contrib><contrib contrib-type="author"><name><surname>Mauldin</surname><given-names>E.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Stellar</surname><given-names>S.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>De Meulder</surname><given-names>M.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Kao</surname><given-names>M. L.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Ory</surname><given-names>D. S.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Davidson</surname><given-names>C.</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Vanier</surname><given-names>M. T.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Walkley</surname><given-names>S. U.</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</aff><aff id="A2"><label>2</label>Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</aff><aff id="A3"><label>3</label>Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey</aff><aff id="A4"><label>4</label>Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium</aff><aff id="A5"><label>5</label>Diabetic Cardiovascular Disease Center, School of Medicine, Washington University School of Medicine, St Louis, Missouri</aff><aff id="A6"><label>6</label>Dominick P Purpura Department of Neuroscience, Rose F Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York</aff><aff id="A7"><label>7</label>Institut National de la Santé et de la Recherche Médicale (INSERM U820); EA4611, Université Claude Bernard Lyon1, Lyon, France</aff><author-notes><corresp id="FN1"><label>*</label>Correspondence to: <email>vite@vet.upenn.edu</email></corresp><fn id="FN2" fn-type="present-address"><label>†</label><p>Current addresses:</p><p>Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Niedersachsen, Germany</p></fn><fn id="FN3" fn-type="present-address"><label>‡</label><p>School of Veterinary Medicine, Kansas State University, Manhattan, Kansas</p></fn><fn id="FN5" fn-type="conflict"><p><bold>Competing Interests:</bold></p><p>Vite and Ory have received honoraria from Actelion and Biomarin.</p><p>Vanier has received travel expenses, consulting fees and presentation honoraria from Actelion Pharmaceuticals, Ltd.</p><p>Patents: Ory – Disease specific biomarkers for Niemann-Pick C disease (US Patent 8,497,122</p><p>Walkley – Methods for therapeutic use of glucosylceramide synthesis inhibitors and composition thereof (US Patent 6,683,076)</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>14</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="ppub"><day>25</day><month>2</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>30</day><month>4</month><year>2015</year></pub-date><volume>7</volume><issue>276</issue><fpage>276ra26</fpage><lpage>276ra26</lpage><pmc-comment>elocation-id from pubmed: 10.1126/scitranslmed.3010101</pmc-comment>
<abstract><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></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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