High-dose enzyme replacement therapy in murine Hurler syndrome
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10years. MPS I results from deficiency of α-l-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminogly...
Gespeichert in:
| Veröffentlicht in: | Molecular genetics and metabolism 2014-02, Vol.111 (2), p.116-122 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 122 |
|---|---|
| container_issue | 2 |
| container_start_page | 116 |
| container_title | Molecular genetics and metabolism |
| container_volume | 111 |
| creator | Ou, Li Herzog, Tyler Koniar, Brenda L. Gunther, Roland Whitley, Chester B. |
| description | Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10years. MPS I results from deficiency of α-l-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood–brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6mg/kg, once per week, 4weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p |
| doi_str_mv | 10.1016/j.ymgme.2013.09.008 |
| format | Article |
| fullrecord | <record><control><sourceid>elsevier_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4014311</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S109671921300320X</els_id><sourcerecordid>S109671921300320X</sourcerecordid><originalsourceid>FETCH-LOGICAL-c459t-4c5ea90e5fb6cccd188f28c24a1f72e180ecc46fff3f91423668f773d797c9a53</originalsourceid><addsrcrecordid>eNp9kN1KAzEQhYMotlafQJB9gV1nstmfXFiQolYoeKPXIc1O2pT9Kdm2sD69W2uL3ng1A3POmZmPsVuECAHT-1XUVYuKIg4YRyAjgPyMDRFkGmYc0vNjj5IP2FXbrgAQEyku2YALBOAiHrLx1C2WYdG0FFD92VUUeFqX2lBF9SbYLMnrdRe4Oqi23tUUTLe-JB-0XV34pqJrdmF12dLNTx2xj-en98k0nL29vE4eZ6ERidyEwiSkJVBi56kxpsA8tzw3XGi0GSfMgYwRqbU2thIFj9M0t1kWF5nMjNRJPGLjQ-56O6-oMP1xXpdq7V2lfaca7dTfSe2WatHslAAUMWIfEB8CjG_a1pM9eRHUHqdaqW-cao9TgVQ9zt5193vtyXPk1wseDgLqn9858qo1jmpDhfNkNqpo3L8LvgCyZYmd</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>High-dose enzyme replacement therapy in murine Hurler syndrome</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Ou, Li ; Herzog, Tyler ; Koniar, Brenda L. ; Gunther, Roland ; Whitley, Chester B.</creator><creatorcontrib>Ou, Li ; Herzog, Tyler ; Koniar, Brenda L. ; Gunther, Roland ; Whitley, Chester B.</creatorcontrib><description>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10years. MPS I results from deficiency of α-l-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood–brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6mg/kg, once per week, 4weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p<0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.
•We conducted high-dose ERT in MPS I mice.•High-dose ERT leads to enzyme activity increase in the CNS.•High-dose ERT leads to GAG accumulation reduction in the CNS.•High-dose ERT leads to neurological improvements.</description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/j.ymgme.2013.09.008</identifier><identifier>PMID: 24100243</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Blood-Brain Barrier - metabolism ; Blood–brain-barrier ; Brain - drug effects ; Brain - metabolism ; Brain - pathology ; Capillary Permeability ; Cognition - drug effects ; Disease Models, Animal ; Drug Administration Schedule ; Drug Dosage Calculations ; Enzyme Replacement Therapy ; Glycosaminoglycans - metabolism ; High dose ; Humans ; Hurler syndrome ; Iduronidase - blood ; Iduronidase - deficiency ; Iduronidase - pharmacokinetics ; Iduronidase - pharmacology ; Maze Learning - drug effects ; Mice ; Mice, Transgenic ; Mucopolysaccharidosis I ; Mucopolysaccharidosis I - enzymology ; Mucopolysaccharidosis I - pathology ; Mucopolysaccharidosis I - psychology ; Mucopolysaccharidosis I - therapy ; Recombinant Proteins - pharmacokinetics ; Recombinant Proteins - pharmacology</subject><ispartof>Molecular genetics and metabolism, 2014-02, Vol.111 (2), p.116-122</ispartof><rights>2013 Elsevier Inc.</rights><rights>2013.</rights><rights>2013 Elsevier Inc. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-4c5ea90e5fb6cccd188f28c24a1f72e180ecc46fff3f91423668f773d797c9a53</citedby><cites>FETCH-LOGICAL-c459t-4c5ea90e5fb6cccd188f28c24a1f72e180ecc46fff3f91423668f773d797c9a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S109671921300320X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24100243$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ou, Li</creatorcontrib><creatorcontrib>Herzog, Tyler</creatorcontrib><creatorcontrib>Koniar, Brenda L.</creatorcontrib><creatorcontrib>Gunther, Roland</creatorcontrib><creatorcontrib>Whitley, Chester B.</creatorcontrib><title>High-dose enzyme replacement therapy in murine Hurler syndrome</title><title>Molecular genetics and metabolism</title><addtitle>Mol Genet Metab</addtitle><description>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10years. MPS I results from deficiency of α-l-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood–brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6mg/kg, once per week, 4weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p<0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.
•We conducted high-dose ERT in MPS I mice.•High-dose ERT leads to enzyme activity increase in the CNS.•High-dose ERT leads to GAG accumulation reduction in the CNS.•High-dose ERT leads to neurological improvements.</description><subject>Animals</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood–brain-barrier</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Capillary Permeability</subject><subject>Cognition - drug effects</subject><subject>Disease Models, Animal</subject><subject>Drug Administration Schedule</subject><subject>Drug Dosage Calculations</subject><subject>Enzyme Replacement Therapy</subject><subject>Glycosaminoglycans - metabolism</subject><subject>High dose</subject><subject>Humans</subject><subject>Hurler syndrome</subject><subject>Iduronidase - blood</subject><subject>Iduronidase - deficiency</subject><subject>Iduronidase - pharmacokinetics</subject><subject>Iduronidase - pharmacology</subject><subject>Maze Learning - drug effects</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mucopolysaccharidosis I</subject><subject>Mucopolysaccharidosis I - enzymology</subject><subject>Mucopolysaccharidosis I - pathology</subject><subject>Mucopolysaccharidosis I - psychology</subject><subject>Mucopolysaccharidosis I - therapy</subject><subject>Recombinant Proteins - pharmacokinetics</subject><subject>Recombinant Proteins - pharmacology</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN1KAzEQhYMotlafQJB9gV1nstmfXFiQolYoeKPXIc1O2pT9Kdm2sD69W2uL3ng1A3POmZmPsVuECAHT-1XUVYuKIg4YRyAjgPyMDRFkGmYc0vNjj5IP2FXbrgAQEyku2YALBOAiHrLx1C2WYdG0FFD92VUUeFqX2lBF9SbYLMnrdRe4Oqi23tUUTLe-JB-0XV34pqJrdmF12dLNTx2xj-en98k0nL29vE4eZ6ERidyEwiSkJVBi56kxpsA8tzw3XGi0GSfMgYwRqbU2thIFj9M0t1kWF5nMjNRJPGLjQ-56O6-oMP1xXpdq7V2lfaca7dTfSe2WatHslAAUMWIfEB8CjG_a1pM9eRHUHqdaqW-cao9TgVQ9zt5193vtyXPk1wseDgLqn9858qo1jmpDhfNkNqpo3L8LvgCyZYmd</recordid><startdate>20140201</startdate><enddate>20140201</enddate><creator>Ou, Li</creator><creator>Herzog, Tyler</creator><creator>Koniar, Brenda L.</creator><creator>Gunther, Roland</creator><creator>Whitley, Chester B.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20140201</creationdate><title>High-dose enzyme replacement therapy in murine Hurler syndrome</title><author>Ou, Li ; Herzog, Tyler ; Koniar, Brenda L. ; Gunther, Roland ; Whitley, Chester B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-4c5ea90e5fb6cccd188f28c24a1f72e180ecc46fff3f91423668f773d797c9a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Blood–brain-barrier</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Capillary Permeability</topic><topic>Cognition - drug effects</topic><topic>Disease Models, Animal</topic><topic>Drug Administration Schedule</topic><topic>Drug Dosage Calculations</topic><topic>Enzyme Replacement Therapy</topic><topic>Glycosaminoglycans - metabolism</topic><topic>High dose</topic><topic>Humans</topic><topic>Hurler syndrome</topic><topic>Iduronidase - blood</topic><topic>Iduronidase - deficiency</topic><topic>Iduronidase - pharmacokinetics</topic><topic>Iduronidase - pharmacology</topic><topic>Maze Learning - drug effects</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mucopolysaccharidosis I</topic><topic>Mucopolysaccharidosis I - enzymology</topic><topic>Mucopolysaccharidosis I - pathology</topic><topic>Mucopolysaccharidosis I - psychology</topic><topic>Mucopolysaccharidosis I - therapy</topic><topic>Recombinant Proteins - pharmacokinetics</topic><topic>Recombinant Proteins - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ou, Li</creatorcontrib><creatorcontrib>Herzog, Tyler</creatorcontrib><creatorcontrib>Koniar, Brenda L.</creatorcontrib><creatorcontrib>Gunther, Roland</creatorcontrib><creatorcontrib>Whitley, Chester B.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular genetics and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ou, Li</au><au>Herzog, Tyler</au><au>Koniar, Brenda L.</au><au>Gunther, Roland</au><au>Whitley, Chester B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High-dose enzyme replacement therapy in murine Hurler syndrome</atitle><jtitle>Molecular genetics and metabolism</jtitle><addtitle>Mol Genet Metab</addtitle><date>2014-02-01</date><risdate>2014</risdate><volume>111</volume><issue>2</issue><spage>116</spage><epage>122</epage><pages>116-122</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10years. MPS I results from deficiency of α-l-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood–brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6mg/kg, once per week, 4weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p<0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.
•We conducted high-dose ERT in MPS I mice.•High-dose ERT leads to enzyme activity increase in the CNS.•High-dose ERT leads to GAG accumulation reduction in the CNS.•High-dose ERT leads to neurological improvements.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24100243</pmid><doi>10.1016/j.ymgme.2013.09.008</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1096-7192 |
| ispartof | Molecular genetics and metabolism, 2014-02, Vol.111 (2), p.116-122 |
| issn | 1096-7192 1096-7206 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4014311 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Blood-Brain Barrier - metabolism Blood–brain-barrier Brain - drug effects Brain - metabolism Brain - pathology Capillary Permeability Cognition - drug effects Disease Models, Animal Drug Administration Schedule Drug Dosage Calculations Enzyme Replacement Therapy Glycosaminoglycans - metabolism High dose Humans Hurler syndrome Iduronidase - blood Iduronidase - deficiency Iduronidase - pharmacokinetics Iduronidase - pharmacology Maze Learning - drug effects Mice Mice, Transgenic Mucopolysaccharidosis I Mucopolysaccharidosis I - enzymology Mucopolysaccharidosis I - pathology Mucopolysaccharidosis I - psychology Mucopolysaccharidosis I - therapy Recombinant Proteins - pharmacokinetics Recombinant Proteins - pharmacology |
| title | High-dose enzyme replacement therapy in murine Hurler syndrome |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T04%3A49%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-elsevier_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=High-dose%20enzyme%20replacement%20therapy%20in%20murine%20Hurler%20syndrome&rft.jtitle=Molecular%20genetics%20and%20metabolism&rft.au=Ou,%20Li&rft.date=2014-02-01&rft.volume=111&rft.issue=2&rft.spage=116&rft.epage=122&rft.pages=116-122&rft.issn=1096-7192&rft.eissn=1096-7206&rft_id=info:doi/10.1016/j.ymgme.2013.09.008&rft_dat=%3Celsevier_pubme%3ES109671921300320X%3C/elsevier_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/24100243&rft_els_id=S109671921300320X&rfr_iscdi=true |