Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder
To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence suppo...
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| Veröffentlicht in: | Experimental neurology 2016-04, Vol.278, p.11-21 |
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| container_title | Experimental neurology |
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| creator | King, Barbara Setford, Meghan L. Hassiotis, Sofia Trim, Paul J. Duplock, Stephen Tucker, Justin N. Hattersley, Kathryn Snel, Marten F. Hopwood, John J. Hemsley, Kim M. |
| description | To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence supporting treatment of symptomatic patients, principally because few studies have been designed to examine disease reversibility.
Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed.
Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed.
Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage.
•Few studies have examined disease reversibility in animal models of MPS III.•Continual infusion of replacement enzyme into ventricular CSF was undertaken in symptomatic-stage MPS IIIA mice.•Improvement in some but not all behavioural parameters occurred.•Reductions in substrate accumulation and microgliosis were observed•Astrogliosis and axonal spheroid numbers did not change |
| doi_str_mv | 10.1016/j.expneurol.2015.11.013 |
| format | Article |
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Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed.
Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed.
Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage.
•Few studies have examined disease reversibility in animal models of MPS III.•Continual infusion of replacement enzyme into ventricular CSF was undertaken in symptomatic-stage MPS IIIA mice.•Improvement in some but not all behavioural parameters occurred.•Reductions in substrate accumulation and microgliosis were observed•Astrogliosis and axonal spheroid numbers did not change</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2015.11.013</identifier><identifier>PMID: 26626972</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Brain - drug effects ; Brain - metabolism ; Cerebrospinal fluid ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Drug Delivery Systems ; Enzyme replacement therapy ; Female ; G(M3) Ganglioside - metabolism ; Gangliosidoses, GM2 - metabolism ; Humans ; Hydrolases - administration & dosage ; Lysosomal storage disorder ; Male ; Maze Learning - drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity - drug effects ; Motor Activity - genetics ; Mouse ; MPS IIIA ; Mucopolysaccharidosis III - complications ; Neurodegenerative Diseases - drug therapy ; Neurodegenerative Diseases - etiology ; Neurodegenerative Diseases - pathology ; Osmotic pump ; Sulfatases - genetics ; Sulfatases - metabolism</subject><ispartof>Experimental neurology, 2016-04, Vol.278, p.11-21</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-d3022f73a346c58c78e1566b7de0ce53348f8382b1a9aa48c5256ae16fbebc753</citedby><cites>FETCH-LOGICAL-c404t-d3022f73a346c58c78e1566b7de0ce53348f8382b1a9aa48c5256ae16fbebc753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014488615301266$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26626972$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>King, Barbara</creatorcontrib><creatorcontrib>Setford, Meghan L.</creatorcontrib><creatorcontrib>Hassiotis, Sofia</creatorcontrib><creatorcontrib>Trim, Paul J.</creatorcontrib><creatorcontrib>Duplock, Stephen</creatorcontrib><creatorcontrib>Tucker, Justin N.</creatorcontrib><creatorcontrib>Hattersley, Kathryn</creatorcontrib><creatorcontrib>Snel, Marten F.</creatorcontrib><creatorcontrib>Hopwood, John J.</creatorcontrib><creatorcontrib>Hemsley, Kim M.</creatorcontrib><title>Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence supporting treatment of symptomatic patients, principally because few studies have been designed to examine disease reversibility.
Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed.
Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed.
Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage.
•Few studies have examined disease reversibility in animal models of MPS III.•Continual infusion of replacement enzyme into ventricular CSF was undertaken in symptomatic-stage MPS IIIA mice.•Improvement in some but not all behavioural parameters occurred.•Reductions in substrate accumulation and microgliosis were observed•Astrogliosis and axonal spheroid numbers did not change</description><subject>Animals</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Cerebrospinal fluid</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Routes</subject><subject>Drug Delivery Systems</subject><subject>Enzyme replacement therapy</subject><subject>Female</subject><subject>G(M3) Ganglioside - metabolism</subject><subject>Gangliosidoses, GM2 - metabolism</subject><subject>Humans</subject><subject>Hydrolases - administration & dosage</subject><subject>Lysosomal storage disorder</subject><subject>Male</subject><subject>Maze Learning - drug effects</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Motor Activity - drug effects</subject><subject>Motor Activity - genetics</subject><subject>Mouse</subject><subject>MPS IIIA</subject><subject>Mucopolysaccharidosis III - complications</subject><subject>Neurodegenerative Diseases - drug therapy</subject><subject>Neurodegenerative Diseases - etiology</subject><subject>Neurodegenerative Diseases - pathology</subject><subject>Osmotic pump</subject><subject>Sulfatases - genetics</subject><subject>Sulfatases - metabolism</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFu1DAURS0EokPhF8BLFiT42Y6dLKsKKNJIbGBtOfYL41ESD3amdPgUvhanU7qFla_ke9_18yHkDbAaGKj3-xrvDjMeUxxrzqCpAWoG4gnZAOtYxaVgT8mGMZCVbFt1QV7kvGeMdZLr5-SCK8VVp_mG_N7Gn5WPGd9RF-clzEc7Upx_nSakHsdwi-lE7VRUTHbBTHMsNzYf0C2ZxoFiXmw_hrxDT_tkw0x9yGgz0iItneKxyCmWWavbUrcLo9_F6Ks4Z1zo_RIev-OMpaD0rfmYPKaX5Nlgx4yvHs5L8u3jh6_XN9X2y6fP11fbykkml8oLxvmghRVSuaZ1ukVolOq1R-awEUK2Qyta3oPtrJWta3ijLIIaeuydbsQleXuee0jxx7HsY6aQHY6jnbG83oDuWKcFgPwPq-atgAbWqfpsdSnmnHAwhxQmm04GmFkZmr15ZGhWhgbAFIYl-fqh5NhP6B9zf6EVw9XZgOVXbgMmk13A2aEPqWAxPoZ_lvwBEMS1Zw</recordid><startdate>201604</startdate><enddate>201604</enddate><creator>King, Barbara</creator><creator>Setford, Meghan L.</creator><creator>Hassiotis, Sofia</creator><creator>Trim, Paul J.</creator><creator>Duplock, Stephen</creator><creator>Tucker, Justin N.</creator><creator>Hattersley, Kathryn</creator><creator>Snel, Marten F.</creator><creator>Hopwood, John J.</creator><creator>Hemsley, Kim M.</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>7X8</scope><scope>7TK</scope></search><sort><creationdate>201604</creationdate><title>Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder</title><author>King, Barbara ; Setford, Meghan L. ; Hassiotis, Sofia ; Trim, Paul J. ; Duplock, Stephen ; Tucker, Justin N. ; Hattersley, Kathryn ; Snel, Marten F. ; Hopwood, John J. ; Hemsley, Kim M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-d3022f73a346c58c78e1566b7de0ce53348f8382b1a9aa48c5256ae16fbebc753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Cerebrospinal fluid</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Administration Routes</topic><topic>Drug Delivery Systems</topic><topic>Enzyme replacement therapy</topic><topic>Female</topic><topic>G(M3) Ganglioside - metabolism</topic><topic>Gangliosidoses, GM2 - metabolism</topic><topic>Humans</topic><topic>Hydrolases - administration & dosage</topic><topic>Lysosomal storage disorder</topic><topic>Male</topic><topic>Maze Learning - drug effects</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Motor Activity - drug effects</topic><topic>Motor Activity - genetics</topic><topic>Mouse</topic><topic>MPS IIIA</topic><topic>Mucopolysaccharidosis III - complications</topic><topic>Neurodegenerative Diseases - drug therapy</topic><topic>Neurodegenerative Diseases - etiology</topic><topic>Neurodegenerative Diseases - pathology</topic><topic>Osmotic pump</topic><topic>Sulfatases - genetics</topic><topic>Sulfatases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>King, Barbara</creatorcontrib><creatorcontrib>Setford, Meghan L.</creatorcontrib><creatorcontrib>Hassiotis, Sofia</creatorcontrib><creatorcontrib>Trim, Paul J.</creatorcontrib><creatorcontrib>Duplock, Stephen</creatorcontrib><creatorcontrib>Tucker, Justin N.</creatorcontrib><creatorcontrib>Hattersley, Kathryn</creatorcontrib><creatorcontrib>Snel, Marten F.</creatorcontrib><creatorcontrib>Hopwood, John J.</creatorcontrib><creatorcontrib>Hemsley, Kim M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>King, Barbara</au><au>Setford, Meghan L.</au><au>Hassiotis, Sofia</au><au>Trim, Paul J.</au><au>Duplock, Stephen</au><au>Tucker, Justin N.</au><au>Hattersley, Kathryn</au><au>Snel, Marten F.</au><au>Hopwood, John J.</au><au>Hemsley, Kim M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2016-04</date><risdate>2016</risdate><volume>278</volume><spage>11</spage><epage>21</epage><pages>11-21</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><abstract>To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence supporting treatment of symptomatic patients, principally because few studies have been designed to examine disease reversibility.
Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed.
Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed.
Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage.
•Few studies have examined disease reversibility in animal models of MPS III.•Continual infusion of replacement enzyme into ventricular CSF was undertaken in symptomatic-stage MPS IIIA mice.•Improvement in some but not all behavioural parameters occurred.•Reductions in substrate accumulation and microgliosis were observed•Astrogliosis and axonal spheroid numbers did not change</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26626972</pmid><doi>10.1016/j.expneurol.2015.11.013</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Brain - drug effects Brain - metabolism Cerebrospinal fluid Disease Models, Animal Dose-Response Relationship, Drug Drug Administration Routes Drug Delivery Systems Enzyme replacement therapy Female G(M3) Ganglioside - metabolism Gangliosidoses, GM2 - metabolism Humans Hydrolases - administration & dosage Lysosomal storage disorder Male Maze Learning - drug effects Mice Mice, Inbred C57BL Mice, Transgenic Motor Activity - drug effects Motor Activity - genetics Mouse MPS IIIA Mucopolysaccharidosis III - complications Neurodegenerative Diseases - drug therapy Neurodegenerative Diseases - etiology Neurodegenerative Diseases - pathology Osmotic pump Sulfatases - genetics Sulfatases - metabolism |
| title | Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder |
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