Salmeterol enhances the cardiac response to gene therapy in Pompe disease
Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to E...
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| description | Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p |
| doi_str_mv | 10.1016/j.ymgme.2016.03.006 |
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•GAA knockout mice for treated with 4 new drugs in combination with an adeno-associated virus (AAV) vector encoding GAA•Heart GAA activity was increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice•Glycogen content was reduced in the heart by adding DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) to the AAV vector, in comparison with untreated mice•Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance in comparison with the vector alone (p<0.001)•The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice]]></description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/j.ymgme.2016.03.006</identifier><identifier>PMID: 27017193</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adeno-associated virus ; Adeno-associated virus vector ; alpha-Glucosidases - genetics ; alpha-Glucosidases - metabolism ; Animals ; Clenbuterol - administration & dosage ; Dehydroepiandrosterone - administration & dosage ; Dependovirus - genetics ; Disease Models, Animal ; Enzyme Replacement Therapy ; Genetic Therapy - methods ; Genetic Vectors - administration & dosage ; Glycogen - metabolism ; Glycogen storage disease ; Glycogen Storage Disease Type II - genetics ; Glycogen Storage Disease Type II - metabolism ; Glycogen Storage Disease Type II - therapy ; Humans ; Mannose-6-phosphate receptor ; Mice ; Mice, Knockout ; Myocardium - metabolism ; Pompe disease ; Salmeterol Xinafoate - administration & dosage</subject><ispartof>Molecular genetics and metabolism, 2016-05, Vol.118 (1), p.35-40</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c492t-a69c58caf7a54ea844c9e02bb82f6742f960733d6ff268e3dcc42541b28958bf3</citedby><cites>FETCH-LOGICAL-c492t-a69c58caf7a54ea844c9e02bb82f6742f960733d6ff268e3dcc42541b28958bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ymgme.2016.03.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27017193$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Sang-oh</creatorcontrib><creatorcontrib>Li, Songtao</creatorcontrib><creatorcontrib>Koeberl, Dwight D.</creatorcontrib><title>Salmeterol enhances the cardiac response to gene therapy in Pompe disease</title><title>Molecular genetics and metabolism</title><addtitle>Mol Genet Metab</addtitle><description><![CDATA[Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.
•GAA knockout mice for treated with 4 new drugs in combination with an adeno-associated virus (AAV) vector encoding GAA•Heart GAA activity was increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice•Glycogen content was reduced in the heart by adding DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) to the AAV vector, in comparison with untreated mice•Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance in comparison with the vector alone (p<0.001)•The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice]]></description><subject>Adeno-associated virus</subject><subject>Adeno-associated virus vector</subject><subject>alpha-Glucosidases - genetics</subject><subject>alpha-Glucosidases - metabolism</subject><subject>Animals</subject><subject>Clenbuterol - administration & dosage</subject><subject>Dehydroepiandrosterone - administration & dosage</subject><subject>Dependovirus - genetics</subject><subject>Disease Models, Animal</subject><subject>Enzyme Replacement Therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Glycogen - metabolism</subject><subject>Glycogen storage disease</subject><subject>Glycogen Storage Disease Type II - genetics</subject><subject>Glycogen Storage Disease Type II - metabolism</subject><subject>Glycogen Storage Disease Type II - therapy</subject><subject>Humans</subject><subject>Mannose-6-phosphate receptor</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Myocardium - metabolism</subject><subject>Pompe disease</subject><subject>Salmeterol Xinafoate - administration & dosage</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1r3DAQhkVpaL76CwpFx17W0Zf1cWihhDYJBBJocxayPN7VYluO5A3sv6-2m4TkEnLSSPPOO5p5EPpCSUUJlWfrajssB6hYuVSEV4TID-iIEiMXihH58Smmhh2i45zXhFBaG_EJHTJFaHnnR-jqj-sHmCHFHsO4cqOHjOcVYO9SG5zHCfIUxwx4jngJI-ySyU1bHEZ8G4cJcBsyuAyn6KBzfYbPj-cJuvv96-_55eL65uLq_Of1wgvD5oWTxtfau065WoDTQngDhDWNZp1UgnVGEsV5K7uOSQ289V6wWtCGaVPrpuMn6Mfed9o0A7Qexjm53k4pDC5tbXTBvs6MYWWX8cEKzblUshh8ezRI8X4DebZDyB763o0QN9lSZYgRWlH2DqkuK2W1MkXK91KfYs4JuucfUWJ3vOza_udld7ws4bbwKlVfXw7zXPMEqAi-7wVQVvoQINnsAxRKbUjgZ9vG8GaDfxetqIg</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Han, Sang-oh</creator><creator>Li, Songtao</creator><creator>Koeberl, Dwight D.</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20160501</creationdate><title>Salmeterol enhances the cardiac response to gene therapy in Pompe disease</title><author>Han, Sang-oh ; Li, Songtao ; Koeberl, Dwight D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c492t-a69c58caf7a54ea844c9e02bb82f6742f960733d6ff268e3dcc42541b28958bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adeno-associated virus</topic><topic>Adeno-associated virus vector</topic><topic>alpha-Glucosidases - genetics</topic><topic>alpha-Glucosidases - metabolism</topic><topic>Animals</topic><topic>Clenbuterol - administration & dosage</topic><topic>Dehydroepiandrosterone - administration & dosage</topic><topic>Dependovirus - genetics</topic><topic>Disease Models, Animal</topic><topic>Enzyme Replacement Therapy</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - administration & dosage</topic><topic>Glycogen - metabolism</topic><topic>Glycogen storage disease</topic><topic>Glycogen Storage Disease Type II - genetics</topic><topic>Glycogen Storage Disease Type II - metabolism</topic><topic>Glycogen Storage Disease Type II - therapy</topic><topic>Humans</topic><topic>Mannose-6-phosphate receptor</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Myocardium - metabolism</topic><topic>Pompe disease</topic><topic>Salmeterol Xinafoate - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Sang-oh</creatorcontrib><creatorcontrib>Li, Songtao</creatorcontrib><creatorcontrib>Koeberl, Dwight D.</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</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>Han, Sang-oh</au><au>Li, Songtao</au><au>Koeberl, Dwight D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Salmeterol enhances the cardiac response to gene therapy in Pompe disease</atitle><jtitle>Molecular genetics and metabolism</jtitle><addtitle>Mol Genet Metab</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>118</volume><issue>1</issue><spage>35</spage><epage>40</epage><pages>35-40</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract><![CDATA[Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.
•GAA knockout mice for treated with 4 new drugs in combination with an adeno-associated virus (AAV) vector encoding GAA•Heart GAA activity was increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice•Glycogen content was reduced in the heart by adding DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) to the AAV vector, in comparison with untreated mice•Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance in comparison with the vector alone (p<0.001)•The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice]]></abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27017193</pmid><doi>10.1016/j.ymgme.2016.03.006</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adeno-associated virus Adeno-associated virus vector alpha-Glucosidases - genetics alpha-Glucosidases - metabolism Animals Clenbuterol - administration & dosage Dehydroepiandrosterone - administration & dosage Dependovirus - genetics Disease Models, Animal Enzyme Replacement Therapy Genetic Therapy - methods Genetic Vectors - administration & dosage Glycogen - metabolism Glycogen storage disease Glycogen Storage Disease Type II - genetics Glycogen Storage Disease Type II - metabolism Glycogen Storage Disease Type II - therapy Humans Mannose-6-phosphate receptor Mice Mice, Knockout Myocardium - metabolism Pompe disease Salmeterol Xinafoate - administration & dosage |
| title | Salmeterol enhances the cardiac response to gene therapy in Pompe disease |
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