The Development and Characterization of an scFv-Fc Fusion-Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics..
Methamphetamine (METH) continues to be among the most addictive and abused drugs in the United States. Unfortunately, there are currently no Food and Drug Administration-approved pharmacological treatments for METH-use disorder. We have previously explored the use of adeno-associated viral (AAV)-mediated gene transfer of an anti-METH monoclonal antibody. Here, we advance our approach by generating a novel anti-METH single-chain variable fragment (scFv)-Fc fusion construct (termed 7F9-Fc) packaged into AAV serotype 8 vector (called AAV-scFv-Fc) and tested in vivo and ex vivo. A range of doses [1 × 1010, 1 × 1011, and 1 × 1012 vector copies (vcs)/mouse] were administered to mice, eliciting a dose-dependent expression of 7F9-Fc in serum with peak circulating concentrations of 48, 1785, and 3831 µg/ml, respectively. Expressed 7F9-Fc exhibited high-affinity METH binding, IC50 = 17 nM. Between days 21 and 35 after vector administration, at both 1 × 1011 vc/mouse and 1 × 1012 vc/mouse doses, the AAV-7F9-Fc gene therapy significantly decreased the potency of METH in locomotor assays. On day 116 post-AAV administration, mice expressing 7F9-Fc sequestered over 2.5 times more METH in the serum than vehicle-treated mice, and METH concentrations in the brain were reduced by 1.2 times the value for vehicle mice. These data suggest that an AAV-delivered anti-METH Fc fusion antibody could be used to persistently reduce concentrations of METH in the central nervous system. SIGNIFICANCE STATEMENT: In this manuscript, we describe the testing of a novel antimethamphetamine (METH) single-chain variable fragment-Fc fusion protein delivered in mice using gene therapy. The results suggest that the gene therapy delivery system can lead to the production of significant antibody concentrations that mitigate METH's psychostimulant effects in mice over an extended time period.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:374 |
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| Enthalten in: |
The Journal of pharmacology and experimental therapeutics - 374(2020), 1 vom: 03. Juli, Seite 16-23 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hay, Charles E [VerfasserIn] |
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| Links: |
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| Themen: |
44RAL3456C |
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| Anmerkungen: |
Date Completed 12.11.2020 Date Revised 02.07.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1124/jpet.119.261180 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM30831297X |
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| 100 | 1 | |a Hay, Charles E |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Development and Characterization of an scFv-Fc Fusion-Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Revised 02.07.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics. | ||
| 520 | |a Methamphetamine (METH) continues to be among the most addictive and abused drugs in the United States. Unfortunately, there are currently no Food and Drug Administration-approved pharmacological treatments for METH-use disorder. We have previously explored the use of adeno-associated viral (AAV)-mediated gene transfer of an anti-METH monoclonal antibody. Here, we advance our approach by generating a novel anti-METH single-chain variable fragment (scFv)-Fc fusion construct (termed 7F9-Fc) packaged into AAV serotype 8 vector (called AAV-scFv-Fc) and tested in vivo and ex vivo. A range of doses [1 × 1010, 1 × 1011, and 1 × 1012 vector copies (vcs)/mouse] were administered to mice, eliciting a dose-dependent expression of 7F9-Fc in serum with peak circulating concentrations of 48, 1785, and 3831 µg/ml, respectively. Expressed 7F9-Fc exhibited high-affinity METH binding, IC50 = 17 nM. Between days 21 and 35 after vector administration, at both 1 × 1011 vc/mouse and 1 × 1012 vc/mouse doses, the AAV-7F9-Fc gene therapy significantly decreased the potency of METH in locomotor assays. On day 116 post-AAV administration, mice expressing 7F9-Fc sequestered over 2.5 times more METH in the serum than vehicle-treated mice, and METH concentrations in the brain were reduced by 1.2 times the value for vehicle mice. These data suggest that an AAV-delivered anti-METH Fc fusion antibody could be used to persistently reduce concentrations of METH in the central nervous system. SIGNIFICANCE STATEMENT: In this manuscript, we describe the testing of a novel antimethamphetamine (METH) single-chain variable fragment-Fc fusion protein delivered in mice using gene therapy. The results suggest that the gene therapy delivery system can lead to the production of significant antibody concentrations that mitigate METH's psychostimulant effects in mice over an extended time period | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 650 | 7 | |a Immunoglobulin Fc Fragments |2 NLM | |
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| 650 | 7 | |a Methamphetamine |2 NLM | |
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| 700 | 1 | |a Ewing, Laura E |e verfasserin |4 aut | |
| 700 | 1 | |a Hambuchen, Michael D |e verfasserin |4 aut | |
| 700 | 1 | |a Zintner, Shannon M |e verfasserin |4 aut | |
| 700 | 1 | |a Small, Juliana C |e verfasserin |4 aut | |
| 700 | 1 | |a Bolden, Chris T |e verfasserin |4 aut | |
| 700 | 1 | |a Fantegrossi, William E |e verfasserin |4 aut | |
| 700 | 1 | |a Margaritis, Paris |e verfasserin |4 aut | |
| 700 | 1 | |a Owens, S Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Peterson, Eric C |e verfasserin |4 aut | |
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