The Development and Characterization of an scFv-Fc Fusion-Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse

Charles E Hay; Laura E Ewing; Michael D Hambuchen; Shannon M Zintner; Juliana C Small; Chris T Bolden; William E Fantegrossi; Paris Margaritis; S Michael Owens; Eric C Peterson

doi:10.1124/JPET.119.261180

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The Development and Characterization of an scFv-Fc Fusion-Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse

Journal article

Peer reviewed

The Development and Characterization of an scFv-Fc Fusion-Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse

Charles E Hay, Laura E Ewing, Michael D Hambuchen, Shannon M Zintner, Juliana C Small, Chris T Bolden, William E Fantegrossi, Paris Margaritis, S Michael Owens and Eric C Peterson

The Journal of pharmacology and experimental therapeutics, Vol.374(1), pp.16-23

2020-07

DOI: https://doi.org/10.1124/JPET.119.261180

PMID: 32245884

Abstract

Methamphetamine - pharmacology

Artificial Gene Fusion

Dependovirus - genetics

Central Nervous System Stimulants - pharmacology

Locomotion - genetics

Male

Amphetamine-Related Disorders - physiopathology

Animals

Single-Chain Antibodies - genetics

Amphetamine-Related Disorders - therapy

Amphetamine-Related Disorders - genetics

Mice

Mice, Inbred BALB C

Immunoglobulin Fc Fragments - genetics

Genetic Therapy - methods

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 × 10 , 1 × 10 , and 1 × 10 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, IC = 17 nM. Between days 21 and 35 after vector administration, at both 1 × 10 vc/mouse and 1 × 10 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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.100 Substance Abuse; 1.100.1893 Cocaine
Web Of Science research areas: Pharmacology & Pharmacy
ESI research areas: Pharmacology & Toxicology

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Title: The Development and Characterization of an scFv-Fc Fusion-Based Gene Therapy to Reduce the Psychostimulant Effects of Methamphetamine Abuse
Creators: Charles E Hay - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Laura E Ewing - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Michael D Hambuchen - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Shannon M Zintner - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Juliana C Small - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Chris T Bolden - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
William E Fantegrossi - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Paris Margaritis - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
S Michael Owens - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.)
Eric C Peterson - University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.E.H., L.E.E., M.D.H., C.T.B., W.E.F., S.M.O., E.C.P,); The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (S.M.Z., J.C.S., P.M.,); The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (P.M.); and Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (P.M.) epeterson@uams.edu
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.374(1), pp.16-23
Grant note: M01 RR000080 / NCRR NIH HHS R01 DA036600 / NIDA NIH HHS T32 GM008792 / NIGMS NIH HHS
Academic Unit: Miller School of Medicine; UMMG Dept of Neurological Surgery
Language: English
Resource Type: Journal article
PMID: 32245884
Record Identifier: 991031599832302976