title: An Autogenously Regulated Expression System for Gene Therapeutic Ocular Applications.
abstract: The future of treating inherited and acquired genetic diseases will be defined by our ability to introduce transgenes into cells and restore normal physiology. Here we describe an autogenous transgene regulatory system (ARES), based on the bacterial lac repressor, and demonstrate its utility for controlling the expression of a transgene in bacteria, eukaryotic cells, and in the retina of mice. This ARES system is inducible by the small non-pharmacologic molecule, Isopropyl β-D-1-thiogalactopyranoside (IPTG) that has no off-target effects in mammals. Following subretinal injection of an adeno-associated virus (AAV) vector encoding ARES, luciferase expression can be reversibly controlled in the murine retina by oral delivery of IPTG over three induction-repression cycles. The ability to induce transgene expression repeatedly via administration of an oral inducer in vivo, suggests that this type of regulatory system holds great promise for applications in human gene therapy.
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.|Department of Biochemistry and Biophysics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sochor
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Vidyullatha
authors.initials: V
authors.lastname: Vasireddy
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Drivas
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Wojno
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Thu
authors.initials: T
authors.lastname: Doung
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Shpylchak
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bennicelli
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chung
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, F. M. Kirby Center for Molecular Ophthalmology, Philadelphia, PA 19104, USA.|Department of Biochemistry and Biophysics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Lewis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000008:administration & dosage; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D012160:Retina / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D019076:Transgenes
chemical_list: D007544:Isopropyl Thiogalactoside; D008156:Luciferases