title: Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum.
abstract: A system for direct pharmacologic control of protein secretion was developed to allow rapid and pulsatile delivery of therapeutic proteins. A protein was engineered so that it accumulated as aggregates in the endoplasmic reticulum. Secretion was then stimulated by a synthetic small-molecule drug that induces protein disaggregation. Rapid and transient secretion of growth hormone and insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion resulted in a transient correction of serum glucose concentrations in a mouse model of hyperglycemia. This approach may make gene therapy a viable method for delivery of polypeptides that require rapid and regulated delivery.
authors.affiliation: ARIAD Gene Therapeutics, 26 Landsdowne Street, Cambridge, MA 02139, USA. vrivera@ariad.com
authors.forename: V M
authors.initials: VM
authors.lastname: Rivera
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Wardwell
authors.forename: N L
authors.initials: NL
authors.lastname: Courage
authors.forename: A
authors.initials: A
authors.lastname: Volchuk
authors.forename: T
authors.initials: T
authors.lastname: Keenan
authors.forename: D A
authors.initials: DA
authors.lastname: Holt
authors.forename: M
authors.initials: M
authors.lastname: Gilman
authors.forename: L
authors.initials: L
authors.lastname: Orci
authors.forename: F
authors.initials: F
authors.lastname: Cerasoli
authors.forename: J E
authors.initials: JE
authors.lastname: Rothman
authors.forename: T
authors.initials: T
authors.lastname: Clackson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D016503:Drug Delivery Systems; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D045683:Furin; D015316:Genetic Therapy; D006056:Golgi Apparatus / Q000378:metabolism; D019382:Human Growth Hormone / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020104:Immunophilins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007700:Kinetics; D008024:Ligands; D051379:Mice; D011384:Proinsulin / Q000737:chemistry / Q000378:metabolism; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000378:metabolism*; D013381:Subtilisins / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D014407:Tumor Cells, Cultured
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008024:Ligands; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; D011384:Proinsulin; D013381:Subtilisins; D045683:Furin; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins