Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum.
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.
Rivera
V M
VM
ARIAD Gene Therapeutics, 26 Landsdowne Street, Cambridge, MA 02139, USA. vrivera@ariad.com
Wang
X
X
Wardwell
S
S
Courage
N L
NL
Volchuk
A
A
Keenan
T
T
Holt
D A
DA
Gilman
M
M
Orci
L
L
Cerasoli
F
F
Rothman
J E
JE
Clackson
T
T
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
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