Publication Date:
2000-02-05
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rivera, V M -- Wang, X -- Wardwell, S -- Courage, N L -- Volchuk, A -- Keenan, T -- Holt, D A -- Gilman, M -- Orci, L -- Cerasoli, F Jr -- Rothman, J E -- Clackson, T -- New York, N.Y. -- Science. 2000 Feb 4;287(5454):826-30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ARIAD Gene Therapeutics, 26 Landsdowne Street, Cambridge, MA 02139, USA. vrivera@ariad.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10657290" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Blood Glucose/metabolism
;
Cell Line
;
Diabetes Mellitus, Experimental/drug therapy/metabolism
;
Drug Delivery Systems
;
Endoplasmic Reticulum/*metabolism/secretion
;
Furin
;
Genetic Therapy
;
Golgi Apparatus/metabolism
;
Human Growth Hormone/chemistry/metabolism/secretion
;
Humans
;
Immunophilins/chemistry/genetics/metabolism
;
Insulin/secretion
;
Kinetics
;
Ligands
;
Mice
;
Proinsulin/chemistry/metabolism
;
Protein Engineering
;
Recombinant Fusion Proteins/*chemistry/*metabolism/secretion
;
Subtilisins/metabolism
;
Tacrolimus Binding Proteins
;
Tumor Cells, Cultured
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
