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Science 4 February 2000:
Vol. 287. no. 5454, pp. 826 - 830
DOI: 10.1126/science.287.5454.826
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Research Articles

Regulation of Protein Secretion Through Controlled Aggregation in the Endoplasmic Reticulum

Victor M. Rivera, 1* Xiurong Wang, 1 Scott Wardwell, 1 Nancy L. Courage, 1 Allen Volchuk, 2 Terence Keenan, 1 Dennis A. Holt, 1 Michael Gilman, 1 Lelio Orci, 3 Frank Cerasoli Jr., 1 James E. Rothman, 2 Tim Clackson 1*

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.

1 ARIAD Gene Therapeutics, 26 Landsdowne Street, Cambridge, MA 02139, USA.
2 Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
3 Department of Morphology, University of Geneva Medical School, 1211 Geneva 4, Switzerland.
*   To whom correspondence should be addressed. E-mail: vrivera{at}ariad.com and clackson{at}ariad.com

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