Rivera V M, Wang X, Wardwell S, Courage N L, Volchuk A, Keenan T, Holt D A, Gilman M, Orci L, Cerasoli F, Rothman J E, Clackson T
ARIAD Gene Therapeutics, 26 Landsdowne Street, Cambridge, MA 02139, USA.
Science. 2000 Feb 4;287(5454):826-30. doi: 10.1126/science.287.5454.826.
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.
开发了一种用于直接药理控制蛋白质分泌的系统，以实现治疗性蛋白质的快速和脉冲式递送。对一种蛋白质进行工程改造，使其在内质网中以聚集体形式积累。然后通过诱导蛋白质解聚的合成小分子药物刺激分泌。在体外和体内均实现了生长激素和胰岛素的快速和瞬时分泌。在高血糖小鼠模型中，胰岛素分泌的调节脉冲导致血清葡萄糖浓度的瞬时校正。这种方法可能使基因治疗成为递送需要快速和调节递送的多肽的可行方法。
