Science · 2000 · 344 citations · 29 references
PharmacyPharmaceutical BiotechnologyPharmaceuticsDrug DeliveryGene TherapyProtein EngineeringGene Delivery SystemsGene Delivery VectorsGrowth HormoneHormone SecretionProtein DeliveryTherapeutic Protein EngineeringDisaggregation MechanismsGlucose-stimulated Insulin SecretionProtein Delivery CarriersProtein Secretion EngineeringProtein Secretion SystemsPulsatile Drug ReleasePulsatile Hormone ReleaseTherapeutic Proteins
A system was developed to directly control protein secretion pharmacologically, enabling rapid and pulsatile delivery of therapeutic proteins. An engineered protein that aggregates in the ER is disaggregated by a synthetic small‑molecule drug to trigger secretion. Rapid, transient secretion of growth hormone and insulin was achieved in vitro and in vivo, and a pulse of insulin transiently corrected serum glucose in a hyperglycemic mouse, suggesting this method could enable gene therapy for polypeptides requiring rapid, regulated delivery.
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.
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