Exploration of alpha 1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

摘要

Lifelong weekly infusions of human alpha 1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Because the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for isletrelated injury. Islet-grafted mice were treated with hAAT (Glassia; intraperitoneally or subcutaneously) under an array of clinically relevant dosing plans. Serum hAAT and immunocyte cell membrane association were examined, as well as parameters of islet survival. Results indicate that dividing the commonly prescribed 60 mg/kg i.p. dose to three 20 mg/kg injections is superior in affording islet graft survival; in addition, a short dynamic descending dose protocol (240 -> 120 -> 60 -> 60 mg/kg i.p.) is comparable in outcomes to indefinite 60 mg/kg injections. Although pharmacokinetics after intraperitoneal administration in mice resembles exogenous hAAT treatment in humans, subcutaneous administration better imitated the physiologic progressive rise of hAAT during acute phase responses; nonetheless, only the 60 mg/kg dose depicted an advantage using the subcutaneous route. Taken together, this study provides a platform for extrapolating an isletrelevant clinical protocol from animal models that use hAAT to protect islets. In addition, the study places emphasis on outcome-oriented analyses of drug efficacy, particularly important when considering that hAAT is presently at an era of drug-repurposing toward an extended list of clinical indications outside genetic AATD.