Alpha-1 Antitrypsin Substitution for Extrapulmonary Conditions in Alpha-1 Antitrypsin Deficient Patients.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder which most commonly manifests as pulmonary emphysema. Accordingly, alpha-1 antitrypsin (AAT) augmentation therapy aims to reduce the progression of emphysema, as achieved by life-long weekly slow-drip infusions of plasma-derived affinity-purified human AAT. However, not all AATD patients will receive this therapy, due to either lack of medical coverage or low patient compliance. To circumvent these limitations, attempts are being made to develop lung-directed therapies, including inhaled AAT and locally-delivered AAT gene therapy. Lung transplantation is also an ultimate therapy option. Although less common, AATD patients also present with disease manifestations that extend beyond the lung, including vasculitis, diabetes and panniculitis, and appear to experience longer and more frequent hospitalization times and more frequent pneumonia bouts. In the past decade, new mechanism-based clinical indications for AAT therapy have surfaced, depicting a safe, anti-inflammatory, immunomodulatory and tissue-protective agent. Introduced to non-AATD individuals, AAT appears to provide relief from steroid-refractory graft-versus-host disease, from bacterial infections in cystic fibrosis and from autoimmune diabetes; preclinical studies show benefit also in multiple sclerosis, ulcerative colitis, rheumatoid arthritis, acute myocardial infarction and stroke, as well as ischemia-reperfusion injury and aberrant wound healing processes. While the current augmentation therapy is targeted towards treatment of emphysema, it is suggested that AATD patients may benefit from AAT augmentation therapy geared towards extrapulmonary pathologies as well. Thus, development of mechanism-based, context-specific AAT augmentation therapy protocols is encouraged. In the current review, we will discuss extrapulmonary manifestations of AATD and the potential of AAT augmentation therapy for these conditions.

Exploration of α1-antitrypsin treatment protocol for islet transplantation: dosing plan and route of administration.

Life-long weekly infusions of human α1-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. Since 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 islet-related injury. Islet-grafted mice were treated with hAAT (Glassia™; i.p. or s.c.) 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. While hAAT pharmacokinetics after i.p. administration in mice resembles exogenous hAAT treatment in humans, s.c. administration better imitated the physiological progressive rise of hAAT during acute phase responses; nonetheless, only the 60 mg/kg dose depicted an advantage using the s.c. route. Taken together, this study provides a platform for extrapolating an islet-relevant 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 towards an extended list of clinical indications outside genetic AATD.