AAT treatment was safe and well tolerated in pediatric subjects with recently diagnosed autoimmune diabetes. Placebo-controlled studies with larger cohorts and dose range are warranted in order to assess efficacy in maintaining pancreatic beta cell reserve and glycemic control.

Utilizing endogenous molecules as a therapeutic approach is almost unequivocally superior to engineered or synthetic molecules. However, one rarely encounters an anti-inflammatory, cytoprotective, immunomodulatory and wound-healing molecule that has been available for use for decades. α1-antitrypsin (AAT), a circulating protein that rises more than 4-fold during acute-phase responses, has been administered for a rare genetic deficiency at large doses, for life. Aside from advances in insulin therapy, medical research in type 1 diabetes (T1D) has predominantly focused on autoimmunity-controlling the adaptive immune response. However, it is now appreciated that one may need to extend therapeutic targets to incorporate immune responses to cellular injury, as well as promote selective control over excessive inflammation and early tissue repair. Recent data suggest that tissue damage related to lung and renal ischemia-reperfusion injury, stroke, and ischemic heart disease is markedly reduced by AAT. AAT was also shown to protect pancreatic islet β cells at multiple levels. Unlike classic immunosuppressive and anti-inflammatory approaches, AAT exerts some antiviral and antibacterial activities. Based on these and other reports, AAT is under evaluation for treatment of T1D patients in multiple clinical trials. Initial results suggest that AAT therapy could potentially improve insulin production without adverse effects. Up to 50% of individuals displayed improved islet function. It is a rare occurrence in T1D research that a therapy is offered that holds a safety profile equal or superior to that of insulin alone. While placebo-controlled trials are ongoing, the mechanism(s) behind these favorable activities of AAT are still being explored.

Maintaining serum levels of alpha-1-proteinase inhibitor (A1PI) >11 μM by augmentation with plasma-derived human A1PI is currently the only specific therapy available to treat patients with the genetic deficiency of A1PI. In this study, a new, high-purity (≥90% A1PI in monomeric form), ready-to-use, liquid formulation of A1PI-GLASSIA (Kamada, Ness Ziona, Israel) was compared to PROLASTINÆ (Talecris, Research Triangle Park, NC, now Grifols), both commercially available, FDA-approved products. This multicenter, double-blind, randomized controlled trial with partial cross-over was designed to test the non-inferiority and safety of GLASSIA compared to PROLASTIN, assessing both antigenic and functional A1PI trough levels in subject serum. Non-inferiority of GLASSIA to PROLASTIN was demonstrated by remaining within the lower bounds of the confidence intervals (≤3 μM) for both antigenic and functional A1PI. The study concluded that GLASSIA, a new liquid, ready to use, formulation of A1PI, was not inferior to PROLASTIN and it was well tolerated with a safety profile comparable to PROLASTIN.

Lifelong 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. 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 islet-related 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 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 toward an extended list of clinical indications outside genetic AATD.

diabetische Schwerhorigkeit", in seiner Abgrenzung oder gar in seiner Häufigkeit etwa der diabetischen Retinopathie vergleichbar, ist nicht bekannt. Zahlreiche Untersucher+ haben vor allem wegen der ausgepragten Mikro-und Makroangiopathie des zuckerkranken Menschen vermutet, daL Horverminclerungen beim Diabetiker als Folge seiner Krankheit auftreten. Die HNO-ärztliche Untersuchung zuckerkranker Patienten hat widersprüchliche Ergebnisse gezeigt (40, 51, 55, 69, 78). Die histologische Aufarbeitung von Felsenbeinen zuckerkranker Menschen ergab Hinweise auf Gefaveranderungen, wie sic als Mikroangiopathie in anderen Organen beschrieben sind (36, 38, 51, 75). Eine Untersuchung, die systematisch den vor dem Tode bestimm ten Hörverlust beim Diabetiker zu den mikroskopisch im Felsenbein nachweisbaren Veränderungen in Bezug setzt, fehit. Hier liegen nur Einzelbeobachtungen vor. Ebenso fehlen Untersuchungen an diabetischen