Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus

Rachmiel, Marianna; Strauss, Pnina; Dror, Nitzan; Benzaquen, Hadassa; Horesh, Orit; Tov, Nave; Weintrob, Naomi; Landau, Zohar; Ben‐Ami, Michal; Haim, Alon; Phillip, Moshe; Bistritzer, Tzvy; Lewis, Eli C.; Lebenthal, Yael

doi:10.1111/pedi.12283

Cited by 31 publications

(24 citation statements)

References 32 publications

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“…Currently, clinical trials with hAAT are performed in acute graft-versus-host disease (GvHD), diabetes mellitus type I, and acute myocardial infarction. Preliminary results from trials in type 1 diabetes patients indicate that hAAT was safe and well-tolerated in pediatric subjects [ 62 ], and improved β-cell function reducing the need for insulin after hAAT treatment in recently diagnosed patients [ 63 ]. In addition, administration of Prolastin ® in patients with ST-segment elevation myocardial infarction was also well-tolerated and decreased the acute inflammatory response [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

et al. 2017

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Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

et al. 2017

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“…Administered in the early stages of these pathologies, hAAT appears to shift the profile of the immune system toward tolerance (Lewis et al, 2008a; Koulmanda et al, 2014). These studies provided the rationale for the use of hAAT infusions for patients with T1D (Gottlieb et al, 2014; Rachmiel et al, 2016) and for clinical islet transplantation, as reviewed (Fleixo-Lima et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

“…Administering hAAT to humans once a week is the equivalent of administering hAAT to mice every 3 days (Lewis et al, 2005). Based on this frequency of infusions, 21 days of treatment (6 infusions in mice) were established as sufficient to achieve immune tolerance (Lewis et al, 2008a), hence the 8–18 infusions in the T1D trials (Gottlieb et al, 2014; Rachmiel et al, 2016). Based on the present results, however, it is possible that future trials may explore a shorter course of hAAT, provided it is distributed so as to better overlap a physiologic acute phase response.…”

Section: Discussionmentioning

confidence: 99%

Exploration ofα1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

Baranovski

Ozeri

Shahaf

et al. 2016

J Pharmacol Exp Ther

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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.

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“…AAT therapy (80 mg/kg/dose) was reported to be beneficial to β-cell function in adult type 1 diabetic patients [ 39 ]. Rachmiel et al [ 40 ] reported that AAT treatment was feasible, without serious adverse complications, and improved glycemic control and serum peak c-peptide levels in pediatric patients with recently diagnosed autoimmune diabetes during a 37-week study period. Currently, 2 phase III, double-blind, randomized, placebocontrolled trials enrolling type 1 diabetic patients at the time of onset are underway [ 40 ], and research into the function of AAT in diabetes is ongoing ( Table 1 ).…”

Section: Overview Of Aat Therapymentioning

confidence: 99%

Therapeutic potential of alpha-1 antitrypsin in human disease

Kim

Cai

2018

Ann Pediatr Endocrinol Metab

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Alpha-1 antitrypsin (AAT), an alpha globulin glycoprotein, is a member of the serine protease inhibitor (serpin) superfamily. The clinical significance of AAT is highlighted by AAT deficiency. Genetic deficiency of AAT can present as several neutrophilic diseases associated with emphysema, liver cirrhosis, panniculitis, and systemic vasculitis. Recently, animal and human studies have shown that AAT can control inflammatory, immunological, and tissue-protective responses. In addition, AAT treatment can prevent overt hyperglycemia, increase insulin secretion, and reduce cytokine-mediated apoptosis of pancreatic β-cells in diabetes. These multifunctional roles of AAT draw attention to the glycoprotein’s therapeutic potential for many inflammatory and autoimmune diseases beyond AAT deficiency. As underlying mechanisms, recent studies have suggested the importance of serine protease inhibitory activity of AAT in obesity-associated insulin resistance, chronic obstructive pulmonary disease, and cystic fibrosis. In this review, we explore the multiple functions of AAT, in particular, the anti-inflammatory and serine protease inhibitory functions, and AAT’s therapeutic potential in a variety of human diseases through published literature.

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Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus

Abstract: 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.

Cited by 31 publications

References 32 publications

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

Exploration ofα1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

Therapeutic potential of alpha-1 antitrypsin in human disease

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