Update on alpha-1 antitrypsin deficiency: new therapies

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin within the endoplasmic reticulum of hepatocytes. The retention of mutant protein causes hepatic damage and cirrhosis whilst the lack of an important circulating protease inhibitor predisposes the individuals with severe α1-antitrypsin deficiency to early onset emphysema. Our work over the past 25 years has led to new paradigms for the liver and lung disease associated with α1-antitrypsin deficiency. We review here the molecular pathology of the cirrhosis and emphysema associated with α1-antitrypsin deficiency and show how an understanding of this condition provided the paradigm for a wider group of disorders that we have termed the serpinopathies. The detailed understanding of the pathobiology of α1-antitrypsin deficiency has identified important disease mechanisms to target. As a result, several novel parallel and complementary therapeutic approaches are in development with some now in clinical trials. We provide an overview of these new therapies for the liver and lung disease associated with α1-antitrypsin deficiency

Chain-reaction Ca2+ signaling in the heart

Mutations in Ca2+-handling proteins in the heart have been linked to exercise-induced sudden cardiac death. The best characterized of these have been mutations in the cardiac Ca2+ release channel known as the ryanodine receptor type 2 (RyR2). RyR2 mutations cause “leaky” channels, resulting in diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) that can trigger fatal cardiac arrhythmias during stress. In this issue of the JCI, Song et al. show that mutations in the SR Ca2+-binding protein calsequestrin 2 (CASQ2) in mice result not only in reduced CASQ2 expression but also in a surprising, compensatory elevation in expression of both the Ca2+-binding protein calreticulin and RyR2, culminating in premature Ca2+ release from cardiac myocytes and stress-induced arrhythmia (see the related article beginning on page 1814). In the context of these findings and other recent reports studying CASQ2 mutations, we discuss how CASQ2 influences the properties of Ca2+-dependent regulation of RyR2 and how this contributes to cardiac arrhythmogenesis