New Patient-Centric Approaches to the Management of Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed genetic predisposition for COPD and emphysema and other conditions, including liver disease. Although there have been improvements in terms of awareness of AATD and understanding of its treatment in recent years, current challenges center on optimizing detection and management of patients with AATD, and improving access to intravenous (IV) AAT therapy - the only available pharmacological intervention that can slow disease progression. However, as an orphan disease with geographically dispersed patients, international cooperation is essential to address these issues. To achieve this, new European initiatives in the form of the European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) have been established. These organizations are striving to address the current challenges in AATD, and provide a new platform for future research efforts in AATD. The first objectives of ERN-LUNG are to establish a quality control program for European AATD laboratories and create a disease management program for AATD, following the success of such programs in the United States. The main purpose of EARCO is to create a pan-European registry, with the aim of understanding the natural history of the disease and supporting the development of new treatment modalities in AATD and access to AAT therapy. Going further, other patient-centric initiatives involve improving the convenience of intravenous AAT therapy infusions through extended-interval dosing and self-administration. The present review will discuss the implementation of these initiatives and their potential contribution to the optimization of patient care in AATD.

Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method.

Recombinant adeno-associated virus (rAAV) vectors offer promise for gene therapy of alpha-1 antitrypsin (AAT) deficiency. A toxicology study in mice evaluated intramuscular injection of an rAAV vector expressing human AAT (rAAV-CB-hAAT) produced using a herpes simplex virus (HSV) complementation system or a plasmid transfection (TFX) method at doses of 3 × 10(11) vg (1.2 × 10(13) vg/kg) for both vectors and 2 × 10(12) vg (8 × 10(13) vg/kg) for the HSV-produced vector. The HSV-produced vector had favorable in vitro characteristics in terms of purity, efficiency of transduction, and hAAT expression. There were no significant differences in clinical findings or hematology and clinical chemistry values between test article and control groups and no gross pathology findings. Histopathological examination demonstrated minimal to mild changes in skeletal muscle at the injection site, consisting of focal chronic interstitial inflammation and muscle degeneration, regeneration, and vacuolization, in vector-injected animals. At the 3 × 10(11) vg dose, serum hAAT levels were higher with the HSV-produced vector than with the TFX-produced vector. With the higher dose of HSV-produced vector, the increase in serum hAAT levels was dose-proportional in females and greater than dose-proportional in males. Vector copy numbers in blood were highest 24 hr after dosing and declined thereafter, with no detectable copies present 90 days after dosing. Antibodies to hAAT were detected in almost all vector-treated animals, and antibodies to HSV were detected in most animals that received the highest vector dose. These results support continued development of rAAV-CB-hAAT for treatment of AAT deficiency.

AANA journal course. Update for nurse anesthetists--part 4--life in the balance: the role of serpins in disease genesis and prevention.

Complex biological systems are often shaped and maintained by opposing forces. A relevant biological example is the delicate balance between proteases and their inhibitors. Serine proteases contain a serine residue in the active site of the molecule that is essential to the activity of the enzyme. Protease inhibitors limit the activity of proteases in the body. As examples, aprotinin (Trasylol), a serine protease inhibitor, and aminocaproic acid (Amicar), a lysine protease inhibitor, are used to decrease the rate of fibrinolysis and have recently been the subject of considerable controversy in the literature regarding safety and efficacy. This AANA journal course reviews 2 common examples of protease inhibitor disorders, angioedema and a form of emphysema, that are of particular anesthetic relevance.

[Diagnosis and therapy of inheritable liver diseases: hemochromatisis, Wilson's disease and alpha-1-antitrypsin deficiency]. / Diagnostik und Therapie hereditärer Lebererkrankungen: Hämochromatose, M. Wilson, alpha1-antitrypsinmangel.

The recent years have seen significant progress in the area of genetically determined liver diseases. For hereditary hemochromatosis, Wilson's disease and alpha-1 antitrypsin deficiency the underlying genetic defects have been described and well characterized. Although a direct relationship between genetic defect and disease manifestation exists genetic test only have a limited diagnostic usefulness which requires exact knowledge of the underlying molecular pathology. The classical C282Y and H63D mutations of the HFE gene only show a penetrance of 10-20% in hemochromatosis and are not useful for population screening. Genetic screening for ATP7B (Wilson's disease) and alpha-1 antitrypsin deficiency variants is limited by the existence of a plethora of individual mutations. Genetic tests are mainly restricted to the counseling of families in whom these diseases are present. Foremost the diagnosis of the three diseases is reached by clinical, biochemical and in some instances also histological means which are supplemented and confirmed by the use of appropriate genetic tests.