Editorial: How Can We Target Pulmonary Inflammation in Cystic Fibrosis?

Editorial: How Can We Target Pulmonary Inflammation in Cystic Fibrosis

Developmental control of CFTR: from bioinformatics to novel therapeutic approaches.

miRNA-binding blocker oligonucleotides offer an appealing option for developing tools to correct CFTR function http://ow.ly/AjS8

High-throughput profiling for discovery of non-coding RNA biomarkers of lung disease.

In respiratory medicine there is a need for clinical biomarkers for diagnosis, prognosis and assessment of response to therapy. Noncoding RNA (ncRNA) is expressed in all human cells; two major classes - long ncRNA and microRNA - are detectable extracellularly in the circulation and other biofluids. Altered ncRNA expression is associated with lung disease; collectively this indicates that ncRNA represents a potential biomarker class. This article presents and compares existing platforms for detection and quantification of ncRNA, specifically hybridization, qRT-PCR and RNA sequencing, and outlines methods for data interpretation and normalization. Each approach has merits and shortcomings, which can affect the choice of method when embarking on a biomarker study. Biomarker properties and pre-analytical considerations for ncRNA profiling are also presented. Since a variety of profiling approaches are available, careful study and experimental design are important. Finally, challenges and goals for reliable, standardized high-throughput ncRNA profiling in biofluids as lung disease biomarkers are reviewed

Alpha-1 Antitrypsin Deficiency: Recent Developments in Gene Therapy Research

Alpha-1 antitrypsin (AAT) deficiency is a hereditary disorder associated with mutations in the SERPINA1 gene (Kelly et al., 2008; Greene et al., 2008). Over 100 different alleles have been identified however the most common disease-causing mutation, termed Z, encodes a glutamic acid to lysine substitution at position 342 of the mature AAT protein. As a member of the serine proteinase inhibitor family, the role of AAT is to inhibit serine proteases throughout the body but principally in the lung. The ZAAT protein fails to adopt the correct protein conformation and polymerises and accumulates intracellularly in AAT-producing cells. The liver is the major source of the body’s pool of AAT. The major consequences of ZAAT accumulation in hepatocytes are toxic gain of function events leading to endoplasmic reticulum (ER) expansion and dilation and activation of multiple ER stress signalling pathways (Lomas et al., 1992; Teckman & Perlmutter, 2000; Lawless et al., 2004; Hidvegi et al., 2005; Hidvegi et al., 2007; Miller et al., 2007). These predispose to liver failure. The second major clinical consequence of ZAAT deficiency is a lower than normal antiprotease protective screen throughout the body, but most importantly in the lung (Lomas et al., 1993). ZAAT deficient individuals can develop emphysematous lung disease as early as in their 4th decade. Gene therapies to treat both aspects of the disease are currently at various stages of development. For the liver disease approaches that can be considered include ribozymes, antisense, peptide nucleic acids and small-interfering RNAs; all designed to inhibit expression of the mutant gene (recently reviewed in McLean et al., 2009). For the lung disease gene therapies using non-viral, lentiviral and adeno-associated viral approaches to express the normal gene either locally or intramuscularly have been reported (Chulay et al., 2011; Brantly et al., 2006; Flotte et al., 2007; Argyros et al., 2008; Brantly et al., 2009; Liqun Wang et al., 2009); all aim to increase AAT levels in the circulation above the deficiency threshold of 11 μM. New approaches are focused on coupling haematopoietic stem cell therapy with AAT-lentiviral gene therapy (Ghaedi et al., 2010; Argyros et al., 2008). This chapter will review the history and current state-of-the-art in these areas.</p

Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition

Candida species in cystic fibrosis: A road less travelled.

Candida species are isolated with high frequency from cystic fibrosis patients, yet their definitive role in the disease remains unclear. Previously considered to have minimal inherent virulence owing to their commensal ability, the last decade has heralded an increasing recognition of Candida infection among patients with cystic fibrosis. What has been more recently hypothesized is that the organism possesses virulence factors that play diverse roles at different body sites during varied stages of an infection. Currently, limited data is accessible in the area of cystic fibrosis. This review aims to provide an overview of the role of Candida species in cystic fibrosis as it is currently understood including the common local and systemic infections observed in clinical practice. The uncertain role of airway colonization and insight into emerging fields such as Candida-bacterial interactions are also addressed. Finally, we outline the current understanding of the innate, cellular and humoral immune responses associated with this genus which has been the major focus of work performed to date