Gene Therapy for Cystic Fibrosis

Abstract

Cystic Fibrosis (CF) is an autosomal recessive disorder due to mutations in the CF transmembrane conductance regulator (CFTR) gene that lead to defective ion transport in the conducting pulmonary airways and exocrine glands. Through a process that is not fully understood, CFTR defects predispose affected patients to chronic endobronchial infections with organisms such as Pseudomonas aeruginosa and Staphylococcus aureus. Following the discovery of the CFTR gene in 1989, CF became one of the primary targets for gene therapy research. Early enthusiasm surrounded the new field of gene therapy during most of the 1990s and it led academics and clinicians on a big effort to apply gene therapy for cystic fibrosis. Clinical studies have been pursued using recombinant adenovirus, recombinant adeno-associated virus, cationic liposomes, and cationic polymer vectors. Although to this date no dramatic therapeutic benefits have been observed, a lot of information has been gained from the pre-clinical and clinical studies that were performed. This learning curve has led to the optimization of vector technology and an appreciation of immune and mechanical barriers that have to be overcome for successful delivery.

The Importance of the M470V Polymorphism

“…M470 and the combined V frequency are seen in the subSaharan Africa. Although there was polymorphism, M470V may cause clinical issues, such as congenital bilateral absence of the vas deferens in Chinese males (2,4,5) .…”

“…The frequency of the disease show significant differences between ethnical groups and countries due to the autosomal recessive inheritance because of consanguineous marriage, (1,(5)(6)(7) . In this study, we aimed to investigate the clinical importance of M470V mutation in the Antiochia region (ancient commercial center and capital of Syria; an early center of Christianity) a region with frequent consanguineous marriages due to ethnical reasons.…”

Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy

“…[32][33][34] These failures are likely due to several issues, including (1) the lack of efficient gene transfer to cellular targets required to correct in vivo CFTR function, 35 (2) the animal models in which various preclinical vectors were tested, [36][37][38][39] and (3) previously unknown intracellular and extracellular barriers that limit viral transduction. [40][41][42][43] Basic research on airway biology has found that gene delivery to airway epithelial cells in vivo must overcome a number of intracellular and extracellular barriers that physically or biologically hinder the delivery of DNA or viral vectors to the nucleus, 40,41,44,45 or target clearance of the vectors or infected cells through host immune surveillance. [46][47][48][49][50][51] Importantly, lung infection and inflammation in CF lung disease enhance these barriers.…”

A Novel Pancreatropic Coxsackievirus Vector Expressing Glucagon-Like Peptide 1 Reduces Hyperglycemia in Streptozotocin-Treated Mice

“…In particular, vector integration is a double-edged sword, allowing longer expression of the gene in question but associated with hazards that are not always predictable (38,46,47). Despite this, when the goal is gene replacement for a patient with a potentially lethal genetic disease, integrating vectors such as lentiviruses (5,9), adenoviruses, and adeno-associated viruses (31,42,45) have received the most attention, as lifelong expression is necessary. However, for other situations, short-term therapy using a nonintegrating vector is a safer option (24,37).…”