Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights

Abstract

In cystic fibrosis (CF), mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupt the capacity of the encoded protein to function as a channel to transport chloride ions and water across cell membranes. The consequences are deleterious, system-wide, and immensely variable, even among patients with the same CFTR genotype. This underscores the need to characterize the mechanisms contributing to CF pathophysiology. Gene replacement and gene editing therapies have been pursued intensively and are expected to provide a one-time treatment for CF. However, gene replacement therapy is limited by the lack of efficient vectors to deliver functional copies of CFTR to cells without immunological complications, while gene editing technologies such as CRISPR/Cas9 are still in their infancy, mainly useful in somatic cells and limited by off-target insertions. Small molecule treatments targeted at potentiating or correcting CFTR have shown clinical benefits, but they are limited to a few CFTR mutations and insufficient to overcome challenges related to clinical heterogeneity. Transcriptome profiling approaches have emerged as robust tools capable of characterizing phenotypic variability and revealing novel molecular targets with therapeutic potential for CF. We summarize current insights gained through transcriptome profiling approaches in CF studies and recent advances in molecular therapeutics.

Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue

“…GSEA revealed 242 gene sets out of 1710 tested that were significantly enriched; 240 of them (99%) had positive scores indicating up-regulation. As expected, the enriched terms included many signaling pathways related to immune or inflammatory responses, such as "IL6 JAK STAT3 signaling", "TNFα signaling via NF-κB", "Toll-like receptor signaling", "Nodlike receptor signaling", and "Interferon gamma response", many of which were mentioned by Ideozu et al 18 . Other enrichments suggested increased levels of TGFβ signaling, MAPK signaling, and apoptosis.…”

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

“…In this intricate scenario, the integration of various biological knowledge could be an effective strategy to delineate molecular mechanisms contributing to the disease pathophysiology. Transcriptome and proteome profiling can be useful to reveal specific biological signatures, thus providing insights not only for the understanding of the pathomechanisms but also for the identification of reliable tools for therapeutic options [118,119,120,121,122].…”

Cystic fibrosis: current treatment and future direction

“…With gene replacement and gene editing approaches still in their infancy, transcriptome analysis have emerged as robust tools, with potential of determining phenotypic variability and providing novel molecular targets. 47 Microarray and RNA-sequencing are two important transcriptome profiling technologies that have proven powerful in deducing and quantifying transcriptomes in many CF studies. Microarray techniques are based on hybridization and focus on quantifying a predefined set of transcripts, whereas RNA-sequencing is sequence-based and performs an unbiased quantification of all transcripts within a cell even without prior knowledge of a particular gene.…”

“…A recent study carried out using neutrophils isolated from CF patients, identified 83 unique transcript isoforms which may be responsible for pulmonary exacerbations, providing us with some novel diagnostic and therapeutic targets. 47,51…”