Unmet needs in cystic fibrosis

ABSTRACT

Introduction: Cystic fibrosis (CF) is a multisystem illness caused by abnormalities in the CF transmembrane conductance regulator (CFTR) gene and protein. CFTR is an ion channel regulating transport of chloride, bicarbonate, and water, and influencing sodium resorption. It is inherited as an autosomal recessive disorder, and with about 70,000 CF patients worldwide, it is the most common life shortening disease among persons of European descent. CFTR disease-causing mutations have been organized into six classes.

Areas covered: Recently, small molecule targeted therapy for specific classes of CFTR abnormalities have included CFTR correctors that decrease protein degradation and CFTR potentiators that increase channel open probability enhancing chloride transport.

Expert opinion: Although there are many novel medications in preclinical and clinical testing, there is need for safe and effective CFTR modulating drugs and immunomodulatory medications to decrease the abundant neutrophilic inflammation response in the airway without unwanted adverse effects. Thymosin alpha 1 treatment of airway cells isolated from phe508del CF patients and from CF knockout mice, decreased inflammation, increased CFTR maturation, and facilitated translocation of CFTR protein to the plasma membrane increasing channel activity. If similar results are seen in humans with CF, thymosin alpha 1 has the unique potential to be a single molecule therapy for treating CF airway disease.

KEYWORDS:

• Airway clearance
• CF corrector
• CF modulator
• CF potentiator
• CFTR
• thymosin

Article highlights

• Despite significant advances in CF care, there is a need for effective anti-inflammatory therapy directed at neutrophil-dominated inflammation

• The introduction of ivacaftor and the combination of ivacaftor and lumacaftor have opened a new chapter in personalized medicine for CF by targeting specific CFTR protein defects. There are a large number of companies working on similar therapies.

• With these many novel therapies, there is a pressing need for comparative studies, studies of appropriate combination therapies, studies evaluating the long-term effects and effectiveness of these CFTR modifier therapies, and perhaps most impactful, studies introducing these novel therapies to neonate and infants with CF before there is significant airway infection and damage.

• There are data suggesting that thymosin alpha 1 may correct and potentiate (modify) phe.508del CFTR and also have anti-inflammatory properties

• With the future introduction of gene editing techniques, like CRISPR, to correct the abnormal CFTR gene, we need to understand how present therapies might be complementary.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper has been published as part of a supplement issue covering the proceedings of the Fifth International Symposium on Thymosins in Health and Disease and is funded by SciClone Pharmaceuticals.