Repurposing therapies for the personalised treatment of cystic fibrosis

ABSTRACT

Introduction: Cystic Fibrosis (CF) is an inherited, lethal and expensive rare disease affecting more than 85,000 people worldwide. CF is caused by more than 2000 loss-of-function mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Personalized interventions on individual CF patients probably constitute the future of CF management.

Areas covered: The molecular genetics exploration of CF has led in the last years to the development of mutation-specific therapies that aim at directly targeting the mutant CFTR to reverse disease phenotype. Here, we will summarize the strategies of drug repositioning, i.e. the use of ‘old drugs’ for ‘new purposes’ in the perspective of a personalized approach to CF treatment.

Expert opinion: Rare diseases like CF may well enter the era of precision medicine. A personalized/repositioning medicine in CF could help to provide the right drug to the right patient and potentially reduce the costs of developing disease-modifying drugs.

KEYWORDS:

• Cystic fibrosis
• drug repositioning
• precision medicine

Article highlights

• Repositioning of drugs already approved for the treatment of other human diseases is an emerging tool in drug discovery programs for rare diseases.

• A deep knowledge of the mechanisms of diseases is mandatory to identify disease-relevant target(s) of intervention.

• Searching (through in silico filtered approaches) “old drugs” or naturally occurring (over-the-counter) compounds with established safety profiles that are putatively affecting pathogenically relevant targets could facilitate the identification of compounds for in vitro and in vivo validation.

• Selecting appropriate preclinical models is mandatory for the validation of candidate drugs

• CF therapies are afflicted by a high variability in the response rate to treatment, even in patients bearing the same CFTR mutations.

• A personalized approach to treatment may represent the ideal way to test the efficacy of candidate drugs in CF as well as in other rare diseases.

• Mutation-specific therapies that aim at targeting the mutant CFTR, can be viewed as an example of stratified medicine, which is the level of treatment between empirical and true personalized medicine.

• The paradigm of precision medicine posits that treatments should benefit patients and not disease, by targeting the right medicine to the right patient in the right time frame.

• CF is ideally placed to allow a personalized approach to therapy, provided that appropriate biomarkers are identified. These biomarkers should either predict individual patient’s responsiveness before in vivo treatment and monitor the response to the therapy in vivo before clinical benefits become evident.

• CFTR does not act as a pure ion chloride channel, but it can be considered as a hub protein for a PN, which influences multiple cellular functions and major cellular platforms, including autophagy. The loss of a functional CFTR generates oxidative stress, TG2 activation, and disables autophagy.

• Targeting TG2 and autophagy, as well as the disordered phosphoproteome, may be a useful strategy to circumvent CFTR defect though repurposed drugs and/or over-the-counter nutraceutical.

• The combination of cysteamine and EGCG is an example of how a repositioning strategy could benefit rare diseases.

• Repositioning of approved drugs with new indications for rare diseases that lack effective treatment could have benefits over innovative treatments in terms of time and cost.

• The repositioning strategy in CF could be viewed as a general strategy for the adjuvant treatment of other rare unrelated diseases that, as true for CF, are linked to a mismanaged proteostasis network. This applies in particular to conformational diseases as some neurodegenerative diseases or lysosomal storage disorders.

This box summarizes key points contained in the article.

Declaration of interests

L Maiuri, G Kroemer and V Raia are listed as inventors on a patent application (No. 13/895,741) owned by the No-profit Foundation European Institute for Research in Cystic Fibrosis, describing the use of cysteamine for the treatment of CF. The authors have no other 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 apart from those disclosed.

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

Additional information

Funding

This paper was not funded.