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Cystic Fibrosis Treatment: New 'Amplifier' Drug Enhances Orkambi(R) Response

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Cystic Fibrosis is a genetic disorder estimated to affected 70,000 to 100,000 people globally, although the actual number is probably far higher. 

Sufferers of the condition produce abnormally thick mucus throughout their body, which obstructs breathing in their lungs and affects digestion by hindering the pancreas.

This video from the Cystic Fibrosis Trust, UK, explains more about the condition.

Cystic Fibrosis is an autosomal recessive disorder in which the sufferer inherits a mutation-bearing copy of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene from each parent.

Two drugs, Kalydeco® and Orkambi®, are approved for the treatment of Cystic Fibrosis, however, they are not effective in all patients.

We caught up with Dr Steven Molinski and Prof. Christine Bear at the SickKids Research Institute, Ca, who explain why the latter of these drugs is not effective in some CF cases, and also tell us how their recently published research is improving drug discovery efforts for CF sufferers.

1. In a few sentences could you provide a non-technical summary of your research findings?

Our team provided the first evidence for the effectiveness of a new investigational Cystic Fibrosis (CF) 'amplifier' compound in enhancing the response of the current treatment (Orkambi®, developed for patients with the most common mutation: ΔF508) in tissue from patients with a rare CFTR mutation. To do this, we comprehensively studied a rare CF‐causing mutation: c.3700 A>G (ΔI1234_R1239), and showed that this variant exhibited several defects at the protein level which could be partially repaired using Orkambi® in laboratory cell lines. Yet, the rescue with this treatment was minimal in nasal cells from patients with this mutation. Interestingly, the nasal cells revealed an additional defect, namely reduced abundance of the mutant protein, a defect that was recapitulated in a new lung cell line wherein the CFTR gene was edited (by CRISPR/Cas9) to bear the specific rare mutation. This new cell line permits screening of hundreds to thousands of new potential therapies for this mutant in a relevant cell type.  In a partnership with the company – Proteostasis Therapeutics, we found that an investigational intervention aimed at enhancing CFTR protein abundance, improved the rescue effect of the approved drug Orkambi®.  We showed this rescue effect, first in the edited cell line and then in nasal cells from the individuals with this rare mutation.

2. Why did you carry out this study? -What was the unmet medical need that needed addressing?

Two drugs have been approved for the treatment of CF patients bearing specific CFTR gene mutations. Unfortunately, more than half the total CF patient population does not yet have access to approved drugs because of the nature of the CFTR mutation. A major challenge in the field is to determine how many other patients, bearing rare mutations, could benefit from the approved drugs. Computer simulations and biochemical studies of such mutant proteins in a laboratory setting are effective in defining the molecular basis for disease and the potential response to certain drugs. Yet, it is well recognized in the field that the drug responses observed in laboratory cell lines are not always recapitulated in patient‐derived tissues with fidelity. Hence, relevant cellular models of rare CF‐causing mutations are required to enable effective testing of approved drugs (i.e. lumacaftor and ivacaftor, or Orkambi®) and to evaluate companion therapies with the potential to enhance the effectiveness of approved drugs.

3. What experiments did you undertake and what were the key findings of the paper? 

We used a multi-disciplinary approach in our study, including: computer simulations, drug testing in standard cell lines and novel genetically-engineered (CRISPR/Cas9) cell lines, as well as validation of drug combinations in patient tissue. The main strength of our approach is that we could comprehensively interrogate and thus understand the molecular defects exhibited by this rare CF mutation in generic laboratory cell lines, in an edited lung cell line and in tissues from individuals. These same tissues showed that combination of an investigational compound (an “amplifier”) may be necessary in order to boost the response of the approved CF drug -Orkambi®, in individuals with this mutation.

4. What do your findings mean for sufferers of cystic fibrosis?

This study is significant in that we describe new cell-based strategies (one created by gene editing) to understand the response of rare CF-causing mutations to existing drugs and to test new interventions when necessary. Accordingly, our study provides a strategy to further facilitate therapy development for all patients with rare CF mutations.

5. What are your future research plans and what are the challenges for Cystic Fibrosis research you hope to overcome?

Next steps for this research include using our multi-disciplinary approach for novel, mutation-specific drug development and thus personalized medicine for individuals with other less common CF mutations. By studying rare CF-causing mutations, including c.3700 A>G (ΔI1234_R1239) as described in this report, we are learning more about how to “repair” various defects in CFTR protein, to achieve our goal of identifying drugs that have the potential to become cost-effective therapies that will enhance the quality of life for all individuals living with CF.