2020-05-13| In-Depth

An Outlook on the Evolution of Cystic Fibrosis Care

by Pavel Ryzhov
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Cystic Fibrosis (CF) is an inherited genetic disease, affecting nearly 30,000 people in the US with almost 1,000 new cases registered every year. It is a leading autosomal recessive disorder among Caucasians and is characterized by a progressive decline in respiratory and digestive systems. CF is a result of defective mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene on Chromosome 7. Carriers of the disease have one normal gene copy to compensate for the defect. However, CF patients are those who have inherited two defective copies from parents who are both carriers.

The CFTR protein belongs to the ATB binding cassette (ABC) transporter superfamily. It is a chloride channel that maintains the salt and water balance. A dysfunctional protein causes dehydration and leads to the production of thick, sticky mucus obstructing the lungs and pancreas. This leads to a significant reduction in the quality of life (QoL) and life expectancy (LE). The progress in our understanding of genetic causes and extensive R&D efforts has led to the entry of various drugs that increases both QoL and LE. In addition, gene therapy is also currently explored as a potential cure for patients.

The current COVID-19 pandemic has added a new level of uncertainty and distress. Respiratory troubles put CF patients at higher risk of developing severe complications on contracting SARS-CoV-2 infection. Therefore, stricter precautions (travel restrictions, self-isolation measures, telemedicine checkups) are recommended by the CDC for the foreseeable future.


The Early Years

Before the 1930s, cystic fibrosis (CF) was not recognized as a single disease. However, reports dating back to the seventeenth century described cases of children with “sweaty brows“. The chloride content of sweat is one of the recognized biomarkers used today for diagnosis. Earlier reports have also described pancreatic cysts and chronic lung disease among infants and children.

In 1938, Dr. Dorothy Andersen published a seminal paper, “Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study” that described the dramatic changes in the pancreas of affected children. Furthermore, she identified the autosomal recessive nature of CF inheritance. Later, in 1945, Dr. Sidney Farber coined the term “mucoviscidosis”, and expanded the understanding of CF to general problems in mucus production.

In the next four decades, no underlying molecular mechanisms (CF-factor) were identified. However, with the advent of novel antibiotics, other treatment options became available. In addition, changes in nutrition, supplementation of the diet with various types of pancreatic enzymes, and rigorous physical therapy contributed to improved patient outcomes like increased life expectancy past childhood. Besides Newborn screening programs are in place in many countries for the early detection of CF.


Discovery of Causative Gene

In the 1980s, the discovery of abnormal transepithelial electrolyte transport function in newborns led researchers to narrow it down to chloride ion impermeability in the sweat ducts. Advances in the field of Genetics led to the identification of the CFTR gene in the year 1989, linking both genomic and phenotypic data.

The hallmark discovery of CFTR protein paved the way for the identification of over 1,000 gene mutations. The most common mutation is F508del (88%), which causes the protein to misfold, ablating its transporter function. Other identified mutations were found to decrease the efficiency of the channel gate. For instance, the nonsense mutations (leading to shorter protein products after translation from mRNA) reduced the quantity of available protein on the cell surface.


Symptomatic Therapies

With the advances in medical interventions, life expectancy has continued to increase into the 40s or 50s as compared to a century ago where the majority of patients did not survive past childhood.

The discovery of CF as a standalone disease, together with the basic understanding of associated lung infections, came at the time when antibiotics became more available [1]. The introduction of penicillin and many subsequent antibiotics into the regular standard of care (SOC) resulted in dramatic improvements where some patients could survive into their adulthood. Although bacterial resistance and side-effects exist, the administration of prophylactic antibiotics is common-place even today.

Due to the obstruction of the pancreatic ducts, the secretion of trypsin, lipase, and other essential digestive enzymes are severely affected in CF patients. As a result, they develop malabsorption and other digestive tract complications. To circumvent that, patients are put on a fat-restricted diet, which in turn severely limits their growth and development. The development of acid-resistant pancreatic enzymes eased some of the dietary restrictions. Improved versions like Ultresa, Creon, and others are routinely administered to patients today [2].


CFTR Modulators

Before the discovery of the CFTR gene, these aforementioned treatments did not significantly improve life expectancy or quality of life. Understanding the protein structure, complex enzymatic kinetics, and the various mutations, provided the basis for the development of novel therapeutics called CFTR modulators.

These small molecule drugs, developed by Vertex Pharmaceuticals have gained much praise for their efficacy in re-establishing the function of mutated protein either as a single drug (ivacaftor, Kalydeco®), or combination of two (lumacaftor/ivacaftor, Orkambi®, and tezacaftor/ivacaftor, Symdeko®) or three drugs (elexacaftor/tezacaftor/ivacaftor, Trikafta).


First Disease-Modifying Therapy

CFTR is an ion channel that moves chloride ions to the outside of the cell. Its transport function is made possible by the unique 3D shape it occupies. However, if the protein synthesis is halted due to a nonsense mutation, no full-length or stable protein product is produced. The occurrence of this type of mutation is ~5-10% and is called class I.

Even if CFTR is synthesized in its entirety, other mutations may decrease its function. The most common misfolding mutation, F508del, is found in up to 80% of CF patients (depending on homo- or heterozygotic character of that mutation) and is considered a class II mutation.

A mutation that disrupts the protein fold may decrease channel activity due to the preference for the closed state. G551D is one such mutation because it disrupts the ATP-dependent gating function of CFTR, which results in a 100x lower chance of open state as compared to wild-type (normal) protein. This type of mutation is called class III (or gating mutation), which accounts for ~6% of all CF cases.

The development of small molecule drugs began almost immediately after the protein was identified. After almost two decades of R&D that included the application of high-throughput screening, novel cell-based assay techniques (harvesting lung cells from CF patients) and multiple rounds of optimizations, the research team led by Dr. Paul Negulescu at Aurora Biosciences and later at Vertex Pharmaceuticals, arrived at the compound VX-770 (ivacaftor).

This compound showed potency in opening the closed state of the G551D mutant and is classified as a “potentiator” that restored the disrupted gating function. The oral, bioavailable form (that gained FDA approval in 2012 as Kalydeco®), was first demonstrated to rescue CF airway epithelial cell function in isolated cultured human CF bronchial epithelia and later validated across multiple clinical trials in adults and children [3,4]. Ultimately, this was a tremendous success story for Vertex, which developed first-in-class disease-modifying therapy for CF patients.


Combination Therapies

Despite the success of Kalydeco, the clinical application was restrictive to CF patients with heterozygous F508del mutation and was not applicable to a larger population. This was due to the highly specific nature of this “potentiator” molecule. However, concurrently Vertex scientists developed lumacaftor, which was shown to act as a corrector, improving the conformational stability of F508del mutant CFTR and allowing it to transport to the cell surface. Following the clinical trials [5,6], it gained FDA approval for a significantly larger CF patient population as Orkambi®.

This combination therapy of lumacaftor/ivacaftor encountered challenges in the form of drug-drug interactions. This was addressed by novel combination therapy with a different corrector molecule tezacaftor, which gained FDA approval in 2018 as tezacaftor/ivacaftor (Symdeko®) [7,8].


Triple Combination Therapy

In Symdeko, Vertex had a combination therapy that was able to address the CFTR trafficking and gating issues. However, it was not as successful in patients with F508del mutation. Therefore, the search for additional corrector molecules alongside this established therapy was necessary.

This effort resulted in the first-of-its-kind triple therapy combination involving elexacaftor (that has a different binding site on CFTR as compared to tezacaftor) [9,10]. This therapy provided compelling benefits in clinical trials and gained FDA nod in 2019 as Trikafta for patients >12 years with at least one F508 mutation. Trikafta could benefit ~90% of all CF patients. Currently, Vertex is seeking to expand the label to include younger patients in the ongoing clinical trials.


The Promise of Gene Therapy

With the introduction of Trikafta, a vast majority of CF patients now have access to disease-modifying medicines that help to address various issues with mutated CFTR. However, a small percentage of people ~10% cannot benefit from these previously approved therapies. This is because no CFTR is produced in these patients. This challenge is currently being addressed by the preclinical gene therapy efforts from Vertex and other companies.



Over the last hundred years, with the introduction of antibiotic treatments, dietary supplements, physiotherapy, and lately, various CFTR modulators, the life expectancy of CF patients has improved drastically. And despite the pandemic, the research into gene therapy approaches to treat and cure more CF patients is still ongoing. The future beholds great promise for these patients.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Cystic Fibrosis: ZFN Mediated Gene Editing Results in Functional CFTR Correction

  1. Editors: Hodson, M, et al. (2007) Cystic Fibrosis. p. 3-19
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