Curing Cystic Fibrosis (CF) once seemed so simple. Yet, decades later, we are still striving to cure all patients afflicted with CF.
Introduction
You may remember Cystic Fibrosis from your Genetics 101 course—it is often used as a classic example of a recessive monogenic disease. And yet, as with so many things that seem simple at the outset, especially in science, the past thirty-five years have taught us a lot about the complicated disease that is CF.
A majority of CF morbidity and mortality is due to decreased lung function [1]. Physiologically, mutations in an ion channel prevent it from working properly, which causes sticky, thick mucus to build up and not be cleared from the lungs. This mucus traps bacteria, promoting lung infections and eventually impeding lung function. Besides a decrease in lung function, patients with Cystic fibrosis also have pancreatic, renal, liver, gastrointestinal and fertility complications [2].
Although it may have a simple genetic cause, finding a cure for all patients has proven much more challenging than expected. Diverse genetic causes of unique cell biological outcomes mean the research and clinical communities will need to be more creative to fully cure CF.
Tell me about this rare disease
Genetic basis: Cystic fibrosis is caused when one individual has two loss of function mutations in the CFTR (cystic fibrosis transmembrane receptor) gene. It is categorized as a rare recessive genetic disease. CFTR protein is a chloride channel found in the apical surface of epithelial cells. The epithelia particularly affected in CF are of the
respiratory tract and gastrointestinal systems, although other organs are also affected. Clinically, CF-causing mutations are
divided into “theratypes” that describe how the mutation affects protein function. These classifications are relevant to understand which mutations have targeted therapeutics and which do not [3] [4].
Incidence: Nearly 105,000 people
worldwide and 40,000 people in the United States [5].
Geographical locale of patients: CF is more common in people of white European descent, but it affects people of all racial and ethnic backgrounds.
Brief history:
1938: Cystic fibrosis is named in a publication by Doctor Dorothy Andersen [6]
1989: CFTR mutations are discovered as the molecular cause of the disease [7] [8] [9]
1993: The FDA approves the first drug specifically designed for CF, Pulmozyme [10]
2010: Universal newborn screening for (the most common mutations that cause) CF is required in all 50 states [10]
2012: The first CFTR-targeted drug, ivacaftor, was approved by the FDA
2019: A historic FDA approval of a triple combination therapeutic for patients with at least one copy of the most common mutation, F508del.
The state of the disease today: A growing number of patients with CF have therapeutics available to them that alleviate their symptoms and treat the underlying genetic cause of their disease. However, there remains a group of CF patients with no molecularly targeted drug. New complications and treatment challenges arise as the worldwide CF population ages.
What is it like to be a patient with this disease?
Who are the patients? Cystic fibrosis used to be exclusively a pediatric disease. However, with improvements to diagnosis, treatments and care, the average age of all people with CF is in their 40’s in some developed countries and over half, a majority, of patients are over the age of 18 [11]. As the CF population ages, new challenges arise for these patients and the research and clinical communities that support them [2] [12].
What do current treatment options look like? Although drugs exist, the life of a CF patient is still dominated by treatment regimens, with hours every day spent using inhalers, nebulizers, vibrating vests, and taking dozens of pills and vitamins. A growing number of drug options treat the underlying protein defect in CFTR [2]. These CFTR-modulating drugs are still paired with more “traditional” approaches to best improve quality of life.
Are there advocacy groups? Yes, many. The largest in the US is the Cystic Fibrosis Foundation. Other North American advocacy groups include the CF Research Institute, Cystic Fibrosis Canada, and Vertex Pharmaceuticals’ patient advocacy group. The European Cystic Fibrosis Society is the main group in Europe. Other countries also have their own CF advocacy groups. Worldwide, these groups have access to critical reagents for basic science, care centers for running clinical studies, fund basic, clinical and social studies related to the disease, and support a vast network of patients, their families, physicians, caregivers and researchers.
Are there genetic tests available? Yes. In the United States, there is mandatory newborn screening in place in all 50 states for the most common mutations that cause CF. Additionally, over 2000 causative mutations in CFTR have been documented [13]. If a patient and/or physician suspect CF, a sweat chloride test is performed for diagnosis and the CFTR gene can be sequenced to determine causative mutations.
Other factors influencing life with CF? In addition to the CF-causing mutations in CFTR, the research community is learning more about “CF modulating mutations” that, although they do not cause CF, alter the severity, symptoms and thus everyday life for CF patients. There are no targeted therapies available for CF modulating mutations.
Life with CF has been called “cyclical”. Patients go through periods of decent health when they can do many things as in a “normal” life, while they follow their intense treatment regimens. Then come times of pulmonary exacerbations, infections, hospitalization and isolations. The CF community is actively addressing the mental health challenges of this chronic, life-shortening disease [14] [15].
How do researchers and clinicians study this disease?
What are the major challenges facing this disease? For the entire CF community, a major challenge toward developing therapeutics for all patients is the lack of good animal models (see next point). For clinicians and caregivers, the high burden of treatment makes adhering to treatment regimens challenging in this historically pediatric population. For patients for whom there is no targeted therapeutic, establishing and making available model systems of their mutation to test possible drug candidates is greatly needed. Additionally, challenges remain unknown and newly identified as the Cystic Fibrosis population lives longer.
Are there any (good) model systems scientists can use to develop drugs? There are many model systems that recapitulate at least parts of CF. However, major hurdles and shortcomings exist with many of them.
Mouse models exist, but mice have very different lung structure and symptoms with loss of CFTR than humans. Porcine and ferret models are in use but are not widespread and require specific expertise and facilities.
Cell models also exist, are improving and track well with some clinical parameters. The cell culture conditions and techniques needed also require special expertise and/or training, specific equipment and are labor and time intensive.
Importantly, there is a tremendous lack of accessible models for the rarer mutations that cause CF. For example, a set of mutations that cause CF are the result of nonsense mutations in the gene. About 10% of all CF patients have at least one nonsense mutation [16]. However, the (primary) model systems for these mutations are precious and not well recapitulated with substitutes.
Are there natural history studies (in the past or on going)? At this point, CF natural history, symptoms and progression is well documented for pediatric patients. However, for adult CF patients, natural history is an ongoing process that is not yet amassed.
Certain physicians or centers that are experts? Yes, worldwide. The CF community is a rich, diverse, caring community.
The Cure Corner: What is needed for a cure?
What does an ideal therapeutic look like? Likely, there will be multiple ideal treatments to completely cure CF—both because of the diverse number of causative mutations and the diverse symptoms that require treatment.
An incredibly powerful treatment would treat CFTR defects throughout the body. If the mutation’s effects are not corrected early in development, it will need to treat multiple organ systems. I expect a series of drugs will address the different classes of CFTR mutations that differentially affect CFTR protein function. Alternatively, a compelling option would be a drug that treated all mutations. An ideal therapeutic will be sustained throughout a patient’s life.
Are there companies already developing drugs? If so, what kind of molecules and what stage in development are they?
The CF drug development pipeline is a busy space. Vertex Pharmaceuticals leads-- one could say dominates-- the CF space; they developed the three CFTR-targeted compounds that are currently in the clinic. Many other companies are dabbling, likely due to the clear genetic cause and well understood pathology of the disease. As of November 3, 2022, The Cystic Fibrosis Foundation lists 59 active drugs in their CF drug pipeline [17] and there are others not supported by the foundation. As mentioned, current therapies treat mostly symptoms and certain classes of CFTR mutations.
The table below is a selected list of current clinical studies applying various therapeutic approaches targeting CFTR:
What are current therapies/treatments lacking? As discussed, major lacking features of current drugs include an applicability to all patients, an array of options to cover all patients and/or options for patients whose mutations are not improved with CFTR-modulators.
Could an RNA therapeutic fit the need? Yes, various RNA therapeutics offer possible solutions for CF patients [18] [19] [20], especially those for whom the CFTR-modulators will not be effective [21].
Typically, RNA therapeutics include antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). Since siRNAs act to decrease the expression of their target, working directly on CFTR would not be logical. Programs have considered decreasing the expression of the ENaC epithelial sodium channel. Its function in CF patients exacerbates the airway dehydration and poor mucociliary clearance.
However, a more direct option would be using an ASO to increase CFTR expression. While the most well-known use of ASOs is also to decrease expression through gapmer technology and RNase H, multiple other mechanisms could be used to increase CFTR expression. Three examples include to increase translation of a corrected mutant CFTR, to promote readthrough of terminal nonsense mutations and to promote exon skipage of an in-frame mutated exon with little functional importance.
Both ASOs and siRNAs have been in development for CF.
mRNA replacement through AAVs or CRISPR are also highly attractive drug candidates for CF [22]. Since it is a monogenic disease, there is only one mRNA, and likely only one small piece of that one mRNA, that needs replacing. With thousands of mutations across the gene, to be more cost effective, corrective therapies would need to be amenable across mutations. AAV- and CRISPR- therapeutics based companies are working on CFTR replacement options.
Many chemical modifications and/or conjugations can help tackle arguably the biggest issue of (m)RNA therapeutics: delivery. For CF, local delivery to the lung is an option with aerosolized drugs [23]. However, mRNA replacement therapies are finding that mRNA delivery directly to the lung is an extremely challenging venture, both scientifically and technically. Yet, LNP+siRNA or LNP+mRNA formulations are being developed for aerosolized administration and are showing more promise [24] [25]. ASOs can be effectively aerosolized, delivered and act deep in the lungs [26].
Conclusion
The amount of progress made in the last 30+ years on Cystic fibrosis is remarkable. At this stage of research, development and understanding, CF really feels like it is on the brink of being fully cured. I can’t wait to see it happen.
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