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Cystic Fibrosis

Current landscape of Cystic Fibrosis gene therapy



Cystic fibrosis is a life-threatening disease that is caused by mutations in CFTR, a gene which encodes an ion channel that supports proper function of several epithelial tissues, most critically the lung. Without CFTR, airway barrier mechanisms are impaired, allowing for chronic, recurrent infections that result in airway remodeling and deterioration of lung structure and function. Small molecule modulators can rescue existing, defective CFTR protein; however, they still leave a subset of people with CF with no current disease modifying treatments, aside from lung transplantation. Gene therapy directed to the lung is a promising strategy to modify CF disease in the organ most associated with morbidity and mortality. It is accomplished through delivery of a CFTR transgene with an airway permissive vector. Despite more than three decades of research in this area, a lung directed gene therapy has yet to be realized. 

There is hope that with improved delivery vectors, sufficient transduction of airway cells can achieve therapeutic levels of functional CFTR. In order to do this, preclinical programs need to meet a certain level of CFTR protein expression in vitro and in vivo through improved transduction, particularly in relevant airway cell types. Furthermore, clinical programs must be designed with sensitive methods to detect CFTR expression and function as well as methods to measure meaningful endpoints for lung structure, function and disease. Here, we discuss the current understanding of how much and where CFTR needs to be expressed, the most advanced vectors for CFTR delivery and clinical considerations for detecting CFTR protein and function in different patient subsets.

Cystic fibrosis (CF) is the most common autosomal recessive disease and affects approximately 40,000 people in the United States and 80,000 people worldwide (Cromwell et al., 2023). It is caused by variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) which encodes a chloride channel that is found on the membrane of many cell types in the body (Riordan, 1989; Saint-Criq and Gray, 2017). Lack of CFTR function at the apical surface of secretory epithelial tissues such as the lung and pancreas is the cause of morbidity, although many organs are affected including the reproductive system, intestine, liver, bone, and kidney. In the classic CF disease progression, pulmonary complications as a result of thick inspissated mucus, chronic bacterial colonization and ongoing lung destruction are the principal cause of death. The average life span of people with CF (PwCF) has drastically improved over the years to mid to late 40s (mid-50s if born after 2018) but has historically struggled to get beyond childhood without therapeutic intervention (Castellani and Assael, 2017; McBennett et al., 2022). A person with CF experiences an annual decline in lung function of 1%–2%, and without a lung transplantation or disease-modifying therapy, 80% will succumb to respiratory failure (Lyczak et al., 2002; Leung et al., 2020). Significant understanding of the genetic basis for CF and the resulting pathophysiology has led to the development of CFTR modulators, small molecules that correct and/or potentiate dysfunctional CFTR protein to clinically meaningful output with daily medication (Middleton et al., 2019). 

However, there is still great unmet need for PwCF that are unable to benefit from modulators due to their specific CFTR variant, intolerable side effects or lack of access (10%–20% of patients) (Hubert et al., 2017; Burgener and Moss, 2018). Therefore, a gene therapy for CF which introduces a functional CFTR gene into patients’ cells could treat >4,000 patients in the US unable to use modulators. Despite identification of the genetic cause more than three decades ago, CFTR gene therapy has yet to progress beyond clinical trials due to a lack of sustained efficacy and prolonged lung function improvements in patients. New insights into the expression and function of CFTR in relevant cell types, novel delivery methods for introducing CFTR into target airway cells and more sensitive measurements for lung function in the clinic, particularly in young children or those patients with milder disease most likely to benefit from early CFTR intervention, are promising steps toward a clinically approved CF gene therapy.

Cystic Fibrosis, CFTR gene, lung infections, mucus buildup, respiratory system, genetic disorder, chloride channels, pulmonary disease, pancreatic insufficiency, chronic cough, digestive problems, CFTR protein, sweat test, genetic mutation, airway clearance, lung function, Pseudomonas aeruginosa, inflammation, antibiotic therapy, enzyme supplementation, gene therapy, newborn screening, life expectancy, personalized medicine, CFTR modulators.

#CysticFibrosis, #CFTR, #GeneticDisorder, #LungHealth, #MucusBuildup, #RespiratoryCare, #ChronicIllness, #PancreaticInsufficiency, #GeneticMutation, #SweatTest, #AirwayClearance, #PulmonaryDisease, #LungFunction, #CFResearch, #GeneTherapy, #NewbornScreening, #CFTreatment, #LifeExpectancy, #PersonalizedMedicine, #CFCommunity, #Inflammation, #AntibioticTherapy, #CFTRModulators, #EnzymeSupplementation, #RareDisease.

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