Ocular development after highly effective modulator treatment early in life

Abstract

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

“…In people with CF (pwCF), the functionality of the CFTR protein is compromised in different ways depending on the mutation of the CFTR gene, there are more than 2000 variants that have been identified. ,, The defective or absent CFTR chloride channel results in the accumulation of chloride ions within the cell, and hyperabsorption of sodium. The altered cellular osmotic pressure increases the passive movement of water into the cell, leading to thicker and dehydrated mucus in the airway, resulting in impaired mucus clearance and decreased airflow. , The gastrointestinal tract (GIT), reproductive tract, sweat and salivary glands, and lungs of people with CF (pwCF) are affected and are usually characterized by chronic bacterial infection of the airways due to the CF patients commonly have dysregulated immunity and impaired mucus clearance. ,,− The CFTR variants are traditionally categorized into 6 classes, and each class has a unique CFTR defect (Table ). Class I variants cause defective CFTR production, ultimately leading to the absence of the CFTR protein on the cell surface .…”

Ocular Changes in Cystic Fibrosis: A Review

“…This condition may result from metabolic abnormalities in the course of CF. However, current research into new therapies for CF has also indicated an association between the use of CFTR protein modulators and an increased occurrence of lens opacification in the pediatric population [ 63 ].…”

“…Similarly, cases of lens opacification in the pediatric population following ivacaftor, both as monotherapy and in combination, have also been reported. Data from published studies have shown that the incidence of cataracts in the pediatric population ranges from 0.57% to 4.17% [ 63 ].…”

“…Current research has shown that in CF patients aged 2–6 years treated with ivacaftor, cortical cataracts occurred in 4.17% of participants within 84 weeks of treatment initiation, while in the age group over 12 years, the presence of posterior subcapsular cataracts was observed in 0.57% of individuals within 96 weeks of initiating ivacaftor therapy [ 63 , 66 ]. Another study reported the presence of cataracts of unspecified type in 1.72% of CF patients aged 6–11 years within 24 weeks of starting treatment with the ivacaftor–lumacaftor combination, as well as in 1.54% of individuals over 6 years after treatment with the ivacaftor–tezacaftor combination [ 63 ]. However, it is noteworthy that in some of the reported cases, exposure to other factors that may promote lens opacification (e.g., the use of systemic corticosteroids and exposure to radiation) was also present [ 64 ].…”

“…To date, the exact mechanism underlying the occurrence of lens opacification in both rats and humans has yet to be fully understood [ 63 ], and this issue requires further research. Initial and follow-up ophthalmic examinations of CF patients, especially in the pediatric population, as well as pregnant and breastfeeding women receiving CFTR modulators, are crucial to further determining the potential association between the use of these drugs and the incidence of lens opacification.…”