Since the approval of the highly effective modulator therapies (HEMT) targeting the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the use of HEMT have been crucial alongside the supplementary symptomatic treatments for cystic fibrosis (CF) (Bell et al., 2020a). HEMT are small molecules designed to target the specific underlying gene defect, with the ability to modulate CFTR protein synthesis, trafficking, and functioning, ultimately restoring the CFTR channels residing on various epithelial cell surfaces. From the early first-generation modulator ivacaftor as a monotherapy to the progression of ivacaftor combination therapies including ivacaftor-lumacaftor and ivacaftor-tezacaftor, HEMT have displayed safety and efficacy in preclinical and clinical trials (Cai et al., 2011). In recent years, triple combination of elexacaftor-tezacaftor and ivacaftor (ETI), as well as the ongoing phase II trials involving vanzacaftor-tezacaftor-deutivacaftor combination have been the main focus to increase treatment options for CF patients (Ghelani and Schneider-Futschik, 2020).

Along with the progression in drug development, some adverse events have been noticed through preclinical and clinical trials involving HEMT. The use of ivacaftor in juvenile rodents and young patients is associated with non-congenital cataracts and this has been observed in several ivacaftor—combination therapies (FDA, 2021). Due to the ongoing lens development in humans from birth to adulthood, the influence of chemicals including drugs is hypothesised as a potential explanation for the ocular defects observed in clinical studies (Van Cruchten et al., 2017).

As a result of the novel ETI therapy, more women with CF (wwCF) are reaching childbearing age, doubling the number of pregnancies from 2019 to 2021 (Figure 1) (Foundation, 2022). Since pregnant patients and babies are typically excluded from clinical trials, all safety data to date stems from case reports/series. Recently, clinical case series provided evidence of an increased risk of developing congenital cataracts in newborns after in utero exposure to ETI (Jain et al., 2022). The embryonic and fetal stages are particularly vulnerable to exogenous agents, making drug use during these stages highly likely to influence ocular development (Sachdeva et al., 2009; Li D and Schneider-Futschik, 2023).

CF is an autosomal recessive condition resulting from variations in the CFTR gene, which encodes for the CFTR ion channel that conducts chloride and bicarbonate transport (Kerem et al., 1989; Rang et al., 2020). Since CFTR is abundant on epithelial cells, CF symptoms can manifest in various organs e.g., lung, liver, and pancreas (Rang et al., 2020; Li D and Schneider-Futschik, 2023). Therefore, despite lung symptoms being the primary cause of mortality, CF is considered a multi-organ disease (Bell et al., 2020a).

The CFTR gene has over 2,000 possible variants that can be categorised into 6 classes (Rang et al., 2020). These classes provide the basis for “mutation-specific therapies” which aim to use the same therapeutic strategy for mutations categorized in the same class (Amaral and Kunzelmann, 2007). This propelled the discovery of highly effective modulator therapies (HEMT) through high throughput screening of compounds tested on specific CFTR mutation expressing cell lines (Lopes-Pacheco, 2019). Currently, HEMT can be categorised into either correctors or potentiators which both act to modulate the CFTR protein directly to target the underlying gene defect in CF. Correctors can rescue the defect trafficking of CFTR onto the cell surface and can be used in combination with potentiators that maintains the opening time and opening probability of CFTR channels (Ramsey et al., 2011; Bell et al., 2020a; Ghelani and Schneider-Futschik, 2020).

Ivacaftor is the first CFTR potentiator approved for patients ≥3 months old with at least one gating variation e.g., G551D class III, which is present in around 4% of the CF patient population (Ghelani and Schneider-Futschik, 2020). In 2023, after the completion of a phase 3 ARRIVAL clinical trial that evaluated ivacaftor use in infants under 24 months old, the United States Food and Drug Administration expanded the use of ivacaftor for infants up to 1 month old that are carrying at least one mutation responsive to ivacaftor (FDA, 2023a). The ARRIVAL study revealed that the pharmacokinetics of ivacaftor in children aged 12–24 months were similar in distribution to older children and adults, and the adverse events were unlikely to be associated with ivacaftor use (Rosenfeld et al., 2018; Davies et al., 2021). In addition, the observed clinical efficacy through biomarkers of CFTR function overall supports the use of ivacaftor to slow or prevent CF progression in newborns and young patients.

Since ivacaftor is limited to mostly class III and rarer mutations, correctors that target the F508del mutation which would be available for 90% of CF patients were developed to benefit the wider population (Cai et al., 2011). Lumacaftor-ivacaftor combination as a corrector-potentiator combination acts to first rescue the defective processing of CFTR protein in the endoplasmic reticulum and then enhance the gating activity of CFTR proteins with F508del mutations (Van Goor et al., 2011). In vitro studies highlighted the combination effect of lumacaftor-ivacaftor inducing greater CFTR-mediated chloride transport than lumacaftor alone, and this similar observation of higher clinical benefit compared to ivacaftor alone was replicated in studies on homozygous F508del patients (Van Goor et al., 2011; Wainwright et al., 2015). Based on the successful phase 3 study in 2021, FDA has approved the use of lumacaftor-ivacaftor for children over 1 year old with the homozygous F508del mutation (FDA, 2022a; Rayment et al., 2022). Similarly, tezacaftor-ivacaftor is a synergistic corrector-potentiator combination therapy that is available for children aged 6 years old who have at least one mutation responsive to therapy (FDA, 2022b). Compared to the lumacaftor-ivacaftor combination, tezacaftor-ivacaftor does not interact with CYP3A4 enzymes which reduces potential drug interaction and metabolising issues but maintains its clinical efficacy (Donaldson et al., 2018; Schneider, 2018).

In 2019 (US) and 2021 (Australia), the first triple combination therapy involving elexacaftor-tezacaftor-ivacaftor was approved for patients aged over 12 years old. Elexacaftor is a next-generation modulator that is proposed to act as both corrector and potentiator (Shaughnessy et al., 2021). In phase 3 studies, clinical end points of FEV1 were superior to the tezacaftor-ivacaftor combination with fewer adverse events (Heijerman et al., 2019; Middleton et al., 2019). Following on, clinical trials have confirmed the safety profile, efficacy and pharmacokinetics of ETI in patients aged 2–5 years old (Rayment et al., 2022; FDA, 2023b; Goralski et al., 2023). To date, the FDA has announced the availability of ETI for children from 2 years old with an F508del allele or any mutation responsive to therapy.

Apart from the approved modulators, there is ongoing development involving a novel triple combination of vanzacaftor-tezacaftor-deutivacaftor that has undergone phase 2 clinical trials in patients over 18 years. It is aimed to achieve once daily dosing for patients who have at least one copy of the F508del mutation and exceed the clinical benefit of ETI which is currently the benchmark therapy for F508del mutations (Uluer et al., 2023). Undoubtedly, if it displays superior efficacy and tolerable safety profiles, clinical trials will proceed to young patients since it is hoped that HEMT treatment options can extend to younger age groups to control manifestations of CF symptoms early.

Symptoms of CF extend to the reproductive system (Kaplan et al., 1968). Since the 1970 s, wwCF were described having lower fertility rates compared with healthy women (Kopito et al., 1973; Shteinberg et al., 2019). Dehydrated cervical mucus and disrupted pH balance can disrupt sperm viability for successful fertilisation (Kopito et al., 1973; Chan et al., 2002; Wang et al., 2003; Hughan et al., 2019). Furthermore, CFTR has been identified in the hypothalamus of both rats and humans where the regulation of homeostatic reproductive functions such as gonadotrophin-releasing hormone production may consequently be disrupted in CF patients (Mulberg et al., 1998; Hughan et al., 2019; Qiu et al., 2020).

Apart from indirectly enhancing health status, CFTR modulators may also directly restore fertility by correcting CFTR channel located in the cervix to decrease cervical mucus tenacity (Jones and Walshaw, 2015). Jones et al. support the hypothesis by displaying restored fertility in women despite no significant changes in the overall health status (Jones and Walshaw, 2015). Additionally, hysteroscopic images of the vagina highlights the clearance of mucus plugs after starting ivacaftor, further emphasising that restoration of CFTR localised in the reproductive system can improve fertility (Jain and Taylor-Cousar, 2021). The approval of ETI consequently escalated the number of pregnancies due to the high drug efficacy and mild adverse events with wide population suitability (Figure 1) (Middleton et al., 2019). Specifically, ETI have been proposed to have the potential to increase conception, even in patients with a history of subfertility (O'Connor et al., 2021).

It is well established in preclinical and clinical studies that all components of HEMT will pass through the placenta which raises concern for the effect it may have on fetal development (Trimble et al., 2018; FDA, 2021; Qiu et al., 2021; Collins et al., 2022; Jain et al., 2022). As more pregnancies are reported under ETI treatment, this paragraph focuses on ETI.

In animal reproductive models, the use of ETI during the organogenesis period at normal doses is safe, and at maternally toxic doses, ETI does not cause significant developmental defects (FDA, 2021). Similarly, in clinical cases reported, first-generation CFTR modulatory drugs are well tolerated, and emerging case reports of ETI use indicates that most maternal and fetal complications are unrelated to its use (Table 1) (Nash et al., 2020; Taylor-Cousar, 2020). Moreover, a withdrawal effect initially proposed by Trimble et al. is observed after stopping ETI treatment in which the patient’s pulmonary function deteriorates significantly (Trimble and Donaldson, 2018). The impact of the withdrawal effect has prompted many wwCF to re-initiate therapy (Trimble and Donaldson, 2018; Nash et al., 2020; Taylor-Cousar and Jain, 2021). Conversely, despite some promising and increasing use of ETI reported, the government’s drug for pregnancy categorisation systems have indicated that ultimately, the lack of sufficient clinical studies of ETI use during pregnancy makes it difficult to establish certainty in its safety. Therefore, observations of complications from individual case reports should be prioritized for evaluation.

To gain preclinical insight from animal toxicity studies on eye development, it is essential to identify the differences between rat models and humans. Structurally, rat eyes are a quarter the size of humans’, but the ratio of their lens thickness to axial length is around four-fold greater than humans’ (Shibuya et al., 2015). Zonular fibres that originate from the ciliary muscle and attach to the lens capsule are present in both species (Van Cruchten et al., 2017). Yet due to the poor development of this ciliary musculature in and the apparent lack of accommodation needs in rat eyes, the functional significance of the zonular fibres to modulate lens shape is less clear in rat eyes (Parker and Picut, 2016). Despite these differences, the embryogenesis process in rats is similar to humans, where the invagination of the ventral forebrain from GD11 begins the process of optic vesicle formation (Parker and Picut, 2016). However, in the short 21–23 days of gestational period, rat eye morphogenesis is significantly less developed at birth as seen in the eyelids, iris, and hyaloid vasculatures (Table 3).

Cataracts are opacifications within the lens that can be classified based on their location and time of onset (Bell et al., 2020b). Childhood cataracts of both congenital and juvenile onset have a rarer incidence of 1.8–3.6/10,000 per year compared to age-related cataracts (Sheeladevi et al., 2016). The aetiology of childhood cataracts is diverse and, in some cases, the cause is unknown (Lam et al., 2015; Sheeladevi et al., 2016). While hereditary genetic conditions account for a majority of congenital bilateral cataracts, environmental factors including metabolic disorders and trauma can also lead to cataracts at birth (Bell et al., 2020b). Additionally, intrauterine influences including maternal infections, radiation exposure and maternal drug use may also increase the risks (Churchill and Graw, 2011).

Emerging data from case reports and case series (paired with some animal reproduction data) of the use of HEMT during pregnancy provides encouragement about drug safety during pregnancy and breastfeeding. However, due to reports of acute deterioration in health following cessation of HEMT risks to the mother’s health due to discontinuation of HEMT must be weighed carefully against the unknown risks to the fetus. The development of non-congenital cataracts in juvenile rats and published case reports in paediatric patients highlight the need for infant ophthalmologic exams. Thus, a better understanding of the potential risks of HEMT during early life exposure is urgently needed.