vx-770 and Cataract

Elexacaftor-tezacaftor-ivacaftor (ETI) is known to pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of ivacaftor in rats demonstrated infant cataracts, but cataracts were not reported in human infants exposed to ivacaftor. We describe 3 cases of infants exposed to elexacaftor-tezacaftor-ivacaftor (ETI) in utero and while breast feeding who were found to have bilateral congenital cataracts within six months of birth. None of the infants had significant visual impairment from the cataracts nor any report of elevated liver function testing. These data highlight the need to counsel females who continue ETI throughout pregnancy and while breast feeding to consider cataract screen for their infants.

Topics: Aminophenols; Animals; Benzodioxoles; Breast Feeding; Cataract; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Female; Humans; Infant, Newborn; Mutation; Rats

Cataracts cause vision loss and blindness by impairing the ability of the ocular lens to focus light onto the retina. Various cataract risk factors have been identified, including drug treatments, age, smoking and diabetes. However, the molecular events responsible for these different forms of cataract are ill-defined, and the advent of modern cataract surgery in the 1960s virtually eliminated access to human lenses for research. Here, we demonstrate large-scale production of light-focusing human micro-lenses from spheroidal masses of human lens epithelial cells purified from differentiating pluripotent stem cells. The purified lens cells and micro-lenses display similar morphology, cellular arrangement, mRNA expression and protein expression to human lens cells and lenses. Exposing the micro-lenses to the emergent cystic fibrosis drug Vx-770 reduces micro-lens transparency and focusing ability. These human micro-lenses provide a powerful and large-scale platform for defining molecular disease mechanisms caused by cataract risk factors, for anti-cataract drug screening and for clinically relevant toxicity assays.

Topics: Aminophenols; Cataract; Humans; Lens, Crystalline; Models, Biological; Pluripotent Stem Cells; Quinolones