Editors' ChoiceGene Therapy

A sight for sore eyes (or ones with glaucoma)

See allHide authors and affiliations

Science Translational Medicine  22 May 2019:
Vol. 11, Issue 493, eaax4880
DOI: 10.1126/scitranslmed.aax4880


Transduction of the exoenzyme C3 transferase gene into the trabecular meshwork reduces intraocular pressure in monkeys.

Luxturna is a gene therapy that treats congenital blindness. It was approved by the U.S. Food and Drug Administration in 2017, and treatment comprises direct injection of the RPE65 gene under the retina. Luxturna is the first gene therapy approved in the U.S. that targets a monogenic disorder, and it is a seminal achievement. Still, there is considerable room for the platform to improve, especially if gene therapies for more prevalent ocular disorders, such as primary open-angle glaucoma (POAG), are to be developed.

Luxturna packages RPE65 in an adeno-associated viral (AAV) vector. These vectors have been shown to transduce nonretinal ocular tissues such as the trabecular meshwork. However, they have been unable to modulate the physiology and microenvironment of these tissues, which are highly consequential for reversing the pathophysiology of disorders such as POAG. To this end, Tan et al. used a lentiviral vector to transduce the C. botulinum gene encoding exoenzyme C3 transferase (C3) into the trabecular meshwork of healthy adult male Rhesus monkeys. C3 inactivated Rho GTPase and disrupted the assembly of the actomyosin network, which contributed to lowering the intraocular pressure. The team observed cytoskeletal modulation and a reduction in intraocular pressure in the monkeys for as long as 112 days. However, they also observed individual differences in the extent and duration of intraocular pressure reduction in the subjects. Any corneal inflammation that occurred in the treatment group entirely disappeared within one week after injection, and no corneal inflammation was observed in the control group.

These results suggest that the inflammation was not caused by the lentiviral vector, and that individual differences in treatment response and incidence of inflammation may be the result of differences in the natural resistance of individuals to foreign genetic material. Likewise, the eventual loss of efficacy and individual differences in the duration of the therapeutic window is speculated to be the result of host-specific responses. One caveat is that expression of the C3 gene in the lentiviral vector was driven by the cytomegalovirus (CMV) promoter, which is particularly susceptible to silencing and disruption by restriction factors in the host. Nevertheless, Tan et al. have established strong foundations for future optimization of the gene therapy and its eventual testing in humans.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article