UCL Institute of Ophthalmology researchers have investigated the use of targeted antisense oligonucleotide (ASO) therapy to treat patients with Fuchs endothelial corneal dystrophy. The proof-of-concept study, with funding from Fight for Sight, is geared in particular toward individuals with a mutation in the TCF4 gene. The findings are published in The American Journal of Human Genetics.
Fuchs endothelial corneal dystrophy (FECD) affects the inner endothelium of the cornea, which normally acts as a leaky barrier, tightly regulating levels of corneal hydration and nutrition. In FECD, this barrier becomes impaired resulting in corneal swelling and clouding leading to loss of vision and blindness. Patients with FECD usually begin to exhibit symptoms at age 50. Invasive corneal transplantation is the only treatment option, and this surgical procedure has a risk of graft rejection.
Dr. Alice Davidson, a recipient of Fight for Sight’s early career investigator award, led the study. Her team demonstrated that the formation of RNA aggregates have a toxic effect and underlie the disease pathology of FECD. The use of a corneal endothelial cell (CEC) model derived from FECD patients, revealed that triplet DNA repeats led to the formation of these toxic nuclear RNA aggregates.
The team found that treatment using antisense oligonucleotides (ASO) led to a reduction of the RNA aggregates and their toxic downstream events in patient cells. These results highlight the potential of using an ASO therapy to treat the toxic entities that arise due to a mutation in the TCF4 gene.
“We have developed an antisense oligonucleotide (ASO) drug which targets a specific genetic mutation that is responsible for approximately 75% of FECD cases. Using patients’ corneal cells grown in the lab, we have demonstrated the utility of this treatment,” said Davidson. “With continued research and investment we hope our proof-of-concept study will pave the way for a new effective and less invasive way to treat this common and sight-threatening condition.”
“We are pleased that this research has uncovered a potential new treatment for FECD patients. The current treatment option depends upon acquiring healthy donor material and the use of specialist facilities,” said Neil Meemaduma, Research Manager at Fight for Sight. “This potential approach addresses the genuine need for alternative treatments for individuals living with FECD.”