Retinal Fibrosis

Retinal Fibrosis

eyes

Diseases of the eye are well suited to therapeutic intervention using sd-rxRNA compounds. Local administration to the eye is an accepted method of administration and generally avoids systemic exposure. The use of sd-rxRNAs may change the landscape of ocular oligonucleotide-based therapeutics, enabling rapid discovery and validation of a wide range of novel therapeutic targets and creating the potential for next generation therapeutics for the treatment of serious ocular disorders. RXi’s sd-rxRNA technology is particularly well-suited this therapeutic area, having improved cellular uptake compared to ‘standard’ siRNAs and potent silencing activity. A clinical trial is ongoing to evaluate the safety and clinical activity of RXI-109 to prevent the progression of retinal scarring, a harmful component of numerous retinal diseases.

 

CTGF: A Therapeutically-Relevant Ocular Target

Connective tissue growth factor (CTGF) is an extracellular matrix (ECM) protein that plays a key role in tissue regeneration and repair and is central in the fibrotic pathway that leads to scarring. In the eye, CTGF is correlated with pathologic fibrosis in vitreoretinal disorders, and as such is a good target for therapeutic intervention. RXI-109 is an sd-rxRNA compound in in development to reduce or inhibit scar formation in the skin and in the eye. As described below, subretinal fibrosis is an issue in many individuals with advanced age-related macular degeneration (AMD) and we believe that reducing CTGF locally in the eye will help to reduce the damage to the retina that results contributes to continued vision loss.

 

Retinal Scarring

Age-related macular degeneration (AMD) is a leading cause of vision loss in the United States8. Two forms of AMD exist: dry (non-exudative) and the more common and damaging, wet form (exudative). The dry form of AMD results from an accumulation of cellular debris (called drusen) and atrophy leading to damage to the retina. In the wet form of AMD, blood vessels from behind the retina grow under the macula. These new blood vessels can be fragile and leak blood and fluid causing damage and vision loss9.

One of the most common treatments for wet AMD is injections of anti-VEGF agents. VEGF (vascular endothelial growth factor) is a secreted protein that promotes new blood vessel growth. Elevated VEGF levels cause aggressive blood vessel growth, leakage and disruption of the retina at the back of the eye, leading to vision loss and blindness. Patients with wet-AMD are currently treated with anti-VEGF therapies to block VEGF from causing blood vessel leakiness and subsequent damage to the retina. However, as the disease progresses, patients can also experience retinal scarring which leads to further vision loss. Results have shown that after two years of anti-VEGF treatment, over half of the patients have scarring on their retina, which cannot be reversed and is a major component of continued vision loss. Our goal is to block the scarring that is secondary to this vascular disease and in doing so preserve vision for a longer time.   RXi is currently conducting a clinical trial in individuals with advanced wet AMD to evaluate the safety and tolerability of RXI-109, and to study its potential to reduce subretinal fibrosis or retinal scaring.

Currently, there are no approved therapeutics in the U.S. for the treatment and prevention of subretinal fibrosis. Such a therapy could benefit patients with the advanced wet AMD as well as those with other ocular indications with a scarring component such as proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR).

 

PVR

Another ocular indication implicated by the overproduction of CTGF is proliferative vitreoretinopathy (PVR), a retinal disease in which cells grow on the surface of the retina causing it to detach. Approximately 6 to 12 percent of people who suffer from a retinal detachment continue on to have PVR. There are several procedures that can be done to repair retinal detachments, one of which is surgery. In individuals with PVR, scar-like membranes grow and may result in traction and re-detachment of the retina even after the surgery. If an individual is prone to PVR, this may happen numerous times. A drug such as RXI-109 that could potentially prevent or slow these scarred membranes from growing would be a great clinical benefit.