A Novel Approach to Preventing Fibrosis Post-Glaucoma Surgery

Glaucoma, according to the World Glaucoma Association, is the leading cause of irreversible blindness, with approximately 80 million people worldwide living with the condition – half of whom are unaware of it (1). It is a chronic disease that requires early diagnosis and effective treatment to prevent vision loss later in life.

The current, primary goal of treatment is to reduce the risk of further optic nerve damage by reducing pressure in the eye. However, if pharmaceutical management is ineffective, patients may require surgical intervention, such as trabeculectomy. This procedure carries the risk of fibrosis, which can result in failure of the surgery.

An area that is often overlooked are the key challenges associated with glaucoma surgery and how novel small interfering ribonucleic acid (siRNA) therapies show promise for the prevention of fibrosis and reduced scarring in ophthalmic procedures.

Treatment options for glaucoma
 

While there have been many innovations in surgical treatment, trabeculectomy remains the gold standard surgery for glaucoma (2). Here, an alternative pathway or channel is created for the exit of aqueous humor into a reservoir (bleb) underneath the surface of the eye where it is absorbed. The natural response of the body, however, is to ‘heal’ the newly created drainage pathway, which can lead to fibrosis and often to failure of the surgery. Despite an initial success rate and even with the use of adjunctive anti-fibrotic therapy, 30 percent of trabeculectomy procedures fail within three years, and this rate can increase to as high as 50 percent within five years (3).

Off-label cytotoxic anti-fibrotic drugs 5-fluorouracil (5-FU) and, more recently, mitomycin C (MMC), have been used to improve success rates in patients at high risk of trabeculectomy failure, reducing postoperative scarring. Although, the use of antimetabolites such as these to modulate healing post-trabeculectomy by inhibiting DNA synthesis and causing widespread apoptosis has been accompanied by an increased risk of complications – including early and late bleb leaks, hypotony, maculopathy, and endophthalmitis (4).

The downsides of MMC are multiple; it is a cytotoxic, carcinogenic, difficult molecule to work with and is very unstable. Following its use, some patients still scar, leading to failure of the surgery. This means there is a large unmet need for alternative treatments with more targeted physiological effects and less cytotoxicity. Furthermore, development of resistance to MMC leads to more limited options if repeat surgery is required (5).

MRTF inhibition and siRNA delivery
 

Myocardin-related transcription factor B (MRTF-B) is a key regulator of fibrosis at many sites in the body, as well as the eye. Following mechanical stress or growth factor stimulation, such as that experienced following glaucoma surgery, MRTF-B translocates to the nucleus to initiate fibrosis. Therefore, blocking MRTF-B production in the eye would be a compelling strategy to improve the outcomes from glaucoma surgery.

siRNAs are double-stranded RNA molecules 20-25 nucleotides in length that regulate gene expression by specifically degrading mRNA targets, resulting in gene silencing. This naturally-occurring mechanism has garnered major interest due to its ability to silence genes in a highly specific manner.

Arguably, though, the use of siRNA for this purpose is yet to reach its true potential due to the challenges of delivering the therapeutic payload in a safe and targeted manner. A major hurdle to implementing siRNA therapies generally is the method of delivery, but optimized lipid-peptide-siRNA (LPR) nanoparticles containing MRTF-B siRNAs offer potential as a targeted approach to prevent conjunctival fibrosis.

A case study: ECP-105
 

ECP-105 is an anti-fibrotic siRNA therapy that can provide a more targeted approach to improve surgical outcomes and reduce re-repeat surgery rates for patients with severe glaucoma (6). ECP-105 targets MRTF-B, which drives myofibroblast proliferation post-surgery. The active component of ECP-105 is a siRNA which highly selectively silences this transcription factor.

To ensure safe, simple, and reliable delivery to the eye, the siRNA is encapsulated in a novel delivery system, LipTide. LipTide is an artificial self-assembling peptide nanoparticle (virus-like); which combines the properties of liposomes and viruses, without the inherent safety risks of viral delivery. It mimics viruses by protecting its fragile genetic cargo in a peptide package (capsid) while using cell specific sequences to target active uptake into only the desired cell types.

The platform enables higher delivery rates and target specificity than traditional liposomal vectors; greater versatility and lower safety risks than viral vectors; high tolerability suitable for repeat dosing; reduced cost; and ease of manufacturing.

ECP-105 has also demonstrated siRNA silencing of genes related to fibrosis in vivo. A single subconjunctival administration of LipTide containing a MRTF-B siRNA (ECP-105 prototype, MRTF-B LYR) during a rabbit glaucoma filtration surgery model of scar tissue formation, reduced MRTF-B expression by 30 percent.

The treatment is soon to enter pre-clinical studies to determine an appropriate dose and dose schedule for clinical trials.

sIRNA promise
 

The use of siRNA gene silencing holds promise for preventing fibrosis following glaucoma surgery, especially when combined with an effective delivery system. Thus, exploring the combined approach of siRNA with other therapeutic agents could further enhance efficacy and specificity, leading to better surgical outcomes for glaucoma.