The search for an antifibrotic drug for use with pediatric glaucoma devices

(Image Credit: AdobeStock/Monster Ztudio)

The search for drugs suitable for use with glaucoma drainage devices (GDDs) is ongoing. The challenge is to identify drugs and associated substances that do not cause adverse effects or complications in pediatric patients with GDD implants. Maryo Kohen, MD, assistant professor in the Department of Ophthalmology at Case Western Reserve University School of Medicine and a pediatric ophthalmologist and adult strabismus specialist at University Hospitals Rainbow Babies and Children’s Hospital, both in Cleveland, Ohio, described his team’s most recent research in this area at the Fourth Annual Cleveland Eye Bank Foundation Virtual Vision Research Symposium.¹

He explained that in pediatric cases of glaucoma, when surgery to open the angle fails, a GDD is inserted. In his practice, he and his colleagues regularly use Ahmed Glaucoma Valves (New World Medical, Inc). However, they frequently encounter complications related to the development of fibrotic scarring around the GDD plates and the bleb wall, which can impede outflow and necessitate subsequent surgeries to remove excessive scar or capsule formation. Multiple surgeries are costly and can negatively affect the patient’s vision, he noted.

To address this, Kohen and colleagues, in collaboration with the departments of Biomedical Engineering and Pathology at Case Western Reserve University, began searching for a drug that would not cause scarring around GDDs. They had previously used mitomycin C and 5-fluorouracil to inhibit fibrosis and scarring in this scenario, but these drugs are associated with high levels of toxicity. The investigators subsequently focused on pirfenidone (PFD; Esbriet; Genentech), an FDA-approved drug, with the hope of minimizing adverse effects due to its antifibrotic activity.

PFD activity

“We believe that the drug affects multiple fibrogenic pathways to reduce fibrosis in the lungs by downregulating the production of growth factors, decreasing fibroblast proliferation, influencing transforming growth factorβ, and interrupting the differentiation of fibroblasts into myofibroblasts,” Kohen said. The investigators sought to move beyond the use of PFD drops or subconjunctival injections and hypothesized that creating a polymeric GDD sheath capable of sustained PFD release might mitigate fibrosis development.

They fabricated a PFD-doped sheath using blow-molded polycaprolactone (PCL), a synthetic, biocompatible polyester. In their study, they investigated the effects of various PCL concentrations, spray distances, and molecular weights on nanofiber morphology and PFD release, Kohen recounted.

The aim was to cover the GDD valve without inhibiting outflow while ensuring that capsular formation was not completely suppressed, as bleb formation around the GDD is desirable. Using a solution blow-spinning method developed by bioengineers, a PCL scaffold was devised to serve as the biodegradable surface around the GDD. During testing, PCL concentrations of 6%, 8%, and 10% were evaluated, resulting in different fiber diameters and varying PFD release rates.

Experimental results

“Our in vitro results were successful and showed that fibroblast proliferation and collagen production were reduced,” Kohen explained. However, a different result was observed in vivo in rabbits. PCL was found to be highly inflammatory, and the scaffold increased inflammation.

Moving forward

“In another experiment, we may use a poly(lactic-co-glycolic acid) [PLGA] scaffold. PLGA is another synthetic polymer that is biocompatible and biodegradable and can be combined with pirfenidone,” Kohen concluded. “Blow-spun PLGA may be a better option for reducing fibrous encapsulation around GDD plates.”

Maryo Kohen, MD

E: maryo.kohen@uhhospitals.org

Kohen is assistant professor in the Department of Ophthalmology at Case Western Reserve University School of Medicine and active staff at University Hospital Rainbow Babies and Children’s Hospital, both in Cleveland, Ohio. He has no financial interest in this subject matter.

Reference

1. Kohen M. Pirfenidone delivery by blow-molded PCL nanofiber mat to reduce collagen synthesis. Presented at: Fourth Annual Cleveland Eye Bank Foundation Virtual Vision Research Symposium; October 15, 2024; Cleveland, Ohio.