Researchers at the University of Birmingham in the U.K. say they have shown that a novel low molecular weight dextran-sulphate, ILB®, could play a key role in treating open angle glaucoma (OAG), a neurodegenerative disease that affects over 70 million people worldwide and causes irreversible blindness.
OAG develops slowly over many years. Fibrosis within the eye’s main fluid drainage site can lead to increased intraocular pressure (IOP), resulting in damage to the optic nerve.
The team’s study “ILB resolves inflammatory scarring and promotes functional tissue repair,” reported in npj Regenerative Medicine, has shown that that ILB can normalize matrix deposition inside the eye and lower IOP in a preclinical model used to mimic these aspects of human glaucoma, paving the way for new anti-fibrotic therapies to be developed for the disease.
OAG is a complex disease and it has proved difficult to develop effective therapeutics to target the biochemical pathways involved. Existing therapies mainly work by reducing fluid production in the eye, not the underlying causes, and even the newer therapies have shown limited success in the clinic.
The Birmingham scientists focused on an inflammatory pathway that is common to several diseases, and involves Transforming Growth Factor β (TGFβ), a signaling molecule that communicates between cells and orchestrates both inflammation and fibrosis. TGFβ’s role in OAG is well known, with patients demonstrating higher levels in their aqueous humor and laboratory studies showing that artificially increasing TGFβ within the eye can lead to fibrosis.
The scientists found that ILB has multimodal actions across many genes that resolve inflammatory and fibrotic cellular processes. When they progressed their work into a preclinical experimental model of glaucoma, they found that daily subcutaneous injections of ILB significantly (p<0.01) reduced extracellular matrix levels within the eye’s main drainage site, normalized the eye’s pressure and prevented degeneration of retinal neurons.
“We investigated the effects of a newly formulated low molecular weight dextran sulfate (LMW-DS), termed ILB, to resolve inflammation and activate matrix remodeling in rodent and human disease models. We demonstrated modulation of the expression of multiple pro-inflammatory cytokines and chemokines in vitro together with scar resolution and improved matrix remodeling in vivo,” write the investigators.
“Of particular relevance, we demonstrated that ILB acts, in part, by downregulating transforming growth factor (TGF) β signaling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodeling, reduced fibrosis and functional tissue regeneration. These observations indicate the potential of ILB® to alleviate fibrotic diseases.
The research was conducted by Lisa Hill, PhD, from the Institute of Clinical Sciences, and Hannah Botfield, PhD, from the Institute of Inflammation and Aging.
“We are truly excited by these results, which show a way forward for a glaucoma treatment that can reverse the fibrotic process that causes the disease,” say the two scientists.
Clinicians working in ophthalmology generally prefer local over systemically delivered therapeutics, as it is a safer route of administration that is more acceptable to patients.
Hill is leading a project to formulate a topical alternative that will avoid the need for injection. She is working on this with Imran Masood, MRCS(Ed), FRCOphth, a consultant ophthalmic surgeon at Sandwell and West Birmingham NHS Trust and Liam Grover, PhD, a biomaterials expert from the University’s Healthcare glTechnologies Institute, to assess the use of a novel shear thinning fluid gel for the resolution of glaucoma.
The shear thinning fluid gel was developed for use as eye drops that are retained for an extended period of time following administration, and patents have been filed for its use both alone, and in combination with other therapeutics. Previous studies have shown the fluid gel reduces corneal scarring when applied topically, and it is an effective carrier molecule for other therapeutics.