Macquarie University Background
Glaucoma is the number one cause of irreversible vision loss and the second leading cause of blindness worldwide. Globally, around 76 million people live with glaucoma. This number is expected to increase to 111.8 million in 2040 due to demographic expansion and aging population. Over 300,000 Australians live with glaucoma and almost 10% of the population over the age of 80 are affected. The total community cost is expected to increase to $4.3 billion pa by 2025 with the aging population.
Increased Intraocular Pressure (IOP) is considered a prominent manifestation of glaucoma. Current primary management of glaucoma, which aims to control raised IOP, includes topical medications, laser therapy, nonpenetrating glaucoma surgery (NPGS), invasive glaucoma surgeries, and the newer microinvasive glaucoma surgery (MIGS) procedures. Various medications include prostaglandin analogues, beta blockers, alpha-adrenergic agonists and combinations thereof. Current management is therefore limited to lowering the IOP, which only slows the progression of glaucoma, but does not cure the disease.
It is extremely important to better understand mechanisms underlying Retinal Ganglion Cell (RGC) loss and structural damage in glaucoma. Loss of RGCs can occur in glaucoma cases even when IOP is reduced, and some patient still get glaucoma with normal IOP. Alternative treatment approaches are critically needed which target features of the disease other than or in addition to IOP.
Technology Overview
Neuroserpin is a serine protease inhibitor which plays a role in inhibiting plasmin activity in the retina. Neuroserpin is well expressed in the retina and undergoes oxidative inactivation in glaucoma conditions. The research team has shown that oxidative inactivation of neuroserpin results in increased plasmin activity, and that decreased neuroserpin activity is associated with RGC degeneration and optic nerve damage, both of which are associated with glaucoma. The methionine residue in the neuroserpin active site makes the molecule labile to oxidative inactivation. The team has created a novel neuroserpin mutant (single amino acid) protein which retains the ability to inhibit serine proteases (such as plasmin, tissue plasminogen activator, and urokinase plasminogen activator) and is resistant to oxidative inactivation.
This novel and disease-modifying approach is based on a validated Mechanism of Action. The team has previously shown that oxidative inactivation of neuroserpin is associated with increased plasmin activity, RGC degeneration and excavation of the optic nerve head in glaucoma. This approach delivers a mutant neuroserpin molecule that is resistant to oxidative inactivation. In vivo testing in glaucoma models has shown significant protection against glaucoma damage, including RGC degeneration. Its potential uses include both prevention and treatment of glaucoma as well as other conditions associated with plasmin activity or plasmin activator activity.
Stage of Development
Comprehensive validation of the discovery that neuroserpin plays a neuroprotective role in glaucoma and that its modulation in glaucoma conditions influences RGC degeneration and excavation of the optic nerve.
In vivo PoC in two animal models using intravitreal delivery of the novel oxidation-resistant mutant neuroserpin protein into the retina.
Supporting Data:
Mutant form of neuroserpin is significantly more resistant to oxidative stress conditions compared to the WT form, as evident by MetS reactivity and Plasmin Inhibitory Activity (PIA) measurements. Methionine is converted to MetS upon oxidation and MetS reactivity reflects the oxidation of this amino acid. In cell lines expressing neuroserpin (directly exposed to H2O2), PIA of the WT neuroserpin was significantly decreased following H2O2 treatment while the PIA of mutant neuroserpin was preserved even after H2O2 treatment. Furthermore, cells subjected to H2O2 treatment had significantly increased MetS reactivity compared to the control cells. The WT neuroserpin had significantly more MetS reactivity compared to the mutant neuroserpin following H2O2 treatment ( A & B).
Mutant neuroserpin rescues glaucoma model disease phenotype in mice, conferring significant protection against glaucoma damage, as indicated by the measurements of Positive Scotopic Threshold Response (pSTR) amplitudes (a measurement of inner retinal function), Ganglion Cell Layer (GCL) loss, MetS reactivity and PIA ( A, B & C).
Mutant neuroserpin rescues neuroserpin knockout retinal phenotype, conferring significant protection against glaucoma damage (indicated by pSTR amplitudes) and GCL loss than the WT neuroserpin ( A, B & C).
Selected publications by the research team:
Gupta, V., et al. (2017) Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin. Scientific Reports. 10.1038/s41598-017-08688-2.
Gupta, V., et al (2020) Retinal changes in Alzheimer’s disease—integrated prospects of imaging, functional and molecular advances. Progress in Retinal and Eye Research. doi.org/10.1016/j.preteyeres.2020.100899.
Abbasi, M., et al. (2021). Inner retinal injury in experimental glaucoma is prevented upon AAV mediated Shp2 silencing in a caveolin dependent manner. Theranostics (Minor revision).
Abbasi, M., et al. (2020) Caveolin-1 ablation imparts partial protection against inner retinal injury in experimental glaucoma and reduces apoptotic activation. Molecular Neurobiology, 57, 9, 3759-3784
Dheer, Y., et al. (2019) Retinoid x receptor modulation protects against ER stress response and rescues glaucoma phenotypes in adult mice. Experimental Neurology, 314, 111-125.
Benefits
Oxidatively resistant form of neuroserpin molecule protects the retina even under the oxidative stress conditions in glaucoma.
The researchers have developed a first-in-class, novel neuroserpin mutant protein that rescues a glaucoma model disease phenotype and a neuroserpin knock-out phenotype in mice.
Amenable to intravitreal delivery as a naked protein or by delivery vehicles such as AAV.
Applications
This novel and disease-modifying approach is based on a validated Mechanism of Action. The team has previously shown that oxidative inactivation of neuroserpin is associated with increased plasmin activity, RGC degeneration and excavation of the optic nerve head in glaucoma. This approach delivers a mutant neuroserpin molecule that is resistant to oxidative inactivation. In vivo testing in glaucoma models has shown significant protection against glaucoma damage, including RGC degeneration. Its potential uses include both prevention and treatment of glaucoma as well as other conditions associated with plasmin activity or plasmin activator activity.
Opportunity
Macquarie University is seeking an industry partner for further development and commercialisation of this unique and promising therapeutic approach through flexible and optimal partnership models. Furthermore, they are seeking collaboration opportunities in the area of ophthalmological neurodegenerative disease.