Safety of Topical Insulin Drops for Open-angle Glaucoma

Glaucoma: a major health care challenge of the 21st century

Glaucoma is a leading cause of irreversible blindness worldwide and is expected to affect 76 million people by the year 2020. In glaucoma, there is a permanent loss of retinal ganglion cells (RGCs), the long-projecting central nervous system (CNS) neurons that convey visual information from the retina to the brain via their axons. Clinically, such changes translate into a progressive damage of visual field and sometimes result in a complete loss of vision. Currently, intraocular pressure (IOP) reduction remains the sole target of proven glaucoma therapies, consisting of a wide range of eye drops, systemic medications, laser procedures and incisional surgeries. However, many patients continue to lose vision even when these therapies are implemented, exemplifying the unmet need for novel therapies that sustain RGC survival and stimulate their regeneration.

Dendrite pathology: an early sign of neuronal damage in glaucoma Dendrites are specialized processes that determine how neurons receive and integrate information within neuronal circuits. Dendrite retraction and synapse disassembly are early signs of pathology in several psychiatric and neurodegenerative disorders. Dendritic pathology occurs prior to soma or axon loss and correlates with substantial functional deficits. In mammals, CNS neurons have a limited capacity to regenerate after injury. While a large number of studies have focused on axonal regeneration, the ability of mammalian neurons to regrow dendrites and reestablish functional synapses has been largely ignored. This is a critical issue because pathological disconnection from pre-synaptic targets leads to persistent functional impairment and accrued neuronal death, contributing to vision loss in glaucoma.

The role of insulin in dendrite regeneration Aberrant or insufficient insulin signaling, even in the absence of diabetes, has been associated with neurodegeneration in diseases characterized by dendritic pathology, notably Alzheimer's and Parkinson's disease, as well as glaucoma. Traditionally viewed solely as a peripherally acting hormone, insulin crosses the blood-brain-barrier readily and can influence a number of physiological brain processes including neuronal survival, neurotransmission, and cognitive performance. Using a model of optic nerve transection (axotomy), members of our team (Agostinone et al. Brain 2018) showed that insulin administered as eye drops or systemically after dendrites had retracted, promoted robust dendritic growth that restored arbor area and complexity. Remarkably, insulin rescued excitatory postsynaptic sites and light-triggered retinal responses while promoting robust cell survival. This study provides the first evidence of successful dendrite regeneration in mammalian neurons. Unpublished data (manuscript in preparation) from a mouse glaucoma model by our colleagues at the CHUM (Agostinone et al., in preparation) also showed that insulin stimulates similar dendrite regeneration after ocular hypertension damage. These results confirm that injured murine RGCs can effectively regenerate dendrites and validate insulin as a powerful strategy to restore dendritic morphology in glaucoma, providing the basis for need of further investigation of insulin use as glaucoma treatment in humans.

Currently, insulin is approved for subcutaneous or intravenous use as a treatment for diabetes mellitus. Adverse events of systemic insulin include hypoglycemia, hypokalemia,allergies, weight gain, peripheral edema and drug interactions. Experimental use of ocular topical insulin have been tested in small cohorts of healthy individuals and diabetic patients, reporting no significant adverse events. However, these protocols varied in insulin posology and adverse events were only mentioned briefly, if at all, in most of these studies, indicating the necessity of better characterizing the safety profile of such off-label use of insulin prior to implementing its use as neuroprotective and regenerative treatment for glaucoma.

Experimental nature of the medication / treatment:

Topical application of insulin with concentrations of 100 U/ml (Humulin R U-100, Eli Lilly Canada, St-Laurent, Quebec, Canada) and 500 U/ml (Entuzity, Eli Lilly Canada, St-Laurent, Quebec, Canada) once per day to eyes diagnosed with open angle glaucoma. Both products of insulin are approved by Health Canada for subcutaneous and intravenous use for the treatment of diabetes mellitus. The proposed route of administration and indication of insulin use in this current study are therefore of off-label nature, for which the investigators will request a non-objection letter from Health Canada.

Hypothesis of the study: Topical ocular insulin (up to 500 U/ml) at once per day dosing is safe in patients with open angle glaucoma.

Objectives: To document and to report any ocular and/or systemic adverse events associated with topical insulin eye drops.