Calpains are a family of ubiquitously-expressed, calcium-dependent, non-lysosomal cysteine proteases which are present in the cells of many optic and neuronal tissues. There are two major isoforms of this family of proteases - Calpain 1 and Calpain 2. Calpains are activated by an influx of calcium ions into cells, with Calpain 1 requiring less calcium for activation than Calpain 2.
Upon activation, both Calpain 1 and Calpain 2 can transform into their more dangerous and active states that can, if left unregulated, lead to the indiscriminate breaking of peptide bonds resulting in protein or cellular breakdown.
Calpain has been linked to a range of different disorders depending on where in the body Calpain is activated. In ophthalmology, protein or cellular damage can occur in the front (lens) and/or the back (retina) of the eye.
Cataract is a condition where the lens of an eye becomes increasingly clouded, resulting in blurred vision, which if untreated can eventually result in blindness. The clouding is due to degradation of lens and cytoskeletal proteins. The most common cause of cataracts is age however a range of other triggers include UV exposure, smoking, physical trauma, genetic predisposition and medications may lead to sustained activity of Calpain in the lens. The most common type of cataract is cortical cataract which generally appears as a cloudy opacity in the peripheral part of the lens called the cortex. These cataracts often resemble wheel spokes that point inward toward the center of the lens. Calpain is thought to be associated with the development of cortical cataract.
Our of our compounds is a potent inhibitor of Calpain and it is being investigated as a novel means to halt or significantly slow cortical cataract onset or progression.
Glaucoma is a group of eye diseases that steals sight without warning and often without symptoms. It is a condition in which normal fluid pressure inside the eyes (intraocular pressure, IOP) slowly raises when the fluid cannot drain properly. The collection of fluid causes pressure damage to the optic nerve. Subsequent loss of vision under such stressful conditions of elevated IOP arises on the molecular level from death of retinal ganglion cells, with activated Calpain suspected as being one of the major molecular level culprits.
We are developing a first-in-class pre-clinical drug formulation capable of selectively blocking Calpain activation. This neuroprotectant significantly protects retinal ganglion cells in animal models tested thusfar.
Calpain Therapeutics has exclusively in-licensed a novel class of proprietary Calpain inhibitors. These inhibitors were developed using a combination of computational medicinal chemistry and other rational drug-design techniques.
These inhibitors are structurally-unique, macrocyclic, and potent inhibitors of Calpain that have applications to treating front and back of the eye diseases.