Granzyme B (GzmB), an immune-secreted serine protease, is abundant in skin conditions characterized by excessive inflammation (such as burns, blisters, or scarring) at the hair follicle or at or just under the epidermis, and has been identified as a therapeutic target for autoimmune and chronic skin diseases.
Studies have defined a role for GzmB at the interface between the outermost (epidermis) and inner (dermis) layers of skin known as the dermal-epidermal junction (DEJ). In fact, many of the key proteins that anchor these two layers together are proteolytic substrates of GzmB. Given that it is well-documented that GzmB accumulates in the DEJ in many autoimmune conditions associated with separation of these layers (e.g. blistering and skin peeling conditions), it is plausible that GzmB-mediated cleavage of such anchoring proteins would contribute to disruption of the DEJ leading to blistering. In support of this concept, when human GzmB is added to freshly obtained human skin, complete separation of the DEJ ensues.
Dr. Granville has developed a topical first-in-class inhibitor of GzmB and have identified a condition known as Discoid lupus erythematosus (DLE) as our lead indication to enter the clinic. DLE is a rare, autoimmune skin condition that is usually triggered by sunlight. DLE lesions are characterized by DEJ inflammation, scarring, alopecia, and microvascular damage. Importantly, GzmB levels are highly elevated in this form of cutaneous lupus.
The aim is to obtain first approval of our GzmB inhibitor for DLE followed by subsequent approvals for other skin conditions. This project will generate further proof-of-concept data to support the clinical development and commercialization of a topical GzmB therapeutic for inflammatory skin conditions.