Modulation of soluble Adenylyl Cyclase (sAC) as a Method of Altering Melanocyte Pigmentation

Background & Unmet Need

• Melanin is a natural pigment responsible for giving color and protecting the skin and eyes from excess ultraviolet (UV) radiation
• Oculocutaneous albinism (OCA) is a group of pigment diseases defined by a loss of pigment in the eyes, skin, and hair
• Loss of pigment has significant psychosocial effects and can lead to vision defects and skin cancer
• Melanin is also implicated in the brain, where neuromelanin is produced using similar mechanisms as the skin
• Patients with Parkinson's only have about 50% of the normal amount of neuromelanin in the substantia nigra, and increased levels of neuromelanin could potentially be used to treat these patients
• Unmet Need: Methods of modulating melanin production and pigmentation for treatment of melanin-related diseases

Technology Overview

• The Technology: Methods to modulate melanin production via soluble Adenylyl Cyclase (sAC) by altering melanosome pH
• The Discovery: The inventor has discovered that sAC, a non-canonical source of cAMP, acts as a pH sensor in a second cAMP-signaling pathway which regulates pigmentation
• Through this pathway, the loss or inhibition of sAC-specific cAMP increases melanin production
• As the most common forms of OCA are due to improper melanosome pH levels, treatment with sAC inhibitors can rescue abnormal pH and pigmentation
• PoC Data: Topical treatment of mice with sAC inhibitors has been shown to increase pigmentation in the skin, eyes and hair
• Intraperitoneal injection of sAC inhibitors restored melanosomal pH to normal levels and increased pigmentation of eyes in a mouse model of OCA type 2

Technology Applications

• Treatment of patients with albinism including oculocutaneous albinism, a group of rare diseases
• Reduction of risk for skin cancer by increasing pigmentation
• Treatment of Parkinson’s Disease via increasing levels of neuromelanin
• Cosmetic applications for the darkening of skin or hair, such as self-tanning lotions or hair coloring

Technology Advantages

• sAC-specific cAMP acts in a distinct cAMP signaling cascade to induce melanin induction, so sAc inhibitors represent a new class of pigment regulators
• sAC inhibitors can be applied topically for area-specific modulation

Figure 1: Top: Loss of sAc via genetic knockout in mice increases pigmentation in the hair Bottom: Topical application of sAC inhibitors LRE1 or KH7 increased melanin and pigmentation in the epidermis.