UVA-2 and ultraviolet B (UVB) rays damage the cells of the skin (keratinocytes) and cause sunburn, skin aging, and skin cancer. When these cells are damaged by the UV light it causes them to die. In healthy people without lupus, these dead cells are cleared away quickly and any inflammation caused by the sun-induced skin damage is short-lived (sunburn). However, in people with lupus, the skin cells may be more sensitive to sun-induced damage and there is increasing evidence that the dying cells are not cleared away efficiently. As a result, the contents of the dying cells may be released, including those found in their nuclei. These nuclear proteins are particularly responsible for interacting with the immune system of a person who has lupus, encouraging it to become more active and cause inflammation and damage to various parts of the body.

Immune system molecules called type I interferons are one of the main factors that lead to tissue damage and disease symptoms in lupus. Type I interferons are a family of 17 similar molecules that help protect us from infections. Since the 1970’s it has been known that interferons are involved with lupus, up to 80% of patients have a high level of type I interferon signature in their blood. However, why these levels are higher are unknown. Recent research has suggested that the protein cGAS may be responsible to the high levels of interferons in lupus patients, also it has just recently been a probable participant in the inflammatory process in the skin post UV damage.

In this application we would like to achieve an in depth understanding of how cGAS is involved in UV-induced inflammation in the skin of lupus patients. This will be done by assessing the effects of inhibiting cGAS in lupus animal models post UV exposure and also exploring cGAS in lupus patient skin cells post UV exposure.

The proposed project falls in line with “Understanding the biological mechanisms of lupus disease” since we are exploring the protein cGAS and its role in post UV inflammation of the skin in lupus patients.

The Lupus Foundation of America estimates that 1.5 million Americans, and at least 5 million people worldwide, have a type of lupus. Photosensitivity is common in people with lupus: 40% to 70% of people with lupus will find that their disease is made worse by exposure to UV rays from sunlight or artificial light.

New immune responses can take over a week to develop, so the effects of sunlight will not necessarily be on the same day. Sun exposure can cause different types of rashes in people who have lupus. One is acute cutaneous lupus erythematosus (ACLE), better known as the butterfly or malar rash that appears on the face, across the bridge of the nose. It usually heals within weeks without scarring. Another type is discoid lupus erythematosus (DLE), which appears as disk-shaped lesions on skin that has been exposed to the sun. They develop slowly and may take months to heal. They may leave scars. Subacute lupus erythematosus (SCLE) appears as red circles on the arms, chest, and back. It may look scaly, like psoriasis, and heals over weeks or months. It may occur again with more sun exposure.

These skin conditions can cause severe social anxiety and depression. In addition to the physical changes these patients undergo, all people with lupus are advised to change their lifestyles – avoid sun exposure, and if they need to be in the sun, multiple protective measures must be taken, such as sunscreen, protective clothing etc.

The research we are proposing in this application will generate data of high importance for the development of a new therapeutic for UV induced skin inflammation in lupus patients. This new therapeutic will address a dire need in lupus patients looking for a solution for post UV exposure inflammation in the skin and system. Potentially this could be developed as a topical patients would use prior to UV exposure, just like sunscreen, to treat the inflammation during the UV exposure.

This would have a high impact on the quality of life of patients, improving the appearance of their skin, thus increasing their self-confidence and allowing them to go out in the sun without fear of the repercussions that may come after. This would be life changing for so many people on a global scale.

Future plans include within the coming year to begin IND enabling studies and then a phase 1 FIH clinical trial.