DNA Repair

About DNA Repair

All human life originates from one single cell, the fertilised egg cell, before rapidly expanding into trillions of specialised cells which combine to form complex organ systems over a period of nine months. To maintain the delicate balance necessary for both survival and diversity, evolution has equipped us with the tools to either remove or tolerate DNA damage.

Ultraviolet radiation (UVR) in sunlight often triggers deformation of DNA within the nucleus of our skin cells. For every hour skin is exposed to the sun, approximately 80,000 of the most common forms of DNA damage occur.¹ It is believed that these mutations in DNA can initiate melanoma and non-melanoma skin cancers.²

This direct damage to our DNA is accompanied by indirect damage caused by reactive oxygen species (ROS).

Our bodies have formulated a variety of strategies to repair damaged DNA, depending on the severity, and whether the cell is replicating.

1. DiGiovanna, J. J., & Kraemer, K. H. (2012). Shining a light on xeroderma pigmentosum. Journal of investigative dermatology, 132(3), 785–796.
2. Barnes, J. L., Zubair, M., John, K., Poirier, M. C. & Martin, F. L. Carcinogens and DNA damage. Biochemical Society Transactions 46, 1213–1224 (2018).Excision repairs, rely on identifying the damaged areas, cutting away individual or longer sections of the DNA strand and replacing them with accurate replication.

DNA damage and repair

Ultraviolet (UVB, wavelengths 290-320 nm and UVA of 320-400 nm) and high-energy visible (HEV, 380-500 nm) light penetrate the skin, leading to cellular oxidative stress and damage to DNA within the nucleus of skin cells. This damage consists of changes to the DNA structure (photoproducts) which, if left unrepaired, can replicate and increase the risk of skin cancers such as melanoma.

Under normal conditions, the body is capable of repairing DNA damage through nucleotide excision repair (NER) and base excision repair (BER); processes in which defective strands of DNA are “snipped”, removed and then replaced by the correct DNA sequences. XP patients, recipients of an organ transplant and people of Anglo-Saxon origin with red hair, blue eyes and fair skin are at the highest risk of developing skin cancers because they have either insufficient or defective NER and BER. This reduces their capacity to repair damaged DNA.

During CLINUVEL’s development of afamelanotide, a number of categories of scientific evidence have been accumulated: systemic photoprotection to skin cells; optimisation of skin cells’ response to UV radiation; anti-oxidative capacity; elimination of photoproducts (chemical damage to DNA); increased activity of DNA repair genes (as part of NER and BER); and reduction of cell death (apoptosis) following UV exposure.

Figure 1 illustrates how CLINUVEL’s DNA repair programme has placed emphasis on the safety of patients and volunteers exposed to afamelanotide—more than 10,000 doses in over 1,400 subjects—during 20 years of clinical use, a requisite to being able to complete the clinical use of the hormone as a DNA restorative drug in
patients at the highest risk of developing skin cancers.

Stages S1 to S5 have been evaluated by the Company and regulatory authorities as satisfactory and complete, enabling Stage 6 of clinical investigation in the scope of afamelanotide as a DNA-regenerative pharmaceutical therapy. Clinical stage S6 consists first of a Special Access Program in XP to confirm the safety of the drug in this highest-risk population, followed by a pilot study in XP-C (CUV150), and a parallel control study in healthy volunteers (CUV151) who are exposed to UV radiation under standardised conditions.