Translational research in disorders of DNA repair: the challenges in the application of therapeutic discoveries to the treatment of human disease

Abstract

Our DNA is continually being damaged by a variety of endogenous and exogenous sources and we have evolved a number of complex and effective systems to recognize and repair this damage. Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two rare disorders of DNA repair caused by mutations in genes that play critical roles in nucleotide excision repair (NER). XP is divided into seven main complementation groups (XP-A to XP-G) and CS is divided into three clinical types based on severity of disease. XP is characterized by an increased risk of skin cancers because of an inability to repair ultraviolet radiation (UVR)-induced DNA damage. About 50% of affected individuals are photosensitive and about 30% develop progressive neurological degeneration. There is no cure and the management of XP focuses on prevention of skin cancers by avoidance of UVR exposure. The neurodegeneration in XP is not understood. Input from physiotherapy and occupational therapy help maintain function for as long as possible. However, in those with progressive neurological dysfunction, the prognosis is poor (mean age of death 29 years). CS is characterized by short stature, photosensitivity, distinctive facial appearance, ocular defects, premature ageing and progressive neurological dysfunction. The prognosis is often very poor (mean age of death 8 4 years). Novel therapeutic approaches to XP and CS are urgently needed and in this issue of the BJD, Weon and Glass summarize three new possible treatment options. Firstly, acetohexamide, a drug used to treat diabetes, that removes UVR-induced DNA damage through an NER independent pathway in XP cells lines. Secondly, nicotinamide, that causes a 23% reduction in nonmelanoma skin cancers but this has not yet been tried in patients with XP. In addition, nicotinamide promotes recovery of repressed expression of genes involved in neuronal development in some XP and CS cell lines. Thirdly, caloric restriction in some XP and CS mouse models delays the neuronal loss (neurodegeneration). All these studies demonstrate potential therapies at the cellular level or in mouse models of disease but what is their clinical application in patients? Weon and Glass makes us think about the challenges in the translation of potential therapeutic approaches, from cellular work and mouse models, to clinical practice in these rare diseases. Clinical therapeutic trials for rare disorders such as XP and CS are very difficult as the number of patients is small. International collaborations are essential to study the effects of a potential treatment in larger cohorts, in order to come to more meaningful and robust conclusions. Careful consideration must be given to clear and relevant clinical end points. It is well known that there is significant heterogeneity of clinical features across and within complementation groups in XP. The natural history of neurodegeneration is very variable and this makes it difficult to assess the potential benefits of a new treatment. Moreover, the progressive neurological degeneration usually starts in childhood and therefore any potential treatment will ideally need to be assessed in children in an attempt to prevent or delay neurological decline. However, the design of therapeutic clinical studies that include children are complex and challenging. Mouse models are not always a true reflection of the disease in humans. For example, XP-A mice show very mild neurological abnormality in comparison with the severe neurodegeneration seen in XP-A patients. Therefore, potential therapeutic benefits seen in mice may not correlate correctly with response in humans. Nevertheless, currently there are no treatments available for the devastating progressive neurodegeneration observed in these diseases and it is the responsibility of scientists and clinicians working in these fields to come together and take laboratory discoveries safely into clinical practice.