Pain Pediatric & Elderly AXA Research Lab (PEARL)

Chronic pain is recognized as a major public health problem affecting patients in their daily activity, physical and mental health, as well as their family and social circle. Striking, the estimated prevalence of chronic pain is higher as 25–50% in community-dwelling elders, reaching up to 80% in institutionalized individuals. In a similar way, the prevalence of chronic pain in children worldwide is estimated at 30%. 

However, the current analgesic therapies are dramatically poor despite thousands of molecules already on the market for different indications. We juggle around ten molecules for the management of nociceptive pain and 3 classes of drugs for neuropathic pain. Therefore, chronic pain in children or elderly is viewed as a “significant public health concern globally” by the World Health Organization marked by the paucity of research. Pain in children and elderly is neglected, unaddressed and mismanaged!

It is therefore essential to bring to the market suitable and necessary analgesics for children and elderly with reflection on the method of delivery of these molecules (such as for example topical route) to limit as much as possible the side effects. However, these requirements could be met through therapeutic innovation, personalized medicine and molecular repositioning.

The main causes of chronic pain in the elderly but also in children are secondary to another previous disorder, encompassing cancer, chronic or genetic diseases, neuropathic pain, musculoskeletal pain, skin pain, chronic post-traumatic or postsurgical pain, chronic visceral pain, chronic headache, and orofacial pain.

Among these pains, skin pain is probably the most difficult to manage while dermatologic disorders are the fourth leading cause of nonfatal disease burden worldwide. The skin is the largest organ in the body serving as a primary protective barrier against environmental challenges and responsible for sensory perception. This organ is therefore linked to the immune and sensory systems in a "neuro-immuno-cutaneous endocrine" (NICE) structure. To better understand the physiopathological mechanisms involved in the transmission of painful information between the keratinocytes and the peripheral nervous system, the team led by Prof. Greco decided to work on a model of genetic skin diseases called “Hereditary palmoplantar keratodermas (hPPKs)”, characterized by focal hyperkeratosis associated with intense pain and inflammation. More specifically, Olmsted syndrome, a severe form of hPPK, linked to activating mutations in the TRPV3 channel, is particularly painful. By targeting the EGFR signaling pathway in this disease, they observed for the first time a lasting remission in children profoundly disabled by their clinical manifestations and presenting a major depressive syndrome, as well as an arrest of their growth and progressive social isolation. Interestingly, they achieved not only an almost total regression of hyperkeratosis, but also a complete disappearance of pain in less than a month.

The research will aim at identifying the signaling pathways within keratinocytes that generate pain and inflammation to understand the complex interactions involving the components of the NICE system in hPPK diseases. A combined approach of analyzing gene expression and signaling pathways in keratinocytes will make it possible to find out how a single mutation expressed in basal keratinocytes can lead to hPPK and trigger pain and inflammation. In this work, the team will use Olmsted syndrome as a model to conduct this research and extend our approach to another types of painful hPPK, Epidermolysis Bullosa Simplex-Dowling Meara type (EBS-DM). This research involves the development of human pluripotent stem cell lines (hiPSCs) in which patient’s mutation is introduced by Crispr-Cas gene editing or hiPSC derived from patients’ cells. Mutated hiPSCs are then differentiated into keratinocytes and subjected to genomic, functional and biochemical analysis. Results will be compared between the different types of hiPSC derived keratinocytes (hiKCs) and normal human primary keratinocytes.

The comparative analysis of biological properties should lead to the identification of specific therapeutic targets for these different forms of painful hPPK and allow us, particularly through the repositioning of existing molecules, to treat them effectively.

A better comprehension of the mechanism of skin pain and the repurposing of existing molecules by choosing an absorption route suitable for children and elderly will help relieve the pain of no less than 7% of the world's population