Neurotrophic factors to prevent the development of neuropathic pain in RDEB. (Calvo 1)Completed
|Project lead||Prof Margarita Calvo|
|Organisation||Pontificia Universidad Católica de Chile, Santiago, CHILE|
|Project budget||USD 105,390.00|
|Start date / Duration||01. Jul 2019 / 23 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria, MSAP/EBEP Recommended|
|Research area||Symptom prevention & relief|
Short lay summary
In the skin of RDEB patients, repeated cycles of blistering and healing that lead to a lack of adhesion of the epidermis to the dermis may result in the injury of small fibres that carry sensory information to the central nervous system. This damage leads to signals that are interpreted by the brain as painful stimuli, hence the name neuropathic pain. Previous research from this group has suggested that injured sensory fibres might underlie chronic and debilitating pain in RDEB patients.
Sensory regeneration of the nervous system depends on the local production in the skin of molecules called neurotrophic factors that can stimulate regrowth of sensory fibres and repair their damage. This project will establish the presence of these growth factors in the skin of patients with a confirmed diagnosis of RDEB who experience neuropathic pain. To achieve this goal, researchers will quantify neurotrophic factors in small skin samples of patients and control volunteers using standard molecular biology methods.
Chronic pain in RDEB patients is a common and debilitating problem, and its management is often complex due to the mixed aetiologies of pain. We have recently shown that these patients are at an increased risk of developing neuropathic pain, and we demonstrated that this is secondary to a dysfunction of the small unmyelinated fibres that innervate the skin. Functional impairment and reduction in intraepidermal fibres correlate well with the severity of this dermatological condition. These results suggest that repeated cycles of injury and healing at the dermo-epidermal boundary in RDEB patients lead to injury to the distal terminals of small fibres. Interestingly, this neuropathy presented with a length-dependent distribution pattern.
Sensory nervous system regeneration is dependent on the production of neurotrophic factors by targets of innervation such as the skin. These growth factors are retrogradely transported to the dorsal root ganglia (DRG), where the soma of sensory neurons is. It has been shown that in other length dependant small fibre neuropathies, the ability of C fibres to regenerate into the skin is diminished, and this can be due to a lack of growth factors. Topical delivery of growth factors in the skin has been shown to prevent the development of certain types of small fibre neuropathy. In this project, we aim to evaluate the role of neurotrophic factors in small fibre neuropathy and pain in RDEB. We hypothesize that in RDEB the axons of long C fibres are not able to get enough neurotrophic factors in their DRG to stimulate regeneration of the distal terminals in the skin. This could be due to a lack or reduction of the production of the neurotrophic factors in the skin, or due to reduced transport of these factors through the axon to the DRG. Using a highly translational approach, we aim at finding factors that are deregulated in the skin of RDEB patients, and the skin and somatosensory system of animal models. We would explore the effect of topically applying these factors to try to prevent/reverse the neuropathy and neuropathic pain in RDEB animals and subsequently in patients.
This research project addresses neuropathic pain, which is of clinical relevance to RDEB patients. Although this is a basic research study, it could potentially illuminate a novel route for the effective management of disabling chronic pain in RDEB patients. Previous work by other groups has provided evidence of neurotrophic factors' stimulation by the topical administration of molecules to the skin (Hedstrom et al., PNAS, 2014). This aspect is now under investigation for the first time in the context of RDEB.