Inflammation et douleur : thérapie génique expérimentale

Abstract

Récemment, plusieurs équipes ont montré l’intérêt potentiel des transferts de gènes, à l’aide de divers vecteurs, dans des modèles animaux de douleurs chroniques. Le transfert de gènes codant pour des précurseurs de peptides opioïdes endogènes, conduisant à la production - dans la moelle épinière ou les neurones sensoriels primaires - de grandes quantités de peptides physiologiquement actifs qui en dérivent, se traduit par une diminution marquée des douleurs chroniques d’origine inflammatoire ou neurologique. D’autres molécules, comme les cytokines, impliquées dans l’induction ou la persistance des douleurs, représentent des cibles potentielles de ces approches. Bien que des progrès importants aient été réalisés dans le développement des vecteurs utilisés, leur innocuité reste à démontrer chez l’homme avant d’envisager la thérapie génique des douleurs chroniques rebelles aux traitements actuellement disponibles.

Chronic pain is frequently associated with profound alterations of neuronal systems involved in pain processing and should be considered as a real disease state of the nervous system. Unfortunately, some forms of chronic pain remain difficult to be satisfactorily treated. In the search for new therapeutic strategies, the gene-based approaches are of potential interest as they offer the possibility to introduce a therapeutic protein into some relevant structures and to drive its continuous production in the near vicinity of targeted cells. Recently, these techniques have been experimented in several animal models of chronic pain, showing that transfer at the spinal level of some genes, in particular those of opioid precursors proopiomelanocortin or proenkephalin A, leading to the overproduction of products that they encode, attenuated persistent pain of both inflammatory and neuropathic origin. Thus, in polyarthritic rat, a model of chronic inflammatory pain, we demonstrated that herpes simplex virus vector mediated overexpression of proenkephalin A in primary sensory neurons at the lumbar level elicited both antihyperalgesic and anti-inflammatory activities. Apart from opioids, numerous other molecules involved in pain processing are of potential therapeutic interest for gene-based protocols. For instance, targeting some molecules involved in pain induction and perpetuation, such as proinflammatory cytokines, raises an interesting possibility to block the « development » of pain. The clinical application of these approaches remains to be established, and, presently, one of the main problems to be solved is the innocuity of virus-derived vectors. However, the experimental use of gene-based techniques might be particularly useful for the evaluation of the therapeutic interest of some recently identified molecules involved in pain processing and might finally lead to the development of new “classical” pharmacological tools.