AVALIAÇÃO CLÍNICA E MOLECULAR EM PORTADORES DE FIBRODISPLASIA OSSIFICANTEPROGRESSIVA TRATADOS COM ÁCIDO ASCÓRBICO, PROPRANOLOL E EPIGALOCATEQUINA

Abstract

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by a severe form of heterotopic ossification. There is no curative treatment, however, recent therapies demonstrate the potential to improve the control of heterotopic flare-ups and ossification, as well as the quality of life of patients. Treatment with ascorbic acid (AA) combined with propranolol (FOPCON) has demonstrated benefits for FOP symptoms, mainly due to its analgesic, anti-angiogenic and anti-inflammatory combination. Due to the complexity of its multifactorial pathophysiology, it is crucial to continue investigating putative pharmacological components in minimizing the neuroinflammatory mechanisms of this orphan disease, which culminate in the formation of ectopic bone. In this context, an analysis of the effects of an anti- inflammatory flavonoid, Epigallocatechin gallate, administered in combination with FOPCON (FOPCONEpi) was carried out, aiming to extend the beneficial effects. With the objective of evaluating the effects of FOPCONEpi regarding the clinical and molecular benefits of the expression of four genes involved in the inflammatory neuropathophysiological of FOP symptoms, COL1, ADRB2, TNFα and RUNX2, using oral mucosa samples as target tissue. Furthermore, the results of this study were compared with in vitro human peripheral blood mononuclear cell (PBMC) samples from previous studies involving the same individuals. This research was conducted with four groups: (1) healthy volunteers, (2) patients with FOP without prior treatment (3) patients with FOP treated with FOPCON, (4) individuals with FOP undergoing treatment with FOPCONEpi and (5) patients with FOP in wash-out period. For statistical analysis, we used the comparative method ∆∆CT, unpaired Student's t-test and ANOVA (p<0.05). Results demonstrated differences in the expression of target genes between experimental groups. Patients with FOP and treated with FOPCONEpi showed overexpression of the Col1, TNFα and RUNX2 genes compared to controls, and overexpression of the RUNX2 gene compared to those treated with FOPCON. The ADBR2 gene was overexpressed in FOP patients during wash-out (interruption between FOPCON and use of FOPCONEpi). It was found that the use of FOPCON had a beneficial effect in response to levelling the gene expression of Col1, TNFα and RUNX2 close to the control group, and consequently, corroborating the reduction of flare-ups. The association of FOPCONEpi suggests pharmacokinetic competition between components of this formulation and requires further investigation. The innovative approach to collecting samples from the oral mucosa and the results consistent with previous studies offer promising prospects for advancing research and treatment of FOP. Keywords: Anti-inflammatory; Anti-angiogenic; Flare-ups; Ascorbic acid; Propranolol; Epigallocatechin Galate.