ABSTRACT
Fibrodysplasia Ossificans Progressiva (FOP) is a rare congenital intractable disease associated with a mutation in ACVR1 gene, characterized by skeleton malformations. Ascorbic acid (AA) and propranolol (PP) in combination is reported to minimize flare-ups in patients. FOP leukocyte phenotype may possibly be modulated by AA and PP treatment. In this study, expression of 22 potential target genes was analyzed by RT-PCR in peripheral blood mononuclear cells culture (PBMC) from FOP patients and controls to determine effectiveness of the combination therapy. PBMC were treated with AA, PP and AA+PP combination. Basal expression of 12 of the 22 genes in FOP PBMC was statistically different from controls. ACVR1, ADCY2, ADCY9 and COL3 were downregulated while COL1 was upregulated. ADRB1, ADRB2, RUNX2, TNF-α and ACTB, were all overexpressed in FOP PBMC. In control, AA upregulated COL1, SVCT1, ACTB, AGTR2 and downregulated ADCY2. In FOP cells, AA upregulated ACVR1, BMP4, COL1, COL3, TNF-α, ADCY2, ADCY9, AGTR2 and MAS, while downregulated ADBR2, RUNX2, ADCY1, SVCT1 and ACTB. PP increased ADBR1 and decreased RUNX2, TNF-α, AGTR1, ACTB and CHRNA7 genes in treated control PBMC compared to untreated. PP upregulated ADBR1, ADBR2 and MAS, and downregulated TNF-α and ACTB in treated FOP PBMC versus untreated. AA+PP augmented ADRB1 and ADRB2 expressions in control PBMC. In FOP PBMC, AA+PP augmented ACVR1, COL1, COL3, ADBR1, AGTR2 and MAS expression and downregulated ADBR2, RUNX2, ACTB and MRGD. These data show distinct gene expression modulation in leukocytes from FOP patients when treated with AA and or PP.
ABSTRACT
Fibrodysplasia ossificans progressiva (FOP) is a rare, intractable and devastating genetic connective tissue disorder characterized by progressive ectopic ossification in the soft tissues and skeleton. Three patients, one teenage girl (P1), one male adult (P2) and one male child (P3), were studied and treated with FOPCON (combined formulation of 14 mg of propranolol and 250 mg of ascorbic acid), given three times per day. P1 started treatment in March 2012, P2 in October 2012 and P3 in July 2015. The clinical follow-up of these three patients, before initiating treatment with FOPCON, showed that FOP flare-ups used to occur frequently and that under FOPCON therapy, none of these patients had flare-ups. The striking feature of this treatment with FOPCON, is that, all three cases suffered accidental falls with documented injures until complete healing and that where major flare-ups should occur, injures or sequels, there was none. The present clinical observation shows that ascorbic acid plus the nonspecific beta blocker propranolol can be effectively useful, when administered previously and continually, in the prophylaxis of FOP flare-ups, especially for accidental falls. In this regard, FOPCON could be a prophylactic aid in cases of surgery of patients with FOP, hoping that it may benefit patients from having the severe sequels, characteristic of heterotopic bone formation. All three patients reported, to date, they no longer had flare-ups nor heterotopic ossification and showed normal scar healing.
