OC 36.4 - miRNA expression profiles as a potential biomarker of joint and bone health in haemophilia A

Background: Haemophilic arthropathy (HArt) is a serious complication in patients with haemophilia. Early diagnosis and treatment are essential to minimise the development of HArt. The use of biomarkers may improve early diagnosis of HArt. Circulating microRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression, and are being investigated as promising biomarkers due to their role in joint and bone metabolism.

Aims: To investigate differential expression miRNAs and their relationship to arthropathy in patients with haemophilia A.

Methods: miRNA expression was examined in a pilot study followed by a validation study (99 haemophilia A patients with [n=82] and without HArt [n=17], 14 controls). Differential miRNA expression was investigated using real-time quantitative PCR.

Results: The pilot study identified 2 miRNAs differentially expressed in patients with HArt (Pettersson score ≥1), after adjusting for the false discovery rate (FDR). The validation study evaluated these 2 miRNAs. The results demonstrated that two miRNAs (miR- 208a-3p and 524-3p) were significantly underexpressed in plasma of patients with HArt compared to patients without arthropathy, with FDR < 0.05 (Figure 1). In addition, 3 miRNAs (miR- 130a-3p, 335-5p and 506-3p) were significantly underexpressed in patients with moderate HArt (Pettersson score 4 to 7).

Conclusion(s): In this proof-of-concept study we identified a signature of 5 circulating miRNAs associated with HArt which could potentially be used as diagnostic tools. These miRNAs are potential negative regulators of gene expression, suggesting their activity in HArt by interfering with osteoblastic (miR-208a-3p) and osteoclastic (miR-506-3p) differentiation to impair bone mineralisation and remodelling processes, or regulating chondrogenesis (miR-335-5p). miRNAs associated with earlier stages of HArt will be further investigated in a sub-study of the prospective clinical trial PROVE, which will investigate the effects of long-term prophylaxis with simoctocog alfa versus emicizumab in adults with haemophilia A.