AAV mediated repression of Neat1 lncRNA combined with F8 gene augmentation mitigates pathological mediators of joint disease in haemophilia.

Haemophilic arthropathy (HA), a common comorbidity in haemophilic patients leads to joint pain, deformity and reduced quality of life. We have recently demonstrated that a long non‐coding RNA, Neat1 as a primary regulator of matrix metalloproteinase (MMP) 3 and MMP13 activity, and its induction in the target joint has a deteriorating effect on articular cartilage. In the present study, we administered an Adeno‐associated virus (AAV) 5 vector carrying an short hairpin (sh)RNA to Neat1 via intra‐articular injection alone or in conjunction with systemic administration of a capsid‐modified AAV8 (K31Q) vector carrying F8 gene (F8‐BDD‐V3) to study its impact on HA. AAV8K31Q‐F8 vector administration at low dose, led to an increase in FVIII activity (16%–28%) in treated mice. We further observed a significant knockdown of Neat1 (~40 fold vs. untreated injured joint, p = 0.005) in joint tissue of treated mice and a downregulation of chondrodegenerative enzymes, MMP3, MMP13 and the inflammatory mediator‐ cPLA2, in mice receiving combination therapy. These data demonstrate that AAV mediated Neat1 knockdown in combination with F8 gene augmentation can potentially impact mediators of haemophilic joint disease. [ABSTRACT FROM AUTHOR]