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

Author:

Sarangi Pratiksha1,Senthilkumar Mohankumar B.1ORCID,Amit Sonal2,Kumar Narendra1,Jayandharan Giridhara R.1ORCID

Affiliation:

1. Laurus Center for Gene Therapy, Department of Biological Sciences and Bioengineering and Mehta Family Centre for Engineering in Medicine and Gangwal School of Medical Sciences and Technology Indian Institute of Technology Kanpur Kanpur Uttar Pradesh India

2. Department of Pathology Autonomous State Medical College Kanpur Uttar Pradesh India

Abstract

AbstractHaemophilic 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.

Funder

Science and Engineering Research Board

Publisher

Wiley

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