AAV mediated repression of Neat1 lncRNA combined with F8 gene augmentation mitigates pathological mediators of joint disease in haemophilia.
Animals
Hemophilia A
/ genetics
Dependovirus
/ genetics
RNA, Long Noncoding
/ genetics
Matrix Metalloproteinase 13
/ metabolism
Mice
Matrix Metalloproteinase 3
/ genetics
Genetic Vectors
/ genetics
Factor VIII
/ genetics
Joint Diseases
/ therapy
Humans
Genetic Therapy
/ methods
Mice, Inbred C57BL
Cartilage, Articular
/ metabolism
Disease Models, Animal
Male
Neat1
F8
adeno‐associated virus
haemophilic arthropathy
matrix metalloproteinases
murine model
shRNA
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
Jun 2024
Jun 2024
Historique:
revised:
24
04
2024
received:
03
12
2023
accepted:
16
05
2024
medline:
12
6
2024
pubmed:
12
6
2024
entrez:
12
6
2024
Statut:
ppublish
Résumé
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.
Substances chimiques
RNA, Long Noncoding
0
Matrix Metalloproteinase 13
EC 3.4.24.-
Matrix Metalloproteinase 3
EC 3.4.24.17
Factor VIII
9001-27-8
Mmp13 protein, mouse
EC 3.4.24.-
Mmp3 protein, mouse
EC 3.4.24.17
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e18460Subventions
Organisme : Science and Engineering Research Board
ID : CRG/2019/001211
Informations de copyright
© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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