Restoring ciliary function to differentiated primary ciliary dyskinesia cells with a lentiviral vector.
Gene Ther
; 21(3): 253-61, 2014 Mar.
Article
in En
| MEDLINE
| ID: mdl-24451115
ABSTRACT
Primary ciliary dyskinesia (PCD) is a genetically heterogenous autosomal recessive disease in which mutations disrupt ciliary function, leading to impaired mucociliary clearance and life-long lung disease. Mouse tracheal cells with a targeted deletion in the axonemal dynein intermediate chain 1 (Dnaic1) gene differentiate normally in culture but lack ciliary activity. Gene transfer to undifferentiated cultures of mouse Dnaic1(-/-) cells with a lentiviral vector pseudotyped with avian influenza hemagglutinin restored Dnaic1 expression and ciliary activity. Importantly, apical treatment of well-differentiated cultures of mouse Dnaic1(-/-) cells with lentiviral vector also restored ciliary activity, demonstrating successful gene transfer from the apical surface. Treatment of Dnaic1(flox/flox) mice expressing an estrogen-responsive Cre recombinase with different doses of tamoxifen indicated that restoration of â¼20% of ciliary activity may be sufficient to prevent the development of rhinosinusitis. However, although administration of a ß-galactosidase-expressing vector into control mice demonstrated efficient gene transfer to the nasal epithelium, treatment of Dnaic1(-/-) mice resulted in a low level of gene transfer, demonstrating that the severe rhinitis present in these animals impedes gene transfer. The results demonstrate that gene replacement therapy may be a viable treatment option for PCD, but further improvements in the efficiency of gene transfer are necessary.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Therapy
/
Ciliary Motility Disorders
/
Lentivirus
/
Axonemal Dyneins
Limits:
Animals
Language:
En
Journal:
Gene Ther
Journal subject:
GENETICA MEDICA
/
TERAPEUTICA
Year:
2014
Document type:
Article
Affiliation country:
Estados Unidos