Effective gene therapy with nonintegrating lentiviral vectors.
Retroviral and lentiviral vector integration into host-cell chromosomes carries with it a finite chance of causing insertional mutagenesis. This risk has been highlighted by the induction of malignancy in mouse models, and development of lymphoproliferative disease in three individuals with severe combined immunodeficiency-X1 (refs. 2,3). Therefore, a key challenge for clinical therapies based on retroviral vectors is to achieve stable transgene expression while minimizing insertional mutagenesis. Recent in vitro studies have shown that integration-deficient lentiviral vectors can mediate stable transduction. With similar vectors, we now show efficient and sustained transgene expression in vivo in rodent ocular and brain tissues. We also show substantial rescue of clinically relevant rodent models of retinal degeneration. Therefore, the high efficiency of gene transfer and expression mediated by lentiviruses can be harnessed in vivo without a requirement for vector integration. For therapeutic application to postmitotic tissues, this system substantially reduces the risk of insertional mutagenesis.
Yáñez-Muñoz
Rafael J
RJ
Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. rafael.yanez@genetics.kcl.ac.uk
Balaggan
Kamaljit S
KS
MacNeil
Angus
A
Howe
Steven J
SJ
Schmidt
Manfred
M
Smith
Alexander J
AJ
Buch
Prateek
P
MacLaren
Robert E
RE
Anderson
Patrick N
PN
Barker
Susie E
SE
Duran
Yanai
Y
Bartholomae
Cynthia
C
von Kalle
Christof
C
Heckenlively
John R
JR
Kinnon
Christine
C
Ali
Robin R
RR
Thrasher
Adrian J
AJ
D000818:Animals; D001921:Brain / Q000166:cytology; D002352:Carrier Proteins; D004596:Electroretinography; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D010857:Pigment Epithelium of Eye / Q000166:cytology; D051381:Rats; D012160:Retina / Q000166:cytology; D014407:Tumor Cells, Cultured; D016662:Virus Integration / Q000235:genetics; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C485184:enhanced green fluorescent protein