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.
Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. rafael.yanez@genetics.kcl.ac.uk
Rafael J
RJ
Yáñez-Muñoz
Kamaljit S
KS
Balaggan
Angus
A
MacNeil
Steven J
SJ
Howe
Manfred
M
Schmidt
Alexander J
AJ
Smith
Prateek
P
Buch
Robert E
RE
MacLaren
Patrick N
PN
Anderson
Susie E
SE
Barker
Yanai
Y
Duran
Cynthia
C
Bartholomae
Christof
C
von Kalle
John R
JR
Heckenlively
Christine
C
Kinnon
Robin R
RR
Ali
Adrian J
AJ
Thrasher
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