TY - JOUR
T1 - In utero injection of α-L-iduronidase-carrying retrovirus in canine mucopolysaccharidosis type I
T2 - Infection of multiple tissues and neonatal gene expression
AU - Meertens, Lisa
AU - Kohn, Donald
AU - Kruth, Stephen
AU - Hough, Margaret R.
AU - Dubé, Ian D.
AU - Zhao, Yongjun
AU - Rosic-Kablar, Suzana
AU - Li, Liheng
AU - Chan, Kin
AU - Dobson, Howard
AU - Gartley, Cathy
AU - Lutzko, Carolyn
AU - Hopwood, John
PY - 2002
Y1 - 2002
N2 - Canine α-L-iduronidase (α-ID) deficiency is caused by a single base pair mutation in the α-ID gene, resulting in no enzyme activity in homozygous affected pups. The disease clinically resembles human mucopolysaccharidosis type I (MPSI). We used the canine MPSI model system to address the efficacy of a new retroviral vector, MND-MFG, containing the human α-ID cDNA (MND-MFG-α-ID) for direct in utero gene delivery to MPSI cells. In vitro, the MND-MFG-α-ID vector showed high-level, long-term expression of the transgene in both canine and human α-ID-deficient fibroblasts. The effectiveness of this vector for in utero gene transfer and expression in multiple tissues was assessed by injecting viral supernatants into MPSI fetuses and evaluating transduction efficiency and enzyme expression at various times after birth. Transduction of a spectrum of cell types and tissues was observed in all seven live-born pups and in one stillborn pup. Although enzyme activity was not detected in adult tissues from the seven surviving pups, significant α-ID enzyme activity was detected in both the liver and kidney of the deceased pup. Our combined gene delivery vector and in utero transfer approach, while encouraging in terms of overall gene transfer efficiency to multiple tissues and successful short-term gene expression, was unable to meet the important requirement of sustained in vivo gene expression.
AB - Canine α-L-iduronidase (α-ID) deficiency is caused by a single base pair mutation in the α-ID gene, resulting in no enzyme activity in homozygous affected pups. The disease clinically resembles human mucopolysaccharidosis type I (MPSI). We used the canine MPSI model system to address the efficacy of a new retroviral vector, MND-MFG, containing the human α-ID cDNA (MND-MFG-α-ID) for direct in utero gene delivery to MPSI cells. In vitro, the MND-MFG-α-ID vector showed high-level, long-term expression of the transgene in both canine and human α-ID-deficient fibroblasts. The effectiveness of this vector for in utero gene transfer and expression in multiple tissues was assessed by injecting viral supernatants into MPSI fetuses and evaluating transduction efficiency and enzyme expression at various times after birth. Transduction of a spectrum of cell types and tissues was observed in all seven live-born pups and in one stillborn pup. Although enzyme activity was not detected in adult tissues from the seven surviving pups, significant α-ID enzyme activity was detected in both the liver and kidney of the deceased pup. Our combined gene delivery vector and in utero transfer approach, while encouraging in terms of overall gene transfer efficiency to multiple tissues and successful short-term gene expression, was unable to meet the important requirement of sustained in vivo gene expression.
UR - http://www.scopus.com/inward/record.url?scp=0036412405&partnerID=8YFLogxK
U2 - 10.1089/104303402760372918
DO - 10.1089/104303402760372918
M3 - Article
C2 - 12396614
AN - SCOPUS:0036412405
SN - 1043-0342
VL - 13
SP - 1809
EP - 1820
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 15
ER -