Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy

Lentiviral transduction of the murine lung provides efficient pseudotype and developmental stage-dependent cell-specific transgene expression

“…We hypothesized that this would avoid immune elimination of the transgenic protein 12 and increase lung stem-cell transduction to result in longterm gene expression. Transduction of the murine lung was assessed at three developmental stages by the most amenable administration routes; adult (6 weeks), neonatal (1 day after birth) and fetal (16 days pcm).…”

“…Such observations have also been made on the livers of mice after in utero intra-vascular injection of VSV-G pseudotyped HIV and equine infections anemia virus (EIAV) vectors. 12,43 We speculate that this clustering of transduced cells may be evidence of infection of progenitor cells and the result of clonal expansion.…”

“…11 The fetal/ neonatal period is characterized by reduced immune reactivity and stem-cell niches may also be more accessible to transduction. For example, Waddington et al 12 recently showed that in utero gene delivery of a lentiviral vector carrying human factor IX resulted in lifelong correction of the bleeding diathesis, permanent expression of and immune tolerance to the xenoprotein.…”

Fetal and neonatal gene therapy: benefits and pitfalls

“…In contrast, adult administration resulted in brief expression, antibody production and a robust in vitro response of lymphocytes to inactivated vectors. 33 Tolerance to human factor IX has been demonstrated after in utero delivery using adenovirus 34 and lentivirus 12 vectors in mice, and following administration of oncoretroviral vectors in mice and dogs. 11 There is some concern that immune tolerance to viral proteins might predispose the individual to unchecked infection by the wild-type pathogen postnatally.…”

“…These include glycogen storage disease type Ia, 1 mucopolysaccharidosis type VII, [2][3][4][5][6] bilirubin-UDP-glucuronosyltransferase deficiency (Crigler-Najjar syndrome), 7,8 haemophilias A 9 and B [10][11][12] and congenital blindness (Leber congenital amaurosis). 13 To fully understand the basis of these successful experiments in order to move towards clinical application, several key factors concerning early gene transfer must be closely examined.…”