Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction

Abstract

Pompe disease results from the deficiency of the lysosomal enzyme acid a-glucosidase (GAA), leading to accumulated glycogen in the heart and the skeletal muscles, which causes cardiomyopathy and muscle weakness. In this study, we tested the feasibility of gene therapy for Pompe disease using a lentivirus vector (LV). Newborn GAA knockout mice were treated with intravenous injection of LV encoding human GAA (hGAA) through the facial superficial temporal vein. The transgene expression in the tissues was analyzed up to 24 weeks after treatment. Our results showed that the recombinant LV was efficient not only in increasing the GAA activity in tissues but also in decreasing their glycogen content. The examination of histological sections showed clearence of the glycogen storage in skeletal and cardiac muscles 16 and 24 weeks after a single vector injection. Levels of expressed hGAA could be detected in serum of treated animals until 24 weeks. No significant immune reaction to transgene was detected in most treated animals. Therefore, we show that LV-mediated delivery system was effective in correcting the biochemical abnormalities and that this gene transfer system might be suitable for further studies on delivering GAA to Pompe disease mouse models.

RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy

“…A number of studies suggest that there are advantages to initiating gene therapy in the neonate 14–19. These include: (i) gene expression may avoid the development of irreversible pathology; (ii) the earlier vector is administered, the greater the vector to cell ratio allowing for less vector administration; (iii) stem and progenitor cells, likely less accessible later in life, may be more easily transduced; and (iv) immune responses may be reduced or absent 18.…”

Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII

“…A number of reports suggest that there are advantages to initiating gene therapy in the neonatal period (3)(4)(5)(6)(7)(8). These advantages include the following: (i) early gene expression to avoid the development of irreversible pathology; (ii) administering vector earlier results in greater vector to cell ratio, allowing for less vector administration; (iii) stem and progenitor cells, likely less accessible later in life, may be more easily transduced; and (iv) immune responses may be reduced or absent (7).…”

Minimum requirement of donor cells to reduce the glycolipid storage following bone marrow transplantation in a murine model of Fabry disease

“…ERT and BMT) might be more effective than BMT alone 28–30. There are reports that gene therapy can reduce the risk of antibody formation to administration of recombinant enzyme in Pompe mice 31, 32 and immunomodulatory GT also may prevent antibody formation and lethal hypersensitivity 33.…”