Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer

Abstract

A single intravenous injection with 4 Â 10 7 PFU of recombinant adenovirus encoding mouse b-galactosidase cDNA to newborn mice provided widespread increases of b-galactosidase activity, and attenuated the development of the disease including the brain at least for 60 days. The bgalactosidase activity showed 2-4 times as high a normal activity in the liver and lung, and 50 times in the heart. In the brain, while the activity was only 10-20% of normal, the efficacy of the treatment was distinct. At the 30th day after the injection, significant attenuation of ganglioside GM1 accumulation in the cerebrum was shown in three out of seven mice. At the 60th day after the injection, the amount of ganglioside GM1 was above the normal range in all treated mice, which was speculated to be the result of reaccumulation. However, the values were still definitely lower in most of the treated mice than those in untreated mice. In the histopathological study, X-gal-positive cells, which showed the expression of exogenous b-galactosidase gene, were observed in the brain. It is noteworthy that neonatal administration via blood vessels provided access to the central nervous system because of the incompletely formed blood-brain barrier.

Effects of cyclodextrins on GM1-gangliosides in fibroblasts from GM1-gangliosidosis patients

“…Without enough functional β‐galactosidase which in humans is encoded by the GLB1 gene, GM1‐gangliosides cannot be degraded in lysosomes, and eventually GM1‐gangliosides accumulate to toxic levels in many tissues and organs, particularly in the brain [1]. Several approaches for the treatment of GM1‐gangliosidosis were developed, such as enzyme replacement therapy,[2] gene therapy,[3] chemical chaperone therapy [4]. However, at present, there is no treatment available for patients with ganglioside storage diseases [5].…”

N‐butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis

“…These approaches include enzyme replacement therapy, bone marrow transplantation, gene therapy, and stem cell therapy (Jeyakumar et al . 2002; Schiffmann and Brady 2002; Takaura et al . 2003).…”

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice

“…Most therapies for ganglioside storage diseases focus on augmenting lysosomal enzyme levels and involve bone marrow transplantation, enzyme replacement, stem cell therapy, gene therapy, and chemical chaperone therapy (4)(5)(6)(7)(8)(9)(10)(11). These therapeutic approaches, however, have difficulty reducing GSL storage products throughout the CNS.…”