Engraftment of Genetically Engineered Amniotic Epithelial Cells Corrects Lysosomal Storage in Multiple Areas of the Brain in Mucopolysaccharidosis Type VII Mice

Abstract

Cell-mediated gene therapy for visceral lesions of lysosomal storage diseases is promising; however, the treatment of central nervous system (CNS) lesions remains a challenge. In this study, we generated rat amniotic epithelial cells (AEC) that overexpress and secrete human beta-glucuronidase (GUSB) following transduction with an adenoviral vector encoding human GUSB. The AEC were used as donor cells for cell-mediated gene therapy of CNS lesions in mice with mucopolysaccharidosis type VII (MPSVII), a lysosomal storage disorder caused by an inherited deficiency of GUSB activity. After confirmation that the secreted GUSB was taken up mainly via mannose 6-phosphate receptors in primary cultured neurons, the AEC were transplanted into the brains of adult MPSVII mice. Histochemical analysis showed extensive GUSB activity throughout the ipsilateral hemisphere of the recipient brains, and pathological improvement of the lysosomal storage was observed even in regions far from the site of injection. These results suggest that intracerebral transplantation of genetically engineered AEC has therapeutic potential for the treatment of CNS lesions in lysosomal storage disorders.

Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII

“…Mental retardation is a frequent manifestation in several types of mucopolysaccharidoses as well as other lysosomal storage disorders. 33 We and other groups achieved successful pathological correction in the CNS by transplantation of GUSB-producing cells, 11,18 or by generation of GUSB-producing cells in the brain with direct vector administrations. 16 Although these therapeutic strategies may be effective, less invasive approach is required for widespread clinical applications.…”

“…As an alternative, gene therapy for MPSVII has been explored using several viral vectors such as retroviruses, [10][11][12] herpes viruses, 13,14 adenoviruses, [15][16][17][18][19][20] lentiviruses, 21,22 and adeno-associated viruses. [23][24][25][26] Both in vivo and ex vivo gene transduction methods have been tested experimentally; however, only limited therapeutic success has been reported, when studies were carried out using adult B6/MPSVII.…”

Encapsulation Cell Therapy for Mucopolysaccharidosis Type VII Using Genetically Engineered Immortalized Human Amniotic Epithelial Cells

“…nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), glia-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) (Sakuragawa et al 1995Elwan and Sakuragawa 1997;Uchida et al 2000). If a stable and long-term supply of HAE cells were realized, we could apply them to the transplantation therapy for LSDs and a wide variety of diseases other than LSDs (Kakishita et al 2000;Ohsugi et al 2000;Kosuga et al 2001;Naganawa et al 2002). From this point of view, we used immortalize HAE cells for polymer-encapsulated geneengineered cell therapy in the treatment of Mucopolysaccharidosis type VII.…”

“…293 cells were cotransfected with cosmid pAxCAhGUS and the adenovirus DNA-terminal protein complex, which had already been digested at several sites with EcoT22I. A recombinant adenovirus was generated through homologous recombination in the 293 cells (Kosuga et al 2001). …”

Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice

“…1,2 A murine model of MPS VII is available and its clinical, biochemical and pathological features closely reflect those of human MPS VII. [3][4][5] Using this mouse model, various therapeutic approaches including enzyme replacement therapy, [6][7][8] bone marrow transplantation (BMT), [9][10][11] gene therapy [12][13][14] and cell therapy [15][16][17] have previously been attempted with varying degree of success. In case of enzyme replacement therapy, patients must continue to receive enzyme replacement in their whole life and the cost of recombinant enzyme is another big burden to patients.…”