Bone marrow transplantation in canine mucopolysaccharidosis I. Effects within the central nervous system.

Abstract

Five dogs with mucopolysaccharidosis I, a model of human Hurler/Scheie syndrome, were transplanted with marrow from phenotypically normal littermates at 5 mo of age. At 3 and 9 mo posttransplantation, biopsies of cerebral cortex, liver, and cerebrospinal fluid were obtained. The a-L-iduronidase levels in these tissues were 0.8-7.4, 26-45, and 6.3-14.9% of the paired donor tissues, respectively. Although iduronidase was present in relatively low levels in the recipients' brains and cerebrospinal fluid at both biopsy times, reduction in brain glycosaminoglycan (GAG) was comparable to that observed in liver. Ultrastructural studies of cells within the transplanted dogs' brains showed less lysosomal distension and storage product than in affected, nontransplanted, littermate controls. The most marked clearing of stored GAG was in cells surrounding blood vessels, but decreased lysosomal storage in neurons and glial cells was also observed. Urinary GAG excretion also decreased to near normal levels by 5 mo posttransplantation.

Uptake of α-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro

“…6 BMT in patients or in experimental animals can lead to correction of the enzyme defect, a decrease in abnormal lysosomes in soft tisssues, and in some cases stabilisation of the neurological status. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] However, while there is general agreement on the effectiveness of BMT for the treatment of liver, spleen or soft tissue disease, there is no consensus on whether it has a beneficial effect on the disease induced progressive deterioration of brain function. The outcome of the neurological manifestations appears to depend on the initial mental status, the age of the patient, the engraftment of the grafted bone marrow and the development of graft-versus-host diseases (GVHD).…”

Improved gene transfer into canine hematopoietic repopulating cells using CD34-enriched marrow cells in combination with a gibbon ape leukemia virus–pseudotype retroviral vector

“…[17][18][19] We have used the dog to study gene transfer strategies for hematopoietic stem cell gene transfer, 5,6,20 given that, in contrast to nonhuman primates, there are many spontaneous canine disease models to study gene therapy, eg alpha-l-iduronidase deficiency, pyruvate kinase deficiency and various immunodeficiencies. 1,2,21 In previous studies we showed that GALV-pseudotype vectors increased gene transfer into human progenitor cells and baboon marrow repopulating cells in comparison to amphotropic vectors. 4,5,7 We, therefore, investigated whether GALV-pseudotype vectors would also increase gene transfer into canine marrow repopulating cells.…”

“…These models can be used to study the clinical effectiveness of gene therapy for genetic diseases such as metabolic (alpha-l-iduronidase deficiency) or hematologic (pyruvate kinase deficiency) disorders. 1,2 In contrast to recent reports in nonhuman primates, 3,4 gene transfer efficiencies in the dog have remained low. 5,6 In this study we have therefore tested whether techniques employed in the nonhuman primates would also result in improved gene transfer efficiencies in the dog.…”

Glycan Engineering and Production of 'Humanized' Glycoprotein in Yeast Cells

“…Likewise, problems arise during the clinical application of gene therapy, such as difficulties in controlling the expression and localization of the enzyme, 77) and BMT is a potentially dangerous procedure. 79) Differences in the degree of improvement among LSD patients following treatment 70,78,[80][81][82][83] suggest the need for careful consultation prior to treatment. Enzyme replacement therapy (ERT) is the most advanced therapeutic for treating LSDs and has been applied to Gaucher disease, 61) Fabry disease, 62,63) Pompe disease, 84,85) and mucopolysaccharidosis I, 64) II 86) and VI.…”