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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3169-3178
GENE THERAPY
Functional amelioration of murine galactosialidosis by
genetically modified bone marrow hematopoietic progenitor
cells
Thasia Leimig,
Linda Mann,
Maria del Pilar Martin,
Erik Bonten,
Derek Persons,
James Knowles,
James A. Allay,
John Cunningham,
Arthur W. Nienhuis,
Richard Smeyne, and
Alessandra d'Azzo
From the St Jude Children's Research Hospital,
Memphis, TN.
Protective protein/cathepsin A (PPCA), a lysosomal
carboxypeptidase, is deficient in the neurodegenerative lysosomal
disorder galactosialidosis (GS). PPCA / mice
display a disease course similar to that of severe human GS, resulting
in nephropathy, ataxia, and premature death. Bone marrow
transplantation (BMT) in mutant animals using transgenic BM
overexpressing the corrective enzyme in either erythroid cells or
monocytes/macrophages has proven effective for the improvement of the
phenotype, and encouraged the use of genetically modified BM cells for
ex vivo gene therapy of GS. Here, we established stable donor
hematopoiesis in PPCA/ mice that received
hematopoietic progenitors transduced with a murine stem cell virus
(MSCV)-based, bicistronic retroviral vector overexpressing PPCA and
the green fluorescent protein (GFP) marker. We observed complete
correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA+ BM-derived cells were
detected in all tissues, with the highest expression in liver, spleen,
BM, thymus, and lung. In addition, a lysosomal immunostaining was seen
in nonhematopoietic cells, indicating efficient uptake of the
corrective protein by these cells and cross-correction. Expression in
the brain occurred throughout the parenchyma but was mainly localized
on perivascular areas. However, PPCA expression in the central nervous
system was apparently sufficient to delay the onset of Purkinje cell
degeneration and to correct the ataxia. The long-term expression and
internalization of the PPCA by cells of systemic organs and the clear
improvement of the neurologic phenotype support the use of this
approach for the treatment of GS in humans.
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