Zhou X Y, Morreau H, Rottier R, Davis D, Bonten E, Gillemans N, Wenger D, Grosveld F G, Doherty P, Suzuki K, Grosveld G C, d'Azzo A
Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Genes Dev. 1995 Nov 1;9(21):2623-34. doi: 10.1101/gad.9.21.2623.
The lysosomal storage disorder galactosialidosis results from a primary deficiency of the protective protein/cathepsin A (PPCA), which in turn affects the activities of beta-galactosidase and neuraminidase. Mice homozygous for a null mutation at the PPCA locus present with signs of the disease shortly after birth and develop a phenotype closely resembling human patients with galactosialidosis. Most of their tissues show characteristic vacuolation of specific cells, attributable to lysosomal storage. Excessive excretion of sialyloligosaccharides in urine is diagnostic of the disease. Affected mice progressively deteriorate as a consequence of severe organ dysfunction, especially of the kidney. The deficient phenotype can be corrected by transplanting null mutants with bone marrow from a transgenic line overexpressing human PPCA in erythroid precursor cells. The transgenic bone marrow gives a more efficient and complete correction of the visceral organs than normal bone marrow. Our data demonstrate the usefulness of this animal model, very similar to the human disease, for experimenting therapeutic strategies aimed to deliver the functional protein or gene to affected organs. Furthermore, they suggest the feasibility of gene therapy for galactosialidosis and other disorders, using bone marrow cells engineered to overexpress and secrete the correcting lysosomal protein.
溶酶体贮积症半乳糖唾液酸贮积症是由保护性蛋白/组织蛋白酶A（PPCA）原发性缺乏所致，这反过来又影响β-半乳糖苷酶和神经氨酸酶的活性。PPCA基因座纯合无效突变的小鼠在出生后不久就出现疾病症状，并发展出与人类半乳糖唾液酸贮积症患者极为相似的表型。它们的大多数组织显示特定细胞的特征性空泡化，这归因于溶酶体贮积。尿中唾液酸寡糖的过度排泄是该疾病的诊断依据。由于严重的器官功能障碍，尤其是肾脏功能障碍，受影响的小鼠会逐渐恶化。通过将无效突变体与在红系前体细胞中过表达人PPCA的转基因品系的骨髓进行移植，可以纠正缺陷表型。与正常骨髓相比，转基因骨髓对内脏器官的纠正更有效、更完全。我们的数据证明了这种与人类疾病非常相似的动物模型对于试验旨在将功能性蛋白质或基因递送至受影响器官的治疗策略的有用性。此外，它们还表明了使用经过工程改造以过表达和分泌校正性溶酶体蛋白的骨髓细胞对半乳糖唾液酸贮积症和其他疾病进行基因治疗的可行性。
