Snyder E Y, Taylor R M, Wolfe J H
Department of Neurology, Harvard Medical School, Children's Hospital, Boston, Massachusetts 02115.
Nature. 1995 Mar 23;374(6520):367-70. doi: 10.1038/374367a0.
Many metabolic diseases affecting the central nervous system are refractory to treatment because the blood-brain barrier restricts entry of therapeutic molecules. It may be possible to deliver therapeutic gene products directly to the brain by transplantation of neural progenitor cells, which can integrate into the murine central nervous system in a cytoarchitecturally appropriate manner. We tested this approach in mucopolysaccharidosis VII (Sly disease), a lysosomal storage disorder of humans, dogs and mice caused by an inherited deficiency of beta-glucuronidase. Lysosomal accumulation of glycosaminoglycans occurs in the brain and other tissues, causing a fatal progressive degenerative disorder, including mental retardation. Treatments are designed to provide a source of normal enzyme for uptake by diseased cells. We report here that by transplanting beta-glucuronidase-expressing neural progenitors into the cerebral ventricles of newborn mice, donor cells engrafted throughout the neuraxis. At maturity, donor-derived cells were present as normal constituents of diverse brain regions. beta-Glucuronidase activity was expressed along the entire neuraxis, resulting in widespread correction of lysosomal storage in neurons and glia in affected mice.
许多影响中枢神经系统的代谢性疾病难以治疗，因为血脑屏障限制了治疗分子的进入。通过移植神经祖细胞有可能将治疗性基因产物直接递送至大脑，神经祖细胞能够以细胞结构合适的方式整合到小鼠中枢神经系统中。我们在黏多糖贮积症VII型（斯利病）中测试了这种方法，该病是一种人类、犬类和小鼠的溶酶体贮积病，由β-葡萄糖醛酸酶的遗传性缺乏引起。糖胺聚糖在大脑和其他组织中的溶酶体中蓄积，导致一种致命的进行性退行性疾病，包括智力迟钝。治疗旨在为患病细胞提供正常酶的来源。我们在此报告，通过将表达β-葡萄糖醛酸酶的神经祖细胞移植到新生小鼠的脑室中，供体细胞植入整个神经轴。在成熟时，供体来源的细胞作为不同脑区的正常成分存在。β-葡萄糖醛酸酶活性沿整个神经轴表达，导致受影响小鼠神经元和神经胶质细胞中溶酶体贮积的广泛纠正。
