Karolewski Brian A, Wolfe John H
W.F. Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Pennsylvania, USA; Stokes Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylania 19104, USA.
Mol Ther. 2006 Jul;14(1):14-24. doi: 10.1016/j.ymthe.2006.02.012. Epub 2006 Apr 19.
Neurogenetic diseases typically have globally distributed lesions, and pathology usually develops early in life, requiring early diagnosis and treatment. We investigated the effects of transferring a corrective gene into the fetal brain before the onset of pathology in the mucopolysaccharidosis (MPS) type VII mouse, a model of a lysosomal storage disease. A single adeno-associated virus serotype 1 vector injection into the ventricle at 15.5 days of gestation resulted in widespread distribution and lifelong expression of the normal gene in the brain and spinal cord. The normal enzyme was distributed to neighboring cells (as expected) and completely prevented the development of storage lesions throughout the central nervous system (CNS). No vector transfer was found outside the CNS, including the gonads, but a small amount of enzyme was present in visceral tissues, consistent with transfer from cerebrospinal fluid to venous circulation. The enzyme was present peripherally in such low amounts that it did not result in the severe skeletal dysmorphology that occurs readily when systemic treatment is used in neonates. However, the survival probability of the treated animals was significantly increased. The results suggest that the nervous system disease may contribute to the overall physiologic health of the animal in this type of disease.
神经遗传疾病通常具有广泛分布的病变，且病理变化通常在生命早期就会出现，需要早期诊断和治疗。我们研究了在黏多糖贮积症VII型小鼠（一种溶酶体贮积病模型）病理发作前将校正基因导入胎儿大脑的效果。在妊娠15.5天时向脑室注射单一腺相关病毒血清型1载体，导致正常基因在脑和脊髓中广泛分布并终身表达。正常酶分布到邻近细胞（如预期），并完全阻止了整个中枢神经系统（CNS）中贮积病变的发展。在包括性腺在内的中枢神经系统之外未发现载体转移，但在内脏组织中存在少量酶，这与从脑脊液向静脉循环的转移一致。外周组织中酶的含量很低，不会导致新生儿全身治疗时容易出现的严重骨骼畸形。然而，治疗动物的存活概率显著增加。结果表明，在这类疾病中，神经系统疾病可能会影响动物的整体生理健康。
