Genetic correction of the fetal brain increases the lifespan of mice with the severe multisystemic disease mucopolysaccharidosis type VII

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.