Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene.

Murine models of lysosomal storage diseases provide an opportunity to evaluate the potential for gene therapy to prevent systemic manifestations of the disease. To determine the potential for treatment of mucopolysaccharidosis type I using a gene delivery approach, a recombinant adeno-associated virus (AAV) vector, vTRCA1, transducing the human iduronidase (IDUA) gene was constructed and 1 x 10(10) particles were injected intravenously into 1-day-old Idua(-/-) mice. High levels of IDUA activity were present in the plasma of vTRCA1-treated animals that persisted for the 5-month duration of the study, with heart and lung of this group demonstrating the highest tissue levels of gene transfer and enzyme activity overall. vTRCA1-treated Idua(-/-) animals with measurable plasma IDUA activity exhibited histopathological evidence of reduced lysosomal storage in a number of tissues and were normalized with respect to urinary GAG excretion, craniofacial bony parameters, and body weight. In an open field test, vTRCA1-treated Idua(-/-) animals exhibited a significant reduction in total squares covered and a trend toward normalization in rearing events and grooming time compared to control-treated Idua(-/-) animals. We conclude that AAV-mediated transduction of the IDUA gene in newborn Idua(-/-) mice was sufficient to have a major curative impact on several of the most important parameters of the disease.

Craniofacial abnormalities in a murine knock-out model of mucopolysaccharidosis I H: a computed tomography and anatomic study.

The genetic mucopolysaccharidoses are a group of lysosomal storage diseases in which mucopolysaccharides (glycosaminoglycans) accumulate as the result of a malfunction or lack of a lysosomal degradation enzyme. There are currently seven known forms of mucopolysaccharidoses. Type I results from an enzymatic deficiency of alpha-L-iduronidase. There are three subtypes of mucopolysaccharidoses I that are commonly recognized: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. Of the three subtypes, Hurler syndrome has the most severe clinical picture. Craniofacial anomalies and cognitive impairment are some of the more pronounced features of Hurler syndrome. Hurler syndrome has been described in cats, dogs, mice, and human beings and is inherited as an autosomal recessive trait. The biochemical nature of the disease is preserved across species lines. Clinically, the disease has similar effects in human beings and animals. It has been difficult to reverse the phenotype of the disease even with replacement of the defective alpha-L-iduronidase enzyme. The purpose of this study is to characterize the cranio-facial differences in the murine knock-out model of Hurler syndrome objectively. Twenty-three measurements were taken from computed tomographic scans in a coronal and sagittal plane on 24 black C57/B6 knock-out Hurler syndrome mice. The seven statistically significant measurements are width of the cervical canal, height of the foramen magnum, width between the external auditory canals, width of the skull base at the mandibular condyles, midocular distance, spread of the mandibular condyles, and width of the zygoma at the maxilla. This information now provides researchers with objective data from living Hurler syndrome-affected mice that will allow them to follow therapies directed at improving craniofacial outcomes for any therapy over time.