Functional Correction of CNS Phenotypes in a Lysosomal Storage Disease Model Using Adeno-Associated Virus Type 4 Vectors

Mechanisms of distribution of mouse β-galactosidase in the adult GM1-gangliosidosis brain

“…As in situ hybridization for vector-associated mRNA showed no signal in bgal-positive cortical regions except the entorhinal cortex (arrowheads in Figures 2c and d), we conclude that bgal activity in cortex is mostly the result of diffusion, a mechanism shown to be involved in the distribution of several other lysosomal enzymes. 11,20 The significance of vector mRNA in the entorhinal cortex will be addressed below.…”

“…However, the first interpretation is consistent with data available for b-glucuronidase, 11 a-L-iduronidase, 15 and tripeptidyl peptidase 16 and is likely the basis for the success in using intracerebroventricular (i.c.v.) 11 or intrathecal infusion 15 of AAV vectors or purified recombinant enzymes 16 in adult animals to achieve widespread correction of lysosomal storage in the brain. Previously we have shown i.c.v.…”

“…Thus it is of paramount importance to understand the mechanisms by which these enzymes can be distributed in the brain. In addition to diffusion in the brain parenchyma, 10,11 it has been shown that at least two of these enzymes, b-glucuronidase and arylsulfatase A, can be transported by axonal transport within neurons from the site of production. [12][13][14] Moreover, CSF flow has been shown to contribute to the distribution of both b-glucuronidase, a-L-iduronidase and tripeptidyl peptidase 1 throughout the CNS.…”

“…[12][13][14] Moreover, CSF flow has been shown to contribute to the distribution of both b-glucuronidase, a-L-iduronidase and tripeptidyl peptidase 1 throughout the CNS. 11,15,16 Given our continued interest in developing an AAVmediated gene therapy approach to treat GM1-gangliosidosis, we set out to investigate whether the mechanisms of distribution earlier described for GUSB, Arylsulfatase A and tripeptidyl peptidase 1 are also functional for bgal. This has obvious implications for choosing target structures to be engineered by AAVmediated gene delivery to achieve global distribution of enzymes in the brain with the minimum number of injections possible.…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…Direct delivery by intraparenchymal injections has proven effective for targeting neurons in various neurodegenerative diseases and it limits transduction to those tissues most relevant to disease. Widespread exposure of a transgene product occurs after intraventricular or intrathecal delivery of AAVs, when the transgene product is a secreted molecule [75]. Recently, intrathecal injection of AAV9 or AAV2.5 showed robust transduction of the brain and spinal cord in nonhuman primates [76].…”