The mucopolysaccharidoses (MPS) are a group of recessively inherited conditions caused by deficiency of lysosomal enzymes essential to the catabolism of glycosaminoglycans (GAG). MPS I is caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA), while MPS II is caused by a lack of iduronate-2-sulfatase (IDS). Lack of these enzymes leads to early mortality and morbidity, often including neurological deficits. Enzyme replacement therapy has markedly improved the quality of life for MPS I and MPS II affected individuals but is not effective in addressing neurologic manifestations. For MPS I, hematopoietic stem cell transplant has shown effectiveness in mitigating the progression of neurologic disease when carried out in early in life, but neurologic function is not restored in patients transplanted later in life. For both MPS I and II, gene therapy has been shown to prevent neurologic deficits in affected mice when administered early, but the effectiveness of treatment after the onset of neurologic disease manifestations has not been characterized. To test if neurocognitive function can be recovered in older animals, human IDUA or IDS-encoding AAV9 vector was administered by intracerebroventricular injection into MPS I and MPS II mice, respectively, after the development of neurologic deficit. Vector sequences were distributed throughout the brains of treated animals, associated with high levels of enzyme activity and normalized GAG storage. Two months after vector infusion, treated mice exhibited spatial navigation and learning skills that were normalized, that is, indistinguishable from those of normal unaffected mice, and significantly improved compared to untreated, affected animals. We conclude that cognitive function was restored by AAV9-mediated, central nervous system (CNS)-directed gene transfer in the murine models of MPS I and MPS II, suggesting that gene transfer may result in neurodevelopment improvements in severe MPS I and MPS II when carried out after the onset of cognitive decline.
|Original language||English (US)|
|Number of pages||11|
|Journal||Human gene therapy|
|State||Published - Jan 1 2023|
Bibliographical noteFunding Information:
The authors thank Dr. Joseph Muenzer for providing the IDS KO strain and Dr. Elizabeth Neufeld for providing the IDUA KO strain. Behavioral studies were performed in the Mouse Behavior Core at the University of Minnesota (supported by NIH grant NS062158). We thank core director Dr. Benneyworth for help with the Barnes maze testing. This study has been previously presented at conferences and has been published in abstract form in conference proceedings.
The work described in this article was supported by REGENXBIO. Karen Kozarsky was an employee of REGENXBIO.
© Copyright 2023, by Mary Ann Liebert, Inc., publishers 2023.
- MPS I
- MPS II
- gene therapy