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Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice. | LitMetric

AI Article Synopsis

  • Mucopolysaccharidosis type IVA (MPS IVA) is a genetic disorder caused by a deficiency in the GALNS gene, leading to serious bone growth issues and limited treatment options like enzyme replacement therapy and stem cell transplantation.
  • A recent study demonstrated that delivering AAV vectors with the hGALNS gene can restore enzyme activity in blood and various tissues, showing promise for better treatment outcomes.
  • The current research found that using ubiquitous promoters in AAV vectors led to significantly higher levels of enzyme activity in bone and improved cartilage issues in mice models, suggesting a breakthrough in the treatment for MPS IVA.

Article Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal congenital metabolic lysosomal disease caused by a deficiency of the -acetyl-galactosamine-6-sulfate sulfatase (GALNS) gene, leading to severe skeletal dysplasia. The available therapeutics for patients with MPS IVA, enzyme replacement therapy and hematopoietic stem cell transplantation, revealed limitations in the impact of skeletal lesions. Our previous study, a significant leap forward in MPS IVA research, showed that liver-targeted adeno-associated virus (AAV) gene transfer of human GALNS (hGALNS) restored GALNS enzymatic activity in blood and multiple tissues and partially improved the aberrant accumulation of storage materials. This promising approach was further validated in our current study, where we delivered AAV8 vectors expressing hGALNS, under the control of a liver-specific or ubiquitous promoter, into MPS IVA murine disease models. The results were highly encouraging, with both AAV8 vectors leading to supraphysiological enzymatic activity in plasma and improved cytoplasmic vacuolization of chondrocytes in bone lesions of MPS IVA mice. Notably, the ubiquitous promoter constructs, a potential game-changer, resulted in significantly greater enzyme activity levels in bone and improved pathological findings of cartilage lesions in these mice than in a liver-specific one during the 12-week monitoring period, reinforcing the positive outcomes of our research in MPS IVA treatment.

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Source
http://dx.doi.org/10.1089/hum.2024.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659441PMC

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