MPSIVA Mouse Model via CRISPR-Cas9 [WES]

Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disease (LSD) caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes the accumulation of keratan (KS) and chondroitin sulphate (CS). MPSIVA patients typically present with severe skeletal and joint disorders, which are not addressed by the conventional therapies. Currently, no animal model accurately replicates the human disease, hindering the development of novel therapeutic interventions. To overcome this limitation, we have established a novel Galns-/- mouse model by CRISPR-Cas9 technology that expresses a non-functional enzyme and accumulates CS and KS in the urine, plasma, and distinct tissues, and glycosaminoglycans in the spleen. The mice exhibit shortened long bones, trabecular bone alterations, and skeletal abnormalities at the growth plate. Additionally, we observed increased levels of inflammatory and oxidative markers in visceral organs and plasma. Our newly developed MPSIVA model demonstrates clear and quantifiable signs of skeletal alterations, providing novel means of assessment for safety and efficacy of innovative therapies, including hematopoietic stem and progenitor cell-gene therapy (HSPC-GT), which has recently been shown to provide a beneficial effect on skeletal alterations in Hurler syndrome.