Abstract
Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.
Highlights
Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation
In MPSIVA rats we have demonstrated that the use of AAV9 vectors in conjunction with the ubiquitous CAG promoter mediated widespread expression of Galns in bones, cartilage and in all key peripheral organs affected in Morquio A disease
We found that AAV9-Galns treatment corrected the severe whole-body alterations of MPSIVA rats, skeletal dysplasia and cartilage deterioration
Summary
Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to longterm (1 year) increase of GALNS activity and whole-body correction of KS levels, preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. Mucopolysaccharidosis type IVA (MPSIVA; Morquio A disease: OMIM #253000) is an autosomal recessive Lysosomal Storage Disorder (LSD) caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase AAV vectors have demonstrated high transduction efficiencies in vivo, longterm durability of therapeutic gene expression, and very good safety profiles in clinical studies[19,20,21]
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