Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy

Abstract

Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes α-L-iduronidase and β-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs.

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

“…However, other studies on murine and canine MPS I models have failed to identify significant shortening of long bones or severe growth plate abnormalities, although they did report bone thickening. [31][32][33] In this study, we investigated the subepiphyseal growth plate area of Idua Ϫ/Ϫ mice and compared it to wild-type and Ctsk. Ϫ/Ϫ As mentioned, it is thought that some of the skeletal abnormalities are a result of insufficient endochondral ossification.…”

Therapies for the bone in mucopolysaccharidoses

“…Here we summarize the recent achievements for bone lesions in gene therapies of animal models of MPS. [115,116], sleeping beauty transposon [117,118], gamma-retrovirus [58,[119][120][121], lentivectors [122], and adenoassociated virus (AAV) vectors [123,124]. Non-viral vectors (i.e.…”

“…Adult MPS I mice treated with the γ-retroviral vector intravenously resulted in relative low IDUA activity, although a complete correction of hearing and vision abnormalities, and partial correction in femur diameters and bone mineral density was observed [120,121]. Neonatal treatment of MPS I dogs led to an increase in serum IDUA activity that was up to 28-fold greater than wild-type levels and was maintained for 1.8 years [119].…”

“…After two years of follow-up of treated dogs, skeletal disease evaluation showed no improvement in lengths of cervical or lumbar vertebral bodies, reduction of vertebral fusion, modest improvement in widening, beaking, and tipping in cervical spine, reduction in vertebral space, and reduction in severity of stifle joint effusions. In summary, neonatal gene therapy in MPS I dogs ameliorates, but does not prevent, skeletal disease even with supraphysiological enzyme activity levels in serum and several organs [120,121].…”

“…Nevertheless, there was limited effect in cervical vertebrae, cervical vertebral fusion, and intervertebral disc degeneration [131].These results showed that an early treatment with a long-term supraphysiological enzyme activity levels was not able to completely resolve all skeletal abnormalities. [132] sleeping beauty transposon [117], gamma-retroviral [120,121,132,133], lentiviral [134], and AAV [135,136] vectors. Favorable results for bone lesions were reported in MPS VII dogs by neonatal gene therapy using a gamma-retroviral vector [133].…”