Bone Growth Induction in Mucopolysaccharidosis IVA Mouse

Abstract

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is caused by a deficiency of the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) enzyme, leading to the accumulation of glycosaminoglycans (GAG), keratan sulfate (KS) and chondroitin-6-sulfate (C6S), mainly in cartilage and bone. This lysosomal storage disorder (LSD) is characterized by severe systemic skeletal dysplasia. To this date, none of the treatment options for the MPS IVA patients correct bone pathology. Enzyme replacement therapy with elosulfase alpha provides a limited impact on bone growth and skeletal lesions in MPS IVA patients. To improve bone pathology, we propose a novel gene therapy with a small peptide as a growth-promoting agent for MPS IVA. A small molecule in this peptide family has been found to exert biological actions over the cardiovascular system. This work shows that an AAV vector expressing a C-type natriuretic (CNP) peptide induces bone growth in the MPS IVA mouse model. Histopathological analysis showed the induction of chondrocyte proliferation. CNP peptide also changed the pattern of GAG levels in bone and liver. These results suggest the potential for CNP peptide to be used as a treatment in MPS IVA patients.

Adeno-associated virus-based gene therapy delivering combinations of two growth-associated genes to MPS IVA mice

“…In our earlier experiments, we examined the effectiveness of incorporating the CNP into the AAV8 vector expression cassette for the first time. When MPS IVA mice were treated with this CNP-containing AAV vector, we observed a notable increase in growth, accompanied by consistent maintenance of body weight, 33 similar to other studies. 61 , 62 , 63 , 64 Furthermore, we observed a more organized chondrocyte structure within the growth plate, characterized by enhanced proliferation and differentiation.…”

“…The mouse model used in this study was the MPS IVA knockout mice (MKC2; C57BL/6 background), as described previously. 33 These mice lack GALNS enzyme activity, resulting in the accumulation of storage material (KS) in various tissues and plasma. These biomarkers (enzyme activity and substrate accumulation) were extensively used to assess the severity of the phenotype and measure the effectiveness of various therapeutic approaches in MPS IVA patients and animal models.…”

“…Thus, to address the bone, we used an AAV8 vector expressing the peptide that previously showed bone growth induction in the MPS IVA mice. 33 CNP, a potential bone-penetrating agent, stimulates bone growth by activating the natriuretic peptide receptor B on chondrocytes. Despite its therapeutic promise for skeletal dysplasia, the short half-life of natural CNP and the need for repeated injections of modified CNP currently limit its effectiveness.…”

“…Our previous results showed that CNP effectively targets chondrocytes, activating its proliferation and differentiation in the growth plate of MPS IVA mice. 33 …”

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

“…It is also speculated that vitamin D deficiency plays a key role in osteological manifestations of MPS [ 11 ]. Despite ERT and stem cell transplant being available for some MPS subtypes, currently, there are no accepted treatments for the bone disease manifestations of MPS [ 12 , 13 , 14 ]. Orthopedic complications of MPS III in particular remain an area poorly characterized, in part because of the rarity of the disease and the perceived mildness of osteological defects compared to other MPS types [ 15 , 16 ].…”