Impact of enzyme replacement therapy andhematopoietic stem cell transplantation inpatients with Morquio A syndrome

• Published in: Drug design, development and therapy development and therapy, 2015-04, Vol.2015 (default), p.1937-1953
• Main Authors: Tomatsu S, Sawamoto K, Alméciga-Díaz CJ, Shimada T, Bober MB, Chinen Y, Yabe H, Montaño AM, Giugliani R, Kubaski F, Yasuda E, Rodríguez-López A, Espejo-Mojica AJ, Sánchez OF, Mason RW, Barrera LA, Mackenzie WG, Orii T
• Format: Article
• Language: English
• ISSN: 1177-8881; 1177-8881

Shunji Tomatsu,1,2 KazukiSawamoto,1 CarlosJ Alméciga-Díaz,3 Tsutomu Shimada,1 Michael BBober,1 Yasutsugu Chinen,4 HiromasaYabe,5 AdrianaMMontaño,6 Roberto Giugliani,7 Francyne Kubaski,1,8 ErikoYasuda,1 AlexanderRodríguez-López,3 Angela J Espejo-Mojica,3 OscarF Sánchez,9 Robert WMason,1 LuisABarrera,3 WilliamG Mackenzie,1 TadaoOrii2 1Nemours/Alfred I duPont Hospital for Children, Wilmington, DE, USA; 2Department of Pediatrics, Gifu University, Gifu, Japan; 3Institute for the Study of Inborn Errors of Metabolism, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia; 4Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, Okinawa, 5Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; 6Department of Pediatrics, Saint Louis University, St Louis, MO, USA; 7Medical Genetics Service/HCPA and Department of Genetics/UFRGS, Porto Alegre, Brazil; 8Department of Biological Sciences, University of Delaware, Newark, DE, 9School of Chemical Engineering, Purdue University, West Lafayette, IN, USA Abstract: Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylga