Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development
Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant accumulation of dermatan sulfate, a glycosaminoglycan (GAG) abundant in cartilage. While clinical severity varies along with age at first...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-11-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.171312 |
| _version_ | 1797634252123144192 |
|---|---|
| author | Elizabeth Hwang-Wong Gabrielle Amar Nanditha Das Xiaoli Zhang Nina Aaron Kirsten Gale Nyanza Rothman Massimo Fante Andrew Baik Ajay Bhargava Arun Fricker Michelle McAlister Jeremy Rabinowitz John Lees-Shepard Kalyan Nannuru Aris N. Economides Katherine D. Cygnar |
| author_facet | Elizabeth Hwang-Wong Gabrielle Amar Nanditha Das Xiaoli Zhang Nina Aaron Kirsten Gale Nyanza Rothman Massimo Fante Andrew Baik Ajay Bhargava Arun Fricker Michelle McAlister Jeremy Rabinowitz John Lees-Shepard Kalyan Nannuru Aris N. Economides Katherine D. Cygnar |
| author_sort | Elizabeth Hwang-Wong |
| collection | DOAJ |
| description | Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant accumulation of dermatan sulfate, a glycosaminoglycan (GAG) abundant in cartilage. While clinical severity varies along with age at first symptom manifestation, MPS VI usually presents early and strongly affects the skeleton. Current enzyme replacement therapy (ERT) does not provide effective treatment for the skeletal manifestations of MPS VI. This lack of efficacy may be due to an inability of ERT to reach affected cells or to the irreversibility of the disease. To address the question of reversibility of skeletal phenotypes, we generated a conditional by inversion (COIN) mouse model of MPS VI, ArsbCOIN/COIN, wherein Arsb is initially null and can be restored to WT using Cre. We restored Arsb at different times during postnatal development, using a tamoxifen-dependent global Cre driver. By restoring Arsb at P7, P21, and P56–P70, we determined that skeletal phenotypes can be fully rescued if Arsb restoration occurs at P7, while only achieving partial rescue at P21 and no significant rescue at P56–P70. This work has highlighted the importance of early intervention in patients with MPS VI to maximize therapeutic impact. |
| first_indexed | 2024-03-11T12:06:04Z |
| format | Article |
| id | doaj.art-d478567e5dad49448a74c8913282750d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:04Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d478567e5dad49448a74c8913282750d2023-11-07T16:26:22ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01821Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal developmentElizabeth Hwang-WongGabrielle AmarNanditha DasXiaoli ZhangNina AaronKirsten GaleNyanza RothmanMassimo FanteAndrew BaikAjay BhargavaArun FrickerMichelle McAlisterJeremy RabinowitzJohn Lees-ShepardKalyan NannuruAris N. EconomidesKatherine D. CygnarMucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant accumulation of dermatan sulfate, a glycosaminoglycan (GAG) abundant in cartilage. While clinical severity varies along with age at first symptom manifestation, MPS VI usually presents early and strongly affects the skeleton. Current enzyme replacement therapy (ERT) does not provide effective treatment for the skeletal manifestations of MPS VI. This lack of efficacy may be due to an inability of ERT to reach affected cells or to the irreversibility of the disease. To address the question of reversibility of skeletal phenotypes, we generated a conditional by inversion (COIN) mouse model of MPS VI, ArsbCOIN/COIN, wherein Arsb is initially null and can be restored to WT using Cre. We restored Arsb at different times during postnatal development, using a tamoxifen-dependent global Cre driver. By restoring Arsb at P7, P21, and P56–P70, we determined that skeletal phenotypes can be fully rescued if Arsb restoration occurs at P7, while only achieving partial rescue at P21 and no significant rescue at P56–P70. This work has highlighted the importance of early intervention in patients with MPS VI to maximize therapeutic impact.https://doi.org/10.1172/jci.insight.171312Bone biology |
| spellingShingle | Elizabeth Hwang-Wong Gabrielle Amar Nanditha Das Xiaoli Zhang Nina Aaron Kirsten Gale Nyanza Rothman Massimo Fante Andrew Baik Ajay Bhargava Arun Fricker Michelle McAlister Jeremy Rabinowitz John Lees-Shepard Kalyan Nannuru Aris N. Economides Katherine D. Cygnar Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development JCI Insight Bone biology |
| title | Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development |
| title_full | Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development |
| title_fullStr | Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development |
| title_full_unstemmed | Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development |
| title_short | Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development |
| title_sort | skeletal phenotype amelioration in mucopolysaccharidosis vi requires intervention at the earliest stages of postnatal development |
| topic | Bone biology |
| url | https://doi.org/10.1172/jci.insight.171312 |
| work_keys_str_mv | AT elizabethhwangwong skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT gabrielleamar skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT nandithadas skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT xiaolizhang skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT ninaaaron skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT kirstengale skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT nyanzarothman skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT massimofante skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT andrewbaik skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT ajaybhargava skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT arunfricker skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT michellemcalister skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT jeremyrabinowitz skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT johnleesshepard skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT kalyannannuru skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT arisneconomides skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment AT katherinedcygnar skeletalphenotypeameliorationinmucopolysaccharidosisvirequiresinterventionattheearlieststagesofpostnataldevelopment |