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Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy

Hypophosphatasia (HPP) is a multi-systemic metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the mineralization-associated enzyme, tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by defective bone and dental mineralization, leading to skelet...

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Autores principales: Bowden, Sasigarn A, Foster, Brian L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161731/
https://www.ncbi.nlm.nih.gov/pubmed/30288020
http://dx.doi.org/10.2147/DDDT.S154922
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author Bowden, Sasigarn A
Foster, Brian L
author_facet Bowden, Sasigarn A
Foster, Brian L
author_sort Bowden, Sasigarn A
collection PubMed
description Hypophosphatasia (HPP) is a multi-systemic metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the mineralization-associated enzyme, tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by defective bone and dental mineralization, leading to skeletal abnormalities with complications resulting in significant morbidity and mortality. Management of HPP has been limited to supportive care until the introduction of a recently approved enzyme replacement therapy employing bone-targeted recombinant human TNSALP, asfotase alfa (AA). This new therapy has been transformative as it improves survival in severely affected infants, and overall quality of life in children and adults with HPP. This review provides an overview of HPP, focusing on important steps in the development of AA enzyme replacement therapy, including the drug design, preclinical studies in the HPP mouse model, and outcomes from clinical trials and case report publications to date, with special attention given to response to therapy of skeletal manifestations, biochemical features, and other clinical manifestations. The limitations, adverse effects, and outcomes of AA are outlined and the place in therapy for individuals with HPP is discussed.
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spelling pubmed-61617312018-10-04 Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy Bowden, Sasigarn A Foster, Brian L Drug Des Devel Ther Review Hypophosphatasia (HPP) is a multi-systemic metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the mineralization-associated enzyme, tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by defective bone and dental mineralization, leading to skeletal abnormalities with complications resulting in significant morbidity and mortality. Management of HPP has been limited to supportive care until the introduction of a recently approved enzyme replacement therapy employing bone-targeted recombinant human TNSALP, asfotase alfa (AA). This new therapy has been transformative as it improves survival in severely affected infants, and overall quality of life in children and adults with HPP. This review provides an overview of HPP, focusing on important steps in the development of AA enzyme replacement therapy, including the drug design, preclinical studies in the HPP mouse model, and outcomes from clinical trials and case report publications to date, with special attention given to response to therapy of skeletal manifestations, biochemical features, and other clinical manifestations. The limitations, adverse effects, and outcomes of AA are outlined and the place in therapy for individuals with HPP is discussed. Dove Medical Press 2018-09-24 /pmc/articles/PMC6161731/ /pubmed/30288020 http://dx.doi.org/10.2147/DDDT.S154922 Text en © 2018 Bowden and Foster. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Review
Bowden, Sasigarn A
Foster, Brian L
Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
title Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
title_full Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
title_fullStr Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
title_full_unstemmed Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
title_short Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
title_sort profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161731/
https://www.ncbi.nlm.nih.gov/pubmed/30288020
http://dx.doi.org/10.2147/DDDT.S154922
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