From mysteries to medicines: drug development for fibrodysplasia ossificans progressive
Identifieur interne : 003613 ( Pmc/Corpus ); précédent : 003612; suivant : 003614From mysteries to medicines: drug development for fibrodysplasia ossificans progressive
Auteurs : Frederick S. Kaplan ; Robert J. Pignolo ; Eileen M. ShoreSource :
- Expert opinion on orphan drugs [ 2167-8707 ] ; 2013.
Abstract
Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment.
In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification.
Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease.
Url:
DOI: 10.1517/21678707.2013.825208
PubMed: 24800180
PubMed Central: 4007356
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PMC:4007356Le document en format XML
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<author><name sortKey="Kaplan, Frederick S" sort="Kaplan, Frederick S" uniqKey="Kaplan F" first="Frederick S." last="Kaplan">Frederick S. Kaplan</name>
<affiliation><nlm:aff id="A1">Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</nlm:aff>
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<affiliation><nlm:aff id="A2">Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</nlm:aff>
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<affiliation><nlm:aff id="A4">The Center for Research In FOP and Related Disorders; The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</nlm:aff>
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<author><name sortKey="Pignolo, Robert J" sort="Pignolo, Robert J" uniqKey="Pignolo R" first="Robert J." last="Pignolo">Robert J. Pignolo</name>
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<author><name sortKey="Shore, Eileen M" sort="Shore, Eileen M" uniqKey="Shore E" first="Eileen M." last="Shore">Eileen M. Shore</name>
<affiliation><nlm:aff id="A1">Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</nlm:aff>
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<author><name sortKey="Pignolo, Robert J" sort="Pignolo, Robert J" uniqKey="Pignolo R" first="Robert J." last="Pignolo">Robert J. Pignolo</name>
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<author><name sortKey="Shore, Eileen M" sort="Shore, Eileen M" uniqKey="Shore E" first="Eileen M." last="Shore">Eileen M. Shore</name>
<affiliation><nlm:aff id="A1">Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</nlm:aff>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Introduction:</title>
<p id="P1">Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment.</p>
</sec>
<sec id="S2"><title>Areas covered:</title>
<p id="P2">In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification.</p>
</sec>
<sec id="S3"><title>Expert opinion:</title>
<p id="P3">Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease.</p>
</sec>
</div>
</front>
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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101601398</journal-id>
<journal-id journal-id-type="pubmed-jr-id">42374</journal-id>
<journal-id journal-id-type="nlm-ta">Expert Opin Orphan Drugs</journal-id>
<journal-id journal-id-type="iso-abbrev">Expert Opin Orphan Drugs</journal-id>
<journal-title-group><journal-title>Expert opinion on orphan drugs</journal-title>
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<issn pub-type="epub">2167-8707</issn>
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<article-meta><article-id pub-id-type="pmid">24800180</article-id>
<article-id pub-id-type="pmc">4007356</article-id>
<article-id pub-id-type="doi">10.1517/21678707.2013.825208</article-id>
<article-id pub-id-type="manuscript">NIHMS564018</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<title-group><article-title>From mysteries to medicines: drug development for fibrodysplasia ossificans progressive</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kaplan</surname>
<given-names>Frederick S.</given-names>
</name>
<degrees>M.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A4">4</xref>
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<contrib contrib-type="author"><name><surname>Pignolo</surname>
<given-names>Robert J.</given-names>
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<degrees>M.D., Ph.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A4">4</xref>
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<contrib contrib-type="author"><name><surname>Shore</surname>
<given-names>Eileen M.</given-names>
</name>
<degrees>Ph.D.</degrees>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
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<aff id="A1"><label>1</label>
Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</aff>
<aff id="A2"><label>2</label>
Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</aff>
<aff id="A3"><label>3</label>
Department of Genetics, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</aff>
<aff id="A4"><label>4</label>
The Center for Research In FOP and Related Disorders; The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104</aff>
<author-notes><corresp id="CR1">Correspondence to: Frederick S. Kaplan, M.D. Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine The Perelman School of Medicine at the University of Pennsylvania C/o The Department of Orthopaedic Surgery Hospital of the University of Pennsylvania Silverstein 2 3400 Spruce Street Philadelphia, PA 19104 Telephone: 215-349-8726 Fax: 215-349-5298 <email>frederick.kaplan@uphs.upenn.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>13</day>
<month>4</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><month>8</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>8</month>
<year>2014</year>
</pub-date>
<volume>1</volume>
<issue>8</issue>
<fpage>637</fpage>
<lpage>649</lpage>
<pmc-comment>elocation-id from pubmed: 10.1517/21678707.2013.825208</pmc-comment>
<abstract><sec id="S1"><title>Introduction:</title>
<p id="P1">Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment.</p>
</sec>
<sec id="S2"><title>Areas covered:</title>
<p id="P2">In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification.</p>
</sec>
<sec id="S3"><title>Expert opinion:</title>
<p id="P3">Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease.</p>
</sec>
</abstract>
<kwd-group><kwd>Bone morphogenetic protein receptors</kwd>
<kwd>Fibrodysplasia ossificans progressiva</kwd>
<kwd>Heterotopic endochondral ossification</kwd>
<kwd>Skeletal metamorphosis</kwd>
</kwd-group>
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</front>
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