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Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency.


ABSTRACT: 21 INTRODUCTION:WHIM syndrome is a rare combined primary immunodeficiency disorder caused by autosomal dominant gain-of-function mutations in the chemokine receptor CXCR4. It is the only Mendelian condition known to be caused by mutation of a chemokine or chemokine receptor. As such, it provides a scientific opportunity to understand chemokine-dependent immunoregulation in humans and a medical opportunity to develop mechanism-based treatment and cure strategies. 22 AREAS COVERED:This review covers the clinical features, genetics, immunopathogenesis and clinical management of WHIM syndrome. Clinical trials of targeted therapeutic agents and potential cure strategies are also included. 23 EXPERT OPINION:WHIM syndrome may be particularly amenable to mechanism-based therapeutics for three reasons: 1) CXCR4 has been validated as the molecular target in the disease by Mendelian genetics; 2) the biochemical abnormality is excessive CXCR4 signaling; and 3) antagonists selective for CXCR4 have been developed. Plerixafor is FDA-approved for hematopoietic stem cell (HSC) mobilization and has shown preliminary safety and efficacy in phase I clinical trials in WHIM syndrome. Gene editing may represent a viable cure strategy, since chromothriptic deletion of the disease allele in HSCs resulted in clinical cure of a patient and because CXCR4 haploinsufficiency enhances engraftment of transplanted HSCs in mice.

SUBMITTER: Heusinkveld LE 

PROVIDER: S-EPMC5648064 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency.

Heusinkveld Lauren E LE   Yim Erin E   Yang Alexander A   Azani Ari B AB   Liu Qian Q   Gao Ji-Liang JL   McDermott David H DH   Murphy Philip M PM  

Expert opinion on orphan drugs 20170925 10


<h4>21 introduction</h4>WHIM syndrome is a rare combined primary immunodeficiency disorder caused by autosomal dominant gain-of-function mutations in the chemokine receptor CXCR4. It is the only Mendelian condition known to be caused by mutation of a chemokine or chemokine receptor. As such, it provides a scientific opportunity to understand chemokine-dependent immunoregulation in humans and a medical opportunity to develop mechanism-based treatment and cure strategies.<h4>22 areas covered</h4>T  ...[more]

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