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Expert Opin Orphan Drugs. 2017;5(10):813-825. doi: 10.1080/21678707.2017.1375403. Epub 2017 Sep 25.

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency.

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Laboratory of Molecular Immunology, Bldg 10, Room 11N113, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.



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.


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.


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.


CXCR4; G-CSF; WHIM syndrome; X4P-001/AMD11070; myelokathexis; plerixafor/AMD3100

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