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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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1
Laboratory of Molecular Immunology, Bldg 10, Room 11N113, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

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.

KEYWORDS:

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

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