Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency. (3rd October 2017)

• Record Type: Journal Article
• Authors: Heusinkveld, Lauren E.; Yim, Erin; Yang, Alexander; Azani, Ari B.; Liu, Qian; Gao, Ji-Liang; McDermott, David H.; Murphy, Philip M.
• Is Part Of: Expert opinion on orphan drugs. Volume 5:Number 10(2017:Oct.)
• Page Start: 813
• Page End: 825
• Publication Date: 2017-10-03
• Subjects: CXCR4 -- G-CSF -- myelokathexis -- plerixafor/AMD3100 -- WHIM syndrome -- X4P-001/AMD11070; Orphan drugs -- Periodicals; Rare diseases -- Periodicals; Chemotherapy -- Periodicals; 615.1
• DOI: 10.1080/21678707.2017.1375403
• Languages: English
• ISSNs: 2167-8707

Abstract

ABSTRACT: 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. 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. 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.