Abstract |
For gene therapy of gain-of-function autosomal dominant diseases, either correcting or deleting the disease allele is potentially curative. To test whether there may be an advantage of one approach over the other for WHIM ( warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome - a primary immunodeficiency disorder caused by gain-of-function autosomal dominant mutations in chemokine receptor CXCR4 - we performed competitive transplantation experiments using both lethally irradiated WT (Cxcr4+/+) and unconditioned WHIM (Cxcr4+/w) recipient mice. In both models, hematopoietic reconstitution was markedly superior using BM cells from donors hemizygous for Cxcr4 (Cxcr4+/o) compared with BM cells from Cxcr4+/+ donors. Remarkably, only approximately 6% Cxcr4+/o hematopoietic stem cell (HSC) chimerism after transplantation in unconditioned Cxcr4+/w recipient BM supported more than 70% long-term donor myeloid chimerism in blood and corrected myeloid cell deficiency in blood. Donor Cxcr4+/o HSCs differentiated normally and did not undergo exhaustion as late as 465 days after transplantation. Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM syndrome, allowing correction of leukopenia without recipient conditioning.
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Authors | Ji-Liang Gao, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, Ari Azani, Albert Owusu-Ansah, David H McDermott, Philip M Murphy |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 128
Issue 8
Pg. 3312-3318
(08 01 2018)
ISSN: 1558-8238 [Electronic] United States |
PMID | 29715199
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Chemical References |
- CXCR4 protein, mouse
- Receptors, CXCR4
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Topics |
- Allografts
- Animals
- Bone Marrow Transplantation
- Disease Models, Animal
- Haploinsufficiency
- Immunologic Deficiency Syndromes
(genetics, metabolism, pathology, therapy)
- Leukopenia
(genetics, metabolism, pathology, therapy)
- Mice
- Mice, Mutant Strains
- Primary Immunodeficiency Diseases
- Receptors, CXCR4
(genetics, metabolism)
- Transplantation Chimera
(genetics, metabolism)
- Warts
(genetics, metabolism, pathology, therapy)
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