Interaction of Hb South Florida (codon 1; GTG→ATG) and HbE, with β-thalassemia (IVS1-1; G→A): expression of different clinical phenotypes

Tan, Jin‐Ai Mary Anne; Tan, Kong Wai; Omar, Khairul Zaman; Chan, Lee-Lee; Wee, Yong-Chui; George, Elizabeth

doi:10.1007/s00431-008-0877-9

Cited by 4 publications

(2 citation statements)

References 22 publications

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“…We present for the first time the correction of diseases in human somatic cells by CRISPR/GC. Here, we focused on β 0 4142 and some other genetic mutations in HBB coding region s 45, 46 using Cas9 RNP to develop a rapid and extensible gene editing pipeline to introduce mutations into normal human adult HSPCs without supplying DNA repair templates. These reagents efficiently induce non-crossover GC-mediated editing of HBB mutations in HSPCs with minimal genic off-target activity.…”

Section: Discussionmentioning

confidence: 99%

Efficient repair of human homozygous genetic mutation by CRISPR/Cas9 mediated interlocus gene conversion

Yang

Pang²,

Liu

et al. 2022

Preprint

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DNA double-strand breaks (DSBs) induced by gene editing tools are primarily resolved either by non-homologous end joining (NHEJ) or homology-directed repair (HDR) using exogenous synthetic DNA templates. Repaired by error-prone NHEJ may lead to unexpected indels at the targeted site. In the case of most genetic disorders, HDR-mediated precise correction using an exogenous homologous sequence is ideal. However, the therapeutic application of HDR might be especially challenging given the requirement for the codelivery of exogenous DNA templates with toxicity into cells, and the low efficiency of HDR could also limit its clinical application. Here, we used hematopoietic stem cells (HSCs) with genetic mutations to cause β-thalassemia in HBB coding regions and discovered that many cells are actually repaired by CRISPR/Cas9-mediated gene conversion (GC) independent of exogenous synthetic DNA templates. We show that pathogenic mutations in the HBB coding regions of HSCs can be repaired efficiently through CRISPR/GC using the paralog gene HBD as the internal template. Electroporations of Cas9 for ribonucleoprotein with sgRNA into haematopoietic stem and progenitor cells (HSPCs) with a variety of pathogenic gene mutations also resulted in effective conversion of mutations to normal wild-type sequences without exogenous DNA template. Moreover, the edited HSCs can repopulate the haematopoietic system and generate erythroid cells with a greatly reduced propensity for thalassemia after transplantations. Thus, CRISPR/GC, independent of exogenous DNA templates, holds great promise for gene therapy of genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Efficient repair of human homozygous genetic mutation by CRISPR/Cas9 mediated interlocus gene conversion

Yang

Pang²,

Liu

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Only one other patient from Malaysia has been reported since the original report with a compound heterozygote mutation of c.4G>A (GTG>ATG) and IVS1-1 (G→A) [5,6]. Although the combination of Hb South Florida with β-thalassemia was found in the Malay with no associated clinical symptoms except hematological results consistent with the beta thalassemia trait, we knew that the interactions between 2 different Hb variants could result in more severe disease.…”

Section: To the Editormentioning

confidence: 99%