A Novel 26 bp Deletion [HBB: c.20_45del26bp] in Exon 1 of the β-Globin Gene Causing β-Thalassemia Major

Edison, Eunice Sindhuvi; Venkatesan, Rajkumar S; Govindanattar, Sankari Devi; George, Biju; Shaji, R. V.

doi:10.3109/03630269.2011.641135

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…Functional evaluation of the gene modification in the ex vivo differentiated erythroid cells in the individual BMs as well as the CD34 + and CD235 + enriched BM pools through IEC identify that Crispr/Cas9-mediated disruption of codon 6 at exon 1 of HBB results in a reduction of HbA and an increase in HbF compared to the mock-edited cells (Figure 4A, 4C, S7A-D). The increase in HBF with RNP-mediated disruption could possibly be the result of re-capitulating naturally occurring deletional hereditary persistence of fetal hemoglobin (HPFH) phenotype that produces a beneficial functional outcome resulting in an increase in HbF 31, 32 .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of persistence and fate of ex vivo edited-HSC modified with donor template and Its role in correcting Sickle Cell Disease

Pattabhi¹,

Sn²,

Mp³

et al. 2021

Preprint

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Sickle cell disease (SCD) is caused by a single nucleotide transversion in exon 1 of the HBB gene that changes the hydrophobicity of adult globin (βA), leading to substantial morbidity and reduced lifespan. Ex vivo autologous gene editing utilizing co-delivery of a designer nuclease along with a DNA donor template allows for precise homology-directed repair (HDR). These gene corrected cells when engrafted into the bone marrow (BM) can prove to be therapeutic and serves as an alternative to HLA-matched BM transplantation. In the current study, we extensively explored the role of single stranded oligonucleotide (ssODN) and recombinant adeno-associated 6 (rAAV6) donor template delivery to introduce a codon-optimized change (E6optE) or a sickle mutation (E6V) change following Crispr/Cas9-mediated cleavage of HBB in healthy human mobilized peripheral blood stem cells (mPBSCs). We achieved efficient HDR in vitro in edited cells and observed robust human CD45+ engraftment in the BM of NBSGW mice at 16-17 weeks. Notably, recipients of ssODN-modified HSC exhibited a significantly higher proportion of HDR-modified cells within individual BM, CD34+ and CD235+ compartments of both E6optE and E6V cohorts. We further assessed key functional outcomes including RNA transcripts analysis and globin sub-type expression. Our combined findings demonstrate the capacity to achieve clinically relevant HDR in vitro and in vivo using both donor template delivery method. The use of ssODN donor template-delivery is consistently associated with higher levels of gene correction in vivo as demonstrated by sustained engraftment of HDR-modified HSC and erythroid progeny. Finally, the HDR-based globin protein expression was significantly higher in the E6V ssODN-modified animals compared to the rAAV6-modified animals confirming that the ssODN donor template delivery outperforms rAAV6-donor template delivery.

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Section: Discussionmentioning

confidence: 99%

Evaluation of persistence and fate of ex vivo edited-HSC modified with donor template and Its role in correcting Sickle Cell Disease

Pattabhi¹,

Sn²,

Mp³

et al. 2021

Preprint

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“…Sixty-eight mutations have been characterized, [34][35][36] but this number keeps increasing as more studies are reported. The regional distribution of mutations is also known.…”

Section: The Spectrum Of -Thalassemia Mutationsmentioning

confidence: 99%

Control of Thalassemia in India

Colah

Gorakshakar

2014

Thalassemia Reports

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The -thalassemias and sickle cell disorders pose a major health burden in the large and diverse Indian population. Education programs for awareness generation are being done by National Institutions, non-governmental organizations and Thalassemia Societies in different states. Several extensive epidemiological studies have shown that there are many non-tribal and tribal communities where the prevalence of -thalassemia carriers is much higher (5.3 to 17.0%) than the average of 3 to 4% projected for the entire country. These variations have also been shown within small geographic regions in some states, emphasizing the need for micro mapping to estimate the true burden of disease. There are 10 to 12 centers where prenatal diagnosis for hemoglobinopathies is done and the Indian Council of Medical Research is establishing additional regional centers in states where they are most needed. Sixtyeight -thalassemia mutations have been described so far among Indians and the knowledge on their prevalence and regional distribution has helped to undertake prenatal diagnosis in a cost effective way. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright R.B.

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“…4 Around sixty-eight mutations have been characterized. [5][6][7] But this number keeps on increasing as more studies are reported. 8 We run a screening program for detection of thalassaemia carriers.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis and prenatal diagnosis of β thalassemias in the Saurashtra region of Gujarat

Sorathiya¹,

Colah

Vachhani³

et al. 2020

Int J Community Med Public Health

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Background: Hemoglobinopathies pose a significant health burden in the Saurashtra region in western India. Identifying couples at- risk of having a child with a severe hemoglobin disorder prenatally can help in counseling with the option of prenatal diagnosis.Methods: All pregnant carriers of β thalassemia were advised to screen their husbands. If both were carriers, they were counselled to undergo prenatal diagnosis. Prenatal diagnosis was done in 174 couples. Chorionic villus sampling was done at 10 to 12 weeks gestation and the tissue sample was sent to the Genetic laboratory for DNA analysis along with blood samples of the parents. If the couple came after 14 weeks of pregnancy, amniocentesis was done and amniotic fluid was sent for DNA analysis. If the fetus was affected, the option of termination of the pregnancy was given.Results: In 50.5% of couples, the fetus was a carrier of β thalassemia, in 1.7% the fetus had hemoglobin E trait and in 23.0% the fetus was normal. In 20.6% of couples, the fetus had β Thalassaemia major and after counseling, these couples opted for termination. 1.2% of couples had a fetus which was unaffected but remained in distinguished (normal/thalassemia carrier) while in 0.6% of cases the fetus had sickle-β thalassemia. In 1.2% of cases the result was inconclusive. In 1.2% of cases the results were not available for lack of follow up.Conclusions: Screening antenatal women for identifying carriers and referring couples at-risk for prenatal diagnosis helped in preventing the birth of 36 thalassemia major children.

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A Novel 26 bp Deletion [HBB: c.20_45del26bp] in Exon 1 of the β-Globin Gene Causing β-Thalassemia Major

Cited by 6 publications

References 9 publications

Evaluation of persistence and fate of ex vivo edited-HSC modified with donor template and Its role in correcting Sickle Cell Disease

Evaluation of persistence and fate of ex vivo edited-HSC modified with donor template and Its role in correcting Sickle Cell Disease

Control of Thalassemia in India

Molecular analysis and prenatal diagnosis of β thalassemias in the Saurashtra region of Gujarat

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