Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates

Romero, Zulema; Lomova, Anastasia; Saïd, Suzanne; Miggelbrink, Alexandra; Kuo, Caroline Y.; Campo-Fernández, Beatriz; Hoban, Megan D.; Masiuk, Katelyn E.; Clark, David O.; Long, Joseph; Sanchez, Juan M; Vélez, Miriam; Miyahira, Eric; Zhang, Ruixue; Brown, Devin; Wang, Xiaoyan; Kurmangaliyev, Yerbol Z.; Hollis, Roger P.; Kohn, Donald B.

doi:10.1016/j.ymthe.2019.05.014

Cited by 85 publications

(111 citation statements)

References 51 publications

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“…5,[7][8][9][10][11][12] Second, fetal hemoglobin (HbF, a2g2) can be induced in adult red blood cells (RBCs) by using nonhomologous end-joining (NHEJ) mediated mutations to disrupt noncoding DNA regulatory elements that repress transcription of the genes encoding g-globin (HBG1 and HBG2) postnatally. 4,[13][14][15][16][17][18][19] Numerous clinical studies show that elevated HbF production is associated with reduced morbidity and mortality in SCD and b-thalassemia. 20,21 In extreme cases, a rare, benign genetic condition called hereditary persistence of HbF (HPFH) induces high-level pancellular HbF expression in RBCs and eliminates the pathologies of coinherited b-hemoglobinopathies.…”

Section: Introductionmentioning

confidence: 99%

Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

et al. 2019

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Section: Introductionmentioning

confidence: 99%

Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

et al. 2019

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“…For ex vivo gene transfer into human CD34 + HSCs, zinc-finger nuclease mRNA and rAAV6-mediated donor template delivery resulted in~15% targeted integration into the AAVS1 locus [165]. One study found that rAAV6 was more efficient than the first generation of Ad5/35 as a donor vehicle [167]. These high-level HSC gene editing and HDR events are achieved through optimization of experimental parameters, such as modifications of sgRNA, time, and dose of AAV6 transduction.…”

Section: Targeted Integration Into Preselected Sitesmentioning

confidence: 99%

“…Strategies based on shRNA-and CRISPR-mediated down-modulation of BCL11A have entered clinical stage (NCT03282656 and NCT03655678). As an alternative, Romero et al [167] reported that RNP electroporation can be combined with Ad5/35 transduction for ex vivo gene editing of human HSCs to correct the sickle HBB mutation. Alternative strategies include the disruption of binding sites of repressors within the HBG promoter region [212][213][214], the repair of the sickle mutation [215], and the forced modification of chromatin structure [216].…”

Section: In Vivo Hsc Transductionmentioning

confidence: 99%

“…Of interest is to compare the performance of AdV with rAAV6 as the donor template vector. One study found that rAAV6 was more efficient than the first generation of Ad5/35 as a donor vehicle [167]. Recently, we demonstrated the utility of a HDAd5/35++ as a donor vector in mediating high frequency of HDR-and AAVS1-targeted integration [103].…”

Section: Targeted Integration Into Preselected Sitesmentioning

confidence: 99%

“…When combining with rAAV6 transduction to deliver a donor template, over 20% HDR-mediated repair of the sickle mutation has been demonstrated [166]. As an alternative, Romero et al [167] reported that RNP electroporation can be combined with Ad5/35 transduction for ex vivo gene editing of human HSCs to correct the sickle HBB mutation. Li et al [217] demonstrated efficient repair of the sickle mutation in induced pluripotent cells using an HDAd5/35 vector.…”

Section: In Vivo Hsc Transductionmentioning

confidence: 99%

See 2 more Smart Citations

Adenovirus vectors in hematopoietic stem cell genome editing

Lieber

2019

FEBS Letters

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Genome editing of hematopoietic stem cells (HSCs) represents a therapeutic option for a number of hematological genetic diseases, as HSCs have the potential for self-renewal and differentiation into all blood cell lineages. This review presents advances of genome editing in HSCs utilizing adenovirus vectors as delivery vehicles. We focus on capsid-modified, helper-dependent adenovirus vectors that are devoid of all viral genes and therefore exhibit an improved safety profile. We discuss HSC genome engineering for several inherited disorders and infectious diseases including hemoglobinopathies, Fanconi anemia, hemophilia, and HIV-1 infection by ex vivo and in vivo editing in transgenic mice, nonhuman primates, as well as in human CD34 + cells. Mechanisms of therapeutic gene transfer including episomal expression of designer nucleases and base editors, transposase-mediated random integration, and targeted homology-directed repair triggered integration into selected genomic safe harbor loci are also reviewed.

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Advances in therapies for neurological lysosomal storage disorders

Ellison

Parker

Bigger

2023

J of Inher Metab Disea

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Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two‐thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood–brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood–brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug‐related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS‐targeted treatments for neurological LSDs with a particular emphasis on gene therapy‐based modalities, such as Adeno‐Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients.

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Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates

Cited by 85 publications

References 51 publications

Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

Adenovirus vectors in hematopoietic stem cell genome editing

Advances in therapies for neurological lysosomal storage disorders

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