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CRISPR/Cas9 for Sickle Cell Disease: Applications, Future Possibilities, and Challenges

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Cell Biology and Translational Medicine, Volume 5

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1144))

Abstract

Sickle cell disease (SCD) is an inherited monogenic disorder resulting in serious mortality and morbidity worldwide. Although the disease was characterized more than a century ago, there are only two FDA approved medications to lessen disease severity, and a definitive cure available to all patients with SCD is lacking. Rapid and substantial progress in genome editing approaches have proven valuable as a curative option given plausibility to either correct the underlying mutation in patient-derived hematopoietic stem/progenitor cells (HSPCs), induce fetal hemoglobin expression to circumvent sickling of red blood cells (RBCs), or create corrected induced pluripotent stem cells (iPSCs) among other approaches. Recent discovery of CRISPR/Cas9 has not only revolutionized genome engineering but has also brought the possibility of translating these concepts into a clinically meaningful reality. Here we summarize genome engineering applications using CRISPR/Cas9, addressing challenges and future perspectives of CRISPR/Cas9 as a curative option for SCD.

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Abbreviations

AAV:

Adeno-associated virus

BM:

Bone marrow

Cas9:

CRISPR associated protein 9

CRISPR:

Clustered regularly interspaced short palindromic repeats

DSB:

Double strand breaks

dCas9:

Dead Cas9

ddPCR:

Droplet digital PCR

eSpCas9:

Enhanced specificity Streptococcus pyogenes Cas9

GVHD:

Graft-vs-host disease

HbA:

Adult hemoglobin

HbF:

Fetal hemoglobin

HbS:

Hemoglobin S

HDR:

Homology directed repair

HLA:

Human leukocyte antigen

HPFH:

Hereditary persistence of fetal globin

HPLC:

High performance liquid chromatography

HRI:

Heme-regulated inhibitor

HSCT:

Hematopoietic stem cell transplantation

HSPCs:

Hematopoietic stem/progenitor cells

HU:

Hydroxyurea

INDELs:

Insertions/deletions

iPSCs:

Induced pluripotent stem cells

LCR:

Locus control region

MUD:

Matched unrelated donor

NHEJ:

Non-homologous end-joining

OTEs:

Off-target effects

PACE:

Phage-assisted continuous evolution

PAM:

Protospacer-adjacent motif

QTL:

Quantitative trait loci

RBCs:

red blood cells

ScCas9:

Streptococcus canis Cas9

SCD:

Sickle cell disease

shRNAmiR :

MicroRNA-adapted small hairpin (sh) RNAs

SpCas9-HF1:

high fidelity Streptococcus pyogenes Cas9

TALENs:

TAL-effector nucleases

UCBT:

Umbilical cord blood transplantation

ZFNs:

Zinc finger nucleases

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Conflicts of Interest

The authors have no commercial, proprietary, or financial interest in the products described in this article.

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Authors and Affiliations

  1. Cellular and Molecular Therapeutics Branch, NHLBI/NIDDK, National Institutes of Health, Bethesda, MD, USA

    Selami Demirci, Alexis Leonard, Juan J. Haro-Mora & Naoya Uchida

  2. Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute, Bethesda, MD, USA

    Selami Demirci & John F. Tisdale

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  1. Selami Demirci
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  2. Alexis Leonard
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  3. Juan J. Haro-Mora
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  4. Naoya Uchida
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  5. John F. Tisdale
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Correspondence to Selami Demirci or John F. Tisdale .

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  1. (Retired), Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Kursad Turksen

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Demirci, S., Leonard, A., Haro-Mora, J.J., Uchida, N., Tisdale, J.F. (2019). CRISPR/Cas9 for Sickle Cell Disease: Applications, Future Possibilities, and Challenges. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 5. Advances in Experimental Medicine and Biology(), vol 1144. Springer, Cham. https://doi.org/10.1007/5584_2018_331

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