Promise of gene therapy to treat sickle cell disease

ABSTRACT

Introduction: Sickle cell anemia (SCA) is a hereditary blood disease caused by a single-gene mutation that affects millions of individuals world-wide. In this review, we focus on techniques to treat SCA by ex vivo genetic manipulation of hematopoietic stem/progenitor cells (HSPC), emphasizing replacement gene therapy and gene editing.

Areas covered: Viral transduction of an anti-sickling β-like globin gene has been tested in pre-clinical and early-phase clinical studies, and shows promising preliminary results. Targeted editing of endogenous genes by site-directed nucleases has been developed more recently, and several approaches also are nearing clinical translation.

Expert commentary: The indications and timing of gene therapy for SCA in lieu of supportive care treatment and allogeneic hematopoietic cell transplantation are still undefined. In addition, ensuring access to the treatment where the disease is endemic will present important challenges that must be addressed. Nonetheless, gene therapy and gene editing techniques have transformative potential as a universal curative option in SCA.

KEYWORDS:

• Sickle cell disease
• gene therapy
• genomic editing
• β-globin gene

Article highlights

• Vector development for gene transfer in the hemoglobin disorders recently has focused on lentiviral constructs in part because transduction of non-dividing cells hematopoietic stem cells is possible.

• Early phase clinical trials with a β-globin LV, BB305, have shown promising results in a single patient with SCD and in transfusion-dependent β-thalassemia, with an acceptable short-term safety profile.

• The major gene editing technologies are presented. ZFN and Transcription activator-like effector nucleases (TALENs) are arrays of engineered protein modules that edit DNA targets. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 is a recently-developed gene editing technology that enables flexible targeting of a 20 nucleotide sequence within a guide RNA (gRNA).The therapeutic targets of these technologies in SCA are presented.

• Gene addition and gene editing strategies to restore HbA or induce HbF expression are compared and contrasted in this review

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Acknowledgments

The authors would like to thank David IK Martin for helpful suggestions and for editing the manuscript.

Declaration of interest

MC Walters is the Medical Director of AllCells, Inc and ViaCord Processing Lab; Consultant for Sangamo Therapeutics, INc, bluebird bio, Inc., and Bioverativ, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors cite support from the California Institute for Regenerative Medicine (TRAN1-09292) in preparing this manuscript.