Gene Therapy for Haemoglobinopathies


Haemoglobinopathies, including thalassaemia and sickle cell anaemia, are common genetic diseases with significant associated morbidity and mortality. The potentially curative modality, haematopoietic stem cell (HSC) transplant, is restricted to a minority with matched donors, and has potential immunological adverse sequelae. Autologous HSC‐based therapies, using a patient's own genetically modified HSCs as donor cells, eliminates the need for an allogeneic matched donor and the immunological adverse effects of allogeneic HSC transplants. Gene therapy for haemoglobinopathies can be categorised as: (1) gene addition, (2) gene disruption, (3) gene correction, or (4) gene modification resulting in pharmacological upregulation of foetal haemoglobin. Currently, additive gene therapies are in clinical trials, while promising therapies based on gene disruption, editing and modulation of gene regulation are currently under development. Many of these therapies use the latest innovations in gene editing, the designer nucleases, including zinc‐fingers, transcription activator‐like effector nucleases, and clustered regularly interspaced short palindromic repeats/Cas technologies.

Key Concepts

  • Haemoglobin exists as a heterotetramer of two α‐globin subfamily peptides and two β‐globin subfamily peptides; adult haemoglobin primarily composed of α2β2.
  • Haemoglobinopathies are genetic diseases that affect either the function or level of globin peptides.
  • Haemoglobinopathies are the most prevalent genetic diseases with significant morbidity and mortality.
  • Of these, β‐globinopathies (sickle cell anaemia and β‐thalassaemia) are the most common monogenic diseases worldwide and manifest within 6–12 months of birth.
  • Severity of haemoglobinopathies can be ameliorated through the expression of the missing haemoglobin subunit beta (HBB), additional β‐like globins, or genes that upregulate alternative globins.
  • Additive gene therapy using lentivirus vectors has proven to be successful for both β‐thalassaemia and sickle cell anaemia clinically.
  • Gene editing strategies, using ZFNs, TALENs or CRISPR/Cas, can be used as a ‘fix and run’ approach and have the advantage over additive gene therapies by avoiding insertional genotoxicity and restoring innate regulatory mechanisms.
  • Erythroid‐specific modulation of BCL11A has been shown to increase expression of haemoglobin subunits gamma 1 (HBG1) and gamma 2 (HBG2), and may be a viable alternative treatment modality.

Keywords: gene therapy; haemoglobinopathy; thalassaemia; sickle cell anaemia; gene editing

Figure 1. General outline of steps involved in gene therapy for haematopoietic disorders. Haematopoietic stem and progenitor cell (HSPC), induced pluripotent stem cell (iPSC). HSPCs can either be modified directly, or somatic cells, e.g. fibroblasts, can be reprogrammed into iPSCs which are then modified before being differentiated into HSPCs.
Figure 2. Haemoglobin switching. Genetic structure of the α‐globin and β‐globin family loci on chromosomes 16 and 11, respectively. Arrows illustrate order of gene expression (haemoglobin switching) that occurs during development. In the α‐globin family, haemoglobin subunit zeta (HBZ) is expressed in early embryonic stages, before transitioning to alpha 1 (HBA1) and alpha 2 (HBA2), which are expressed during foetal and adult stages. In the β‐globin family, haemoglobin subunit epsilon 1 (HBE1) is expressed during embryonic stages. Expression is then switched to gamma 1 (HBG1) gamma 2 (HBG2), which is the predominant β‐globin family peptide during foetal life. Within several weeks of birth, haemoglobin subunits gamma 1 and gamma 2 are replaced by beta (HBB) as the predominant β‐globin family peptide and haemoglobin subunit delta (HBD) expression begins. HBG1, HBG2 and HBD expression continue throughout life, although at low levels. Predominant globin peptides after first few weeks of life indicated by red arrows. HS40 and the locus control region (LCR) are the dominant regulatory elements controlling haemoglobin switching.
Figure 3. Two mechanisms for insertional genotoxicity mediated by viral vectors. (a) Long terminal repeat (LTR) acts as an enhancer and increases the activity of a cellular proto‐oncogene promoter near insertion site. (b) Integration of the provirus within a putative tumor suppressor gene (TSG) can disrupt/deregulate the gene, even if the LTR self inactivates (SIN) by deleting the viral transcriptional elements upon integration. Here, either premature polyadenylation (pA), stop codon (STOP), or aberrant splicing may occur.


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Further Reading

Breda L, Rivella S, Zuccato C and Gambari R (2013) Combining gene therapy and fetal hemoglobin induction for treatment of β‐thalassemia. Expert Review of Hematology 6 (3): 255–264.

Chandrakasan S and Malik P (2014) Gene therapy for hemoglobinopathies: the state of the field and the future. Hematology/Oncology Clinics of North America 28 (2): 199–216.

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Finotti A, Breda L, Lederer CW, et al. (2015) Recent trends in the gene therapy of beta‐thalassemia. Journal of Blood Medicine 6: 669–685.

Nienhuis AW and Persons DA (2012) Development of gene therapy for thalassemia. Cold Spring Harbor Perspectives in Medicine 2 (11).

Payen E and Leboulch P (2012) Advances in stem cell transplantation and gene therapy in the β‐hemoglobinopathies. ASH Education Program Book 2012 (1): 276–283.

Persons DA and Nienhuis AW (2001) Hemoglobin Disorders: Gene Therapy, eLS. Chichester: John Wiley & Sons, Ltd.

Porteus MH (2015) Genome editing of the blood: opportunities and challenges. Current Stem Cell Reports 1 (1): 23–30.

Villamizar O, Chambers CB and Wilber A (2001) Gene Therapy for Severe Haemoglobin Disorders, eLS. Chichester: John Wiley & Sons, Ltd.

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How to Cite close
Goodman, Michael A, and Malik, Punam(May 2016) Gene Therapy for Haemoglobinopathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025347]