Evolution of Thalassaemia Management Four Decades in Thalassaemia Care – Our Achievements and Challenges

Hope from new therapies

For every patient with TDT, regular transfusion and chelation are the standard and always available. They need to discuss whether to proceed with HSCT as the procedure carries risk of morbidities and mortality. Fig. 17 Research has been ongoing for many years to explore any drugs can help to increase haemoglobin level and thus reduce the need for blood transfusion. Some of the drugs tried were hydroxyurea, butyrate compounds and erythropoietin. Unfortunately, the efficacy was not high and has not been used widely in clinical practice. Luspratacept is a new drug which can raised mild rise in some TDT patients and is now available in Hong Kong for individual use.

The most exciting development in recent years is gene therapy which requires transfer large globin gene expression cassettes to haematopoietic stem cells driven by complex regulatory elements. Preclinical and early clinical studies proved safety and efficacy of stem cell–based gene therapy while showing hurdles and limitations of the existing technology. Although the number of patients in the initial studies are small, a significant proportion of patients achieved transfusion independence. Stem cell procurement, cell dose, transduction efficiency, gene expression level, conditioning regimen, and patient’s age at the time of intervention are key factors affecting the therapeutic range and clinical efficacy of gene therapy. There will be refinements in the gene therapy methodology and at the same time haematopoietic stem cell transplant will also improve. A comparison between the 2 approaches is tabulated. Fig. 18 More and more centers including mainland China are being conducted. It is possible that this approach can be applied to our patients in Hong Kong.

Another approach in gene therapy is gene (genome) editing in which no viral transduction is required. Nucleases are employed to either repair, disrupt or to activate certain globin genes with different approaches aiming at alleviating globin chain imbalance in intermediately severe forms of beta thalassemia. One of the popular nuclease systems is the CRISPR-Cas9, which was adapted from a naturally occurring genome editing system in bacteria. Challenges include selection of the most effective genome editing tools, optimizing their delivery to haematopoietic stem cells (HSCs), improving specificity, and better understanding potential off target effects, particularly those that are biologically relevant.