重要的地贫科研项目 Significant Medical Research Projects

Allocation of funding by the Children’s Thalassaemia Foundation to support research started with thalassaemia screening in high school children, completed in 1997.¹ The reported population carrier frequency of 4.5% for SEA deletion α-thalassaemia and 3.4% for β-thalassaemia and HbE combined formed the basis of educational programs to promote awareness and prevention of thalassaemia by the Foundation. From 1997 onwards, research funds were allocated on an annual basis until 2019 and was halted by fund raising difficulties during the Covid-19 pandemic, but gratifyingly was able to resume in 2023.

A continual theme from the beginning was studies on oral iron chelators. A randomized, open label and controlled clinical trial showed that the short term use of deferiprone (L1), with or without desferrioxamine, was safe and efficacious in the Chinese patient cohort.² The safety of oral iron chelators with respect to the risk of bacterial infection was reported.³ Deferiprone could protect endothelial cells from iron-induced toxic effects and minimize endothelial microparticle release, which could be potentially helpful in a subgroup of thalassaemia patients who have increased thromboembolic complications.⁴ More recently, the use of low dose deferasirox in transfusion-dependent thalassaemia patients after hematopoietic stem cell transplantation, and iron chelation therapy in non-transfusion dependent thalassaemia patients were investigated.

Studies were undertaken to assess iron overload in the different organs of thalassaemia major patients by magnetic resonance imaging (MRI).^{5 6} Study results accumulated into a clinically useful and practical chelation protocol based on stratification of thalassemic patients by serum ferritin and MRI cardiac T2*.⁷ Early data showed that native cardiac MRI T1 values were also useful and correlated with T2* in the assessment of left ventricular (LV) and left atrial myocardial deformation.⁸

Fruitful research addressed the cardiac function of thalassaemia major patients. Arterial dysfunction found in patients with beta-thalassaemia major before and after HSCT may be related to impaired proliferation of endothelial and endothelial progenitor cells.⁹ An exercise echocardiographic study showed that resting LV dyssynchrony was associated with myocardial iron load, while exercise stress further unveiled LV dynamic dyssynchrony and impaired contractile reserve in patients with beta-thalassaemia major.¹⁰ Resting and dynamic LV torsional mechanics was impaired in patients with beta-thalassaemia major. Cell and animal models suggested a potential role of titin degradation in iron overload-induced alteration of LV torsional mechanics.¹¹ Functional and structural remodeling of both the right and left atria occurred in patients with beta-thalassaemia major, even in the absence of ventricular diastolic dysfunction.¹²

Research into other disease complications was undertaken. To address osteoporosis and increased bone fracture risk in thalassaemia major, a comprehensive study showed that iron overload played an important role in adverse bone health and that dual x-ray densitometry was insufficient to predict fracture risk.¹³ Restrictive pulmonary function deficit was commonly observed in thalassaemia major and the severity potentially correlated with myocardial iron content, hence monitoring of lung function was important.¹⁴

The Children’s Thalassaemia Foundation supported the first pre-implantation genetic testing for prevention of Hb Barts hydrops fetalis in Hong Kong.¹⁵ This was a major milestone in prevention of severe thalassaemia in Hong Kong. A successful disease prevention program relied on effective carrier screening and advancement in methods of laboratory diagnosis.¹⁶ Leveraging on next-generation sequencing technology, a local bioinformatics algorithm for molecular diagnosis and carrier screening of thalassaemia and other haemoglobinopathies was successfully developed.¹⁷

Looking beyond haemopoietic stem cell transplantation as the only curative treatment of thalassaemia major, our Foundation is funding research in gene therapy and gene editing as emerging methods of disease cure, in addition to new drug treatment. The Children’s Thalassaemia Foundation spares no effort to support researchers in their quest to find new cures for severe thalassaemia.

References

1. Lau YL, Chan LC, Chan YY, et al. Prevalence and genotypes of alpha- and beta-thalassemia carriers in Hong Kong — implications for population screening. N Engl J Med 1997;336:1298-301. ↑
2. Ha SY, Chik KW, Ling SC, et al. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Hemoglobin 2006;30:263-74. ↑
3. Chan GC, Chan S, Ho PL, Ha SY. Effects of chelators (deferoxamine, deferiprone and deferasirox) on the growth of Klebsiella pneumoniae and Aeromonas hydrophila isolated from transfusion-dependent thalassemia patients. Hemoglobin 2009;33:352-60. ↑
4. Chan S, Lian Q, Chen MP, et al. Deferiprone inhibits iron overload-induced tissue factor bearing endothelial microparticle generation by inhibition oxidative stress induced mitochondrial injury, and apoptosis. Toxicol Appl Pharmacol 2018;338:148-58. ↑
5. Au WY, Lam WW, Chu W, et al. A T2* magnetic resonance imaging study of pancreatic iron overload in thalassemia major. Haematologica 2008;93:116-9. ↑
6. Au WY, Lam WW, Chu WW, et al. A cross-sectional magnetic resonance imaging assessment of organ specific hemosiderosis in 180 thalassemia major patients in Hong Kong. Haematologica 2008;93:784-6. ↑
7. Ha SY, Mok AS, Chu WC, et al. A practical chelation protocol based on stratification of thalassemic patients by serum ferritin and magnetic resonance imaging cardiac T2*. Hemoglobin 2009;33:323-31. ↑
8. See WS, So EK, Hwang GY, et al. Native cardiac magnetic resonance T1 mapping and cardiac mechanics as assessed by speckle tracking echocardiography in patients with beta-thalassaemia major. Int J Cardiol Heart Vasc 2022;38:100947. ↑
9. Cheung YF, Chan S, Yang M, et al. Circulating CD133(+)VEGFR2 (+) and CD34 (+)VEGFR2 (+) cells and arterial function in patients with beta-thalassaemia major. Ann Hematol 2012;91:345-52. ↑
10. Cheung YF, Yu W, Li SN, et al. Dynamic dyssynchrony and impaired contractile reserve of the left ventricle in beta-thalassaemia major: an exercise echocardiographic study. PLoS One 2012;7:e45265. ↑
11. Chen MP, Li SN, Lam WW, et al. Left ventricular torsional mechanics and myocardial iron load in beta-thalassaemia major: a potential role of titin degradation. BMC Cardiovasc Disord 2014;14:49. ↑
12. Cheung YF, So EK, Hwang GY, Chan GC, Ha SY. Left and Right Atrial Function and Remodeling in Beta-Thalassaemia Major. Pediatr Cardiol 2019;40:1001-8. ↑
13. Lee SLK, Wong RSM, Li CK, Leung WK. Prevalence and risk factors of fractures in transfusion dependent thalassemia – A Hong Kong Chinese population cohort. Endocrinol Diabetes Metab 2022;5:e340. ↑
14. Chan KC, Au CT, Leung AWK, et al. Pulmonary function in patients with transfusion-dependent thalassemia and its associations with iron overload. Sci Rep 2023;13:3674. ↑
15. Chan V, Ng EH, Yam I, Yeung WS, Ho PC, Chan TK. Experience in preimplantation genetic diagnosis for exclusion of homozygous alpha degrees thalassemia. Prenat Diagn 2006;26:1029-36. ↑
16. So CC, So AC, Chan AY, Tsang ST, Ma ES, Chan LC. Detection and characterisation of beta-globin gene cluster deletions in Chinese using multiplex ligation-dependent probe amplification. J Clin Pathol 2009;62:1107-11. ↑
17. Cao Y, Ha SY, So CC, et al. NGS4THAL, a One-Stop Molecular Diagnosis and Carrier Screening Tool for Thalassemia and Other Hemoglobinopathies by Next-Generation Sequencing. J Mol Diagn 2022;24:1089-99. ↑