Curing Everyone With Sickle Cell Disease and Thalassemia

Hemoglobinopathies are increasingly recognized as major global health problems. Precise figures are not available, but sickle cell disease (SCD) is thought to affect up to 6 million people worldwide,¹  with about 400,000 experiencing severe forms of thalassemia. Although patients with these conditions live in nearly every country of the world, a disproportionate majority live in low- and middle-income countries — about 70 percent of patients with SCD live in African countries.¹  Financial and socioeconomic limitations mean that most patients in the world do not receive available treatments. In SCD, neonatal screening, prophylaxis against infection, and hydroxyurea should form the basis of treatment for every patient, but only a small minority have access to these treatments.²  Similarly in thalassemia, regular blood transfusions and iron chelation are not widely available. Newer treatments are emerging for hemoglobinopathies; however, so far these are very expensive and only partially effective. Curative treatments involving hematopoietic stem cell transplantation are costly, toxic, and require sophisticated hospitals and infrastructure. Gene therapy is emerging as an exciting and scientifically fascinating option, but is still largely experimental, requires hematopoietic stem cell transplantation, and is prohibitively expensive to use widely for almost every country.³ 

Although these incremental improvements in care are important and will hopefully continue over the coming years, is there any prospect of curing every patient with hemoglobinopathy in the world in the foreseeable future? The article by Dr. Li and colleagues⁴  offers a glimpse of how a global cure might be achieved, building on other significant work throughout the past few years on the control of HbF and approaches to gene editing.⁵  The authors describe using in vivo base editing to increase HbF levels in CD46/b-YAC mice carrying the human ß-globin locus, following a single intravenous injection. This approach offers the prospect of curing hemoglobinopathies with a simple outpatient procedure, which would be possible in almost every health care setting. However, it is still a very long way from being a clinically useful treatment and although it avoids the need for myeloablative chemotherapy, it is not just a simple injection. The hematopoietic stem cells must be mobilized in the body to allow the HDAd5/35++ vector to work, and low doses of chemotherapy were required to select the edited cells, which were also edited to express MGMT to give resistance against O⁶-BG/BCNU. Although the authors did not find any off-target gene editing effects, there are still many questions to answer before this approach could conceivably be tried with patients. Despite the preliminary nature of the data in this paper, it is perhaps one of the most significant papers published in hemoglobinopathy this year, representing the beginning of the beginning of a curative treatment that could be used throughout the world.

Several other papers deserve an honorable mention. The outcomes of clinical trials of ex vivo gene therapy in SCD and thalassemia continue to be reported,^6-8  showing encouraging results, although the speed of technological advances is currently much faster than can be tested in clinical trials. Two important clinical trials were published about the dose of hydroxyurea in primary⁹  and secondary¹⁰  stroke prevention in children with SCD in Nigeria, with no obvious difference between low (10 mg/kg) and medium (20 mg/kg) doses, suggesting that lower dose treatment, not requiring laboratory monitoring, might be effective in this context. Continuing the theme of important data emerging from Africa, a large case-control study tried to define the life expectancy of patients with SCD in five African countries (Burkina Faso, Cote d’Ivoire, Democratic Republic of Congo, Mali, Senegal).¹¹  Although mortality rates were still depressingly high, with 43.3 percent of patients dying in their first 10 years of life, they were significantly lower than previous figures, suggesting that more than 80 percent died during childhood in most African countries. Overall, 2022 did not produce any obvious major breakthroughs in hemoglobinopathies, though important progress continues to be made in many areas, including gene therapy, and studies from Africa.