Thalassaemia Day and the Importance of Thalassaemia in Cyprus
The 8th of May has been established by the World Health Organization and the Cyprus-based International Thalassemia Federation as World Thalassemia Day, which aims to raise public awareness of the disease and of the need to promote health and quality of life for thalassaemia patients.
Thalassaemia or Mediterranean anaemia is an inherited haematologic disease characterised by reduced ability of red blood cells to carry oxygen to tissues.
The disease is unusually common in Cyprus, with more than 1 in 10 Cypriots being carriers of its clinically most important form, β-thalassemia, and with currently about 600 β-thalassaemia patients. For pairs of carriers each pregnancy has a 25% chance of being affected by the disease.
In response, a programme of prevention, diagnosis, research and patient care services is pursued by a multidisciplinary team of experts at the four thalassemia clinics (of Larnaca, Limassol, Nicosia and Paphos), the Population Screening Laboratory at Makarios Hospital Nicosia, and the Molecular Genetics Thalassemia Department (MGTD) of the Cyprus Institute of Neurology and Genetics (CING). Collaboration with additional experts but also with the Pancyprian Thalassaemia Association is critical to providing timely prevention, correct diagnosis, high-quality medical patient care and support for affected families.
Services of the Molecular Genetics Thalassemia Department at the Cyprus Institute of Neurology and Genetics
The MGTD at the CING has been actively involved in the diagnosis of haemoglobinopathies and its research for more than 28 years.
It offers specialised genetic diagnostic services for the entire spectrum of hemoglobinopathies as well as for Duchenne and Becker muscular dystrophies, annually amounting to prenatal diagnosis of thalassemia for approximately 110 pairs of carriers and to genetic analyses for α- and β-thalassemia and other hemoglobinopathies for more than 1,500 individuals.
Additionally, preimplantation genetic diagnosis has been applied since 2004 in a total of 317 cases of β-haemoglobinopathies, but is also offered as a specialised service in families with other rare genetic diseases.
As part of ongoing service and technology development, the MGTD has also been offering non-invasive prenatal determination of foetal sex since 2009, for pregnancies at risk of serious X-linked disorders and for the determination of foetal Rhesus factor for pregnancies at risk for haemolytic disease of the newborn.
The need for a cure
Globally, thalassaemia affects tens of thousands of patients and in its severest form and without adequate care may lead to death in early childhood. Only a fraction of patients find compatible donors for a curative stem cell transplantation, while others require lifelong management with blood transfusions and medication, at inherent risks, substantial cost and overall reduced quality of life. Therefore researchers and clinicians have for decades been working towards a universal cure for thalassaemia patients.
Conditional marketing approval by the European Medicines Agency
Friday, 29th March 2019 was a significant date for thalassaemic patients in this quest, because it saw the conditional marketing approval in Europe of the first universal cure for β-thalassaemia.
Beta-thalassaemia is caused by deficient production of β-globin. The new treatment, marketed by Bluebird Bio Inc. under the name of Zynteglo, is based on the virus-based insertion of a functional β-globin gene in the patients’ own blood stem cells and may therefore provide the patient with functional β-globin for a lifetime. The treatment has proven safe and efficient in long-running clinical trials.
Universal, but not for all
Any transfusion-dependent β-thalassemia patient over the age of 12 and without a compatible donor would be eligible for treatment pending its final approval by the European Commission later in the year. However, as with any new medical development, patients for whom alternative treatments are currently failing may eagerly welcome this new treatment option, while those with good disease management may want to wait until gene therapy for thalassaemia has become more affordable. And potentially still more efficient and safer.
It is as yet unclear if and how gene therapy treatments will be made available to patients in Cyprus. The price of one-off treatment with Zynteglo will likely be in the order of several hundred thousand Euro, based on existing pricing for conceptually similar gene therapy products for other diseases.
However, because of the high lifetime cost of disease management for β-thalassaemia, some health systems may still be willing to pay for curative treatments such as Zynteglo with public money.
Elsewhere, such advanced treatments will be restricted to those few patients able to afford them out of their own pockets.
Efficiency vs safety
There are alternative treatments to Zynteglo, which are still further away from assessment for approval by regulatory authorities. For instance, clinical trials in Italy for an alternative drug, GLOBE, have also shown promising results.
However, from the sum of clinical trials to date it appears that for current gene therapy treatments, correction of severe forms of β-thalassemia may only be partial at low drug doses, while higher doses, which have been suggested for wider application of both Zynteglo and GLOBE, would be more efficient but would increase the risk of adverse events.
Therapy development in Cyprus
Prompted by these shortcomings, the MGTD at the CING has been working on potentially safer and more efficient alternatives for β-thalassaemia gene therapy for Cypriot patients.
With focus on the common β-thalassaemia mutation that affects 76% of disease carriers in Cyprus, the MGTD has been developing two alternative, mutation-specific gene therapies. The first therapy is based on gene addition technology, similar to that of Zynteglo and GLOBE, but uses suppression of an abnormal β-globin product. This innovative approach achieved high levels of therapeutic correction in cells from Cypriot patients and proved superior in direct comparison to GLOBE, as was published last year in the scientific journal Haematologica.1
The second therapy is based on the emerging therapeutic technology of gene editing, for which the MGTD has a pioneering role in Cyprus and has developed substantial expertise.2,3 By virus-free and highly efficient modification with CRISPR/Cas and TALEN gene editing tools, the researchers corrected thalassaemia in cells from Cypriot patients, as has just been published in Haematologica.4 Both therapeutic approaches are currently being optimised and evaluated further towards potential clinical application, in part based on new funding secured from the Research Promotion Foundation of Cyprus. I
n their efforts, the MGTD are indebted to their patients, to clinicians of the thalassaemia clinics in Cyprus and to their international collaborators, without whom their ongoing work would not be possible.
Zynteglo will not be the final word in gene therapy for β-thalassaemia, but its development opens up a new chapter for β-thalassaemia therapies. In order to give Cypriot patients the full benefit of these newly emerging treatment options, regulatory frameworks and infrastructure for clinical application and follow-up urgently needs to be put in place. Developing treatments tailored for Cypriot patients, such as those investigated by the MGTD, will be an important part of this process.
Article by Carsten W. Lederer (PhD), Petros Patsali (PhD), Panayiota Papasavva (MD, MSc), Thessalia Papasavva (PhD) and Marina Kleanthous (PhD, Head of the MGTD).