Sickle cell disease is a common genetic disorder of the red blood cells, causing symptoms such as anemia, violent painful attacks and sometimes repeated infections. It affects 300,000 births worldwide every year, and to date the only curative treatment is a stem cell transplant from a compatible donor.
Sickle cell disease: what is it?
Sickle cell disease is a hemoglobin abnormality caused by a mutation on chromosome 11. In certain circumstances (fever, dehydration, etc.), the hemoglobin in people with sickle cell disease becomes less soluble, leading to deformation of the red blood cells, which are made up of hemoglobin. These then transport oxygen less effectively in the blood, and can also impede blood circulation in the smallest vessels, leading to sometimes severe pain. These blood cells also have a shorter lifespan than normal – three weeks as opposed to two months – which can lead to chronic anemia. Hence the other name for sickle cell disease, sickle cell anemia, which also refers to the sickle shape of the red blood cells.
In France, the prevalence is around 1 case per 1,750 births, making it the most common genetic disease in the country. Sickle cell disease is more prevalent in people of Mediterranean, African and West Indian origin. One explanation seems to be that the mutation responsible for sickle cell disease makes the people concerned more resistant to malaria, which is endemic in these areas. This mutation would therefore have been favored over time.
To date, treatment is essentially symptomatic, controlling anemia, painful attacks and the potential development of infections. For the most severe cases, transplantation of donor hematopoietic stem cells to produce normal hemoglobin may be envisaged, but the procedure is very time-consuming.
Sickle cell disease: Genethon’s role
Genethon’s teams have developed lentiviral vectors containing a hemoglobin beta gene capable of taking the place of the mutated gene in the disease, enabling the production of functional hemoglobin. The researchers produced batches of research-grade vectors and carried out functional tests in the laboratory, which then enabled to select the best vector for a clinical trial.
The aim is to develop ex-vivo gene therapy, i.e. to take hematopoietic (blood) stem cells from the patient, introduce the corrective gene in the laboratory and then reintroduce the modified cells into the patient, so that they can then produce functional hemoglobin to reduce the sickle cell disease.
Sickle cell disease: what about today?
A Phase 1/2 gene therapy trial, based on the product developed at Genethon, is currently underway at Necker Hospital. AP-HP is the promoter. Starting at the end of 2019, it plans to include 6 participants and the estimated end date of the trial is set for the end of 2024.
Today, Genethon’s teams are going even further, participating in networks of experts to develop innovative therapies for sickle cell disease based on genome editing. In particular, they contribute their know-how in the molecular evaluation of these therapies to ensure treatment safety. Since 2022, Genethon’s Gene editing team has also been actively involved in the EDITSCD project, which aims to improve genome editing strategies and optimize targeted DNA integration for sickle cell disease. This project also aims to better control the collateral effects of the use of CRISPR-Cas9, the now famous “genetic scissors”, through the development of different technologies. Around ten European laboratories are collaborating on EDITSCD.
Find out more
Details of the APHP Drepaglobe trial
https://clinicaltrials.gov/ct2/show/study/NCT03964792
The EDITSCD project
