Mohammad, a 19-year-old with beta-thalassemia, is the first patient in Germany to be treated with the CRISPR-based drug Exagamglogene Autotemcel (Exa-cel) as part of standard medical care. He received the gene therapy in May at Charité – Universitätsmedizin Berlin in the presence of CRISPR discoverer and Nobel laureate Prof. Emmanuelle Charpentier. The drug is the world’s first CRISPR-based therapy to achieve approval. Four months after receiving the drug, Mohammad is no longer dependent on blood transfusions and is leading a normal life.
“On May 28, basic research turned into medical care,” says PD Dr. Lena Oevermann, senior physician at Charité’s Department of Pediatric Oncology and Hematology and head of the Hemoglobinopathy Program. That day, she administered Exa-cel to Mohammad. Exa-cel is a novel therapy that modifies the genetic material of the young patient’s blood stem cells to cure his severe inherited disease. Emmanuelle Charpentier laid the foundation for its development through a company she founded.
A milestone in medicine
Together with her colleague Prof. Jennifer Doudna, Emmanuelle Charpentier first described the CRISPR-Cas9 technology in 2012. Originally a bacterial defense mechanism against viruses, it was developed into a precise genetic tool that has become very widely used in bioscientific research. In 2020, the two scientists were awarded the Nobel Prize in Chemistry for this work. “Now, just 14 years after it was first described, the gene-editing tool is part of a treatment that we can offer to seriously ill young patients in routine clinical practice,” emphasizes Prof. Heyo K. Kroemer, Chief Executive Officer of Charité. “The fact that this therapy is now being used for the first time in Germany following its approval—here at Charité—is a milestone in medicine. Charité is committed to bringing medical progress directly to patients, and Mohammad’s treatment demonstrates what this means in practice.”
Every year, approximately 60,000 children worldwide are born with severe beta-thalassemia, and Mohammad was also born with this condition. The cause is a genetic defect that impairs the production of the blood pigment hemoglobin. As a component of red blood cells, hemoglobin transports oxygen to all parts of the body. In beta-thalassemia, insufficient oxygen reaches the tissues, meaning that the cells lack the fuel required for basic metabolic processes. If left untreated, patients with a severe form of the disease die before reaching toddler age.
Gene therapy for particularly severe cases
In order to survive, children with severe beta-thalassemia require blood transfusions every three weeks. These transfusions, however, can have serious side effects over the long term. In such cases, a stem cell transplant is opted for, which can cure the disease. This requires finding a suitable stem cell donor and ensuring that the patient’s health allows for such a major procedure in the first place.
“Unfortunately, a stem cell transplant is only an option up to age 14, because after that the risks of complications simply become too great,” explains Lena Oevermann. “Mohammad was already too old for the procedure. Since there was no other treatment option for him, we administered Exa-cel after a case-by-case review by his health insurance provider.”
A year-long treatment process
Exa-cel is not a substance but a cell-based gene therapy, which is why the treatment process spanned approximately 12 months. “We first stimulated the patient’s blood stem cells to migrate from the bone marrow into the bloodstream,” explains the physician. “After we had filtered out the stem cells, we sent them to the manufacturer’s laboratories in the Netherlands.”
The genetic intervention took place on-site: Using the CRISPR gene-editing tool, the gene for the gamma-globin chain was reactivated in the patient’s stem cells. Every human being produces this hemoglobin subunit while still in the womb; it is a component of what is known as fetal hemoglobin. After birth, the body naturally ceases to produce it. “Thanks to the genetic intervention, the stem cells are now once again able to produce fetal hemoglobin,” explains Lena Oevermann. “Because fetal hemoglobin can transport oxygen just as effectively as the hemoglobin produced in adulthood, it can eliminate the oxygen deficiency in people with beta-thalassemia.”
900 million cells for sufficient oxygen in the blood
Before the genetically modified stem cells could be returned to Mohammad, space had to be created in his bone marrow by way of a process known as chemoconditioning. Then, on May 28, the time had finally come. “We were able to infuse over 900 million of Mohammad’s genetically modified stem cells back into his bloodstream,” says Lena Oevermann. The cells had previously undergone several months of quality testing to ensure the success of the genetic intervention.
Over the next six weeks or so, the stem cells took hold in the patient’s bone marrow and began producing new blood cells. “Within 40 days, Mohammad’s body began producing fetal hemoglobin, which now accounts for 85 precent of his total hemoglobin level,” as his attending physician relates. “It will take about half a year in total to reach full hemoglobin production. Fortunately, however, his total hemoglobin level is already within the normal range, meaning that blood transfusions are no longer necessary. Mohammad’s immune system has also regenerated, and he’s currently doing really exceptionally well.”
A new start in life
Overall, the patient tolerated the treatment well and was discharged from Charité just under six weeks after the genetically modified cells were administered. Nevertheless, the therapy represents an extensive intervention and procedure that is associated with side effects and long-term risks. “Chemoconditioning causes acute side effects such as painful inflammation of the mucous membranes, and it is likely to cause infertility and can lead to liver damage,” says Lena Oevermann. “Furthermore, we do not yet have data on the long-term safety and efficacy of the gene therapy.”
The conditional approval of the drug therefore stipulates that patients receiving Exa-cel must be monitored for 15 years. “But for Mohammad, an entirely new life is now beginning,” as his treating physician emphasizes. “After just this single dose of the gene therapy, he has the chance to lead a symptom-free, normal everyday life, and he would like to start vocational training. We wish him every success and all the best.”
About beta-thalassemia
Beta-thalassemia is a congenital disorder that is life-threatening in its severe form. The underlying genetic defect impairs the production of beta-globin chains – a component of the blood pigment hemoglobin. This results in severe anemia that requires blood transfusions as early as the first months of life. The anemia is accompanied by symptoms such as severe fatigue, pain, impaired physical and cognitive development, and iron overload, which can cause organ damage. Every year, approximately 60,000 children are born worldwide with severe beta-thalassemia.
About Exa ‑ cel
Exagamglogene autotemcel (Exa‑cel) is a cell‑based gene therapy that utilizes the CRISPR‑Cas9 gene‑editing technology. Since 2024 Exa‑cel has received conditional approval in Europe for the treatment of certain patients with transfusion-dependent beta‑thalassemia or severe sickle‑cell disease, with use tied to specific requirements such as 15‑year post‑treatment monitoring. The therapy may be administered only in specialized centers; Charité is the first qualified center in Germany. The drug was developed by CRISPR Therapeutics, a company co‑founded by Prof. Emmanuelle Charpentier, Dr. Rodger Novak, and Shaun Foy, and Vertex Pharmaceuticals.