While we live, our DNA continually suffers damage that could have dire consequences. However, almost all of us have a repair system that prevents them. Children born with Fanconi anemia are not so lucky. This rare hereditary disease affects the FANCA gene, one of the more than 20,000 that humans have, responsible for DNA repair. The defect causes malformations, an increased risk of cancer or bone marrow failure, and could only be cured with a marrow transplant from a compatible donor. This operation is not always possible and involves risks such as a higher incidence of some tumors. Now, the work of more than two decades by a team of researchers led from Spain is changing the perspectives of patients and their families. Today, the magazine The Lancet of a clinical trial showing the efficacy and safety of gene therapy against Fanconi anemia.
stem cells were first extracted from the bone marrow of nine patients, children between three and seven years old, at the Niño Jesús Children’s Hospital in Madrid and in the Vall d’Hebron in Barcelona. Once purified, a team from the Center for Energy, Environmental and Technological Research (Ciemat) used a genetically modified virus to introduce the corrected FANCA gene into these cells. A few hours later, as if it were an autotransfusion, the patients were injected again with their modified cells. After seven years of follow-up, the study shows that the modified stem cells take hold in the patients and replace the damaged ones, exceeding 90% of the total in two of them. The result, which shows for the first time a gene therapy capable of correcting the progression of bone marrow failure, has achieved success where four top-level American teams had failed.
The triumph has been possible due to the collaboration of many researchers and centers through (CIBERER). Now, the pharmaceutical company Rocket Pharmaceuticals, to which the viral vector and the procedure were licensed in 2016, is carrying out an international trial with more patients and is negotiating with the regulatory agencies of the US and Europe, the FDA and the EMA, to approve the treatment. Patients and their families, grouped together in the Fanconi Anemia Foundation, have also played a fundamental role, collaborating with researchers in the development of the therapy.
Juan Bueren, CIEMAT researcher and promoter of the project for two decades, highlights some particularities of his work. “Unlike other gene therapy protocols, we do not give conditioning with chemotherapy, something that is done in other trials to make room in the bone marrow so that the cells that are infused engraft better and faster,” he explains. Giving a treatment such as chemotherapy to a patient with this anemia, which is characterized by a failure in DNA repair, causes significant side effects, but there was a risk of the graft of the new cells failing. But it wasn’t like that.
Julián Sevilla, hematologist at the Niño Jesús University Children’s Hospital and principal investigator of the clinical trials, also highlights the less aggressiveness of this type of therapy compared to bone marrow transplantation. “In a transplant you replace the patient’s marrow and blood with healthy cells from a donor, but when the treatment is done with the patient’s own cells, there is no risk of rejection and the patient does not receive the chemotherapy necessary for the transplant,” points out. “Patients who receive a transplant can spend months in the hospital and with this therapy they only spend 48 hours under observation and can go home,” he adds.
Another of the protagonists of this success is Paula Río, a CIEMAT researcher who worked on this project two decades ago, when it was just beginning. He then found that there were similarities between Fanconi anemia in mice and the human disease and that the animals could be used as a model to then create a curative therapy, first for them and then for people. “It has been a job in which we have had to learn that what had been useful for other gene therapies for other diseases may not be useful in our case,” says Río. They saw that, due to DNA repair defects, the cells of these patients were more damaged than those of those suffering from other rare diseases. That made bone marrow scarce and required special harvesting techniques or reducing culture time. They also changed the viral vector used to introduce the functional gene, something that had caused previous projects to fail because it increased the risk of leukemia and other adverse effects. “We have learned from the negative results, from what did not come out in other trials, so as not to repeat the same mistakes; “There have been many years of small optimizations,” recalls Río.
The last pillar of this project is the one supported by patients and their families, gathered around the Fanconi Anemia Foundation, who have been collaborating closely with researchers and doctors for two decades. Its spokesperson, Aurora de la Cal, comments that, “20 years ago, when patients and relatives began to be told about gene therapy studies, it seemed like science fiction.” Now, families are seeing improvements. “Some tell us: my son couldn’t go to a birthday party, because he couldn’t stand it, or he couldn’t play soccer, or he had to stay home, because he was always tired; We don’t know if it is the gene therapy, but now he can lead a normal life,” says De la Cal. “Other patients, who did not have a marrow donor, have been given a hope of eight or ten years of remaining stable, the experience of families is that it has improved their lives,” he summarizes.
