Fanconi anemia is a low prevalence hereditary disease which, among other serious effects, causes haematological abnormalities, such as bone marrow failure in 90% of cases. The scientific journal “The Lancet” publishes the results of pioneering Spanish research which demonstrates for the first time that gene therapy, a technique that corrects the genetic defect, is effective and safe.
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Fanconi’s anemia research team: (left to right) Josune zubicaray, Paula Río, Juan A. Bueren, Susana Navarro (top), Aurora de la Cal (bottom), and Julián Sevilla. Photos, Faconi Anemia Foundation Calendar
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fanconi’s anemia research team: (left to right) Josune Zubicaray, Paula Río, Juan A. Bueren, Susana Navarro (top), Aurora de la Cal (bottom), and Julián Sevilla. Photos, faconi Anemia Foundation Calendar
This research on gene therapy is the result of over 20 years of preclinical study and seven years of follow-up of patients suffering from Fanconi anemia, a complex disease that usually manifests itself in childhood and which affects the bone marrow stem cells themselves .
The phase I/II clinical study was promoted by the Fundación del Hospital Niño Jesús de Madrid,while the long-term follow-up study is promoted by the company Rocket Pharmaceuticals Inc.
The principal investigator of the clinical studies is Dr.Julián Sevilla with the support of Dr. josune Zubicaray, both hematologists from the Advanced Therapies Unit of the Hospital Infantil Universitario del Niño jesús and members of the Red Center for Biomedical Research for Rare Diseases ( Cyberer).
The scientific direction is entrusted to Professor Juan Bueren, with the close collaboration of doctors Paula Río, first author of this work, and Susana Navarro, all researchers at the university Village -an association dependent on the Ministry of Science, Innovation and University-, the Rare Diseases Area of Cyberer
Fanconi anemia is characterized by the progressive loss of blood cells, frequently enough resulting in severe infections, fatigue, and bleeding, a process known as bone marrow failure. Likewise, it causes a high susceptibility to cancer, both of blood cells and other types of tissues.
The Spanish research team has demonstrated in patients suffering from Fanconi anemia subtype A (caused by mutations in the FANCA gene) that, even in the absence of conditioning with chemotherapy, autotransfusion of hematopoietic stem cells corrected for the genetic defect facilitates progressive increase of corrected cells in most patients.
In two of the treated patients, the percentage of corrected cells reached levels above 90%, thus allowing the natural history of the disease to be corrected, in this case consisting of the progressive loss of blood cells.
“We published the preliminary results of this clinical study in 2019, where we demonstrated for the first time that, even in the absence of chemotherapy, the autotransfusion of the corrected stem cells allowed the progressive engraftment of cells healed from the genetic defect in patients suffering from Fanconi anemia”, underlines Doctor del Río.
If the therapeutic efficacy of this gene therapy treatment for Fanconi anemia is established, it could become the treatment of choice at the time of diagnosis and would be considered an alternative to bone marrow transplant.
Until now, the only definitive therapy for bone marrow failure in these patients was based on bone marrow transplantation from a compatible healthy donor.Although this therapy has improved considerably in recent years, it requires conditioning treatments with chemotherapy to prevent rejection reactions and is associated with risks, both short and long term, often involving prolonged hospitalizations.
The amount of hematopoietic stem cells (those that generate blood cells) is low in patients with Fanconi anemia as they lose them with age and end up needing a transplant due to bone marrow failure.
The first challenge, carried out in the Niño jesús and vall d’Hebron hospitals, was to recruit patients and improve the mobilization of their stem cells in the blood using a combination of drugs that had not been used in these patients. Once mobilized, the stem cells had to be extracted from the blood.
These samples were processed in the CIEMAT laboratory or in the clean room where the corrected version of the mutated gene, the Fanconi A (FANCA) gene, was introduced.
And for the correct copy of the gene to reach the damaged cells, it was necessary to host it in a viral vector, derived from a lentivirus, to act as a vehicle. This carrier was designed at CIEMAT.
The next step was to infuse the corrected stem cells into their donors concentrated at the Niño jesús Hospital in Madrid.
Bags with hematopoietic stem cells already corrected and prepared to infuse patients with Fanconi anemia. Photo: CIEMAT“The teamwork of numerous experts in basic, genetic and preclinical research on Fanconi anemia, together with clinical specialists of this disease, has allowed Spain to be a pioneer in demonstrating that a gene therapy that does not require any chemotherapy has shown therapeutic efficacy in patients with Fanconi anemia”, says researcher juan Bueren.
The next steps
In order for gene therapy for Fanconi anemia to become an established therapy for a large number of patients, Ciemat, Ciberer and IIS-FJD signed a licensing agreement with the newly formed pharmaceutical company Rocket Pharmaceuticals in 2016.
This company has promoted the clinical trial that allows patients to be followed for the 15 years necessary for this type of therapy, and has launched a new global clinical trial in the United States, the United Kingdom and Spain, the results of which confirm those obtained in the Spanish clinical study.
Rocket Pharmaceuticals is currently pursuing the necessary procedures with the drug regulatory agencies of Europe (EMA) and the United States (FDA) to obtain marketing authorization for this new therapy for patients with Fanconi anemia subtype A.
Furthermore, it has funded new preclinical studies to expand the treatment to patients with Fanconi anemia of other subtypes, in particular FA-C and FA-G.
What are the key benefits of gene therapy for patients with Fanconi anemia compared to traditional treatment methods?
Interview between the Editor of Time.news and Dr. Julián Sevilla, Expert in Gene Therapy for Fanconi Anemia
Editor: Welcome, Dr. Sevilla! It’s great to have you with us today. Your recent research published in “The Lancet” has garnered meaningful attention. Can you start by explaining Fanconi anemia and its implications for those affected by this condition?
Dr. Julián Sevilla: Thank you for having me! Fanconi anemia is a rare hereditary disease that primarily impacts the bone marrow. It leads to severe blood cell deficiencies, resulting in frequent infections, fatigue, and increased susceptibility to cancers. The majority of those affected, about 90%, experience bone marrow failure, which can be life-threatening.
Editor: That sounds incredibly challenging. What makes your recent study especially notable in the realm of treatment options for Fanconi anemia?
Dr. Sevilla: Our research is groundbreaking as it demonstrates,for the first time,the safety and efficacy of gene therapy for patients with Fanconi anemia,notably the subtype A caused by mutations in the FANCA gene. This approach involves correcting the genetic defect and using autotransfusion of hematopoietic stem cells, which has shown promising results even without preconditioning chemotherapy.
Editor: That’s quite a breakthrough! can you tell us more about how this gene therapy works and the results you’ve seen in your studies?
Dr. Sevilla: Certainly! Over the course of our 20 years of preclinical studies and follow-up with patients, we found that correcting the genetic defect in stem cells allowed most patients to experience an increase in corrected blood cells. Remarkably, in two patients, we observed corrected cell levels exceeding 90%. This indicates that we can significantly alter the disease’s natural progression.
Editor: Those results are inspiring! How does this new treatment compare to traditional therapies, such as bone marrow transplants?
Dr. Sevilla: Historically, the only definitive treatment for bone marrow failure in Fanconi anemia has been bone marrow transplantation from a compatible donor. while this method has seen success, it comes with risks and complications, including a shortage of compatible donors. Our gene therapy could offer a safer and more effective alternative, particularly at the time of diagnosis. It might soon position itself as the treatment of choice, potentially changing the landscape of care for these patients.
Editor: That’s revolutionary! What steps do you anticipate moving forward to further validate this gene therapy?
Dr. Sevilla: We are committed to conducting more extensive clinical trials to ensure the long-term efficacy and safety of this treatment on a broader patient population. Additionally, we are collaborating with various research entities and biotech companies to secure funding and resources necessary for the next stages of research.
Editor: It sounds like a pivotal time for your research team! How do you see gene therapy influencing the treatment landscape for rare diseases beyond Fanconi anemia?
Dr. Sevilla: Gene therapy holds tremendous promise for a variety of genetic disorders. The technology used in our research could be adapted to treat other rare diseases with genetic underpinnings, opening doors to potentially transformative therapies. As we learn more, the principles of our study may inspire more advancements in personalized medicine.
Editor: Thank you, Dr. Sevilla, for sharing your insights with us today. Your work is helping to illuminate a path toward better outcomes for patients with Fanconi anemia and possibly many other conditions.
Dr. Sevilla: It’s been a pleasure.Thank you for helping raise awareness about this vital research!