A gene therapy based clinical trial for Fanconi anemia patients offers its first successful results

Grup de recerca
Dr. Jordi SurrallÚs (first row) and researchers of the Genome Instability Syndromes Group at the UAB.

A study with the involvement of the team led by Dr Jordi Surrallés, Professor of Genetics at the UAB, presents the first clinical demonstration of engrafment and expansion of gene-corrected cells in the blood of Fanconi anemia patients. The study, published in Nature Medicine, was led by the CIEMAT/CIBERER/IIS-FJD Consortium.


The prestigious journal Nature Medicine publishes the first results of a gene therapy based clinical trial in patients with Fanconi anemia. In this study the authors demonstrate for the first time the production of blood cells derived from the patients’ genetically corrected stem cells.

This clinical trial has been carried out by members of a novel research program, EUROFANCOLEN, coordinated by Dr Juan Bueren, from the Center for Energy, Environment and Technology (CIEMAT), the Center for Biomedical Network Research on Rare Diseases (CIBERER) and the Institute of Health Research of the Jiménez Díaz Foundation (IIS-FJD), under the clinical direction of Dr Julián Sevilla, from the Foundation of the Hospital del Niño Jesús, in Madrid, the clinical sponsor of the trial. The first authors of the study are Dr. Paula Río and Dr. Susana Navarro, affiliated to the CIEMAT / CIBERER / IIS-FJD Consortium. The team led by Dr. Jordi Surrallés, Professor at the UAB, head of the Genetics Service at the Hospital de la Santa Creu i Sant Pau and group leader of the Biomedical Research Networking Centre on Rare Diseases (CIBERER), conducted the genetic studies needed for the recruitment and monitoring of all patients participating in the trial.

Fanconi anemia is a rare genetic disease characterized by bone marrow failure and cancer predisposition that appears in most patients with poor blood cell production at very young ages. Aside from other palliative treatments, the transplantation of hematopoietic stem cells from a healthy donor nowadays constitutes the treatment of choice in these patients. Although this type of transplant has experimented substantial improvements in recent years, not all patients have an adequate donor. Additionally, this treatment requires pre-transplant chemotherapy and is not free of rejection problems and other long-term side effects.

The work published in Nature Medicine is focused on Fanconi anemia patients without a family donor and with mutations in the FANCA gene, which is the gene affected in the majority of Spanish patients with the disease.

This work demonstrates, for the first time, the possibility of performing a new gene therapy based procedure that starts with the mobilization of stem cells from the bone marrow to the blood stream. These cells are subsequently collected from the patients’ blood through a procedure called apheresis, that takes place at the Pediatric Hematolgy Units of the Niño Jesús and Vall d’Hebron Hospitals, in Madrid and Barcelona, respectively. This process is followed by a second stage in which the genetic defect of the stem cells is corrected throught the insertion of the corrected gene by the use of a modified virus. This stage is carried out through a one day manipulation of the cells in a dedicated laboratory at CIEMAT, the CliniStem facility. Finally, the genetically corrected cells are sent to Hospital del Niño Jesús for reinfusion into the patient without the need of any chemotherapy-based treatment like those used in current transplants with healthy donor’s cells.

New treatment expectations

The authors of this work have shown that genetically corrected stem cells engraft and progressively expand in the bone marrow of the four treated patients thanks to a preferential growth of the corrected stem cells, as opposed to the uncorrected ones. Likewise, the authors have proven that the proportion of "healthy" cells (corrected for the genetic defect) increase in peripheral blood over time. After a three-year treatment, more than half of the blood cells from one of the treated patients turned out to be "healthy" cells; that is, corrected for the genetic defect. As a consequence of this treatment, the progressive drop of blood cells was stabilized in patients with a higher proportion of “healthy” cells. The treatment is currently restricted to clinical validation in patients in a phase I/II clinical trial.

The results obtained in this study open new expectations for the treatment of Fanconi anemia patients, since gene therapy has never been proven effective in this disease. The fact that it is not necessary to administer chemotherapy as a previous step to cells infusion, allows patients to be discharged from the hospital much earlier, only two or three days following infusion of their own corrected cells.

"There is an urgent need for new therapies for patients affected by Fanconi anemia, since the current long-term effective treatment is bone marrow transplantation, which is not free of toxicity and risks" stated Dr. Río and Dr. Navarro. "We are very pleased with the long term data obtained so far, which supports our gene therapy approach as an innovative and low toxicity treatment for the hematological component of this devastating disease" affirms Dr. Juan Bueren. "In addition" adds Dr. Julian Sevilla, "we have not observed serious adverse effects associated with the treatment in patients infused with genetically corrected stem cells."

According to Jordi Surrallès, “Our team has spent over 20 years researching the genetics and molecular biology of this syndrome and this has helped us to recruit and monitor the patients for this clinical trial”.

The clinical studies have been carried out in collaboration with numerous researchers from the Spanish Fanconi Anemia Research Network: Dr. Cristina Díaz de Heredia (Vall d’Hebron Hospital in Barcelona), Dr. Jordi Surrallés (Autonomous University of Barcelona, Hospital Sant Pau and CIBERER), Dr. Ricardo López (Osakidetza Basque Health Service), Dr. Albert Catalá (Hospital San Joan de Déu de Barcelona) and Dr. Nagore García de Andoaín (University Hospital of Donostia), among others. Also, numerous researchers from the EUROFANCOLEN European Consortium and the Fundación Anemia de Fanconi de España have participated. International institutions that have contributed to this work include DKZF and Geneward (Germany), the University of Paris, IRSL, INSERM, CNRS, St. Louis Hospital in Paris and Genethon / Yposkesi (France), as well as Rocket Pharmaceuticals (USA).

This work has been possible thanks to grants from the Ministry of Health and Social Affairs of the Government of Spain, the 7th Framework Program of the European Commission (EUROFANCOLEN) and the Community of Madrid.

The lentiviral vector developed by the CIEMAT / CIBERER / IIS-FJD Consortium has obtained the orphan drug designation from the European Medicines Agency and the US Food and Drug Administration, and has been licensed to Rocket Pharmaceuticals in cooperation with the technology transfer program of the Botín Foundation. The upcoming clinical studies in Fanconi anemia patients will be sponsored by Rocket Pharmaceuticals, both in Spain, and in other European countries and the US. The new clinical trials will be aimed at obtaining a Marketing authorization (MA) to use this new therapy for the treatment of Fanconi anemia to patients worldwide.

Reference Article: Successful Engraftment of Gene Corrected Hematopoietic Stem Cells in Non-conditioned Fanconi Anemia Patients. Paula Río et al. Nature Medicine, 9th September, 2019. DOI: 10.1038/s41591-019-0550-z


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