A Spanish clinical trial has shown, for the first time, that gene therapy can be effective and safe in patients with Fanconi anaemia. The results of this trial, the fruit of more than 20 years of pre-clinical research and 7 years of patient follow-up, have just been published in The Lancet, one of the most influential medical journals. The Vall d'Hebron Research Institute's (VHIR) Children's Cancer and Haematological Diseases Group and the Vall d'Hebron University Hospital's Paediatric Oncology and Haematology Service  participated in the trial.

Fanconi anaemia is a complex disease that usually manifests itself in the paediatric age group, affecting the same stem cells as the bone marrow. It is characterised by the progressive loss of blood cells, which often results in severe infections, asthenia and haemorrhages in a process known as bone marrow failure. The disease is also characterised by a high predisposition to cancer, both of blood cells and other tissue types.

None of the clinical studies carried out to date have found gene therapy to be effective in this complex disease. In the research just published in The Lancet, the Spanish research team demonstrated that, in patients affected by Fanconi anaemia subtype A (caused by mutations in the FANCA gene), the autotransfusion of hematopoietic stem cells corrected for the genetic defect facilitates a progressive increase in corrected cells in most patients, even without chemotherapy conditioning. In two of the patients treated, the proportion of corrected cells reached levels of over 90%. This made it possible to correct the natural course of the disease which, in this case, was the progressive decrease in blood cells.

The Phase I/II clinical trial was sponsored by the Hospital Niño Jesús de Madrid Foundation, while the long-term follow-up trial is being sponsored by Rocket Pharmaceuticals Inc. The principal investigator of the clinical trials was Dr Julián Sevilla, who was supported by Dr Josune Zubicaray. Both Sevilla and Zubicaray are haematologists at the Advanced Therapies Unit of the Hospital Infantil Universitari del Niño Jesús and members of the Biomedical Research Networking Center for Rare Diseases (CIBERER). The scientific direction was provided by Prof. Juan Bueren, who worked in close collaboration with Dr Paula Río, first author of this study, and Dr Susana Navarro. Bueren, Río and Navarro are all researchers at CIEMAT (an organisation dependent on the Ministry of Science, Innovation and Universities), the CIBERER Rare Diseases Area and the Institute for Health Research of the Jiménez Díaz Foundation (IIS.FJD). The study was coordinated by the Spanish Network of Advanced Therapies (TERAV) and promoted by the Carlos III Health Institute.

Until now, the only definitive therapy for bone marrow failure in these patients was based on the transplant of bone marrow from a compatible donor. Although this therapy has improved greatly in recent years, it requires conditioning treatments involving chemotherapy to prevent rejection reactions and is associated with both short-term and long-term risks, which often involves lengthy hospitalisations.

A team effort involving many experts

Many teams were involved in the different stages of the genetic therapy study published in The Lancet. The stem cells mobilised from the patients' blood were collected and purified at the Hospital Infantil Universitario del Niño Jesús in Madrid, the Vall d'Hebron University Hospital in Barcelona and the Catalan Blood and Tissue Bank, under the coordination of Dr Cristina Díaz d'Heredia. These cells were then corrected for the genetic defect ex-vivo in CIEMAT's CliniStem Clean Room using a genetically modified virus (a lentiviral vector carrying the FANCA gene), which was previously developed by the centre's research team. Once the genetic defect had been corrected, the cells were reinfused at the Paediatric Haematology Service of the Hospital Niño Jesús as if it were an autotransfusion, without the patients needing to receive any type of chemotherapy. This allowed them to leave the hospital 72 hours after the infusion.

“The preliminary results of this clinical study were published in 2019, when 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 cured of the genetic defect in patients with Fanconi anaemia,” said Dr Riu.

Dr Sevilla, meanwhile, stated that “after 7 years of patient follow-up, we have been able to confirm that the presence of corrected cells has continued to increase in patients, reaching levels of over 90% in two of them, which has made it possible to treat and even improve the bone marrow failure of these patients.”

Highly complex procedures

Unlike other blood diseases currently treated with gene therapy, in patients with Fanconi anaemia, the stem cells of the bone marrow are extremely fragile and already show pronounced defects in their ability to divide. This means that the collection of these cells and their ex-vivo processing are highly complex. This is why, to date, no other international team has been able to demonstrate the efficacy of gene therapy in patients with this disease.

“The teamwork involving numerous experts in basic, genetic and pre-clinical research on Fanconi anaemia, together with clinical specialists in this disease, has allowed Spain to become the first country in the world to demonstrate that a genetic therapy not requiring any chemotherapy has shown therapeutic efficacy in patients with Fanconi anaemia,” affirmed Prof. Bon.

Another medical professional involved in the research into Fanconi anaemia, Prof. Jordi Surrallés, director of the Sant Pau Research Institute (IR Sant Pau) and group leader of the CIBERER, emphasised that “the teamwork carried out by the Spanish Fanconi Anaemia Research Network has allowed the work carried out in Spain to become a global benchmark for the monitoring and development of innovative therapies for these diseases.”

“Despite the fact that none of the studies carried out in the United States have shown the gene therapy to be effective in patients with Fanconi anaemia, we always believed that the work done by our specialists could result in a successful outcome. Now there are new expectations for our children, which were unthinkable just a few years ago,” emphasised Alicia de las Heras, chair of the Fanconi Anaemia Foundation, an organisation created in 2001 which supported this study.

A public-private collaboration

In 2016, CIEMAT, CIBERER and the IIS.FJD signed a licensing agreement with a recently created pharmaceutical company, Rocket Pharmaceuticals, to make Fanconi anaemia gene therapy a consolidated therapy for a large number of patients. Rocket Pharmaceuticals was the sponsor of the clinical trial, which enabled the follow-up of patients over the 15 years required for this type of therapy. It also initiated a new global clinical trial in the United States, the UK and Spain, whose results are confirming those obtained in the Spanish clinical study.

Rocket Pharmaceuticals is currently working with the European Medicines Agency and the US Food and Drug Administration to obtain marketing authorisation for this new therapy for patients with Fanconi anaemia subtype A. It has also supported new pre-clinical studies to expand treatment to patients with other sub-types of Fanconi anaemia, in particular FA-C and FA-G.

More than 20 years of work

The first pre-clinical studies on the efficacy of this type of therapy were carried out in the laboratories of CIEMAT's Biomedical Innovation Unit in 2002. These were followed by other studies to develop the therapeutic vector used in this clinical trial, which was classified as an Orphan Drug in Europe and the United States in 2010 and 2016, respectively. Clinical studies began once this vector's efficacy in correcting the defect in patients' stem cells was demonstrated in experimental in-vivo models, where the cells were transplanted into immunodeficient mice. The first clinical trial (FANCOSTEM-I) demonstrated the conditions required to collect a sufficient number of stem cells from the bone marrow of patients with Fanconi anaemia. This made it possible to conduct the study whose results have just been published (FANCOLEN-I). This served as the basis for the start of the global clinical trial (FANCOLEN-II) aimed at obtaining marketing authorisation in Europe and the United States, which is being sponsored by Rocket Pharmaceuticals Inc.