• Paula Río, Josune Zubicaray, Susana Navarro, Eva Gálvez, Rebeca Sánchez-Domínguez, Eileen Nicoletti, Elena Sebastián, Michael Rothe, Roser Pujol, Massimo Bogliolo, Philipp John-Neek, Antonella Lucía Bastone, Axel Schambach, Wei Wang, Manfred Schmidt, Lise Larcher, José C Segovia, Rosa M Yáñez, Omaira Alberquilla, Begoña Díez, María Fernández-García, Laura García-García, Manuel Ramírez, Anne Galy, Francois Lefrere, Marina Cavazzana, Thierry Leblanc, Nagore García de Andoin, Ricardo López-Almaraz, Albert Catalá, Jordi Barquinero, Sandra Rodríguez-Perales, Gayatri Rao, Jordi Surrallés, Jean Soulier, Cristina Díaz-de-Heredia, Jonathan D Schwartz, Julián Sevilla, Juan A Bueren, and FANCOLEN-1 gene therapy investigators.
• Biomedical Innovation Unit, Center for Research on Energy, Environment and Technology (CIEMAT), Madrid, Spain; Biomedical Network Research Center for Rare Diseases (CIBERER), Madrid, Spain; Sanitary Research Institute Fundación Jiménez Díaz (U.A.M), Madrid, Spain.
• Lancet. 2024 Dec 3.

BackgroundAllogeneic haematopoietic stem-cell transplantation is the standard treatment for bone marrow failure (BMF) in patients with Fanconi anaemia, but transplantation-associated complications such as an increased incidence of subsequent cancer are frequent. The aim of this study was to evaluate the safety and efficacy of the infusion of autologous gene-corrected haematopoietic stem cells as an alternative therapy for these patients.MethodsThis was an open-label, investigator-initiated phase 1/2 clinical trial (FANCOLEN-1) and long-term follow-up trial (up to 7 years post-treatment) in Spain. Mobilised peripheral blood (PB) CD34+ cells from nine patients with Fanconi anaemia-A in the early stages of BMF were transduced with a therapeutic FANCA-encoding lentiviral vector and re-infused without any cytotoxic conditioning treatment. The primary efficacy endpoint of FANCOLEN-1 was the engraftment of transduced cells, as defined by the detection of at least 0·1 therapeutic vector copies per nucleated cell of patient bone marrow (BM) or PB at the second year post-infusion, without this percentage having declined substantially over the previous year. The safety coprimary endpoint was adverse events during the 3 years after infusion. The completed open-label phase 1/2 and the ongoing long-term clinical trials are registered with ClinicalTrials.gov, NCT03157804; EudraCT, 2011-006100-12; and NCT04437771, respectively.FindingsThere were eight evaluable treated patients with Fanconi anaemia-A. Patients were recruited between Jan 7, 2016 and April 3, 2019. The primary endpoint was met in five of the eight evaluable patients (62·50%). The median number of therapeutic vector copies per nucleated cell of patient BM and PB at the second year post-infusion was 0·18 (IQR 0·01-0·20) and 0·06 (0·01-0·19), respectively. No genotoxic events related to the gene therapy were observed. Most treatment-emergent adverse events (TEAEs) were non-serious and assessed as not related to therapeutic FANCA-encoding lentiviral vector. Nine serious adverse events (grade 3-4) were reported in six patients, one was considered related to medicinal product infusion, and all resolved without sequelae. Cytopenias and viral infections (common childhood illnesses) were the most frequently reported TEAEs.InterpretationThese results show for the first time that haematopoietic gene therapy without genotoxic conditioning enables sustained engraftment and reversal of BMF progression in patients with Fanconi anaemia.FundingEuropean Commission, Instituto de Salud Carlos III, and Rocket Pharmaceuticals.Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

13 keywords...

hide…