Río Paula, Zubicaray Josune, Navarro Susana, Gálvez Eva, Sánchez-Domínguez Rebeca, Nicoletti Eileen, Sebastián Elena, Rothe Michael, Pujol Roser, Bogliolo Massimo, John-Neek Philipp, Bastone Antonella Lucía, Schambach Axel, Wang Wei, Schmidt Manfred, Larcher Lise, Segovia José C, Yáñez Rosa M, Alberquilla Omaira, Díez Begoña, Fernández-García María, García-García Laura, Ramírez Manuel, Galy Anne, Lefrere Francois, Cavazzana Marina, Leblanc Thierry, García de Andoin Nagore, López-Almaraz Ricardo, Catalá Albert, Barquinero Jordi, Rodríguez-Perales Sandra, Rao Gayatri, Surrallés Jordi, Soulier Jean, Díaz-de-Heredia Cristina, Schwartz Jonathan D, Sevilla Julián, Bueren Juan A
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.
Biomedical Network Research Center for Rare Diseases (CIBERER), Madrid, Spain; Pediatric Hematology and Oncology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Foundation for the Biomedical Research, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
Lancet. 2025 Dec 21;404(10471):2584-2592. doi: 10.1016/S0140-6736(24)01880-4. Epub 2024 Dec 3.
Allogeneic 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.
This 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.
There 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.
These 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.
European Commission, Instituto de Salud Carlos III, and Rocket Pharmaceuticals.
异基因造血干细胞移植是范可尼贫血患者骨髓衰竭（BMF）的标准治疗方法，但移植相关并发症如后续癌症发病率增加很常见。本研究的目的是评估输注自体基因校正造血干细胞作为这些患者替代疗法的安全性和有效性。
这是一项在西班牙开展的开放标签、研究者发起的1/2期临床试验（FANCOLEN-1）和长期随访试验（治疗后长达7年）。从9例处于BMF早期的范可尼贫血A患者动员的外周血（PB）CD34细胞用治疗性编码FANCA的慢病毒载体转导，且在未进行任何细胞毒性预处理的情况下重新输注。FANCOLEN-1的主要疗效终点是转导细胞的植入，定义为在输注后第二年患者骨髓（BM）或PB的每有核细胞中检测到至少0.1个治疗性载体拷贝，且该百分比在过去一年中未大幅下降。安全性共同主要终点是输注后3年内的不良事件。已完成的开放标签1/2期试验和正在进行的长期临床试验分别在ClinicalTrials.gov（NCT03157804）、EudraCT（2011-006100-12）和NCT04437771注册。
有8例可评估的接受治疗的范可尼贫血A患者。患者于2016年1月7日至2019年4月3日入组。8例可评估患者中有5例（62.50%）达到主要终点。输注后第二年患者BM和PB每有核细胞中治疗性载体拷贝的中位数分别为0.18（IQR 0.01-0.20）和0.06（0.01-0.19）。未观察到与基因治疗相关的基因毒性事件。大多数治疗中出现的不良事件（TEAE）不严重，且评估与治疗性编码FANCA的慢病毒载体无关。6例患者报告了9例严重不良事件（3-4级），1例被认为与药物输注有关，所有事件均无后遗症地得到解决。血细胞减少和病毒感染（常见儿童疾病）是最常报告的TEAE。
这些结果首次表明，无基因毒性预处理的造血基因治疗能够使范可尼贫血患者实现持续植入并逆转BMF进展。
欧盟委员会、卡洛斯三世健康研究所和Rocket制药公司。
