Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A

The main objective of this open-label Phase I / II clinical trial is to evaluate the safety and therapeutic efficacy of a hematopoietic gene therapy procedure with an orphan drug consisting of a lentiviral vector carrying the FANCA gene for patients with Fanconi's Anemia Subtype A.

The drug to be administered to the patients consists of the cellular product resulting from the transduction of autologous CD34 + cells with the therapeutic lentiviral vector PGK-FANCA.Wpre *.

The dose of cells to infuse in the patients will be that obtained from the transduction process of between 3x10\^5 and 4x10\^6 CD34 + cells / kg of patient body weight.

The cells will be infused intravenously in a single dose, after complete the transduction process.

Follow-up period: 3 years after infusion of transduced cells. However, patients will be monitored outside the clinical trial over a 10-year period.

Follow-up of the grafted transduced cells will be performed on peripheral blood and bone marrow samples.

• IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs) (Procedure)
• Genetically Engineered Hematopoietic Stem/Progenitor Cells (Biological), also known as Genetically Engineered HSPCs: Undergo infusion of genetically modified hematopoietic progenitor cell therapy
• Laboratory Biomarker Analysis (Other): Correlative studies
• Filgrastim (Biological), also known as Filgrastim XM02, Filgrastim-sndz, G-CSF (Colony Stimulating Factor), Neupogen, r-metHug-CSF, Recombinant Methionyl Human Granulocyte CSF, rG-CSF, Tbo-filgrastim, Zarxio: Given subcutaneously (SC)
• Plerixafor (Drug), also known as AMD 3100, JM-3100, Mozobil, SDZ SID 791: Given SC
• Bone Marrow Aspiration (Procedure)

Primary outcomes

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Up to 3 years after infusion of transduced cells]: All adverse events will be registered for 3 years from infusion of transduced cells
• Proportion of patients with at least 0.1 copy of the therapeutic vector per nucleated bone marrow or peripheral blood cells two years after infusion. [2 years after infusion of transduced cells]: Detection of at least 0.1 copy of the therapeutic vector per nucleated bone marrow cell or peripheral blood cells two years after infusion.

Secondary outcomes

• Proportion of patients with clinical hematological response after the infusion of autologous CD34 + cells transduced with the therapeutic lentiviral vector [2 years after infusion of transduced cells]: Proportion of patients with clinical hematological response (improvement of cell blood counts at least in one hematological lineage).

Sex: All, ages: 1 Year to 21 Years

Inclusion Criteria:

* Patients diagnosed with Fanconi Anemia complementation group A (FA-A)
* Minimum age 1 year
* Maximum age 21 years
* Lansky Index> 60%.
* Informed consent in accordance with current legal regulations.
* Number of cells to be transduced: At least 3x10\^5 purified CD34+ / kg body weight.
* Negative result in the urine pregnancy test at the baseline visit for women of childbearing age, who should be committed to using an effective contraceptive method during the period of study participation.

Exclusion Criteria:

* Patients with an human leukocyte antigen (HLA) identical family donor.
* Evidence of myelodysplastic syndrome or leukemia, or cytogenetic abnormalities predicting the same in bone marrow aspirates. In this case, the studies carried out two months in advance of the patient's entry into the clinical trial will be considered valid.
* Evidence that the patient to be infused has signs of somatic mosaicism, with hematologic improvement.
* Any illness or concomitant process that in the opinion of the investigator incapacitates the subject for their participation in the study.
* Pre-existing sensory or motor impairment> = grade 2 according to the National Cancer Institute (NCl) criteria.
* Pregnant or lactating women.

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• Molina-Estevez FJ, Nowrouzi A, Lozano ML, Galy A, Charrier S, von Kalle C, Guenechea G, Bueren JA, Schmidt M. Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs. Curr Gene Ther. 2015;15(6):550-62. doi: 10.2174/1566523215666150929110903. PMID 26415575
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• Jacome A, Navarro S, Rio P, Yanez RM, Gonzalez-Murillo A, Lozano ML, Lamana ML, Sevilla J, Olive T, Diaz-Heredia C, Badell I, Estella J, Madero L, Guenechea G, Casado J, Segovia JC, Bueren JA. Lentiviral-mediated genetic correction of hematopoietic and mesenchymal progenitor cells from Fanconi anemia patients. Mol Ther. 2009 Jun;17(6):1083-92. doi: 10.1038/mt.2009.26. Epub 2009 Mar 10. PMID 19277017
• Rio P, Navarro S, Guenechea G, Sanchez-Dominguez R, Lamana ML, Yanez R, Casado JA, Mehta PA, Pujol MR, Surralles J, Charrier S, Galy A, Segovia JC, Diaz de Heredia C, Sevilla J, Bueren JA. Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients. Blood. 2017 Sep 28;130(13):1535-1542. doi: 10.1182/blood-2017-03-774174. Epub 2017 Aug 11. PMID 28801449
• Results publication: Rio P, Navarro S, Wang W, Sanchez-Dominguez R, Pujol RM, Segovia JC, Bogliolo M, Merino E, Wu N, Salgado R, Lamana ML, Yanez RM, Casado JA, Gimenez Y, Roman-Rodriguez FJ, Alvarez L, Alberquilla O, Raimbault A, Guenechea G, Lozano ML, Cerrato L, Hernando M, Galvez E, Hladun R, Giralt I, Barquinero J, Galy A, Garcia de Andoin N, Lopez R, Catala A, Schwartz JD, Surralles J, Soulier J, Schmidt M, Diaz de Heredia C, Sevilla J, Bueren JA. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat Med. 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 9. PMID 31501599
• Results publication: Rio P, Zubicaray J, Navarro S, Galvez E, Sanchez-Dominguez R, Nicoletti E, Sebastian E, Rothe M, Pujol R, Bogliolo M, John-Neek P, Bastone AL, Schambach A, Wang W, Schmidt M, Larcher L, Segovia JC, Yanez RM, Alberquilla O, Diez B, Fernandez-Garcia M, Garcia-Garcia L, Ramirez M, Galy A, Lefrere F, Cavazzana M, Leblanc T, Garcia de Andoin N, Lopez-Almaraz R, Catala A, Barquinero J, Rodriguez-Perales S, Rao G, Surralles J, Soulier J, Diaz-de-Heredia C, Schwartz JD, Sevilla J, Bueren JA; FANCOLEN-1 gene therapy investigators. Haematopoietic gene therapy of non-conditioned patients with Fanconi anaemia-A: results from open-label phase 1/2 (FANCOLEN-1) and long-term clinical trials. Lancet. 2025 Dec 21;404(10471):2584-2592. doi: 10.1016/S0140-6736(24)01880-4. Epub 2024 Dec 3. PMID 39642902

• Juan A Bueren, Study director, CIEMAT/CIBERER/IIS.FJD