Advanced Therapies

Heads

• Juan Antonio Bueren Roncero

Research staff

• Guillermo Guenechea Amurrio
• Jose Carlos Segovia Sanz
• Jose Antonio Casado Olea
• Marina Garin Ferreira
• Maria Luisa Lamana Luzuriaga
• Paula Rio Galdo
• Elena Almarza Novoa
• Maria Garcia Bravo
• Mercedes Lopez Santalla
• Susana Navarro Ordoñez
• Oscar Quintana Bustamante
• Rebeca Sanchez Dominguez
• Rosa Maria Yañez Gonzalez
• Miriam Hernando Rodriguez
• Victoria Moleiro San Emeterio

Trainee staff / junior researchers

• Begoña Diez Cabezas
• Mª Jose Del Pino Del Barrio
• Diego Leon Rico
• Fatima Rodriguez Fornes
• Sergio Lopez Manzaneda
• Francisco Jose Roman Rodriguez
• Cristina Mesa Nuñez

Technical staff

• Montserrat Aldea Garcia
• Lara Alvarez Ramos
• Laura Cerrato Carrasco
• Raquel Chinchon Cordoba
• Sergio Garcia Perez
• Mª De La Luz Lozano Vinagre
• Sergio Losada Bautista
• Miguel Angel Martin Rey
• Israel Orman Bernal

Main lines of research

The Innovative Therapies for the Hematopoietic System Division carries out translational research at the international level, and receives a significant portion of its funding from public and private institutions in Spain and Europe.

Our research focuses on the development of new therapies for difficult-to-treat diseases, including the hereditary disease that causes a form of aplastic anemia known as Fanconi anemia. The first international clinical trial of Fanconi anemia is soon to be launched. This trial will test the effects of gene therapy using a lentiviral vector that was developed in our laboratory and has received orphan drug designation from the European Commission. We also investigate the etiologies of other diseases including anemias and congenital immunodeficiency diseases, rheumatoid arthritis, and graft versus host disease, with a view to developing new therapies for these diseases.

In addition to the aforementioned studies, we conduct studies of the basic biology of hematopoietic and mesenchymal stem cells. Specifically, we are developing new gene therapy strategies using different cell types, including induced pluripotent stem cells (iPSCs), which show significant promise for clinical use given their capacity to generate all tissue cell types. Our laboratory is also interested in developing new therapies based on the administration of mesenchymal cells, given the ability of these cells to facilitate tissue repair and control the inflammation associated with various diseases.

Our goal is to demonstrate the impact of our work through the publication of scientific articles in prestigious international journals, to develop new cellular drugs, and, in collaboration with other groups, to launch new clinical trials of gene and cell therapies to demonstrate the safety and efficacy of advanced therapies in certain difficult-to-treat diseases.

Stem cell gene therapy: safety and associated risks.

Principal Investigator: Guillermo Guenechea Amurrio

Preclinical and clinical trials of gene and cell therapies for rare diseases.

Principal Investigator: Juan A. Bueren Roncero

* Generation of safer and more effective cell therapies (CellCAM). Autonomous Community of Madrid

* Phase I/II clinical trial to evaluate the safety and effectiveness of the mobilization and collection of CD34+ cells after treatment with plerixafor and filgrastim in patients with Fanconi anemia for later use in gene therapy trials (FANCOSTEM). ISCIII

* Phase I/II clinical trial to evaluate the safety and effectiveness of the infusion of autologous CD34+ cells mobilized with mozobil and filgrastim and transduced with a lentiviral vector carrying the FANCA gene (orphan drug) in patients with Fanconi anemia subtype A. (FANCOLEN). ISCIII

* Cell and Gene Therapy for Fanconi anemia (TARGET). Ministry of Economy and Competitiveness

* EUROFANCOLEN Phase I/II gene therapy trial of Fanconi anemia patients with a new orphan drug consisting of a lentiviral vector carrying the FANCA gene: a coordinated international action. FP7. EC

* Regenerative medicine to treat Fanconi anemia: generation of disease-free, patient-specific iPSCs that can differentiate into hematopoietic progenitors and platelets. Fundación La Maratón

Optimization of stem cell transplantation

Principal Investigator: María Luisa Lamana Luzuriaga

* Effect of adipose tissue-derived mesenchymal stromal cells in the treatment of GVHD. ISCIII

Research and therapeutic applications of stem cells.

Principal Investigator: José Carlos Segovia Sanz

* Telematics in Cooperative Health Research: TERCEL. ISCIII

* Advanced cell and gene therapy tools for genetic correction of PK deficiencies. Ministry of Economy and Competitiveness

* Gene correction / direct hepatic reprogramming.

Preclinical and clinical studies of gene and cell therapies for inflammatory and autoimmune diseases.

Principal Investigator: Marina Garin Ferreira

Publications (2014)

1. Rio P, Baños R, Lombardo A, Quintana-Bustamante O, Alvarez L, Garate Z, Genovese P, Almarza E, Valeri A, Díez B, Navarro S, Torres Y, Trujillo JP, Murillas R, Segovia JC, Samper E, Surralles J, Gregory PD, Holmes MC, Naldini L, Bueren JA.Targeted gene therapy and cell reprogramming in Fanconi anemia.EMBO Mol Med 2014; 6(6): 835-48. FI (2012): 7.795. ISSN: 1757-4676..PubMed PMID:24859981

2. Jimeno Rebeca Gomariz Rosa P Garín Marina Gutiérrez-Cañas Irene González-Álvaro Isidoro Carrión Mar Galindo María Leceta Javier Juarranz Yasmina .The pathogenic Th profile of human activated memory Th cells in early rheumatoid arthritis can be modulated by VIP.J Mol Med (Berl) 2014; [Epub ahead of print]. ISSN: 0946-2716..PubMed PMID:25430993

3. Tremblay Jacques P Aartsma-Rus Annemieke Bogdanove Adam Ferreira Marcello Bossois Bueren Juan Huard Johnny .Development of a web course on gene therapy by the international consortium of gene therapy.Development of a web course on gene therapy by the international consortium of gene therapy..PubMed PMID:24584076

4. Liu GH, Suzuki K, Li M, Qu J, Montserrat N, Tarantino C, Gu Y, Yi F, Xu X, Zhang W, Ruiz S, Plongthongkum N, Zhang K, Masuda S, Nivet E, Tsunekawa Y, Soligalla RD, Goebl A, Aizawa E, Kim NY, Kim J, Dubova I, Li Y, Ren R, Benner C, Del Sol A, Bueren J, Tru.Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.Nat Commun 2014; 5; article number 4330. ISSN: 2041-1723..PubMed PMID:24999918

5. Jimeno Rebeca Leceta Javier Martínez Carmen Gutiérrez-Cañas Irene Carrión Mar Pérez-García Selene Garín Marina Mellado Mario Gomariz Rosa P Juarranz Yasmina .Vasoactive intestinal Peptide maintains the nonpathogenic profile of human th17-polarized cells.J Mol Neurosci 2014; 54(3); 512-25. ISSN: 0895-8696..PubMed PMID:24805298

6. Leon-Rico D, Aldea M, Sanchez R, Segovia JC, Weiss LA, Hidalgo A, Bueren JA, Almarza E.Reduced expression of CD18 leads to the in vivo expansion of hematopoietic stem cells in mouse bone marrow.Stem Cells 2014; 32(10): 2794-8. ISSN: 1066-5099..PubMed PMID:24906078

7. Pulecio Julian Nivet Emmanuel Sancho-Martinez Ignacio Vitaloni Marianna Guenechea Guillermo Xia Yun Kurian Leo Dubova Ilir Bueren Juan Laricchia-Robbio Leopoldo Izpisua Belmonte Juan Carlos .Conversion of human fibroblasts into monocyte-like progenitor cells. Stem Cells 2014; 32(11): 2923-38. ISSN: 1066-5099..PubMed PMID:25175072

8. Navarro S Moleiro V Molina-Estevez F J Lozano M L Chinchon R Almarza E Quintana-Bustamante O Mostoslavsky G Maetzig T Galla M Heinz N Schiedlmeier B Torres Y Modlich U Samper E Río P Segovia J C Raya A Güenechea G Izpisua-Belmonte J C Bueren J A, .Generation of iPSCs from genetically corrected Brca2 hypomorphic cells: implications in cell reprogramming and stem cell therapy.Stem Cells 2014; 32 (2): 436-46. ISSN: 1066-5099..PubMed PMID:24420904

9. Segrelles Carmen García-Escudero Ramón Garín Maria I Aranda Juan F Hernández Pilar Ariza José M Santos Mirentxu Paramio Jesús M Lorz Corina .Akt signaling leads to stem cell activation and promotes tumor development in epidermis.Stem Cells 2014; 32 (7): 1917-28. ISSN: 1066-5099..PubMed PMID:24504902

10. Quintana-Bustamante O, Segovia JC..Generation of Patient-Specific induced Pluripotent Stem Cell from Peripheral Blood Mononuclear Cells by Sendai Reprogramming Vectors.Methods Mol Biol. 2014 Dec 19. [Epub ahead of print].PubMed PMID:25523810

11. Groult H, Ruiz-Cabello J, Pellico J, Lechuga-Vieco AV, Bhavesh R, Zamai M, Almarza E, Martìn-Padura I, Cantelar E, Martìnez-Alcázar MP, Herranz F..Parallel multifunctionalization of nanoparticles: a one-step modular approach for in vivo imaging.Bioconjug Chem. 2015 Jan 21;26(1):153-60. doi: 10.1021/bc500536y. Epub 2014 Dec 19..PubMed PMID:25494619

12. Jimeno R, Gomariz RP, Garìn M, Gutiérrez-Cañas I, González-Álvaro I, Carrión M, Galindo M, Leceta J, Juarranz Y..The pathogenic Th profile of human activated memory Th cells in early rheumatoid arthritis can be modulated by VIP.J Mol Med (Berl). 2015 Apr;93(4):457-67. doi: 10.1007/s00109-014-1232-4. Epub 2014 Nov 28..PubMed PMID:25430993

13. Pulecio J, Nivet E, Sancho-Martinez I, Vitaloni M, Guenechea G, Xia Y, Kurian L, Dubova I, Bueren J, Laricchia-Robbio L, Izpisua Belmonte JC..Conversion of human fibroblasts into monocyte-like progenitor cells.Stem Cells. 2014 Nov;32(11):2923-38. doi: 10.1002/stem.1800..PubMed PMID:25175072

14. Liu GH, Suzuki K, Li M, Qu J, Montserrat N, Tarantino C, Gu Y, Yi F, Xu X, Zhang W, Ruiz S, Plongthongkum N, Zhang K, Masuda S, Nivet E, Tsunekawa Y, Soligalla RD, Goebl A, Aizawa E, Kim NY, Kim J, Dubova I, et al..Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.Nat Commun. 2014 Jul 7;5:4330. doi: 10.1038/ncomms5330..PubMed PMID:24999918

15. Leon-Rico D, Aldea M, Sanchez R, Segovia JC, Weiss LA, Hidalgo A, Bueren JA, Almarza E..Brief report: reduced expression of CD18 leads to the in vivo expansion of hematopoietic stem cells in mouse bone marrow.Stem Cells. 2014 Oct;32(10):2794-8. doi: 10.1002/stem.1762..PubMed PMID:24906078

16. Rio P, Baños R, Lombardo A, Quintana-Bustamante O, Alvarez L, Garate Z, Genovese P, Almarza E, Valeri A, Díez B, Navarro S, Torres Y, Trujillo JP, Murillas R, Segovia JC, Samper E, Surralles J, Gregory PD, Holmes MC, Naldini L, Bueren JA.Targeted gene therapy and cell reprogramming in Fanconi anemia.EMBO Mol Med. 2014 May 23;6(6):835-48. doi: 10.15252/emmm.201303374..PubMed PMID:24859981

17. Jimeno R, Leceta J, Martìnez C, Gutiérrez-Cañas I, Carrión M, Pérez-Garcìa S, Garìn M, Mellado M, Gomariz RP, Juarranz Y..Vasoactive intestinal peptide maintains the nonpathogenic profile of human th17-polarized cells.J Mol Neurosci. 2014 Nov;54(3):512-25. doi: 10.1007/s12031-014-0318-3. Epub 2014 May 8..PubMed PMID:24805298

18. Tremblay JP, Aartsma-Rus A, Bogdanove A, Ferreira MB, Bueren J, Huard J..Development of a web course on gene therapy by the international consortium of gene therapy.Mol Ther. 2014 Mar;22(3):482. doi: 10.1038/mt.2014.11. No abstract available. .PubMed PMID:24584076

19. Segrelles Carmen García-Escudero Ramón Garín Maria I Aranda Juan F Hernández Pilar Ariza José M Santos Mirentxu Paramio Jesús M Lorz Corina .Akt signaling leads to stem cell activation and promotes tumor development in epidermis.Stem Cells. 2014 Jul;32(7):1917-28. doi: 10.1002/stem.1669..PubMed PMID:24504902

20. Navarro S, Moleiro V, Molina-Estevez FJ, Lozano ML, Chinchon R, Almarza E, Quintana-Bustamante O, Mostoslavsky G, Maetzig T, Galla M, Heinz N, Schiedlmeier B, Torres Y, Modlich U, Samper E, Rìo P, Segovia JC, Raya A, Güenechea G, Izpisua-Belmonte JC, Bueren JA..Generation of iPSCs from genetically corrected Brca2 hypomorphic cells: implications in cell reprogramming and stem cell therapy.Stem Cells. 2014 Feb;32(2):436-46. doi: 10.1002/stem.1586..PubMed PMID:24420904

21. Saiz-Ladera C, Lara MF, Garìn M, Ruiz S, Santos M, Lorz C, Garcìa-Escudero R, Martìnez-Fernández M, Bravo A, Fernández-Capetillo O, Segrelles C, Paramio JM..p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia.Oncogene. 2014 Sep 11;33(37):4599-612. doi: 10.1038/onc.2013.417. Epub 2013 Oct 14..PubMed PMID:24121270

Projects (2013)

Terapia celular y génica dirigida en anemia de fanconi "TARGET". IP: Juan Antonio BuerenAño comienzo: 2013; Año finalización: 2015. Referencia: saf 2012-39834; Agencia: Ministerio de Economía y Competitividad. Plan Nacional.

Medicina regenerativa para tratar la anemia de Fanconi: generación de células iPSC específicas del paciente, libres de la enfermedad y capaces de diferenciarse en progenitores hematopoyéticos y plaquetas IP: Juan A. Bueren. Año comienzo: 2013; Año finalización: 2015. Referencia: 464/C/2012; Agencia: Fundació La Marató de TV3.

Clinical trial Fase I/II para evaluar la seguridad y eficacia de la movilización y colecta de células CD34+ tras tratamiento con plerixafor y filgrastim en pacientes con Anemia de Fanconi para su posterior uso en ensayos de terapia génica (FANCOSTEM).IP: Cristina Díaz de Heredia, J Bueren. Año comienzo: 2012; Año finalización: 2016. Referencia: EC11-559; Agencia: Ministerio de Sanidad. Convocatoria de Ensayos Clínicos Independientes

Clinical trial Fase I/II para evaluar la seguridad y eficacia de la infusión de células CD34+ autólogas movilizadas con mozobil y filgrastim y transducidas con un vector lentiviral portador del gen FANCA (medicamento huérfano) para pacientes con Anemia de Fanconi del Subtipo A. (FANCOLEN) . IP: Julián Sevilla, J Bueren. Año comienzo: 2012; Año finalización: 2013. Referencia: EC11-060; Agencia: Ministerio de Sanidad. Convocatoria de Ensayos Clínicos Independientes.

Una nueva generación de medicamentos celulares más eficaces y seguros (CellCAM). IP: Juan A. Bueren

Año comienzo: 2012; Año finalización: 2015. Referencia: S2010/BMD-2420; Agencia: Comunidad de Madrid.

REGENER-AR-Bringing Regenerative Medicine into the market: Allogeneic eASCs. Phase IB/IIA clinical trial for treating Rheumatoid Arthritis. IP: Marina I. Garín. Año comienzo: 2012; Año finalización: 2014

Referencia: 279174; Agencia: FP7-HEALTH-2011-two-stage

Redes Telemáticas de Investigación Cooperativa en Salud: TERCEL. IP: José Carlos Segovia

Año comienzo: 2012; Año finalización: 2015. eferencia: RD12/0019/0023; Agencia: Instituto de Salud Carlos III

EUROFANCOLEN Phase I/II Gene therapy trial of Fanconi anemia patients with a new Orphan Drug consisting of a lentiviral vector carrying the FANCA gene: A coordinated International Action. IP: Juan A. Bueren (Coordinador). Año comienzo: 2013; Año finalización: 2018. Referencia: 305421; Agencia: Comisión de la Unión Europea (FP7)

Clinical trials and Observational studies (2013)

Clinical trial FaseI/II para evaluar la seguridad y eficacia de la Infusión de células CD34+ autólogas transducidas con un vector lentiviral portador del gen FANCA (medicamento huérfano) para pacientes con Anemia de Fanconi del Subtipo A. IP: Juan A. Bueren. Año comienzo: 2013; Año finalización: 2016

Referencia: MUH/AEC; Promoter: Julián Sevilla, Hospital del Niño Jesús (Madrid). Fase: Phase II

Clinical trial Fase II para evaluar la seguridad y eficacia de la movilización y colecta de células CD34+ tras tratamiento con plerixafor y filgrastim en pacientes con anemia de Fanconi para su posterior transducción con un vector lentiviral portador del gen FANCA y reinfusión en el paciente. IP: Juan A. Bueren y Cristina Díaz de Heredia. Año comienzo: 2012; Año finalización: 2016. Referencia: Nº Eudra CT 2011-006197-88. Código de protocolo: FANCOSTEM-1. Versión: 2 01-03-2012; Promotor: Cristina Díaz de Heredia. Fase: Phase II

Patents

Lentiviral vector containing the human liver and erythroid pyruvate kinase (PKLR) gene for the treatment of pyruvate kinase deficiency. Propiedad: CIEMAT, CIBERER e IIS-FJD. IP: José C. Segovia. Orphan designation (EU/3/14/1330). Fecha designación: 22 Agosto 2014.