Regenerative Medicine and Tissue Engineering

Head

• Marcela Del Río Nechaevsky

Research staff

• Fernando Larcher Laguzzi
• Claudio Conti
• Álvaro Meana Infiesta
• Rodolfo Murillas Angoiti
• María José Escámez Toledano
• Marta Carretero Trillo
• Marta García Díez

Trainee staff / junior researchers

• Elisabet Zapatero Solana
• Cristina Chamorro Poyo
• Victoria Galvéz Cortés
• Eva García López
• Sara Guerrero Aspizúa
• Lucía Martínez Santamaría
• Ángeles Mencía Rodríguez
• Adela García Martín
• Diego Velasco Bayón
• Carlos León Canseco
• Sara María Gómez Llames

Technical staff

• Blanca Duarte González
• Almudena Holguin Fernández
• María Luisa Retamosa Cervantes
• Nuria Illera Esteban
• Angélica Corral García-Heras

Main lines of research

Cell therapy and tissue engineering

Principal Investigators: Marcela Del Río, Álvaro Meana and María José Escamez

This line of research is focused on the generation of new therapeutic strategies for various types of skin diseases of low and high prevalence, and involves preclinical and clinical studies of adult, epidermal, mesenchymal, and induced pluripotent stem cells. These strategies allow the replacement of damaged or non-functional cellular components and/or the expression of specific proteins that restore deficient functions in the diseased tissue. In fact, a product developed by our team using advanced bioengineering techniques recently received orphan drug designation from the European Medicines Agency (EMA). The group has 5 international patents, one of which is currently being tested in European clinical trials (http://patentscope.wipo.int/search/en/WO2002072800).

Gene Therapy

Principal Investigator: Fernando Larcher and Rodolfo Murillas

The team is part of the GENEGRAFT European project (http://www.genegraft.eu/), which aims to conduct a clinical trial of gene therapy in which epidermal stem cells are corrected by conventional strategies and assembled in a bioengineered skin developed by our group.

Furthermore, we are actively working to develop new approaches to gene-editing using specifically cut nucleases (TALEN and CRISPER/Cas9) that promote homologous recombination and hence gene repair. Currently our efforts are focused on correcting the c.6527insC mutation in the COL7A1 gene. We demonstrated that this mutation is highly prevalent in the Spanish population affected by recessive dystrophic epidermolysis bullosa.

Molecular mechanisms of inflammation/immunity and skin regeneration.

Principal Investigator: Marta Carretero Trillo

The inflammatory response in the skin is important for host defense against pathogens and for tissue repair. However, dysregulation of this response can cause chronic skin diseases. Our team seeks to understand how local immune/inflammatory responses should be regulated to ensure an efficient response, maintaining skin homeostasis and preventing chronic disease. Recent findings of our research group have highlighted the complex regulatory networks that control these events and have identified new targets and therapeutic strategies. Among the pathologies addressed are recalcitrant ulcers, psoriasis, atopic dermatitis, and Netherton syndrome.

Study of the molecular bases and diagnosis of hereditary bullous skin diseases.

Principal Investigators: María José Escamez and Marta García

Molecular diagnosis is essential to predict the possible evolution of hereditary diseases, to provide genetic counseling, and establish prenatal or preimplantation diagnoses. In recent years our group has developed a platform for the molecular characterization of genetic blistering diseases, making us a laboratory of reference in Spain (www.orphanet-espana.es) in the diagnosis of these pathologies. Although monogenic, these diseases are genetically heterogeneous and are associated with mutations in genes encoding proteins that play key roles in anchoring the epidermis to the dermis. Our achievements in this field include the characterization of a mutation in the COL7A1 gene that is highly prevalent in people diagnosed with dystrophic epidermolysis bullosa and, in collaboration with other researchers, characterization of the genotype-phenotype relationship, which will help to improve the prognosis in individual cases.

Generation of humanized animal models of skin diseases of low and high prevalence.

Principal Investigators: Marta García and Fernando Larcher

The diversity of skin diseases has a major impact on public health. Despite knowledge of the underlying pathogenic mechanisms in many cases, current therapeutic tools in dermatology have not advanced to the same extent as our knowledge of the etiology of these diseases. This is due in part to a lack of suitable models in which to test new treatments.

Our group has successfully developed various humanized animal models using tissue engineering techniques based on bioengineered human skin transplants for rare diseases (epidermolysis bullosa, lamellar ichthyosis, xeroderma pigmentosum, Netherton syndrome, and familial melanoma) and more prevalent conditions, with a specific focus on psoriasis, atopic dermatitis, and T-cell-mediated inflammatory skin disorders. The latter are multifactorial diseases whose full understanding requires a multidisciplinary approach including genetic, immunological, and "omics" techniques to elucidate the various molecular pathways involved and their interactions. The transplantation of bioengineered human skin into immunodeficient mice has also allowed us to create useful systems in which to study the effects of ultraviolet radiation, photo-aging, and DNA damage repair.

1. Martín-Mateos Pedro Crespo-Garcia Sergio Ruiz-Llata Marta Lopez-Fernandez José Ramón Jorcano José Luis Del Rio Marcela Larcher Fernando Acedo Pablo .Remote diffuse reflectance spectroscopy sensor for tissue engineering monitoring based on blind signal separation.Biomed Opt Express. 2014 Aug 28;5(9):3231-7. doi: 10.1364/BOE.5.003231. eCollection 2014 Sep 1. PMID: 25401034. .PubMed PMID:25401034

2. Bracke Stefanie Carretero Marta Guerrero-Aspizua Sara Desmet Eline Illera Nuria Navarro Manuel Lambert Jo Del Rio Marcela .Targeted silencing of DEFB4 in a bioengineered skin-humanized mouse model for psoriasis: development of siRNA SECosome-based novel therapies.Exp Dermatol. 2014 Mar;23(3):199-201. ISSN: 0906-6705..PubMed PMID:24428418

3. Gostynski Antoni Pasmooij Anna M G Del Rio Marcela Diercks Gilles F Pas Hendri H Jonkman Marcel F .Pigmentation and melanocyte supply to the epidermis depend on type XVII collagen.Exp Dermatol. 2014 Feb;23(2):130-2. ISSN: 0906-6705..PubMed PMID:24330315

4. Duarte Blanca Miselli Francesca Murillas Rodolfo Espinosa-Hevia Luis Cigudosa Juan Cruz Recchia Alessandra Del Río Marcela Larcher Fernando.Long-term skin regeneration from a gene-targeted human epidermal stem cell clone.Mol Ther. 2014 Nov;22(11):1878-80. doi: 10.1038/mt.2014.187. No abstract available. PMID: 25365983.PubMed PMID:25365983

5. Puig-Butille Joan Anton Escámez María José Garcia-Garcia Francisco Tell-Marti Gemma Fabra Àngels Martínez-Santamaría Lucía Badenas Celia Aguilera Paula Pevida Marta Dopazo Joaquín del Río Marcela Puig Susana .Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.Oncotarget. 2014 Mar 30;5(6):1439-51. ISSN: 1949-2553..PubMed PMID:24742402

6. Llames Sara Recuero Ignacio Romance Ana García Eva Peña Ignacio Del Valle Alvaro Fernández Meana Alvaro Larcher Fernando Del Río Marcela .Tissue-engineered oral mucosa for mucosal reconstruction in a pediatric patient with hemifacial microsomia and ankyloglossia.Tissue-engineered oral mucosa for mucosal reconstruction in a pediatric patient with hemifacial microsomia and ankyloglossia..PubMed PMID:23879858

7. Chiaverini C Charlesworth A Fernandez A Barbarot S Bessis D Bodemer C Bursztejn A-C Cobo A-M Del Rio M D'Incan M Labrèze C Langlet C Mazereeuw J Miquel J Vabres P Meneguzzi G Lacour J-P .Aplasia cutis congenita with dystrophic epidermolysis bullosa: clinical and mutational study.Br J Dermatol. 2014 Apr;170(4):901-6. ISSN: 0007-0963..PubMed PMID:24252097

8. Kiritsi Dimitra Garcia Marta Brander Renske Has Cristina Meijer Rowdy Jose Escámez Maria Kohlhase Jürgen van den Akker Peter C Scheffer Hans Jonkman Marcel F del Rio Marcela Bruckner-Tuderman Leena Pasmooij Anna M G .Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa.J Invest Dermatol. 2014 Aug;134(8):2097-104. doi: 10.1038/jid.2014.118. .PubMed PMID:24577406

9. Gostynski Antoni Llames Sara García Marta Escamez María J Martinez-Santamaria Lucía Nijenhuis Miranda Meana Alvaro Pas Hendri H Larcher Fernando Pasmooij Anna M G Jonkman Marcel F Del Rio Marcela .Long-term survival of type XVII collagen revertant cells in an animal model of revertant cell therapy.J Invest Dermatol. 2014 Feb;134(2):571-4. ISSN: 0022-202X..PubMed PMID:23884316

Projects (2013/2014)

Estudio de seguridad y eficacia preliminar de la infusión de células madre mesenquimales derivadas de tejido adiposo para el tratamiento de la Epidermolisis Bullosa Distrófica Recesiva.

Investigador principal: María José Escámez Toledano

Ministerio de Sanidad, Servicios Sociales e Igualdad. ICI14/00363. 2015-2017

Desarrollo y valoración preclínica de terapias innovadoras para terapias de enfermedades raras de piel asociadas a hiperqueratosis y fragilidad epidérmica. Investigador principal: Fernando Larcher Laguzzi

Ministerio de Sanidad, Servicios Sociales e Igualdad. IP14/00931. 2015-2017

Papel del estrés oxidativo en el desarrollo del melanoma familiar y otras enfermedades raras comunes con predisposición a aneoplasias.

Investigador principal: Joan Antón Puig Butillé

Acciones Cooperativas y Complementarias Intramurales (ACCI). Proyecto Competitivo ISCIII. ACCI 2014:15-726.714. 2015.

Nuevas terapias para enfermedades raras de la piel basadas en mecanismos fisiopatológicos moleculares: terapia génica, celular y proteica.

Investigador principal: Marcela del Río Nechaevsky

Ministerio de Economía y Competitividad. SAF2013-43475-R. 2014-2017

GENEGRAFT: Phase I/II ex vivo gene therapy clinical trial for recessive dystrophic epidermolysis bullosa using skin equivalent grafts genetically corrected with a COL7A1-encoding SIN retroviral vector.

Investigador principal: Marcela Del Río. Coordinador: Alain Hovnanian

Unión Europea. HEALTH-F2-2011-261392. 01/01/2013 al 31/12/2016.

Estudio preclínico de terapia génica para el MNGIE mediante la transducción ex vivo del gen TYMP usando un vector lentiviral en un modelo de ratón con piel.

Investigador principal: Fernando Larcher

Acciones Cooperativas y Complementarias Intramurales (ACCI). Proyecto Competitivo ISCIII. 2013-2015

FIBRODRESS. Desarrollo de un apósito bioactivo basado en fibrina y bioingredientes activos.

Investigador principal: Eusebio Gainza

Ministerio de Economía y Competitividad. IPT-2012-0602-300000. 01/01/2013 al 31/12/2015

CELLCAM: Una nueva generación de medicamentos celulares más eficaces y seguros.

Investigador principal: Marcela Del Río. Coordinador: Juan Bueren

Conserjería de Educación de la Comunidad de Madrid. S2010/BMD-2420. Renovación 02/01/2012 al 30/12/2015

Homeostasis y patología cutánea. Desarrollo de modelos celulares y animales para el estudio de vías de señalización epidérmica y ensayos de nuevos abordajes terapéuticos.

Investigador principal: Fernando Larcher Laguzzi

Comunidad de Madrid. P2010BMD-2359 (SKINMODEL). Renovación 2012-2015

Transplante de piel bioingenierizada para la regeneración cutánea en pacientes con Epidermolisis Bullosa Distrófica.

Investigador principal: María José Escámez Toledano

Fundación Ramón Areces. CIVP16A1864. 27/06/2012 al 27/05/2015

Splicing therapies for Dystrophic Epidermolysis Bullosa.

Investigador principal: Marjon Pasmooij

UE ERA-Net E-rare. 2013-2015

Identificación de mecanismos fisiopatológicos en el Síndrome de Kindler.

Investigador principal: Marcela Del Rio Nechaevsky

CIBERER-ISCIII. INTRA 13-714/172.04. 01/01/2013 al 31/12/2013

Bases moleculares, genéticas y celulares de enfermedades cutáneas: desarrollo de modelos experimentales humanizados y de procedimientos terapéuticos innovadores basados en ingeniería tisular y terapia génica.

Investigador principal: Marcela Del Río Nechaevsky

Ministerio de Ciencia e Innovación. SAF2010-16976. 31/12/2010 al 31/12/2013

Determinantes moleculares de la evolución de pacientes con epidermólisis bullosa.

Investigador principal: Marcela Del Río Nechaevsky

CIBERER. INTRA/09/733.3. 01/01/2010 al 31/12/2013

Clinical trials and Observational studies (2013/ 2014)

Phase I/II clinical trial forex vivogene therapy. Multicentrico

Nombre del Coordinador: Alain Hovnanian

Promotor: EU

Período realización ensayo: 2010-2015

Patents

WO/2011/018545; PCT/ES2010/070551. Humanized psoriasis model

WO2008119855; PCT/ES08/00191. Method for preparing three-dimensional structures for tissue engineering

WO/2007/098954; PCT/EP2007/001801. A mouse model comprising an engrafted human skin having hypersensitivity to UV-light

WO/2002/072800; PCT/ES2002/000087. Artificial dermis and production method therefor

WO/2003/002154; PCT/ES2002/000320. Artificial autologous skin secreting leptin and method for obtaining the same