Exploring new therapeutic strategies in Hutchinson-Gilford progeria syndrome preclinical models
TREAT-HGPS
E-Rare Joint Transnational Call for Proposals 2017
„Transnational Research Projects for Innovative Therapeutic Approaches for Rare Diseases”
Abstract:
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease (prevalence: 1 in 20 million) characterized by multiorgan defects, accelerated aging, and death at an average age of 14 yrs mainly from myocardial infarction or stroke. It is caused by progerin, a permanently farnesylated prelamin A mutant protein (LMNA gene). HGPS has no cure and clinical trials targeting progerin farnesylation showed increased mean survival of only ~1.6 yrs in treated patients. It is therefore urgent to develop new strategies to treat or cure HGPS.
TREAT-HGPS is a transnational 3-yr program involving 4 European nations which will exploit existing HGPS cell and mouse models to a) discover novel combinations of therapeutic drugs to fight HGPS, and b) provide essential new knowledge about reversibility of progerin-induced damage.
Specific Objectives:
1) Evaluate whether combinations of available drugs known to target either progerin (rapamycin, all-transretinoic acid, sulforaphane) or progerin-induced effects (anti-IL6R antibodies) can synergize to ameliorate disease symptoms in cell and mouse models of HGPS.
2) Assess whether systemic progerin suppression at different time-points in the lifespan of progeroid mice reverses HGPS progression to ascertain the potential benefit of future approaches targeting progerin expression.
3) Evaluate whether progerin suppression restricted to vascular smooth muscle cells, main target of progerin, provokes overall beneficial effects in progeroid mice as an alternative approach to more challenging systemic progerin suppression.
Consortium members:
Partner 1 – Coordinator
Vicente Andrés Prof.
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Melchor Fernández Almagro 3, 28029 Madrid, Spain
https://www.cnic.es/en/investigacion/molecular-and-genetic-cardiovascular-pathophysiology
Funding organization: Ministerio de Ciencia, Innovación y Universidades, and The Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII)
Partner 2
David Filgueiras MD, PhD
Fundación Investigación Biomédica Hospital Clínico San Carlos, Hospital Clínico San Carlos
Profesor Martín Lagos, S/N 28040 Madrid, Spain
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC),
Melchor Fernández Almagro 3, 28029 Madrid, Spain
david.filgueiras@salud.madrid.org
Funding organization: Ministerio de Ciencia, Innovación y Universidades, and The Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII)
http://www.isciii.es/
http://www.ciencia.gob.es/
Partner 3
Karima Djabali PhD
Epigenetics of Aging, Department Dermatology, School of Medicine, Technical University of Munich
Boltzmannstr 11, 85748 Garching, Germany
https://www.derma-allergie.med.tum.de/forschung/epigenetik-der-hautalterung.html
Funding organization: Deutsche Forschungsgemeinschaft DFG
http://www.dfg.de
Partner 4
Ryszard Rzepecki PhD, DSc
Department Biotechnology, University of Wroclaw
Fryderyka Joliot-Curie 14a, 50-383 Wrocław, Poland
http://www.nuclearproteins.com/
Funding organization: The National Centre for Research and Development
https://www.ncbr.gov.pl/
Partner 5
Giovanna Lattanzi PhD
CNR Institute of Molecular Genetics
Via di Barbiano 1/10, 40136 Bologna, Italy
Objectives and work packages:
Leader:
Karima Djabali
(Partner 3, Germany)
Descriptions:
Assess therapeutic efficacy of different drug combinations in HGPS cellular models.
Deliverable: Identification of the best combination of drugs in vitro.
Participans:
K. Djabali (P3), R. Rzepecki (P4), G. Lattanzi (P5)
Leader:
Giovanna Lattanzi
(Partner 5, Italy)
Descriptions:
Deliverables: Identification of best new therapeutic options in vivo based on increased lifespan and improved quality of life in treated versus untreated mice.
Participans:
V. Andrés (P1), D. Filgueiras (P2), K. Djabali (P3)
Leader:
Vicente Andrés
(Partner 1, Spain)
Descriptions:
Deliverables: Determination of the degree of reversibility of progerin-induced-damage at different times in the lifespan of LmnaHGPSrev mice.
Participans:
All partners
Leader:
David Filgueiras
(Partner 2, Spain)
Descriptions:
Assess the beneficial effect of vascular smooth muscle cell (VSMC)-specific progerin suppression in HGPS mice
Deliverable: Determination of the potential efficacy of tissue-specific therapies to revert critical pathological HGPS phenotypes versus the more challenging potential therapies based on systemic progerin suppression.
Participans:
K. Djabali (P3), R. Rzepecki (P4), G. Lattanzi (P5)
Leader:
Ryszard Rzepecki
(Partner 4, Poland)
Descriptions:
Dissemination
Deliverable: Dissemination of results through project fact sheet & web page, publications, conferences, etc.
Participans:
All partners
Leader:
Vicente Andrés
(Partner 1, Spain)
Descriptions:
Management and Reporting
Deliverable: management,reports.
Participans:
All partners
Workflow:
