Project Details
Exploring new therapeutic strategies in Hutchinson-Gilford progeria syndrome preclinical models
Applicant
Professorin Dr. Karima Djabali
Subject Area
Pediatric and Adolescent Medicine
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 398640205
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 14.6 years mainly from myocardial infarction or stroke. It is caused by a heterozygous de novo point mutation in the LMNA gene leading to the synthesis of progerin, a permanently farnesylated prelamin A mutant protein. HGPS has no cure and clinical trials targeting progerin farnesylation showed increased mean survival of only ~1.6 years in treated patients. It is therefore urgent to develop new strategies to treat or cure HGPS.TREAT-HGPS is a transnational 3-year program involving scientists from 4 European nations who 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-trans-retinoic acid, sulforaphane, trichostatin A) or progerin-induced effects (anti-IL6r antibodies) can synergize to ameliorate disease symptoms in cell and mouse models of HGPS. RNA interference strategies will be also tested.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.
DFG Programme
Research Grants
International Connection
Poland, Spain
Cooperation Partners
Professor Vicente Andrés, Ph.D.; Dr. David Filgueiras-Rama; Professor Ryszard Rzepecki, Ph.D.