ec.30 – endostem – activation of vasculature associated stem cells

EC.30 – ENDOSTEM – ACTIVATION
OF VASCULATURE ASSOCIATED STEM CELLS
AND MUSCLE STEM CELLS FOR THE REPAIR
AND MAINTENANCE OF MUSCLE TISSUE
Coordinatore scientifico del progetto
DAVID SASSOON
Université Pierre et Marie Curie, France
U.O.22 – Lorenzo Puri
Fondazione Santa Lucia
European Commission – FP7 – HEALTH 2009-1.4-3
Sezione III: Attività per progetti
LIST OF BENEFICIARIES
1 – (Coordinator) Université Pierre et Marie Curie, France (UPMC):
David Sassoon, Giovanna Marazzi, Frederic Relaix, Patrick Debre, Ana Ferreiro
2 – Institute of Genetics and Biophysics, CNR, Italy (CNR):
Gabriella Minchiotti
3 – E. Medea Scientific Institute, Italy (MEDEA): Emilio Clementi
4 – Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne,
Switzerland (EPFL): Jeffrey Hubbell
5 – European Molecular Biology Laboratory, Germany (EMBL):
Nadia Rosenthal
6 – Novartis Ltd, Switzerland (NOV): David Glass
7 – Fondazione Centro San Raffaele del Monte Tabor, Italy (HSR):
Silvia Brunelli
8 – Fondazione Istituto FIRC di Oncologia Molecolare, Italy (IFOM):
Elisabetta Dejana
9 – Pompeu Fabra University, Spain (UPF): Pura Muñoz-Cánoves
10 – Molecular Cardiology, University Frankfurt, Germany (GUF):
Stefanie Dimmeler
11 – HMG Biotech S.r.l., Italy (HMG): Marco Bianchi
12 – Dando Weiss and Colucci Ltd, United Kingdom (DAC): Jonathan Dando
13 – Acceleron limited, United Kingdom (ACC): Jas Seehra
14 – Liverpool John Moores University, United Kingdom (LJMU):
Bernardo Nadal-Ginard
15 – Ital farmaco, Italy (ITF): Paolo Mascagni.
16 – Santhera pharmaceuticals, Switzerland (SANN): Thomas Meier
17 – Institut nationale de la santé et de la recherche médicale, France (Inserm):
David Sassoon, Frederic Relaix, Patrick Debre, Ana Ferreiro, Benedicte Chazaud,
Jacques Demotes
18 – Kings College London, United Kingdom (KCL): Bernardo Nadal Ginard,
Georgina M. Ellison
19 – Fondazione Santa Lucia, Italy (FSL): Pier Lorenzo Puri
ABSTRACT
We propose to develop new strategies to mobilize skeletal muscle tissueassociated stem cells as a tool for efficient tissue repair. This will be combined
with exploring novel approaches that limit tissue damage, and will focus on
agents that modify muscle and muscle vasculature progenitor cells. These
molecules include nitric oxide associated with non-steroidal anti-inflammatory
drugs, HMGB1, Cripto, NAC, and present and improved deacetylase inhibitors.
Three clinical trials will be run in tandem with efforts to dissect the
underlying mechanisms of action. Importantly, we have already initiated a
monocentric clinical trial that focuses on the efficacy of histone deacetylase
inhibitors (HDACi) and NO-donors plus NSAIDs in muscle pathologies. Our
efforts will be complemented by novel biodelivery systems for effective targeting.
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The most promising drugs, used alone or in combination, will be first validated
in small and large animal models. Our project brings together leading
investigators to examine how vascular and muscle progenitors participate in
postnatal growth and muscle tissue repair. A key issue that this project addresses
is the tissue environment in which endogenous stem cells are activated.
We propose that muscle degeneration and fibrosis provokes altered
vascularization and immune responses, which eventually affect negatively stem
cell function. Molecules that can be used to therapeutically target these key cells,
and their communication with neighboring vascular, inflammatory and fibrotic
cell types, will lead to more effective approaches to muscle regenerative medicine
and to novel cures for degenerative diseases, including atherosclerosis, vascular
damage in diabetes and in peripheral ischemic vascular disease.
CONCEPT AND PROJECT OBJECTIVES
Repair of tissue damage in the adult occurs in response to acute or chronic
injury and is mediated by resident stem cells. We will develop new strategies to
activate and mobilize tissue-associated endogenous stem cells as a tool for
efficient tissue repair and as an alternative to stem cell transplantation. In
addition, we will investigate approaches to limit the damage response as a
combined therapeutic approach to augment stem cell function. This effort is
complemented by refinement of biodelivery of these compounds for effective
targeting to muscle tissue.
The starting point for our proposal is the combined research effort by the
partner groups focused upon candidate agents that target muscle and muscle
vasculature progenitor cells as well as preventing tissue damage to optimize
endogenous stem cell function. These molecules act in specific pathways
including nitric oxide (NO) associated with non steroidal anti-inflammatory
drugs (NSAIDs), HMGB1, Cripto, HDACi, and GAPDH/Siah-dependent antiapoptotic pathway. These agents serve as critical tools to dissect muscle and
muscle vasculature stem cell biology and promise to generate therapeutic agents
for chronic degenerative vascular and muscle diseases. This proposal initiates
with well established and overlapping themes of investigation by all the
participants involved, which will lead to synergistic progress towards targeted
drug therapy design. In all our projects, muscle, inflammatory and/or vascular
stem cells are a primary focus within the context of skeletal muscle tissue.
Evidence from efforts of the project participants as well as research efforts
worldwide support the notion that vascular and muscle progenitors share a
common origin and actively participate in postnatal growth and muscle tissue
repair. In parallel to clinical efforts designed to target stem cells in muscle tissue,
there remains much to be understood as to the precise origin, lineage and
functionality of endogenous muscle stem cells. Unraveling the identity of muscle
and vascular stem cells is an obligatory step toward the identification of
pharmacological targets, which activate regenerative potential.
One goal of this call is to bring several agents to clinical trial. Indeed, in work
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Sezione III: Attività per progetti
package 1, we have already initiated clinical trials and clinical data will become
available in the next 6-12 months on the efficacy of HDACi and NO-donors plus
NSAIDs in muscle pathologies. The results of this initiative will become available
to a far wider range of researchers who are participating in this proposal. This
first clinical trial will be in tandem with efforts to dissect mechanisms of action.
The mechanisms whereby candidate therapeutic agents improve muscle and
vascular function remain to be elucidated. One key issue addressed in this
proposal is the tissue environment in which endogenous stem cells are activated.
Muscle degeneration provokes a decrease in vascularization due to fibrosis,
which exacerbates muscle damage and impedes regeneration. There is
increasing evidence that multiple cell types communicate with each other in situ
to correctly drive regeneration and that cells from the immune system regulate
stem cell function directly participating in the regenerative process. Several work
packages address the precise status of muscle and endothelial progenitor cells as
well as identification of novel precursor populations with pluripotent capacity
and their interactions. Molecules that can be used to therapeutically enhance and
directly target these cells will lead to a more effective approach to muscle
regenerative medicine leading to novel cures for degenerative vascular diseases
including atherosclerosis, vascular damage in diabetes and in peripheral ischemic
vascular disease. The most promising drugs used alone or in combination will be
further validated in small animal models of pathology followed by large animal
models. These projects are expected to lead to the design of clinical protocols and
phase I clinical trials.
Presently, there is a focus on the therapeutic use of engrafted stem cells to
treat degenerative diseases or aging, however such efforts are best complemented
by advancing our understanding of the basic biology of stem cell activation.
Regardless of the potential success of engrafted stem cells, such therapies will be
very costly and will require tailoring for each patient given the current state-ofthe-art. Approaches aimed at mobilizing endogenous stem cells become more
plausible in light of a major shift in the field of adult stem cell biology that has
provided increasing evidence that pluripotent stem cells with regenerative
potential are present in adult tissues contrary to the generally accepted view just
5 to 10 years ago. While many tissues possess limited regenerative potential, the
capacity for regeneration declines with age and chronic disease. In addition,
stem cell recruitment in response to injury or disease often produces
inappropriate re-patterning of the tissue culminating in scar tissue formation
(fibrosis), inadequate revascularization, or chronic inflammatory disorders.
Lastly, our basic understanding of the anatomical location of the stem cell niche
in adult tissues has greatly changed. In this proposal, we focus on skeletal muscle
biology, in which the largely acknowledged central stem cell (the satellite cell)
may act in concert with other resident stem cells to generate muscle tissue as well
as receive critical paracrine signals to effectively mobilize.
It is also an objective of this project to leverage its collective competence and
network to ensure complete information exchange with European experts in the
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field of muscle cell biology and regenerative medicine through complementary
projects. In particular, we will capitalize on the ongoing FP7 project Optistem:
optimization of stem cell therapy for degenerative epithelial and muscle diseases
in which their is an overlap of several partners focused upon using exogenous cell
therapy for treating muscular and epithelial disorders. We will organize high
quality joint annual meetings and training sessions with this project consortium
so that all relevant information will be disseminated to EC based experts and
industrial players in the field and new potential avenues for high quality
advances developed. However, it is not exclusive to this project as the partners
are also beneficiaries in or coordinators of other FP7 projects of relevance and
this will be explored in due course. The involvement of a highly experienced team
in both projects as well as key pharma partners will also facilitate movement of
agents from the preclinical to clinical phase and is likely to lead to collaborative
efforts that exceed that outlined in this proposal.
ROLE OF FONDAZIONE SANTA LUCIA
The laboratory of Pier Lorenzo Puri has performed key activities for this
proposal, including basic studies revealing the epigenetic control of lineage
identity and functional phenotype of several cell types that participate to the
regeneration of skeletal muscles. This activity has been made possible by the
outstanding FACS equipment and personnel that enabled the identification and
isolation of specific muscle-derived subpopulations. Moreover, pre-clinical
studies toward the determination of the efficacy of the HDACi Givinostat in the
mouse model of muscular dystrophy – mdx mice – have been made in the animal
facility at Fondazione Santa Lucia.
These two excellent resources have been determinant in the completion of
these studies and have been selected to continue preclinical activities. Of note,
the FACS service has been designed has been instrumental to isolate the same
cell populations from human biopsies of DMD patients enrolled in the clinical
trial with HDACi and will continue to provide a key resource for the whole
duration of the trial.
Website: www.endostem.eu
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