Pharmacological targeting of Endogenous Adult Stem Cells can be used as a treatment of Degenerative Muscle Diseases
26 February 2013
Austria
Pharmacological targeting of Endogenous Adult Stem Cells can be used as a treatment of Degenerative Muscle Diseases
At the annual meeting of the Parent Project Onlus, the EndoStem consortium (www.endostem.eu) which is successfully translating fundamental concepts into clinical advances for the development of novel therapies that target resident stem cells, is excited to present the latest finding on the pharmacological treatment of muscular diseases with epigenetic drugs that promote regeneration, while preventing fibro-adipogenic degeneration, of dystrophic muscles, in a mouse model of Duchenne Muscular Dystrophy (DMD).
Using molecular medicines to control tissue and organ regeneration is a suitable way to slow the progression of neuromuscular degenerative diseases, such as muscular dystrophy (MD) for which there is currently no available therapy. Muscular dystrophies (MDs) include hereditary, fatal disorders characterized by the progressive, functional decline of skeletal muscles, caused by mutations of genes that are supposed to maintain the muscle fibre integrity.
A key feature of the natural history in most MDs is the compensatory response by reactive regeneration that efficiently counterbalances muscle loss during the initial stages of the disease. However, as the disease progresses, this regenerative potential of dystrophic muscles declines, with fibrotic scar and fatty deposition becoming the predominant repair mechanism, ultimately leading to loss of functional muscle.
Dr. Pier Lorenzo Puri’s team from the Fondazione Santa Lucia and Sanford-Burnham Medical Research Institute in collaboration with the Endostem partners, Drs David Sassoon and Giovanna Marazzi from Paris, and Dr Alessandra Sacco (Sanford-Burnham Medical Research Institute) are about to publish an article in the prestigious journal, EMBO Molecular Medicine, in which they report on the key contribution of a population of muscle cells – called fibro-adipogenic progenitor (FAPs) to the disease progression of DMD. Of note, they show that FAPs are the cellular target of a class of drugs - Histone deacetylase inhibitors (HDAC inhibitors) that were originally designed as therapeutics for cancer, but have been repositioned to treat DMD following previous studies from Puri’s team.
Mechanism of action of HDAC Inhibitor on muscle stem cells identified
Puri’s team has previously shown that HDAC inhibitors can promote regeneration of dystrophic muscles while reducing the formation of fibrotic scars and fat deposition in preclinical models . As an extension of this work, the Endostem partnership discovered that HDAC inhibitors promote the functional interactions between FAPs and the adult muscle stem cells (referred to as satellite cells) to regenerate dystrophic muscles.
Regulatory authorities now routinely ask for the mechanism of action of any new drugs, to provide detailed insight into not just how, but why therapies actually function. This effort is essential especially in the context of the difficulty in reproducing the effect of therapies from one patient to another. The mechanism by which HDAC Inhibitors can promote regeneration in dystrophic muscles has been revealed by this study and the knowledge gained is instrumental to design the first clinical trial with an HDAC inhibitor – Givinostat (Italfarmaco) – in DMD patients.
Fundamentally, the FAPs are key components of the cellular machinery that repair injured or diseased skeletal muscles. They can act as modulators of muscle stem cells activity, by providing instruction on how to promote regeneration, via indirect interactions that are mediated by soluble factors. However, in chronic conditions, such as advanced stages of DMD, they adopt an alternative strategy to repair muscles, by fibrotic scars and fat deposition. The study from Puri’s team demonstrates that the repair ability of FAP can be pharmacologically manipulated by HDAC inhibitors toward promoting regeneration. Fascinating discoveries included that this response was limited to age; the younger the tissue being responsive to the HDAC Inhibitor and repairing the damage, while in older tissues the FAP was not responsive.
Not only does this identify the mechanism of action, but also provides insight on a new cellular target which can potentially modulate many age related diseases; in other words if FAPs can be targeted so that they stay responsive then this may open the avenue for the development of many new therapies.
Clinical application of HDAC Inhibitors about to start
Italfarmaco is now very close to initiating a phase II clinical trial using the HDAC inhibitor Givinostat in children with Duchenne Muscular Dystrophy. Givinostat is currently being studied in different indications both in adults and in children. In particular, Givinostat has received an Orphan Drug Designation by EMA for the treatment of systemic-onset juvenile idiopathic arthritis, polycythaemia vera, and Duchenne Muscular Dystrophy (DMD). Following the preclinical demonstration that Givinostat promotes muscle regeneration, reduces inflammation and fibrosis, and consequently improves muscle function, a clinical study in ambulant DMD children is being launched. This study will assess the effects of one year of treatment with Givinostat both at tissue and functional level. In particular Givinostat effects will be assessed on muscle biopsies, Magnetic Resonance Imaging, functional scales and circulating biomarkers. Such a study will allow Italfarmaco to confirm that the beneficial effects observed preclinically translate also into a benefit in humans.
Quotes
“Endostem is proving the direct link between fundamental research and clinical treatment, and that targeting endogenous stem cells is a cost effective and viable strategy" says Dr David Sassoon.
“This emphasizes the importance of the collaboration between Endostem and the associated entities - Italfarmaco, Parent Project Onlus and Fondazione Santa Lucia - that cooperated to generate basic knowledge and translate it into clinical trial” stresses Dr. Pier Lorenzo Puri.
“This study has finally come to its first checkpoint: a phase II clinical trial. This is clear evidence that teamwork is the only way we have to build the future of our children. It 'also very symbolic for us that this class of products can help treat scar tissue in Duchenne, we parents have a scar in our heart that we try to heal, and our hope to make this dream come true, is fueled by these small, but significant, steps forward" says Dr. Filippo Buccella, President of Duchenne Parent Project.
"We are very proud to explore the value potential of Givinostat for the children with such a debilitating disease with the leverage of the Endostem scientific network" says Dr Paolo Bettica, Director Clinical Development Italfarmaco
Contacts
Endostem consortium manager
Jonathan Dando PhD
DWC
St John's Innovation Centre
Cowley Road
Cambridge
CB4 0WS
+ 44 756 831 33 34
jonathan.dando@dwc-alliance.com
www.dwc-alliance.com
Endostem coordinator
David Sassoon, Director - Myology Group
UMR S 787 Inserm
Université Paris VI/Pierre et Marie Curie
Paris, FRANCE
+33 (0)1 40 77 81 31 (tel)
+33 (0)1 53 60 08 02 (fax)
david.a.sassoon@gmail.com
http://www.myologygroup.net/(opens in new window)
www.endostem.eu
Notes to editors
About Endostem: Stimulating Endogenous Stem Cells as a therapy for Degenerative Muscle Disease
EndoStem (www.endostem.eu) is a partnership of 15 research and clinical teams from globally recognised academic centres, small biotech and large pharmaceutical companies working together to develop new strategies aimed at stimulating stem cells that are resident in damaged tissue to repair it in situ. This approach is recognised as one of the most promising approaches to targeting stem cells for regenerative medicine due to the alignment with existing therapeutic development approaches used by large industry and recent advances in understanding the key barriers for tissue regeneration. Coordinated by Professor David Sassoon, co-financed by the European Commission via the 7th Framework Programme the aims of the project over are:
- Implementation of clinical trials, with muscular dystrophies as the primary clinical target using innovative biopharmaceuticals
- Development of novel best in class biopharmaceuticals with highly specific and well defined modes of action
- Fast track clinical translation based on a constant feedback loop between emerging patient responsiveness to new drugs and the development of the next generation of therapeutics
- Better understanding of the key issues preventing effective tissue repair matched with approaches to circumvent them
At the annual meeting of the Parent Project Onlus, the EndoStem consortium (www.endostem.eu) which is successfully translating fundamental concepts into clinical advances for the development of novel therapies that target resident stem cells, is excited to present the latest finding on the pharmacological treatment of muscular diseases with epigenetic drugs that promote regeneration, while preventing fibro-adipogenic degeneration, of dystrophic muscles, in a mouse model of Duchenne Muscular Dystrophy (DMD).
Using molecular medicines to control tissue and organ regeneration is a suitable way to slow the progression of neuromuscular degenerative diseases, such as muscular dystrophy (MD) for which there is currently no available therapy. Muscular dystrophies (MDs) include hereditary, fatal disorders characterized by the progressive, functional decline of skeletal muscles, caused by mutations of genes that are supposed to maintain the muscle fibre integrity.
A key feature of the natural history in most MDs is the compensatory response by reactive regeneration that efficiently counterbalances muscle loss during the initial stages of the disease. However, as the disease progresses, this regenerative potential of dystrophic muscles declines, with fibrotic scar and fatty deposition becoming the predominant repair mechanism, ultimately leading to loss of functional muscle.
Dr. Pier Lorenzo Puri’s team from the Fondazione Santa Lucia and Sanford-Burnham Medical Research Institute in collaboration with the Endostem partners, Drs David Sassoon and Giovanna Marazzi from Paris, and Dr Alessandra Sacco (Sanford-Burnham Medical Research Institute) are about to publish an article in the prestigious journal, EMBO Molecular Medicine, in which they report on the key contribution of a population of muscle cells – called fibro-adipogenic progenitor (FAPs) to the disease progression of DMD. Of note, they show that FAPs are the cellular target of a class of drugs - Histone deacetylase inhibitors (HDAC inhibitors) that were originally designed as therapeutics for cancer, but have been repositioned to treat DMD following previous studies from Puri’s team.
Mechanism of action of HDAC Inhibitor on muscle stem cells identified
Puri’s team has previously shown that HDAC inhibitors can promote regeneration of dystrophic muscles while reducing the formation of fibrotic scars and fat deposition in preclinical models . As an extension of this work, the Endostem partnership discovered that HDAC inhibitors promote the functional interactions between FAPs and the adult muscle stem cells (referred to as satellite cells) to regenerate dystrophic muscles.
Regulatory authorities now routinely ask for the mechanism of action of any new drugs, to provide detailed insight into not just how, but why therapies actually function. This effort is essential especially in the context of the difficulty in reproducing the effect of therapies from one patient to another. The mechanism by which HDAC Inhibitors can promote regeneration in dystrophic muscles has been revealed by this study and the knowledge gained is instrumental to design the first clinical trial with an HDAC inhibitor – Givinostat (Italfarmaco) – in DMD patients.
Fundamentally, the FAPs are key components of the cellular machinery that repair injured or diseased skeletal muscles. They can act as modulators of muscle stem cells activity, by providing instruction on how to promote regeneration, via indirect interactions that are mediated by soluble factors. However, in chronic conditions, such as advanced stages of DMD, they adopt an alternative strategy to repair muscles, by fibrotic scars and fat deposition. The study from Puri’s team demonstrates that the repair ability of FAP can be pharmacologically manipulated by HDAC inhibitors toward promoting regeneration. Fascinating discoveries included that this response was limited to age; the younger the tissue being responsive to the HDAC Inhibitor and repairing the damage, while in older tissues the FAP was not responsive.
Not only does this identify the mechanism of action, but also provides insight on a new cellular target which can potentially modulate many age related diseases; in other words if FAPs can be targeted so that they stay responsive then this may open the avenue for the development of many new therapies.
Clinical application of HDAC Inhibitors about to start
Italfarmaco is now very close to initiating a phase II clinical trial using the HDAC inhibitor Givinostat in children with Duchenne Muscular Dystrophy. Givinostat is currently being studied in different indications both in adults and in children. In particular, Givinostat has received an Orphan Drug Designation by EMA for the treatment of systemic-onset juvenile idiopathic arthritis, polycythaemia vera, and Duchenne Muscular Dystrophy (DMD). Following the preclinical demonstration that Givinostat promotes muscle regeneration, reduces inflammation and fibrosis, and consequently improves muscle function, a clinical study in ambulant DMD children is being launched. This study will assess the effects of one year of treatment with Givinostat both at tissue and functional level. In particular Givinostat effects will be assessed on muscle biopsies, Magnetic Resonance Imaging, functional scales and circulating biomarkers. Such a study will allow Italfarmaco to confirm that the beneficial effects observed preclinically translate also into a benefit in humans.
Quotes
“Endostem is proving the direct link between fundamental research and clinical treatment, and that targeting endogenous stem cells is a cost effective and viable strategy" says Dr David Sassoon.
“This emphasizes the importance of the collaboration between Endostem and the associated entities - Italfarmaco, Parent Project Onlus and Fondazione Santa Lucia - that cooperated to generate basic knowledge and translate it into clinical trial” stresses Dr. Pier Lorenzo Puri.
“This study has finally come to its first checkpoint: a phase II clinical trial. This is clear evidence that teamwork is the only way we have to build the future of our children. It 'also very symbolic for us that this class of products can help treat scar tissue in Duchenne, we parents have a scar in our heart that we try to heal, and our hope to make this dream come true, is fueled by these small, but significant, steps forward" says Dr. Filippo Buccella, President of Duchenne Parent Project.
"We are very proud to explore the value potential of Givinostat for the children with such a debilitating disease with the leverage of the Endostem scientific network" says Dr Paolo Bettica, Director Clinical Development Italfarmaco
Contacts
Endostem consortium manager
Jonathan Dando PhD
DWC
St John's Innovation Centre
Cowley Road
Cambridge
CB4 0WS
+ 44 756 831 33 34
jonathan.dando@dwc-alliance.com
www.dwc-alliance.com
Endostem coordinator
David Sassoon, Director - Myology Group
UMR S 787 Inserm
Université Paris VI/Pierre et Marie Curie
Paris, FRANCE
+33 (0)1 40 77 81 31 (tel)
+33 (0)1 53 60 08 02 (fax)
david.a.sassoon@gmail.com
http://www.myologygroup.net/(opens in new window)
www.endostem.eu
Notes to editors
About Endostem: Stimulating Endogenous Stem Cells as a therapy for Degenerative Muscle Disease
EndoStem (www.endostem.eu) is a partnership of 15 research and clinical teams from globally recognised academic centres, small biotech and large pharmaceutical companies working together to develop new strategies aimed at stimulating stem cells that are resident in damaged tissue to repair it in situ. This approach is recognised as one of the most promising approaches to targeting stem cells for regenerative medicine due to the alignment with existing therapeutic development approaches used by large industry and recent advances in understanding the key barriers for tissue regeneration. Coordinated by Professor David Sassoon, co-financed by the European Commission via the 7th Framework Programme the aims of the project over are:
- Implementation of clinical trials, with muscular dystrophies as the primary clinical target using innovative biopharmaceuticals
- Development of novel best in class biopharmaceuticals with highly specific and well defined modes of action
- Fast track clinical translation based on a constant feedback loop between emerging patient responsiveness to new drugs and the development of the next generation of therapeutics
- Better understanding of the key issues preventing effective tissue repair matched with approaches to circumvent them