Periodic Reporting for period 3 - RESSTORE (REgenerative Stem cell therapy for STroke in Europe)
Période du rapport: 2018-03-01 au 2019-08-31
Stroke is the second leading cause of death in the world population. Stroke affects approximately 6 million people in the European Union, with 1.1 million new cases every year. When not fatal, despite spontaneous recovery, stroke often results in disability (70% of stroke survivors), due to motor and/or cognitive impairments, and secondary health problems affecting not only patients but also their families.
Current treatment options are limited to intravenous thrombolysis, thrombectomy, aspirin, decompressive craniectomy, and management in stroke care units for intensive care and rehabilitation. Effective treatments beyond prevention and acute care are urgently needed. This requires a sophisticated understanding of stroke pathophysiology. It is well-known that stroke effects are not limited to neurons but involve both brain cells and the surrounding extracellular matrix in a “glio-neurovascular niche” that interacts with the peripheral immune system. For these reasons, new therapies should target all these systems rather than narrowly targeting an individual damage process. A promising approach for treatment of stroke is activation of brain repair mechanisms and enhancement of spontaneous functional recovery. The major advantage of cell-based therapies is the extended therapeutic time window up to several weeks or months after the initial insult. This makes the treatment available to a much larger number of stroke patients. Cell-based restorative therapies have emerged as attractive approaches for the treatment of stroke. Transplanted cells, an example of “plastic” biological products, can adapt to different local conditions in damaged brain tissue while not being limited to a unique target. They can act on a wide range of endogenous protective and brain repair processes including immunomodulation, neuronal, vascular and glial remodelling.
Building on emerging preclinical and pilot clinical evidences, RESSTORE project focuses on the clinical assessment of reparative cell therapy to improve stroke recovery and patients’ quality of life. RESSTORE European multicentre randomised trial will explore, for the first time, the safety and efficacy (functional recovery) of intravenous infusion of allogenic adipose tissue derived stem cells (ADSCs) in stroke patients. Therapeutic effects of ADSCs will be assessed in patients using clinical rating scales, multimodal MRI and novel blood biomarkers. Additionally, the societal value and cost-effectiveness of ADSCs-based therapy will be evaluated through health economics and predictive in silico simulations.
Complementary ancillary animal studies support the clinical trial by defining i) if the treatment response can be further enhanced by intensive rehabilitation, ii) the contribution of co-morbidities (diabetes, hypertension) and iii) the mechanism(s) underlying the therapeutic effect.
The European regenerative therapy capacities (France, Spain, Finland, UK and Czech Republic), developed in RESSTORE cover the full value chain: large scale GMP cell production, clinical testing, biomarkers discovery, understanding of the repair mechanisms, modelling, biobanking, economic studies, exploitation and communication plan.
Current treatment options are limited to intravenous thrombolysis, thrombectomy, aspirin, decompressive craniectomy, and management in stroke care units for intensive care and rehabilitation. Effective treatments beyond prevention and acute care are urgently needed. This requires a sophisticated understanding of stroke pathophysiology. It is well-known that stroke effects are not limited to neurons but involve both brain cells and the surrounding extracellular matrix in a “glio-neurovascular niche” that interacts with the peripheral immune system. For these reasons, new therapies should target all these systems rather than narrowly targeting an individual damage process. A promising approach for treatment of stroke is activation of brain repair mechanisms and enhancement of spontaneous functional recovery. The major advantage of cell-based therapies is the extended therapeutic time window up to several weeks or months after the initial insult. This makes the treatment available to a much larger number of stroke patients. Cell-based restorative therapies have emerged as attractive approaches for the treatment of stroke. Transplanted cells, an example of “plastic” biological products, can adapt to different local conditions in damaged brain tissue while not being limited to a unique target. They can act on a wide range of endogenous protective and brain repair processes including immunomodulation, neuronal, vascular and glial remodelling.
Building on emerging preclinical and pilot clinical evidences, RESSTORE project focuses on the clinical assessment of reparative cell therapy to improve stroke recovery and patients’ quality of life. RESSTORE European multicentre randomised trial will explore, for the first time, the safety and efficacy (functional recovery) of intravenous infusion of allogenic adipose tissue derived stem cells (ADSCs) in stroke patients. Therapeutic effects of ADSCs will be assessed in patients using clinical rating scales, multimodal MRI and novel blood biomarkers. Additionally, the societal value and cost-effectiveness of ADSCs-based therapy will be evaluated through health economics and predictive in silico simulations.
Complementary ancillary animal studies support the clinical trial by defining i) if the treatment response can be further enhanced by intensive rehabilitation, ii) the contribution of co-morbidities (diabetes, hypertension) and iii) the mechanism(s) underlying the therapeutic effect.
The European regenerative therapy capacities (France, Spain, Finland, UK and Czech Republic), developed in RESSTORE cover the full value chain: large scale GMP cell production, clinical testing, biomarkers discovery, understanding of the repair mechanisms, modelling, biobanking, economic studies, exploitation and communication plan.
- Cell therapy units have demonstrated that an innovative manufacturing process, as the one developed for RESSTORE, with a subsequent multicentre banking strategy is feasible. They achieved a harmonized manufacturing process is accepted by the regulatory agency in France, Spain and Finland. Currently, 5 ADSC cell banks are available, and ADSCs were already delivered for experimental and clinical trial use . This work of cell manufacturing is promising for the development of new cell therapies using allogeneic ADSC in Europe. The experience emerging from RESSTORE project will pave the way to accelerate future authorizations of clinical trials using allogeneic ADSC in Europe in different diseases.
- To prepare clinical trial, we obtained ethical approval for French and Spanish centres, regulatory approval for France and conditional regualtory approval for Spain. Submissions to other countries are on-going. The trial was officially registered on EudraCT and Clinicaltrials websites. The clinical report forms (eCRF) is currently used. The Contract Research Organization planned the data management and the trial monitoring is ongoing.
- WP3 and WP6 partners (blood biomarkers, MRI, and MRI software development) implemented updated methods. The blood biobank has been implemented.
- The statistical analysis plan was implemented and fulfilled the preliminary requests: primary endpoint choice, expected effect size, description of the selected population. Statistical innovations such as mathematical models to simulate stroke pathophysiology and therapeutic effects (“in silico stroke”) and virtual population are promising for future valorisation of RESSTORE data and health economics.
- Experimental studies researchers are finishing animal studies according to harmonized methods and stroke model in the different laboratories . 5 publications are submtted or will be submitted soon. These multicentre studies will accelerate available data about understanding of cell therapy effects in stroke.
- Valorisation and communication plans were established. A website (www.resstore.eu) and tweeter account were created. Four annual meetings (in Madrid, Lyon, Sevilla, Paris) were organized. RESSTORE first newsletter has been submitted.
- To prepare clinical trial, we obtained ethical approval for French and Spanish centres, regulatory approval for France and conditional regualtory approval for Spain. Submissions to other countries are on-going. The trial was officially registered on EudraCT and Clinicaltrials websites. The clinical report forms (eCRF) is currently used. The Contract Research Organization planned the data management and the trial monitoring is ongoing.
- WP3 and WP6 partners (blood biomarkers, MRI, and MRI software development) implemented updated methods. The blood biobank has been implemented.
- The statistical analysis plan was implemented and fulfilled the preliminary requests: primary endpoint choice, expected effect size, description of the selected population. Statistical innovations such as mathematical models to simulate stroke pathophysiology and therapeutic effects (“in silico stroke”) and virtual population are promising for future valorisation of RESSTORE data and health economics.
- Experimental studies researchers are finishing animal studies according to harmonized methods and stroke model in the different laboratories . 5 publications are submtted or will be submitted soon. These multicentre studies will accelerate available data about understanding of cell therapy effects in stroke.
- Valorisation and communication plans were established. A website (www.resstore.eu) and tweeter account were created. Four annual meetings (in Madrid, Lyon, Sevilla, Paris) were organized. RESSTORE first newsletter has been submitted.
Beyond the “state of art” in stroke research, we implemented innovative tools for a large translational project. Our global aim is to provide in 2020-2021, multicentre databases from stroke patients including multimodal MRI, blood Biobank and clinical follow-up. These unique data will be linked to experimental results rising from animal multicentre studies of cell therapy using same therapeutic cells (ADSC) than in clinics. Beyond the functional results of cell therapy in stroke patient, we will better understand mechanisms of spontaneous recovery and effects of reparative cell-based therapy.
For health economics purposes, the total cost of disorders of the brain was estimated at €798 billion in 2010. Of that €64.1 billion is due to stroke mainly because of long-term special care and rehabilitation. Stroke burden is expected to increase due to aging of the population and diabetes. Thus, interventions to alleviate residual impairment are urgently needed to help stroke patients. Reducing post-stroke handicap could have a positive impact on societal cost. This socio-economic aspect can be studied using mathematical models and virtual population as planned in RESSTORE.
Finally, RESSTORE will surely contribute to improve its public and private (SME) competitiveness and increase the attractiveness of Europe as a reference location to develop and clinically assess new innovative therapeutic options for brain diseases.
For health economics purposes, the total cost of disorders of the brain was estimated at €798 billion in 2010. Of that €64.1 billion is due to stroke mainly because of long-term special care and rehabilitation. Stroke burden is expected to increase due to aging of the population and diabetes. Thus, interventions to alleviate residual impairment are urgently needed to help stroke patients. Reducing post-stroke handicap could have a positive impact on societal cost. This socio-economic aspect can be studied using mathematical models and virtual population as planned in RESSTORE.
Finally, RESSTORE will surely contribute to improve its public and private (SME) competitiveness and increase the attractiveness of Europe as a reference location to develop and clinically assess new innovative therapeutic options for brain diseases.