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Cell-based regenerative therapies have emerged as attractive approaches for the treatment of stroke. Various cell types and treatment strategies have been explored, mostly at the preclinical level, and demonstrated significant improvement. Particularly attractive are mesenchymal stem/stromal cells (MSCs) being easily derived from multiple sources including adipose tissue. In addition, an excellent safety profile and low immunogenicity after allogeneic application may enable their use as an ‘off-the-shelf’ therapeutic product. Concerning the delivery route, intravenous (IV) cell infusion, which is non-invasive, safe and provides a broad distribution of cells to the close proximity of ischemic tissue, has the most immediate access to clinical applications. This strategy has not yet been evaluated in a large patient cohort. Moreover, based on a recent health-economic analysis, the societal value of successful cell therapy for stroke could reach 120 000 € for each patient. The primary objective of the RESSTORE translational project is to provide, through a European multicentre randomised phase IIb clinical study, essential information on the therapeutic efficacy of intravenous delivery of allogenic adipose tissue derived MSCs (ADMSCs) in 400 stroke patients. 

More precisely, RESSTORE objectives are:

  1. To demonstrate the clinical efficacy and safety of ADMSC on functional recovery in 400 stroke patients with a main primary endpoint at 3 months after stroke onset followed by a 2-years follow-up;
  2. To assess and monitor in patients the therapeutic effects of ADMSC using novel biomarkers (multimodal MRI and blood markers);
  3. To validate the societal value and cost-effectiveness of cell-based regenerative therapy based on health economics and predictive in silico (virtual population) models;
  4. To define in experimental rodent stroke models i) whether or not the treatment response can be further enhanced by intensive rehabilitation, ii) the contribution of co-morbidities and mechanism(s) underlying the therapeutic effect.

Stroke is a major reason for death and the leading cause of chronic disability in adults. Recent progress in the field of stem cell research offers attractive strategies to enhance functional outcome after stroke. In particular, mesenchymal stem cells are shown to be beneficial in experimental stroke models by acting through brain own repair mechanisms such as neurogenesis, synaptogenesis, angiogenesis and immunomodulation. The core concept of this project is that the same mechanisms in stroke patients can be enhanced by allogenous stem cells from adipose tissue eventually reflected at the functional level. Current treatment options for stroke are limited to intravenous (IV) thrombolysis by Alteplase within 4.5 h, thrombectomy, aspirin within 48 h, decompressive craniectomy for large strokes, and management in stroke care units for intensive care and rehabilitation. Preventive approaches are effective in reducing stroke mortality and incidence. However, while thrombolysis together with improved acute care has decreased mortality, the surviving patients are left with sensorimotor and cognitive disabilities, resulting in additional burden to rehabilitative care. Thus, 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 therapeutic approaches should target all these systems rather than narrowly targeting an individual damage process, and contributing to avoid the failures of past clinical attempts to develop specific neuroprotective drugs. .