Stem Cells as an Emerging Paradigm in Stroke 3

Savitz, Sean I; Wechsler, Lawrence R.; Aronowski, Jaroslaw; Boltze, Johannes; Borlongan, Cesar V.; Case, Casey; Chase, Thomas N.; Chopp, Michael; Carmichael, S. Thomas; Cramer, Steven C.; Duncan, Pamela W.; Finklestein, Seth P.; Fischkoff, Steven A.; Guzman, Raphaël; Hess, David C.; Huang, David; Hinson, Jim; Kautz, Steven A.; Kondziolka, Douglas; Mays, Robert W.; Misra, Vivek; Mitsias, Panos; Modo, Michel; Muir, Keith W.; Sinden, John D.; Snyder, Evan Y.; Steinberg, Gary K.; Vahidy, Farhaan S; Willing, Alison E.; Wolf, Steven L.; Yankee, Ernest W.; Yavagal, Dileep R.

doi:10.1161/strokeaha.113.003379

Cited by 134 publications

(70 citation statements)

References 33 publications

(36 reference statements)

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“…Although this trial was a randomized clinical trial, we did not choose a double‐blinded format to avoid performing sham procedures in a control group for ethical reasons. We considered the risk of procedures35 and the possibility of compromised recruitment 36. Second, the follow‐up period was only 6 months postinjection.…”

Section: Discussionmentioning

confidence: 99%

Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

Noh

Kwon

et al. 2018

Annals of Neurology

101

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ObjectiveTo assess the safety and efficacy of 2 repeated intrathecal injections of autologous bone marrow–derived mesenchymal stem cells (BM‐MSCs) in amyotrophic lateral sclerosis (ALS).MethodsIn a phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with 2 BM‐MSC injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events. The primary efficacy outcome was changes in Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R) score from baseline to 4 and 6 months postinjection. Post hoc analysis includes investigation of cerebrospinal fluid biomarkers and long‐term survival analysis.ResultsSafety rating showed no groupwise difference with absence of serious treatment‐related adverse events. Mean changes in ALSFRS‐R scores from baseline to 4 and 6 months postinjection were reduced in the MSC group compared with the control group (4 months: 2.98, 95% confidence interval [CI] = 1.48–4.47, p < 0.001; 6 months: 3.38, 95% CI = 1.23–5.54, p = 0.003). The MSC group showed decreased proinflammatory and increased anti‐inflammatory cytokines. In good responders, transforming growth factor β1 significantly showed inverse correlation with monocyte chemoattractant protein‐1. There was no significant difference in long‐term survival between groups.InterpretationRepeated intrathecal injections of BM‐MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety, in ALS patients. A plausible action mechanism is that BM‐MSCs mediate switching from pro‐ to anti‐inflammatory conditions. A future randomized, double‐blind, large‐scale phase 3 clinical trial with additional BM‐MSC treatments is required to evaluate long‐term efficacy and safety. Ann Neurol 2018;84:361–373

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Section: Discussionmentioning

confidence: 99%

Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

Noh

Kwon

et al. 2018

Annals of Neurology

101

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“…4 Furthermore, patient descriptions are not standardized, recovery biomarkers are not well defined, 5 and we lack agreed time-points or measures to examine outcomes in rehabilitation and recovery trials. 6 By creating an international partnership of experts from a broad range of scientific and clinical disciplines, we aim to achieve consensus on developing, conducting and reporting rehabilitation and recovery research, and create a new community of practice.…”

Section: Introduction: the Problem And Solutionmentioning

confidence: 99%

“…Basic scientists need to understand the most pressing issues in stroke recovery and rehabilitation and work closely with their clinical counterparts in designing studies, taking a ''Bedside to Bench'' approach instead of the conventional ''Bench to Bedside'' approach. Understanding the biology and timing of recovery in animals and in humans requires knowledge of underlying molecular mechanisms that may be influenced by different therapies, such as rehabilitation and stem cells, 5 with the potential to augment post-stroke plasticity and brain repair. Methods for enhancing the potential for functional and structural plasticity in surviving brain and spinal cord are needed.…”

Section: Introduction: the Problem And Solutionmentioning

confidence: 99%

Moving rehabilitation research forward: Developing consensus statements for rehabilitation and recovery research

Bernhardt

Borschmann

Boyd

et al. 2016

International Journal of Stroke

132

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Stroke recovery is the next frontier in stroke medicine. While growth in rehabilitation and recovery research is exponential, a number of barriers hamper our ability to rapidly progress the field. Standardized terminology is absent in both animal and human research, methods are poorly described, recovery biomarkers are not well defined, and we lack consistent timeframes or measures to examine outcomes. Agreed methods and conventions for developing, monitoring, evaluating and reporting interventions directed at improving recovery are lacking, and current approaches are often not underpinned by biology. We urgently need to better understand the biology of recovery and its time course in both animals and humans to translate evidence from basic science into clinical trials. A new international partnership of stroke recovery and rehabilitation experts has committed to advancing the research agenda. In May 2016, the first Stroke Recovery and Rehabilitation Roundtable will be held, with the aim of achieving an agreed approach to the development, conduct and reporting of research. A range of methods will be used to achieve consensus in four priority areas: preclinical recovery research; biomarkers of recovery; intervention development, monitoring and reporting; and measurement in clinical trials. We hope to foster a global network of researchers committed to advancing this exciting field. Recovery from stroke is challenging for many survivors. They deserve effective treatments underpinned by our evolving understanding of brain recovery and human behaviour. Working together, we can develop game-changing interventions to improve recovery and quality of life in those living with stroke.

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“…59 Consensus recommendations on trial development largely recognise that clinical data to inform key issues such as dosing, time windows, end-points, biomarkers, and follow-up duration are very limited, and also that animal data may translate poorly to human use. 61 The mechanistic understanding of cell therapies in stroke has advanced and clinical trial designs have adapted to these changes in concepts. Clinical trials have established basic safety information about a range of cell types and routes of delivery, at least in limited populations, and planned clinical trials will deliver preliminary evidence of efficacy.…”

Section: Conclusion: Where Next For Clinical Trials?mentioning

confidence: 99%

Clinical trial design for stem cell therapies in stroke: What have we learned?

Muir

2017

Neurochemistry International

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Stem cells of various sources have been investigated in a series of small, safety and feasibility-focused studies over the past 15 years. Understanding of mechanisms of action has evolved and the trial paradigms have become focused on two different approaches -one being an early subacute delivery of cells to reduce acute tissue injury and modify the tissue environment in a direction favourable to reparative processes (for example by being anti-inflammatory, antiapoptotic, and encouraging endogenous stem cell mobilisation); the other exploring later delivery of cells during the recovery phase after stroke to modulate the local environment in favour of angiogenesis and neurogenesis. The former approach has generally investigated intravenous or intra-arterial delivery of cells with an expected paracrine mode of action and no expected engraftment within the brain. The latter has explored direct intracerebral implantation adjacent to the infarct. Several relevant trials have been conducted, including two controlled trials of intravenously delivered bone marrow-derived cells in the early subacute stage, and two small singlearm phase 1 trials of intracerebrally implanted cells. The findings of these studies and their implications for future trial design are considered.Introduction:

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Stem Cells as an Emerging Paradigm in Stroke 3

Cited by 134 publications

References 33 publications

Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

Moving rehabilitation research forward: Developing consensus statements for rehabilitation and recovery research

Clinical trial design for stem cell therapies in stroke: What have we learned?

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