A randomized <scp>placebo‐controlled</scp> phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis

Cudkowicz, Merit; Lindborg, Stacy; Goyal, Namita; Miller, Robert G.; Burford, Matthew; Berry, James; Nicholson, Katharine; Mozaffar, Tahseen; Katz, Jonathan; Jenkins, Liberty; Baloh, Robert H.; Lewis, Richard A.; Staff, N.; Owegi, Margaret; Berry, Donald A.; Gothelf, Yaël; Levy, Yossef S.; Aricha, Revital; Kern, R.; Windebank, Anthony J.; Brown, Robert H.

doi:10.1002/mus.27472

Cited by 57 publications

(54 citation statements)

References 23 publications

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“…As a less invasive alternative to bypass the BCNSB, repeated intrathecal injections of antisense oligonucleotides targeting SOD1 (Miller et al, 2013 , 2020 ), gene therapy with adeno-associated virus rh10 containing an anti-SOD1 microRNA (AAV-miR-SOD1) (Mueller et al, 2020 ), and mesenchymal stem cells (Petrou et al, 2016 ; Cudkowicz et al, 2021 ) have been safely tested in humans with ALS. Non-invasive magnetic resonance-guided focused ultrasound (MRgFUS) has emerged as a technique to open the BBB safely and temporarily for targeted drug delivery to the motor cortex in patients with ALS (Abrahao et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.

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Section: Discussionmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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“…Most recently, a randomized phase III controlled clinical trial comparing NurOwn ® to placebo has also been completed (NCT03280056) in patients with ALS. The results do not reach statistical significance on the primary endpoint; nevertheless, patients who received NurOwn ® have been significantly improved in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support ( Cudkowicz et al, 2021 ). Although this trial does not support the proposed clinical benefit of cellular therapy for ALS, NurOwn ® is warranted for further investigation.…”

Section: Cellular Therapymentioning

confidence: 99%

Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects

Lin

Cheng

et al. 2022

Front. Cell Dev. Biol.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3–5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.

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“…Stem-cell based therapies have been tested in ALS patients and demonstrated some benefits without substantial improvement in disease progression [ 71 , 72 , 73 ]. To our knowledge, no evaluation of BBB permeability following stem-cell based therapies was performed on patients.…”

Section: Therapeutic Strategies By Correcting Bbb/bscb Alterationsmentioning

confidence: 99%

Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Alarcan

Ojaimi

Lanznaster

et al. 2022

JPM

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.

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A randomized placebo‐controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis

Cited by 57 publications

References 23 publications

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects

Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

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