Cell therapy in ALS: An update on preclinical and clinical studies

Sironi, Francesca; Marchi, Fabiola De; Mazzini, Letizia; Bendotti, Caterina

doi:10.1016/j.brainresbull.2023.01.008

Cited by 22 publications

(13 citation statements)

References 108 publications

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“…Preclinical findings support this, and ongoing phase I and II clinical trials in ALS patients indicate positive results in safety and tolerability. However, substantial improvements for ALS patients necessitate continued collaboration between basic and clinical researchers [ 67 , 68 ].…”

Section: Motor Neuron Disordersmentioning

confidence: 99%

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Zambon,

Falzone,

Bolino

et al. 2024

Cell. Mol. Life Sci.

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Neuromuscular diseases encompass a heterogeneous array of disorders characterized by varying onset ages, clinical presentations, severity, and progression. While these conditions can stem from acquired or inherited causes, this review specifically focuses on disorders arising from genetic abnormalities, excluding metabolic conditions. The pathogenic defect may primarily affect the anterior horn cells, the axonal or myelin component of peripheral nerves, the neuromuscular junction, or skeletal and/or cardiac muscles. While inherited neuromuscular disorders have been historically deemed not treatable, the advent of gene-based and molecular therapies is reshaping the treatment landscape for this group of condition. With the caveat that many products still fail to translate the positive results obtained in pre-clinical models to humans, both the technological development (e.g., implementation of tissue-specific vectors) as well as advances on the knowledge of pathogenetic mechanisms form a collective foundation for potentially curative approaches to these debilitating conditions. This review delineates the current panorama of therapies targeting the most prevalent forms of inherited neuromuscular diseases, emphasizing approved treatments and those already undergoing human testing, offering insights into the state-of-the-art interventions.

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Section: Motor Neuron Disordersmentioning

confidence: 99%

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Zambon,

Falzone,

Bolino

et al. 2024

Cell. Mol. Life Sci.

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“…Recently published reviews 34 , 35 and Cochrane data 36 regarding stem cell therapy for ALS showed that numerous preclinical and early-stage clinical trials have been conducted. The major clinical trials using MSCs for ALS are summarized in Table 1 .…”

Section: Mandatory Factors In An Optimized Therapeutic Strategy Using...mentioning

confidence: 99%

Optimal Therapeutic Strategy of Bone Marrow-Originated Autologous Mesenchymal Stromal/Stem Cells for ALS

Kim,

Oh,

Noh

et al. 2024

Stem Cells Translational Medicine

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Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive neurodegenerative changes in motor neural networks. Given the system complexity, including anatomically distributed sites of degeneration from the motor cortex to the spinal cord and chronic pro-inflammatory conditions, a cell-based therapeutic strategy could be an alternative approach to treating ALS. Lessons from previous mesenchymal stromal/stem cell (MSC) trials in ALS realized the importance of 3 aspects in current and future MSC therapy, including the preparation of MSCs, administration routes and methods, and recipient-related factors. This review briefly describes the current status and future prerequisites for an optimal strategy using bone-marrow-originated MSCs to treat ALS. We suggest mandatory factors in the optimized therapeutic strategy focused on advanced therapy medicinal products produced according to Good Manufacturing Practice, an optimal administration method, the selection of proper patients, and the importance of biomarkers.

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“…ALS has been the MNDs for which the highest number of cell therapy-based clinical trials have been approved in the past two decades to test for safety, tolerability and early efficacy. Although the vast majority of the completed trials have proven safe, regardless of the type and number of cells transplanted and the delivery route, the functional improvement of the patients has been modest, with a mild reduction in the slope decline or diminished levels of pro-inflammatory cytokines being the most common positive outcomes [ 159 , 160 ]. Most approaches used autologous bone marrow-MSC [ 161 ], known to secrete neurotrophic factors and promote cytoprotection, sometimes in combination with already approved drugs (e.g., Riluzole), and administered via intramuscular or intrathecal injections or a combination of both.…”

Section: Stem Cell Types and Scos For Cell Therapy In Motor Neuron Di...mentioning

confidence: 99%

“…Most approaches used autologous bone marrow-MSC [ 161 ], known to secrete neurotrophic factors and promote cytoprotection, sometimes in combination with already approved drugs (e.g., Riluzole), and administered via intramuscular or intrathecal injections or a combination of both. The slow disease progression for a short time window after the transplantation of fetal-SpC-derived NSCs has been also reported [ 159 ] and several clinical trials using genetically modified PSC-derived NPCs are currently ongoing [ 159 , 160 ]. Interestingly, the first FDA-approved one showed that, in postmortem samples of the ALS patients who died of disease progression, the SpC transplanted NPCs engineered to produce GDNF were still engaged in the tissue almost 2 years post-transplantation [ 162 ].…”

Section: Stem Cell Types and Scos For Cell Therapy In Motor Neuron Di...mentioning

confidence: 99%

Spinal Cord Organoids to Study Motor Neuron Development and Disease

Buchner

Dokuzluoglu

Grass

et al. 2023

Life

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Motor neuron diseases (MNDs) are a heterogeneous group of disorders that affect the cranial and/or spinal motor neurons (spMNs), spinal sensory neurons and the muscular system. Although they have been investigated for decades, we still lack a comprehensive understanding of the underlying molecular mechanisms; and therefore, efficacious therapies are scarce. Model organisms and relatively simple two-dimensional cell culture systems have been instrumental in our current knowledge of neuromuscular disease pathology; however, in the recent years, human 3D in vitro models have transformed the disease-modeling landscape. While cerebral organoids have been pursued the most, interest in spinal cord organoids (SCOs) is now also increasing. Pluripotent stem cell (PSC)-based protocols to generate SpC-like structures, sometimes including the adjacent mesoderm and derived skeletal muscle, are constantly being refined and applied to study early human neuromuscular development and disease. In this review, we outline the evolution of human PSC-derived models for generating spMN and recapitulating SpC development. We also discuss how these models have been applied to exploring the basis of human neurodevelopmental and neurodegenerative diseases. Finally, we provide an overview of the main challenges to overcome in order to generate more physiologically relevant human SpC models and propose some exciting new perspectives.

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Cell therapy in ALS: An update on preclinical and clinical studies

Cited by 22 publications

References 108 publications

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Optimal Therapeutic Strategy of Bone Marrow-Originated Autologous Mesenchymal Stromal/Stem Cells for ALS

Spinal Cord Organoids to Study Motor Neuron Development and Disease

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