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. 2024 Jan 19;13(4):309–316. doi: 10.1093/stcltm/szad095

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

Seung Hyun Kim 1,2,✉,#, Ki-Wook Oh 3,4,#, Min-Young Noh 5,6,#, Min-Soo Kwon 7,✉
PMCID: PMC11016834  PMID: 38244235

Abstract

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.

Keywords: amyotrophic lateral sclerosis, MSC therapy, ATMPs-GMP, optimal therapeutic strategy

Graphical Abstract

Graphical Abstract.

Graphical Abstract

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Significance Statement.

Mesenchymal stromal/stem cell (MSC)-based therapy is a promising strategy to address the complex multifactorial pathomechanisms of motor neuronal death in amyotrophic lateral sclerosis (ALS). For enhanced safety and efficacy, protocols for MSC preparation and manufacturing, administration methods, and recipient selection criteria should be optimized based on the results of well-designed randomized controlled trials and current guidelines. Optimized protocols for the potentiation/engineering of MSCs and the development of reliable biomarkers to predict the pretreatment status of the recipient milieu and the therapeutic response are prerequisites for an innovative therapeutic strategy using MSCs for ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both the upper and lower motor neuron systems and eventually results in generalized weakness and, ultimately, death due to respiratory failure.1,2 With the recent breakthroughs in comprehending the pathogenic mechanisms of ALS, several crucial points have emerged: (1) The identification of novel causative genes has broadened our understanding of ALS, shifting it toward a motor neural network syndrome or multisystem proteinopathy. (2) Recognizing noncell autonomous contributions to the pro-inflammatory central nervous system (CNS) milieu underlying motor neuronal cell death underscores the importance of further investigating immune-inflammatory modulation as a potential clinical therapeutic strategy for neurodegenerative diseases, including ALS. To date, only 3 drugs have been approved by the Food and Drug Administration (FDA): riluzole, edaravone, and AMX0035 (Relyvrio).3-5 However, they have modest therapeutic effects.6-8

Despite significant progress in linking clinical heterogeneity with the genetic and pathomechanisms of ALS, most previous clinical trials have not yielded successful outcomes.9,10 Failed trials, primarily based on single molecular targets, underscore the significance of incorporating multiple molecular targets within a broader therapeutic strategy. In this context, clinical trials using mesenchymal stromal/stem cells (MSCs) have been conducted for 2 decades for ALS.

This review briefly describes the current status and future prerequisites for an optimal MSC therapeutic strategy for ALS. We confined this review to autologous bone marrow-originated MSC (BM-MSC) treatment for ALS and described the current status and prerequisites for an optimal therapeutic strategy. We suggest mandatory factors for the strategy focused on advanced therapy medicinal products (ATMPs) produced according to Good Manufacturing Practice (GMP), optimal administration routes and protocols, biomarker-based stratification of patients, the monitoring of post-treatment effectiveness, and an optimized therapeutic schedule. The future development of such a strategy for ALS, including MSC potentiation with priming methods and genetic engineering and the development of reliable biomarkers to predict the recipient’s milieu, could give hope to patients with ALS.

Therapeutic Targets for BM-MSCs Based on the Pathogenic Mechanisms of ALS

Despite the diversity of genetic risk factors associated with ALS, neuroinflammatory responses are known to play a pivotal role in the pathophysiology of the disease and are intimately connected with its progression.11 Neuroinflammation observed in ALS is fueled by an intricate interplay between the peripheral immune system and the brain’s immune system.12 ALS is considered a noncell autonomous disease, where the start and progression of motor neuron degeneration seem to be influenced by interactions among different kinds of cells and the development of a sustained inflammatory environment.13

Notably, decreased numbers and activity of regulatory T cells (Tregs) and decreased forkhead box P3 (FoxP3) expression levels in peripheral lymphocytes have been suggested as biomarkers predicting rapid progression and attenuated survival in patients with ALS.14 Treg cells have been demonstrated to possess the capacity to induce the functional shifting of microglia toward the alternative, protective phenotype15-17 and suppress Type 1 T helper (Th1) lymphocyte proliferation. Microglia, which exist as innate immune cells in the CNS parenchyma as phagocytes, secret various toxic cytokines, as well as tissue-repairing molecules, in a context-dependent manner.18

Given the system complexity and anatomically distributed sites of degeneration from the motor cortex to the spinal cord, cell therapy focused on replacing injured cells and differentiation into motor neurons is challenging.19 Furthermore, even if these new motor neurons are integrated into a diseased neural network, they may remain susceptible to the same pathological processes that destroy original motor neurons.20-23 Therefore, a therapeutic strategy using MSCs should be focused away from neuronal replacement or reconstruction and toward creating an anti-inflammatory microenvironment. As summarized in Fig. 1, besides direct effects, such as the release of neurotrophic factors and the stimulation of intrinsic neurogenesis, intrathecally administered MSCs have diverse immune inflammatory modulatory efficacy that can regulate the onset and progression of ALS by potentiating regulatory T cells and anti-inflammatory microglia in the CNS environment.25,26

Figure 1.

Figure 1.

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BM-MSCs intrathecally injected for ALS and verified according to the minimum ISCT criteria,24 operate through various mechanisms. They release neurotrophic factors, fostering neural health. In cerebrospinal fluid, MSCs increase populations of regulatory T cells and Th2 cells, which move into the CNS, leading to an anti-inflammatory environment marked by anti-inflammatory cytokines, such as interleukin (IL)-4 and IL-10. Additionally, BM-MSCs release balanced transforming growth factor-β (TGF-β) for CNS homeostasis, prompting a transition in microglia from an inflammatory to an anti-inflammatory phenotype. This transformation contributes to an anti-inflammatory environment with balanced IL-4, IL-10, and TGF-β concentrations, promoting CNS homeostasis. BM-MSCs also exhibit diverse immunomodulatory properties and can regulate the onset and progression of ALS by enhancing regulatory T cells and encouraging the development of anti-inflammatory microglia.25-31The image was created with BioRender.com.

Mandatory Factors in an Optimized Therapeutic Strategy Using MSCs for ALS

Guidelines for clinical trials in ALS emphasize a trial duration of 6-12 months to determine treatment effectiveness and recommend using composite endpoints (survival and function) to increase power.32 Recent guidelines also emphasize the importance of excluding genetic and clinical heterogeneity when enrolling subjects and using post hoc analysis of biological markers to identify subgroups of patients who appear to respond better to a specific treatment.33 The guidelines also mention the small number of people with ALS, a rare disease, as a barrier to drug development and the need for adaptive platform trials, in which multiple drugs and a common control group can be shared, to address the disadvantage of patients in the control group who do not receive treatment with an investigational drug that is expected to have a therapeutic effect during the trial. Thus, it is crucial to determine an optimal therapeutic strategy within the context of the current guidelines.

Recently published reviews34,35 and Cochrane data36 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. The route of administration in human trials has mostly been intrathecal, with the remainder being intrathecal with intramuscular, intravascular, or intraspinal. However, only 2 clinical trials were low risk of bias randomized controlled trial (RCT) designs and met current guidelines (NCT01363401, NCT03280056). A lenzumestrocel phase II RCT (NCT01363401) in which patients received 2 intrathecal injections of autologous BM-MSCs with riluzole or riluzole alone (controls) demonstrated transient positive clinical effects on Amyotrophic Lateral Sclerosis Functional Rating Scale‑Revised (ALSFRS-R) scores with good safety. The NurOwn phase III RCT (NCT03280056) in which patients received 3 intrathecal injections of autologous preconditioned BM-MSCs or placebo did not meet the primary outcome. Subgroup analysis in the early and moderate stages of ALS showed a possible clinical benefit according to ALSFRS-R scores.

Table 1.

Summary of major MSC clinical trials for ALS.

Trial number Location/Sponsor Study design Treatment arm Study drug Delivery route Result Reference
NCT01363401 Korea/Corestem Phase I Two injections with a 26-day interval (n = 7) Autologous BM-MSCs (Lenzumestrocel, Neuronata-R® Inj) Intrathecal Safe Oh et al.28
NCT01051882 Israel/Brainstorm Phase I/II, open-label (i) Early-stage ALS group (n = 6) received a single intramuscular injection
(ii) Advanced disease group (n = 6) received a single intrathecal injection		 Autologous preconditioned BM-MSCs (NurOwn®) Intramuscular or intrathecal Safe Petrou et al.37
NCT01777646 Israel/Brainstorm Phase IIa, open-label, dose-escalating Single injection (n = 14) Autologous preconditioned BM-MSCs (NurOwn®) Intramuscular and intrathecal Safe; possible clinical benefit Petrou et al.37
NCT01363401 Korea/Corestem Phase II, RCT without a sham procedure Randomized (1:1)
(i) Two injections with a 26-day interval (n = 32)
(ii) Control group (n = 27)		 Autologous BM-MSCs (Lenzumestrocel, Neuronata-R® Inj) Intrathecal Safe; positive clinical effect, reduced pro-inflammatory cytokines Oh et al.29
NCT03280056 US/Brainstorm Phase III, double-blind RCT with a sham procedure Randomized (1:1)
(i) Three injections (n = 95)
(ii) Placebo (n = 94) group		 Autologous preconditioned BM-MSCs (NurOwn®) Intrathecal Safe, did not meet the primary endpoint of efficacy, possible clinical response in subgroups, improvement in biomarkers. Cudkowicz et al.38
NCT04745299 Korea/CorestemChemon Phase III, double-blind RCT with a sham procedure Randomized (1:2:2)
(i) Two injections with a 26-day interval
(ii) Two injections + 3 additional booster injections
(iii) Placebo group		 Autologous BM-MSCs (Lenzumestrocel, Neuronata-R® Inj) Intrathecal Ongoing study Nam et al.39
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A minimum set of mandatory items is required to develop an optimal treatment strategy for MSCs in ALS. However, the following limitations of current MSC therapies in ALS should be considered first. (1) Because the recipient’s environment is in a pro-inflammatory state, the injected MSCs would be exposed to the same pathological conditions, which can reduce the capabilities of MSCs. (2) It is difficult for MSCs to replace damaged nerve cells or neural networks. Therefore, repeat treatments with less invasive procedures are necessary to overcome these limitations.

The mandatory items can be modified based on a better understanding of the disease and changing perspectives as MSC technology evolves. As shown in Fig. 2, developing safer and more effective BM-MSC therapies for ALS should be considered from 3 perspectives: MSC preparation and manufacturing, administration, and recipient factors.

Figure 2.

Figure 2.

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Factors to be considered in the development of an optimal MSC therapeutic strategy for treating ALS. Key factors affecting the clinical outcome of MSC therapy include (A) the preparation of MSCs, (B) the administration of MSCs, (C) recipient-related factors, and (D) biomarkers. *Items for preparing and manufacturing the Neuronata-R (lenzumestrocel) product in clinical trials for ALS, which are described in previously published papers.28,29,39

Items to be Standardized in MSC Preparation and Manufacturing

Over 40 preclinical and 20 clinical trials using stem cells in ALS have been conducted over 2 decades. However, a detailed GMP manufacturing protocol has yet to be described. Given FDA guidance for ALS drug development32 and trial guidelines,33 data on quality-controlled MSC products compatible with acceptance criteria for potency and safety issues should be shared between researchers based on the expected mode of action. As shown in Fig. 2, guidelines for MSC preparation and manufacturing as ATMPs produced according to GMP and mandatory quality control (QC) items for each final product should be released to the public as open-source materials.

According to the International Society for Cell and Gene Therapy (ISCT) criteria for MSCs, authentic human MSC-like cells for autologous transplantation must express certain MSC-positive surface markers, including 5ʹ-nucleotidase (CD73), Thy-1 (CD90), and endoglin (CD105) and must lack the expression of macrophage marker CD14, HSC marker CD34, lymphocyte marker CD45, B cell marker CD19, B-cell antigen receptor complex-associated protein alpha chain CD79a, and MHC class II cell surface receptor HLA-DR. In addition to the expression fingerprint, the cells must also be able to the capacity to differentiate into adipogenic, osteogenic, and chondrogenic lineages in vitro.24 MSCs secrete bioactive factors that favor tissue remodeling and repair, as well as immunoregulatory properties. These regenerative characteristics of MSCs have collectively made them the most broadly tested adult stem cells in clinical trials. In the case of intrathecal autologous BM-MSCs (Neuronata-R: Lenzumestrocel),27 a potency test for QC was conducted following the administration of at least 120 pg of human vascular endothelial growth factor per 1 × 104 cells.40 MSC criteria and other items are summarized in Figs. 1 and 2, respectively.

The Optimal Delivery Route, Dose, and Therapeutic Schedule of MSC Treatment for ALS

One of the critical factors in ALS drug development is the ability of the drug to cross the blood-brain barrier (BBB) and reach the lesion site. The larger the molecule, the more difficult it is to cross the BBB, which is a strong barrier that restricts the passage of cells. In addition to the intrathecal route, MSCs have been administered through a combined intravenous and intrathecal approach for patients with ALS.41 While the intravenous route for MSCs has limitations, with a significant portion getting trapped in the lungs, liver, and spleen rapidly after injection,42 it remains a more accessible and repeatable administration method. Considering preclinical reports demonstrating the beneficial effects of intravenous MSCs in ALS animal models,43-45 the intravenous route continues to be a viable option in ALS. Intrathecal, intracranial, and intraspinal administration are good delivery methods, given the problem of BBB penetration. The intrathecal administration of MSCs is less invasive than intraspinal or intracranial administration and allows for repeat treatments and serial CSF biomarker analysis.

A post hoc survival analysis in the lenzumestrocel phase II trial showed no long-term survival benefit. This finding may have been associated with the small sample size and relatively short observation period in the control group. A pilot surveillance study with a propensity score-matched external control group was conducted to overcome such limitations, including issues related to sample size and observation time.27 The survival probability was significantly higher in the BM-MSC group than in the external control group. Additionally, the Cox proportional hazard model showed a statistically significant lower hazard ratio for both single-cycle injection and multiple injections compared to the external control after adjusting for prognostic factors. The survival time of intrathecally delivered MSCs is limited to less than 28 days, but its effectiveness is sustained for up to at least 6 months. Considering the immunomodulatory effects of MSC treatment by intrathecal delivery (less-invasive procedure), whether successive booster MSC treatments after single-cycle treatment could improve long-term efficacy should be determined.

The US FDA and the Korean Ministry of Food and Drug Safety approved the phase III ALSUMMIT clinical trial protocol (NCT04745299). ALSUMMIT is a randomized, multicenter, double-blind, parallel-group, sham procedure-controlled phase III trial to evaluate the long-term efficacy and safety of repeated BM-MSCs in the treatment of ALS (56-week main study with five BM-MSC injections followed by a 24-month observational study). 39 All 126 participants were already enrolled, and the ongoing ALSUMMIT trial is expected to have data at the end of 2024. In this protocol, the time interval of booster injections after the single cycle injection was designed to be 3 months. The rationale for 3-month interval booster injections was based on the unpublished data of a post-marketing surveillance study of lenzumestrocel suggesting that CSF cytokine profiles at 3- to 4-month intervals showed more benefits according to ALSFRS-R scores and cytokine levels than those with 5- to 12-month injection intervals. Besides the administration routes, applying a repeated therapeutic protocol at regular intervals is an essential factor for developing an optimal MSC therapeutic strategy for ALS.27 Comparative analytic data of serial CSF biomarkers, ALSFRS-R scores, and other clinical parameters could provide vital information to create a more robust MSCs and to design stratified or precision medicine.

The short survival time of injected MSCs could be a limitation of intrathecal MSC therapy but it can be overcome with repeated treatments. However, short life of MSCs can escape from either accumulated toxic effects or unproven fate of MSCs which might be a hazard to the recipient. Therefore, it is crucial to understand the next-generation optimized MSC therapeutic strategy based on lessons from previous MSC trials for ALS.8,27,34-36 Thus, the development of optimal clinical protocols, such as less invasive repeated injections with optimized therapeutic intervals based on the characteristics of the intrinsic MSCs intrathecally injected, including the survival time of MSCs in CSF and persisting action duration reflected by biomarker change, is required.

Recipient Factors

While the precise mechanisms underlying host factors in clinical settings remain unclear, preclinical studies suggest that the disease stage and the surrounding tissue environment can impact the efficacy of MSC therapies. Inflammation, hypoxia, and the extracellular matrix are dynamic in disease progression, and each parameter can influence MSC function in vivo.46 In addition, early intervention might be more effective in achieving maximal therapeutic benefits in ALS.10

Previous trials28,29,38 and a long-term monitoring study27 showed that recipient factors, such as older age, rapid progression of the disease, and lower ALSFRS-R scores, were associated with poor autologous BM-MSC treatment outcomes. Younger age and early ALS stage measured by ALSFRS-R scores and an inverse transforming growth factor-β (TGF-β)/monocyte chemoattractant protein-1 (MCP-1/CCL2) ratio after MSC treatment were significant predictors of good prognosis in patients with ALS.29,38 Notably, a change in the TGF-β/MCP-1 ratio in CSF, which reflects the patient’s immune-inflammation status, between baseline and after treatment was significantly related to prognosis and long-term outcomes. These findings suggest the importance of host factors and the necessity of a stratification model for the future design of MSC clinical trials. It is challenging to develop a treatment that will be effective for all patients with ALS with varying host factors. Therefore, it is crucial to develop clinical trial designs that consider recipient factors and optimized therapeutic protocols to identify groups of individuals with ALS to maximize treatment benefits.

Biomarkers

Although MSCs clinical trials for ALS have reported that MCP-1 and TGF-β in CSF might be related to stem cell efficacy,29 large-scale clinical trials have not yet been able to objectively evaluate the therapeutic efficacy of MSCs in treating ALS. Plasma phosphorylated neurofilament H was used as a biomarker of efficacy in a clinical trial for the recently approved AMX0035 (Relyvrio), although no significant difference was found after 24 weeks.5 In the case of the ALSUMMIT,39 a clinical trial is currently underway to identify biomarkers that can evaluate the efficacy of MSCs through CSF analysis at each cycle of administration. The discovery of meaningful biomarkers that reflect the treatment response and efficacy is expected to be an essential factor in new drugs for ALS.

Conclusion and Future Perspectives

The development of an optimized therapeutic strategy could enhance the efficacy of MSCs and address safety issues. As shown in Fig. 2, various strategies for MSC preparation and manufacturing, including priming or pretreatment methods,47 QC protocols, such as selective isolation of healthy stem cells,48 genetically modified MSCs with enhanced functionality,49 and the application of MSC-derived exosomes,50 have been proposed to increase the efficacy of MSC treatment. These strategies may overcome the limitations of the currently proposed autologous BM-MSC therapy for ALS. We suggest that future therapeutic strategies should include the following: (1) protocols for producing optimally primed/engineered MSCs by GMP able to escape from senescence, (2) the development of reliable biomarkers to be used as companion diagnostics for predicting the effectiveness of MSC therapy, and (3) the development of the strategy to overcome host pro-inflammatory milieu that injected MSCs will face.

Acknowledgments

The images were created with BioRender.com.

Contributor Information

Seung Hyun Kim, Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.

Ki-Wook Oh, Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.

Min-Young Noh, Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea.

Min-Soo Kwon, Department of Pharmacology, Research Institute of Basic Medical Science, School of Medicine, CHA University, CHA Bio Complex, Gyeonggi-do, Republic of Korea.

Funding

This research was supported by the K-Brain Project of the National Research Foundation (NRF), funded by the Korean government (MSIT; RS-2023-00265515 to SHK).

Conflict of Interest

S.H.K. and K.W.O. declared employment at Hanyang University Hospital; Research funding from Corestemchemon Inc. The other authors declare no potential conflicts of interest.

Author Contributions

M.Y.N., M.S.K.: conception and design, manuscript writing, visualization, and final approval of the manuscript. S.H.K., K.W.O.: conception and design, manuscript writing, and final approval of the manuscript.

Data Availability

No new data were generated or analyzed in support of this research.

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