Researchers say bone marrow transplants may be an effective treatment for ALS

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Along with the central nervous system, the immune system may play a fundamental role in Amyotrophic Lateral Sclerosis (ALS), suggesting that bone marrow transplants may be an effective novel treatment for the neurodegenerative disease, according to findings from a research team that included Albert LaSpada, MD, PhD, distinguished professor of pathology, neurology and biological chemistry at the University of California, Irvine School of Medicine.

The study, “Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4,” recently published in Nature, was a joint collaboration between LaSpada and Mount Sinai microbiology faculty members Laura Campisi, PhD, and Ivan Marazzi, PhD.

The team found both immune and nervous system dysfunctions in animal models and patients with ALS4, a juvenile and slowly progressive form of the condition caused by mutations in the senataxin protein coding gene.

“This is the first study to implicate altered cell-mediated immune system function in ALS and raises the prospect of abnormal cell mediated immunity as a contributing factor in not only ALS4, but also in other forms of the disease, including sporadic ALS, which accounts for 90 percent of all cases,” said LaSpada, a corresponding author on the study.

ALS is characterized by the progressive death of motor neurons, which severely impairs the patients’ ability to move their arms and legs, speak, swallow and eventually, breathe. There is no treatment or cure, and previous research has focused on neurons.

More recent studies, however, have shown evidence of interaction between the central nervous and immune systems.

The team’s most important discovery was that cell-mediated immunity, which does not involve antibodies, is altered in ALS4, based on the presence of expanded CD8 T-cells. These cells contribute to motor neuron degeneration in ALS4, validated by further research showing that replacement of bone marrow in ALS4 mice with normal control mice bone marrow was an effective treatment.

“The therapeutic benefit conferred by bone marrow transplantation in ALS4 mice can now be considered as a treatment for human patients. Furthermore, although ALS4 is a rare familial inherited form of ALS, it shares the same cardinal histopathological findings observed in sporadic ALS and most other familial forms.

“Hence, if future research implicates an aberrant CD8 T-cell response in sporadic ALS, then bone marrow transplantation could be a novel treatment approach for many ALS patients in the future,” LaSpada said.

Considering the potential therapeutic opportunities suggested by this work, LaSpada recommends the next steps should be to re-evaluate cell-mediated immunity in sporadic ALS patients to determine if altered T-cell function is a feature of their disease process.

Funding: This work was supported by the National Institutes of Health; Burroughs Wellcome Fund; and the Chan Zuckerberg Initiative Neurodegeneration Challenge Network.


The present study revealed that the concurrent IT and IV injection of BM-MSCs in patients with ALS is a safe procedure with no major adverse events and provides indications of potential clinical benefits. During the follow-up period, the mild headache was the most frequent treatment-related adverse effect.

Furthermore, ALSFRS-R and FVC values were stable after cell therapy during the 3-month follow-up. However, the ALSFRS-R scores and the FVC values significantly decreased 6 months after the cell therapy. Our data indicate a temporary reduction of ALS progression after a single application of BM-MSCs via concurrent IT and IV injections.

Both experimental and clinical investigations have shown temporary beneficial effects of stem cell-based treatments in neurodegenerative diseases. Administration of motor neurons derived from embryonic stem cells in the spinal cord of an ALS animal model exhibited temporary improvement of motor function before mutant rats succumbed to paralysis [22]. Transplantation of adult olfactory bulb neural precursor cells into the spinal cord of an ALS transgenic mouse model led to the temporary reduction of neuron degeneration and improvement of motor function [23].

Combined BM-MSCs with T-cell vaccination treatment of 7 patients with ALS resulted in temporary improvement of ALSFRS-R scores [24]. Both intramuscularly and intrathecally injection of BM-MSCs expressed neurotrophic factors in 14 patients with ALS temporarily reduced the progression of disease during 6 months of intervention [18]. It has been suggested that the microenvironment of the spinal cord of ALS is detrimental for transplanted stem cells, suggesting that transplanted cells can be targeted by the same hostile condition that leads to degeneration of endogenous cells [22,25].

Repeated injections of BM-MSCs have been suggested as a possible clinical effort to prolong the beneficial effect of stem cell therapy in patients with ALS, presumably via stem cell regulatory action on switching from pro- to anti-inflammatory conditions [26]. The beneficial action of BM-MSCs on damaged spinal cord neurons probably mediated through the secretion of neurotrophic factors, axonal regeneration, and myelin sheath repair [27]. However, it has been demonstrated that stem cell therapy through the secretion of anti-inflammatory cytokines and neurotrophic growth factors can modulate the immune system and influence the progression of ALS [28,29].

Several factors, such as the protocols of stem cell expansion, type and source of stem cells, number of stem cells, route of application, and the appropriate application method, exert a decisive impact on the success of any stem-cell-based therapeutic strategies for ALS [9,11]. The current trial has been demonstrated the safety and temporary efficacy of a high single dose of BM-MSCs through IV and IT injections.

In keeping with our results, a previous study has shown that IV or IT transplantation of BM-derived stromal cells is a safe and feasible therapeutic approach [30]. Furthermore, several investigations have demonstrated that the application of MSCs can slow down the progression of ALS [[12], [13], [14], [15],31,32]. Besides, our results are consonant with the previous experimental studies on motor neuron diseases indicate the efficacy of BM-MSCs in targeting the pathological mechanisms and slowing the progression of the clinical symptoms [33,34].

So far, several clinical trials have been performed to explore the safety and efficacy of stem cells transplantation in patients with ALS. None of these studies have reported serious side effects, including tumorigenesis. Several clinical trials revealed that the application of MSCs in patients with ALS did not lead to any functional modification of the neural tissues, including chromosomal changes or cellular senescence [31,35].

Magnetic Resonance Imaging (MRI) evaluations did not show any structural alterations, including tumor formation, in the brain and spinal cord of ALS patients treated with IT application of MSCs during a 1–12 years follow-up period [12,14,31,35]. Although in the present study, we did not evaluate the MRI of patients during or after cell transplantation, no clinical evidence indicated severe side effects (Table 2).

The outcome of stem cell treatment in ALS patients can be modified by high expectations and psychosocial circumstances [15]. These factors could affect ALSFRS scores during the follow-up period [15]. In addition to ALSFRS scores, we assessed the FVC value as a valid variable in ALS patients. The FVC value obtained before any interventions represents a clinically worthwhile predictor of both survival and disease progression in patients with ALS [36]. In our study, the FVC values remained stable for 3 months and declined after 6 months of treatment, which supports evidence from previous observations [14,15].

It has been shown that the administration of MSCs can convert inflammatory microglia (M1) to anti-inflammatory (M2) cells, which are considered as one of their effective mechanisms in preventing ALS progression [37]. Previous clinical investigations have shown that the direct application of MSCs into the cervical and lumbar spinal cord of patients with ALS was not clinically beneficial [38]. Despite the safety and avoiding surgical interventions, IV application of MSCs, as a non-invasive and reproducible approach, requires large quantities of cells to reach the lesion site [39]. A part of these cells, however, are trapped in other organs, such as the lungs and lymph nodes, with a therapeutically questionable amount of MSCs reaching the lesion site [40].

IT injection of MSCs could be an effective strategy to deliver the cells to the target tissue and generate effective responses [12,14]. IT application of MSCs may increase their immunomodulatory and trophic effects directly on the CNS without producing systemic adverse effects [41]. In the present study, we investigated the effects of concurrent IV and IT injections of MSCs. Using simultaneous IT and IV application of MSCs may increase the chances of transplanted cells reaching the lesion site and improve the outcomes. Several experimental and clinical investigations have emphasized the superior efficacy of simultaneous IV and IT injections in ALS [42,43].

This study has some limitations. It is a phase I clinical trial with small sample size; therefore, randomized control trials with a larger number of patients and appropriate control groups are needed to confirm our findings. In addition, based on demographic data, the mean age of patients was generally low when contrasted to the other clinical studies. One of the probable clarifications is that more young patients participate in new clinical trials. Furthermore, a short pre-operation observation period (1 month) as well as a short follow-up period (6 months) cannot fully justify the long-term beneficial effects of our approach in preventing disease progression. Longer pre and post follow-up periods are required.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377537/


Original Research: Closed access.
Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4” by Albert LaSpada et al. Nature

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