Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive lack of motor function, ultimately resulting in death inside 5 years of onset. This disease causes weakness and atrophy of limbs and other muscles, which affects patients’ ability to talk, eat and even breathe. Some drugs, including riluzole, edaravone, and sodium phenylbutyrate/taurursodiol, are used to treat ALS, but with limited therapeutic advantages. Subsequently, modern, effective methods of treating ALS are the necessity of the hour.

Multilineage-differentiating stress-resistant (Muse) cells are bone marrow-derived pluripotent stem cells that will be administered intravenously into damaged tissue. Recent studies have shown that regular administration of Muse cells leads to tissue repair and functional recovery in mouse models of hepatitis, muscle degeneration and heart attack. As well as, it results in a big improvement in limb muscle weakness, inhibits the activation of inflammation and regulates immune functions. With this in mind, a Muse cell-based product called CL2020 was developed to harness the therapeutic potential of Muse cells for the treatment of ALS patients.

Recently, researchers in Japan conducted a single-center, open-label, phase II clinical trial to guage the protection and treatment efficacy of repeated intravenous injections of CL2020 in patients with ALS. The outcomes of this study were published online in Cell transplant on November 28, 2023. The study was led by Associate Professor Toru Yamashita of the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences at Okama University and Dr. Koji Abe of the National Center for Neurology and Psychiatry in Japan. “Because ALS is a progressive disease, we used multiple regular doses of CL2020, with one monthly dose administered intravenously in six doses. The dose was set at 15×106 cells/dose, which has been proven in studies in other diseases. We recruited only five ALS patients because that is the primary clinical trial to verify the protection of multiple doses of CL2020.” explains Dr. Yamashita.

The research team’s primary goal was to find out the protection and tolerability of CL2020 for as much as 12 months after initial administration. Moreover, the team assessed disease progression by assessing the speed of change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores over 12 months. The ALSFRS-R uses various criteria, including speaking, eating, swallowing, motor function and respiratory distress, amongst others, to reflect the progression of ALS in patients. The team also analyzed serum levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and sphingosine-1-phosphate (S1P), in addition to cerebrospinal fluid chitotriosidase-1 (CHIT-1). and neurofilament light chain (NfL) at baseline and commonly for 12 months after the primary dose. TNF-α, IL-6, and S1P are biomarkers related to the inflammatory response and pathogenesis of ALS. Nonetheless, CHIT-1 and NfL are related to ALS progression and patient survival, which can indicate prognosis and treatment effectiveness.

The study showed that CL2020 is extremely tolerated by all patients and doesn’t cause serious unwanted side effects corresponding to pulmonary embolism and anaphylactic shock. Nonetheless, one patient experienced a bone fracture 1 yr after the initial dose, but this had no significant causal relationship to CL2020 treatment. Furthermore, the speed of change in ALSFRS-R scores improved 12 months after treatment compared with 3 months before treatment, and scores didn’t worsen until 6 months after treatment in three patients. Which means that multiple doses of CL2020 can prevent or delay the worsening of ALS symptoms.

Nonetheless, serum levels of IL-6, TNF-α, CHIT-1, and NfL increased inside 6 months after treatment, suggesting that CL2020 may not inhibit the secretion of inflammatory cytokines in ALS patients; which tends to extend because the disease progresses. In contrast, serum S1P levels steadily decreased over 12 months, indicating that CL2020 may functionally neutralize S1P and thereby reduce associated signaling in ALS patients.

These findings show that multiple doses of CL2020 are secure to be used in ALS patients. Nonetheless, while this treatment has the potential to alleviate the severity of some ALS symptoms, it will not be enough by itself to completely stop the progression of the disease. Subsequently, future treatments should consider combination therapy of CL2020 with other drugs currently used to treat ALS. “Given the promising results of this study, we now must conduct a double-blind study that features a larger variety of ALS patients with an extended follow-up period to verify the effectiveness of CL2020. We will then offer this treatment to ALS patients,” concludes Dr. Yamashita.