International Alliance of ALS/MND Associations

Regulatory T Cell Enhancing Therapies

Background

Neuroinflammation was discovered many years ago to be a key contributor to the degeneration of motor neurons in ALS/MND. Cells called microglia that surround motor neurons and provide immune protection to a healthy central nervous system, lose some of their normal function while becoming abnormally activated, secreting substances that likely increase motor neuron damage. Other cells, called T cells, travel in the bloodstream and are capable of exiting into the area near motor neurons, where they can play a neuroinflammatory role. Through studying the aspects of T cells in ALS more closely it was discovered that certain types of T cells, called regulatory T cells (Tregs), can also be protective and naturally reduce these neuroinflammatory effects. Furthermore, the level of effective Tregs is lower in people with ALS and the amount of Tregs is correlated with rate of disease progression (i.e. more in slower progressors, less in fast). As a result, treatment strategies attempting to increase the body’s production of Tregs or to provide more of them have been advanced to clinical trial in recent years. A number of trials are examining regulatory T cells as a primary means of treating ALS or as a contributor to a treatment strategy.

These include:

  1. Coya Therapeutics – The treatments that Coya Therapeutics are developing are based on the seminal work of Dr Stanley Appel in establishing the potential for targeting Tregs as a treatment for ALS/MND, including founding research over a decade ago that demonstrated their protective effects in mouse models (publication details here).
    • COYA 101
      In this treatment regimen, Tregs are removed from blood (a process called leukapheresis), multiplied in number outside the body (in a lab), and returned intravenously (IV) along with a subcutaneous low dose of a substance called interleukin-2 (IL-2), which helps stabilize the Tregs.An initial clinical trial of Treg treatment in three individuals demonstrated very intriguing results (publication details here) that warranted a phase 2 trial in 7 participants. It is important to note that the first trial was extremely small so interpretation of effect cannot be made at this point. The phase 2 trial looked at a combined treatment of Tregs and IL-2 and was a double-blind, placebo-controlled trial to primarily assess safety and effect on immune and inflammatory ALS effects. There was a six-month open label extension for all participants after six months of study during which they found that Treg/IL-2 was safe and well tolerated and increased the function of Tregs in people with ALS but not the numbers (results published here). ). A larger trial is needed to assess whether Treg/IL-2 treatment can slow disease progression. Such a trial is not currently planned.
    • COYA 302
      A small trial of a combination of IL-2 and CTLA4-Ig (a protein designed to decrease the activity of immune cells that promote inflammation) was conducted in 4 participants. The trial involved treatment with Coya 302 for a total of 48 weeks. It was found to be safe and well tolerated with no serious side effects (results published here). Increased Treg activity and a decrease of other markers of inflammation were found during treatment, but these effects wore off once treatment stopped. The results also suggested a transient and minimal change in ALSFRS-R score, as a measure of disease progression, throughout the study. Due to the small size and open-label nature of the trial, a larger placebo-controlled phase 2 trial was needed to confirm whether this could be beneficial for ALS.A phase 2 trial for COYA 302 has now commenced (trial details here). This is a randomized, double-blind, placebo-controlled phase 2 trial looking to recruit 120 participants across 20-25 sites in the US and Canada. Participants will be randomly assigned to receive one of 2 regimens of COYA 302 or placebo (an inactive substance) for 24-weeks in the double-blind period. Those who complete this part of the study may be eligible to receive one of the two regimens of COYA 302 for an additional 24 weeks in a blinded active extension phase. Recruitment is currently underway.
  2. RAPA-501 Therapy – RAPA-501 Therapy is a process where T cells were removed from blood, treated outside the body (in a lab) with substances to both increase Treg activity and reduce other inflammatory cell activity, followed by IV reintroduction of the cells to the participant with or without a regimen (called PC regimen) designed to assist in the Rapa T cell effectiveness. Rapa Therapeutics conducted an open label phase 1 trial of RAPA-501 T cells which showed the drug to be safe and established an effective dose to use for further trials. A phase 2/3 open label trial of RAPA-501 has now commenced where up to 41 participants will receive treatment with RAPA-501. This is currently underway and assessing the safety of the highest dose and effectiveness on T cell function (trial details here).
  3. Rapamycin (RAP-ALS) – Rapamycin is thought to both increase Treg cell number as well as help autophagic degradation of various aggregate-prone proteins. A randomized, double-blind, placebo-controlled phase 2 trial in 63 participants at eight sites in Italy was run as a non-profit trial financed by ARISLA (Fondazione Italiana di Ricerca per la SLA). The trial studied the effects of oral rapamycin on ALS over 18 weeks of treatment, followed by 36 months of follow up and analysed levels of biomarkers and other key metrics of how the treatment acts in the body. The primary goal of the trial was to measure Treg levels. The trial found that some people on the treatment had an increase in numbers of Tregs compared to those on placebo, but the difference was not statistically significant. It was also found that it may help to decrease inflammation, but further studies are needed to fully assess the effects on Tregs and better understand how rapamycin works in the body (published here). No further studies are currently planned.
  4. MIROCALS Trial – A joint academic effort between UK and French researchers, the Modifying Immune Response and OutComes in ALS (MIROCALS) trial examined low dose IL-2 alone over 18 months to determine if it is sufficient to enhance a person’s own Tregs (results of the trial can be found here). This was a large trial that recruited 220 people across 17 clinics and participants were studied over 18 months for an effect on disease progression and survival. IL-2 was found to be safe and well tolerated. Side effects were minimal across both treatment and placebo. The primary endpoint (measure) for the trial was survival.
    Overall, treatment with IL-2 showed a modest non-statistically significant increase in survival. However, when people on the trial were sub grouped according to levels of a form of neurofilament (cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH)), statistically significant differences were seen. For the 70% of participants who had low neurofilament levels, it was found that they were 18% more likely to be alive at the end of the trial compared to those who were on placebo. Lower CSF-pNFH levels are correlated with slower disease progression, suggesting slow progressors might benefit most from IL-2 treatment. There was also shown to be a 23% decrease in the rate of change in ALSFRS-R score between those with low neurofilament receiving IL-2 and those with low neurofilament on placebo. No differences were seen in the much smaller group with high CSF-pNFH levels.It is not clear what the next steps are for low-dose IL-2 as a standalone treatment for MND/ALS. 
  5. Nebulized RNS60 – Revalesio Corporation tested an inhaled experimental drug that contains oxygenated nanobubbles called RNS60 which demonstrated anti-inflammatory and neuroprotective effects in preclinical ALS models. One of the effects demonstrated in mice was an increase in Tregs. A small investigator-initiated, open label, pilot trial previously established safety and tolerability (results published here). RNS60 was then tested in a phase 2 clinical trial of 147 participants and markers of inflammation were monitored as the primary outcome measures. The trial found no difference in these markers between those on RNS60 and those on placebo, suggesting that it did not have an effect on the immune system or Tregs. However, it was found to have some benefit in some of the secondary outcome measures, slowing decline in respiratory and bulbar functions (e.g. swallowing and talking) (published here). A further analysis of long-term survival of participants has shown median survival was six months longer in the RNS60 group (this was borderline statistically non-significant (0.052)). They also showed that splitting the analysis according to low or high neurofilament light (NfL) levels demonstrated longer survival in those patients with lower NfL levels. Effects on respiratory decline were maintained in the longer-term follow-up (published here). The effects of RNS60 on ALSFRS-R as the primary outcome to better establish the potential benefit of RNS60 as a therapy.
  6. Cellenkos CK08031 modified T-regs – Cellenkos have developed a Treg-based approach that uses an “off-the-shelf” approach deriving therapeutic Tregs from donated human umbilical cord blood (CK0803). Such an approach removes the need to treat the participants’ own cells and does not need to match patient and donor. This reduces the cost, participant burden, and increases the speed and applicability of the treatment. A large Phase 1 A/B trial is currently underway. An initial Phase 1 Safety Run-in Study of 6 participants has been completed. The results of the initial Phase 1 trial in 6 patients have been published showing the treatment was safe. The numbers of participants in this initial trial were too small to derive any conclusions around effectiveness of the treatment.
    The Phase 1b Randomized, Double Blind, Placebo Control Trial of CK0803, neurotropic, allogeneic, umbilical cord blood derived Tregs is currently underway in an additional 60 participants. Recruitment has been completed with results expected in 2026.

Summary

The Scientific Advisory Council (SAC) recommends that caution be taken in interpreting the effectiveness of the different approaches targeting regulatory T cells as a treatment for ALS. While promising preclinical science and clinical trial data exists in small study samples, it is too early to know if any of these strategies are truly effective. Each of these are exciting in their possibilities for treating ALS and the SAC looks forward to learning more from rigorous studies in the time ahead.

International Alliance of ALS/MND Associations
April 2026

Disclaimer: Consult with a healthcare professional to determine if you could potentially participate in a T cell enhancing clinical trial. Always disclose your medical history, including any drugs, natural supplements, or herbal medicines currently being used.

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