Reprogramming Immunity to Deal with ALS

Amyotrophic lateral sclerosis (ALS) is marked by relentless motor neuron loss, but the disease also comes with a deeper immune imbalance. At the heart of this dysregulation is a breakdown in regulatory T cell (Treg) function, which drives inflammation and accelerates disease progression. Coya Therapeutics is addressing this dysregulation with COYA 302, a biologic designed to restore immune equilibrium.

In this Innovation Spotlight, Fred Grossman, the president and chief medical officer of Coya Therapeutics, discusses the company’s efforts to not only slow ALS but also alter its trajectory. COYA 302’s early clinical results are promising, pointing toward a new paradigm in ALS treatment.

What are the hallmarks of ALS, particularly as the disease progresses?

ALS is a devastating, progressive disease marked by the degeneration of motor neurons in the brain and spinal cord, leading to paralysis and often death from respiratory failure within five years. Symptoms include stiffness, weakness, twitching, and difficulties with speech, swallowing, and breathing, ultimately resulting in loss of independence.

At its core, ALS involves a complex network of biological failures, most prominently inflammation. Overactivated microglia and astrocytes release toxic mediators, while immune cells infiltrate the nervous system, worsening neuronal damage.¹ Protein aggregation, mitochondrial dysfunction, and genetic mutations in genes such as C9orf72 and SOD1 further disrupt cellular balance.

At Coya, we focus on Treg dysfunction as a key driver of ALS. Tregs normally maintain immune balance, but in ALS, they are reduced in number and anti-inflammatory function, fueling disease progression. Restoring Treg activity may offer a powerful, multi-target approach to rebalance immunity and protect neurons.

What is known about Treg dysfunction in this disease, and why might restoring or enhancing Treg function be therapeutic?

Tregs act as the immune system’s brakes, suppressing inflammation and maintaining balance. In ALS, those brakes fail, and Tregs decline in number and function. This dysfunction correlates with faster disease progression, greater disability, and shorter survival.^2,3 When Tregs falter, activated macrophages and microglia unleash inflammatory cytokines and oxidative molecules, creating a vicious cycle of neuronal injury and degeneration.⁴

Targeting Treg dysfunction offers a pathway to rebalance immunity and slow ALS progression. Restoring Treg number and function can calm this inflammatory storm, reduce oxidative stress, protect mitochondria, and improve the clearance of proteins including misfolded TDP-43.³ Pioneering work in this area has been executed by Shimon Sakaguchi, a 2025 recipient of the Nobel Prize in Physiology or Medicine for the discovery of Tregs, and Stanley Appel and his team at Houston Methodist, who demonstrated that enhancing Tregs can alter disease trajectory.² Sakaguchi and Appel have been and continue to be key leaders on Coya’s Scientific Advisory Board.

What are the main features of COYA 302, and what are the molecular mechanisms by which each component of the therapy acts?

COYA 302 is a novel biologic combination of low-dose recombinant human IL-2 and CTLA4-Ig (abatacept), designed to reprogram the dysfunctional immune environment in ALS. Low-dose IL-2 expands and enhances Tregs, which are reduced and impaired in ALS. This restoring of Treg numbers and function helps rebuild immune balance.⁵ CTLA4-Ig complements this by selectively tempering effector T cell activation and reducing inflammatory signals from monocytes and macrophages, creating a stable environment for Tregs to thrive. Together, IL-2 strengthens the regulatory arm of the immune system while CTLA4-Ig reduces inflammatory pressure, producing a synergistic rebalancing of the immune system. By dampening inflammatory cytokines, oxidative stress, and lipid peroxides that damage motor neurons, COYA 302 may protect neurons and their axons, slowing neuromuscular degeneration. Through this immune reprogramming, COYA 302 may also reduce neuroinflammation within the CNS, offering a promising disease-modifying approach for ALS.

You have performed several Phase 1 trials with variations of this treatment. What have you learned so far?

Several Phase 1 and investigator-initiated studies have shown that low-dose IL-2 can expand Tregs and enhance their suppressive function. Early clinical experience confirmed that Tregs can be boosted in ALS patients.⁵ However, in a highly pro-inflammatory environment, increasing Tregs alone may be insufficient, as inflammatory signals from activated macrophages and myeloid cells can overwhelm them. This insight shaped the rationale for COYA 302.

Phase 1 findings in ALS patients showed that COYA 302 increased Treg number and function, with no disease progression at six months and minimal progression at 12 months.⁶ These findings suggest that the combination may not only slow disease progression but potentially stabilize it over meaningful periods, supporting its development as a potential disease-modifying therapy.

With the FDA having accepted the IND application for COYA 302, what are the key design features of the upcoming Phase 2 ALS trial, and what do you hope to learn?

The FDA’s acceptance of the IND for COYA 302 marks a key milestone, enabling the launch of ALSTARS, the first randomized, double-blind, placebo-controlled Phase 2 study of this combination in ALS. The trial will enroll around 120 patients, between 18 and 75 years of age, across approximately 25 leading ALS centers in North America. Participants will receive COYA 302 or a placebo via subcutaneous injection over a 24-week blinded period, followed by a 24-week blinded active extension, allowing all participants access to COYA 302 while continuing data collection.

ALSTARS aims to evaluate both safety and efficacy and test whether the dual approach, boosting regulatory T cells with low-dose IL-2 while dampening pro-inflammatory activation with abatacept, can slow functional decline. The traditional ALS endpoints ALSFRS-R, respiratory function, and survival will be measured alongside biomarkers to assess immune rebalancing and correlate these changes with clinical benefit. The study seeks to replicate prior stabilization results and advance ALS treatment toward meaningful disease modification.

Could this treatment strategy work for other neuroinflammatory diseases?

We believe this strategy could extend beyond ALS, as Treg dysfunction is increasingly recognized in other neurodegenerative diseases, including Alzheimer’s, frontotemporal dementia, and Parkinson’s disease. Animal and human studies show that restoring Treg balance in peripheral blood can influence the central nervous system, as the immune system and brain are in constant dialogue, reducing systemic inflammation and creating a less toxic CNS environment.

In Alzheimer’s disease models and early patient studies, correcting Treg dysfunction showed signs of stabilizing the disease. Similar mechanisms appear in frontotemporal dementia and Parkinson’s disease, where overactive innate immune cells and oxidative stress drive neurodegeneration.

By expanding Tregs with low-dose IL-2 while calming inflammation with CTLA4-Ig, a durable, pro-regulatory state can be achieved. This approach may suppress neuronal injury, protect mitochondria, and preserve neurons. In short, this is a broad framework targeting Treg dysfunction and immune overactivation across multiple neurodegenerative conditions, not just ALS.

Is there anything else that you would like our readers to know?

Our Phase 2 COYA 302 trial has been selected by the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS), the largest and most influential ALS research consortium worldwide. NEALS unites leading academic centers, clinicians, and scientists to accelerate the development of new ALS therapies.

Being part of NEALS is more than an endorsement—it integrates our trial into a network with decades of experience in running ALS studies, standardizing endpoints, and maintaining the highest scientific and ethical rigor. It also enables collaboration with top ALS investigators across North America, speeding enrollment, improving trial execution, and increasing patient access to innovative therapies such as COYA 302.

This milestone signals recognition of our dual immunomodulatory approach’s potential. For patients, it means participation in a trusted, world-class effort to develop treatments that could alter the course of this devastating disease. COYA 302 is not being developed in isolation. It’s part of a collective fight against ALS, together offering hope to patients and their families.