Combination Therapies: A New Frontier in Treating Neurodegenerative Diseases
Dec. 23, 2025Physician-researchers Dr. Stanley Appel and Aaron D. Thome, PhD, have made significant progress unraveling the mechanics of amyotrophic lateral sclerosis (ALS) and Parkinson’s and Alzheimer’s diseases.
This understanding of disease mechanisms has led to clinical trial testing of potential therapeutics. As the results of these trials provide further insight into disease treatment, Drs. Appel and Thome continue to refine their therapeutic approach, paving new paths for more effective clinical interventions.
Restoring Tregs to reduce inflammation and slow disease
In previous research, the duo discovered that regulatory T immune cells, or Tregs, play a vital role in neurodegenerative disease progression. Tregs prevent disease by resolving inflammation — the body’s natural response to immune system threats. However, in certain neurodegenerative diseases, such as ALS and Parkinson’s and Alzheimer’s diseases, Tregs are dysfunctional, preventing them from reducing inflammation in the central nervous system and potentially prolonging brain inflammation, leading to neuronal damage.
Drs. Appel and Thome’s research suggests that Tregs can be restored ex vivo and potentially back-injected into patients to suppress inflammation and halt disease progression. This cell-based therapy was proven to be safe and tolerable in clinical trials for ALS, conducted jointly at Houston Methodist and Massachusetts General Hospital Neurological Clinical Research Institute.
Targeting myeloid cells to strengthen Treg-based therapies
Armed with this insight, Drs. Thome and Appel continue to identify treatment challenges and avenues for improved efficacy. One such challenge are myeloid cells, a type of blood cell important in immune function that can directly suppress or dysregulate Treg function, creating a self-reinforcing loop of inflammation and neuronal loss.
“While some of our strategies to boost Treg function have shown promise, their efficacy may be limited when pro-inflammatory myeloid cells remain unaddressed,” Dr. Thome says. “This has led us to exploring combination therapies.”
One combination therapy currently being tested with in vitro and in vivo models involves suppressing those pesky myeloid cells, which can help lessen Treg dysfunction. Immunotherapy treatment can then increase Treg numbers.
Paving the way for combination clinical trials
The strategy is to expedite this neuroprotective treatment approach into clinical trials.
“These dual-modality approaches may help overcome the limitations of single-target strategies and unlock more effective, disease-modifying therapies,” Thome noted. “Ultimately, we believe that immune dysfunction is a tractable and central driver of neurodegeneration. By addressing it through thoughtfully designed combination therapies, we aim to translate these mechanistic insights into patient-ready treatments that can slow or halt disease progression.”