Monocytes May Reflect Parkinson’s Response to Immune Therapy
Changes in gene activity and protein production were seen in immune cells known as monocytes from Parkinson’s disease patients before and after treatment with sargramostim, an immune-modulating therapy, a small study found.
Because these changes were associated with gains in motor function, the researchers suggested that profiling how an immune therapy affects monocytes could be an early and unique biomarker for tracking treatment efficacy. But larger studies are needed to validate their potential.
The study, “Monocyte biomarkers define sargramostim treatment outcomes for Parkinson’s disease,” was published in the journal Clinical and Translational Medicine.
Unusual inflammation in the brain is thought to be among the processes driving Parkinson’s disease, which is marked by the loss of nerve cells that produce dopamine. This signaling molecule controls movement, among other functions.
Sargramostim is a lab-made version of granulocyte-macrophage colony-stimulating factor (GM-CSF) — a protein that helps coordinate the activity of various immune cells. In particular, GM-CSF stimulates the activity of regulatory T-cells, or Tregs, that can suppress inflammation.
In the U.S., sargramostim, marketed by Partner Therapeutics under the brand name Leukine, is approved to lower inflammation in certain conditions, including some infections and problems related to organ transplants.
Helpful changes with sargramostim’s use in small trial
Researchers at the University of Nebraska Medical Center conducted an open-label Phase 1 clinical trial (NCT03790670) to evaluate sargramostim in five men with Parkinson’s (average age of 64, all on standard levodopa-carbidopa treatment). Results showed that treatment over one year — given at a dose of 3 micrograms/kg daily with five days on-treatment and two days off — was well-tolerated and eased Parkinson’s motor symptoms.
This same research team now investigated the impact of sargramostim on monocytes — a type of immune cell that normally fights infections but whose activation and function are impaired in Parkinson’s — in these patients.
By examining changes in monocyte gene activity and protein production, the scientists aimed to identify biomarkers associated with treatment response to the immune-modulating therapy. Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
As Parkinson’s “is difficult to diagnose or treat … an urgent need exists to develop biomarkers that reflect both the underlying pathophysiology and responses to therapy,” the researchers wrote.
Compared to pre-treatment (baseline measures), differences were seen in the production of 25 proteins in monocytes after two months of sargramostim’s use and 262 proteins after six months of treatment.
Some of these proteins, including TPSB2, HMOX1, LRRK2, TLR8, and SOD2, were associated with the induction of antioxidant, anti-inflammatory, and cell recycling (autophagy) activities, the researchers noted. Functional and pathway enrichment analyses of these proteins supported these findings.
A more detailed analysis found a 3.1 times decrease in HMOX1, a 1.66 times decrease in TLR8, and a 2.6 times reduction in TLR8 after six months of treatment, all supporting an “anti-inflammatory neuroprotective signature for sargramostim therapy,” the researchers wrote.
Decreases in RELA and IKBKG at two months of treatment also reinforced the anti-inflammatory mechanism.
Defects in autophagy, a natural process to remove unnecessary or dysfunctional cellular components, underlies the nerve damage associated with Parkinson’s. There was a significant decrease in the related protein LRRK2 after two months of treatment and a significant increase in ATG3, ATG7, and GABARAPL2 after six months, indicating “increased autophagy-inducing functions by sargramostim providing a protective outcome,” the researchers added.
Potential protein and gene biomarkers
Based on these observations, the team selected LRRK2, HMOX1, TLR2, TLR8, RELA, ATG7, and GABARAPL2 as reliable protein biomarkers for detecting patient responses to sargramostim as a treatment.
Gene activity and protein production analysis of individual study participants supported the findings of sargramostim’s antioxidant, anti-inflammatory, and autophagy effects in monocytes from Parkinson’s patients.
Researchers then compared the activity of genes encoding the selected protein biomarkers with scores from Unified Parkinson’s Disease Rating Scale (UPDRS) part III, a standard assessment for motor function in Parkinson’s. Compared to baseline measures, a change in the gene activity of these biomarkers, including LRRK2, HMOX1, TLR2, and ATG7, was associated with improved motor function.
The combined effect of TLR2 and TLR8 gene activity was significant, with TLR2 showing a greater impact, as was the combined effect of TLR2 and ATG7, with ATG7 linked to a greater impact on motor scores. The three parameters producing the strongest correlation from baseline scores, HMOX1, TLR8, and ATG7, accounted for 40% of the score change, with the most substantial effect provided by a change in ATG7 activity.
Overall, the activity of all seven genes accounted for 67% of the beneficial change in total UPDRS motor scores, with ATG7 yielding the most significant changes among them. Similar results were seen when comparing the levels of proteins encoded by these genes.
“To our knowledge, this study is the first to address the association between monocyte profiles and both clinical motor function and disease progression during immune modulatory therapy,” the scientists wrote. “We demonstrated that the monocyte signature profile would present relevant biomarkers to monitor the clinical improvement and disease progression during anti-parkinsonism immune modulatory therapy trials.”
Because of the study limitations, such as the small number of participants and the lack of placebo controls, “further validation in a larger double blinded placebo-controlled phase II trial that includes both sexes” is needed, they added.