Could Neuronal-Derived Exosomes Be Biomarkers of Treatment Target Engagement?

Author(s):

This is the first biomarker evidence that peripherally administered exenatide may both engage and normalize brain insulin signaling in association with the activation of Akt and mTOR cascades in Parkinson disease.

Dimitrios Kapogiannis, MD

A new secondary analysis from a trial in Parkinson disease has revealed the potential widespread ability to use neuronal-derived exosomes as biomarkers to assess treatment target engagement in clinical trials of central nervous system diseases.¹

This analysis is, to the investigators’ knowledge, the first biomarker evidence that peripherally administered exenatide may both engage and normalize brain insulin signaling in association with the activation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR) cascades in Parkinson disease.

By examining serum samples of 60 patients with Parkinson disease from the Exenatide-PD trial,² investigators found that after 48 and 60 weeks of subcutaneous administration, those given the glucagon-like peptide-1 (GLP-1) receptor agonist (n = 30) had high activation of the brain insulin signaling proteins and downstream effectors. Compared to baseline and patients given placebo (n = 29), these levels of activation were significantly raised.

“The previous analysis was focused on clinical outcomes and not the mechanism of action,” senior author Dimitrios Kapogiannis, MD, from the Laboratory of Neurosciences at the National Institute on Aging, told NeurologyLive. “The secondary analysis used plasma exosomes as a window into the brain to look for the mechanism of action at the molecular level in neurons. We found a consistent change in several intracellular signaling molecules in exosomes in response to the drug; these belong to the insulin cascade, therefore, we concluded that the drug engaged the insulin cascade in neurons.”

He added that the “best aspect” of the work was that the investigators selected their target markers and developed their hypothesis based on the known mechanism of action of exenatide, noting that “in that regard, results were not unexpected.”

At 48 weeks, Kapogiannis and colleagues found that those treated with the GLP-1 agonist had augmented tyrosine phosphorylation of insulin receptor substrate 1 (0.27 absorbance units [AU]; 95% CI, 0.09 to 0.44 AU; P = .003) compared to the placebo group. At 60 weeks, the treatment arm remained significantly different, at 0.23 AU (95% CI, 0.05 to 0.41; P = .01).

As well, the exenatide-treated patients had elevated expression of downstream substrates, including total Akt at 0.35 U/mL (95% CI, 0.16 to 0.53; P <.001) and the phosphorylated mToR at 0.22 AU (95% CI, 0.04 to 0.40; P = .02) compared to the placebo group.

“One can use exosome biomarkers as an outcome in a clinical trial—and way down the road in clinical practice—to assess whether a drug engages its target in a cell at the molecular level,” Kapogiannis explained. “This may revolutionize how clinical trials are conducted—give an answer faster, eliminate drugs that don’t engage a target cascade, et cetera. Down the road, it could help with precision medicine by showing whether a prescribed drug engages its target in an individual.”

Additionally, the improvements in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 off-medication scores were associated with levels of total mTOR (F_4,50 = 5.343; P = .001) and phosphorylated mTOR (F_4,50 = 4.384; P = .04).

Kapogiannis and the other investigators did acknowledge that despite the data’s support of the idea that exenatide-associated effects on the insulin and Akt signaling pathway in neurons are associated with a clinical benefit, it is still not definite that these changes are ultimately linked to the alteration of the disease’s pathologic mechanisms.

“For Parkinson, [this] reaffirms the findings of the primary clinical analysis of the Exenatide-PD trial,” Kapogiannis said. That trial showed a 1-point improvement in MDS-UPDRS score at 60 weeks for those on exenatide, working out to a 3.5-point difference between the treatment and placebo arms (P = .0318).

“Nevertheless, [these findings] cannot change current treatment recommendations, as there is still need for larger clinical trials,” Kapogiannis added.

REFERENCES

1. Athauda D, Gulyani S, Karnati H, et al. Utility of neuronal-derived exosomes to examine molecular mechanisms that affect molecular mechanisms that affect motor function in patients with Parkinson disease: a secondary analysis of the Exenatide-PD trial. JAMA Neurol. Published online January 14, 2019. jamanetwork.com/journals/jamaneurology/fullarticle/2719822. Accessed January 17, 2019.

2. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664-1675. doi: 10.1016/S0140-6736(17)31585-4.