Protein-targeting Therapy Found to Lessen Inflammation in Preclinical Study
A novel medication targeting the protein folate receptor-beta (FR-beta) decreased inflammation and brain damage in a rat model of multiple sclerosis (MS).
The findings were published in the Journal of Neuroinflammation, in the study “Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis.”
MS is caused by the immune system attacking the nervous system, and one type of immune cell involved in this attack is the macrophage. In animal models of MS, inflammation-driving macrophages express the protein FR-beta, suggesting that this protein may be a viable therapeutic target.
In the new study, researchers from the University of Turku, Purdue University, and Endocyte (now part of Novartis Institutes for BioMedical Research) tested an investigational FR-beta-targeting medication called EC2319 in a rat model of MS.
The team used a focal delayed-type hypersensitivity model of experimental autoimmune encephalomyelitis (fDTH-EAE). This is a rat model of MS characterized by an initial phase of acute inflammation followed by chronic inflammation, resembling what occurs in people with MS.
“We investigated the efficacy of subcutaneously [under-the-skin injection] administered EC2319 on lesion development during acute and chronic EAE in rats,” the researchers wrote.
In rats in the chronic phase, treatment with EC2319 significantly reduced the size of brain lesions, as well as the levels of FR-beta. Markers of inflammation and macrophage activation also generally were reduced, though not all of these metrics reached statistical significance.
In turn, in the acute phase of the disease, EC2319 treatment generally did not have a significant effect.
Regarding safety, no adverse events were reported in rats across the experiments.
“EC2319 effectively attenuated the inflammation and lesion burden in rats with chronic EAE, but not during the acute phase of inflammation,” the researchers wrote, adding that the treatment “appears to be safe for use during acute and chronic fDTH-EAE.”
FR-beta usually binds to the B vitamin folate. Folate-based imaging tracers have been used to image some kinds of tumors via PET (positron emission tomography), and are also being tested in autoimmune diseases.
The researchers demonstrated that similar PET tracers could be used to assess FR-beta — and, by extension, MS lesions driven by activated macrophages — in these rat models.
“The research in my lab suggests that [folate-based tracers] could also apply to visualize inflammatory demyelinating central nervous system lesions” (i.e., MS lesions), Anne Roivainen, PhD, the study’s senior author and professor at the University of Turku, said in a press release. “It would be ideal to discover a suitable PET tracer with sensitive detection that enables real-time lesion detection in patients and monitoring of therapeutic responses.”
To demonstrate the relevance of the study’s findings in human disease, the team analyzed brain tissue from MS patients. They demonstrated that FR-beta expression was increased near the border of active inflammatory lesions in patients, typically in areas were macrophages are known to be present.
“For the first time, we show that the MS patients have FR-[beta]-positive cells in chronic active plaques, which indicates the translational relevance of these findings,” the researchers wrote.
The team noted, however, that more research is required before the findings can be translated into human treatment.
“The results are fascinating, but after all we have to remember the challenges and unpredictability of drug development,” said Yingjuan June Lu, PhD, of Novartis Institutes for BioMedical Research and study co-author. “Only a small portion of promising new treatments in animal experiments will translate into clinic practice.”