Coated Vesicles Found to Safely Reduce Disease Progression in Mice

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by Steve Bryson, PhD |

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Extracellular vesicles or EVs — tiny sacs of material excreted by cells — that have been coated with protein receptors were found to safely reduce disease progression in a mouse model of multiple sclerosis (MS).

Researchers at the Karolinska Institutet, in Sweden, coated these vesicles with receptors that block pro-inflammatory molecules involved in MS.

The potential therapy also may be an effective treatment for other inflammatory-related diseases, the scientists noted.

The study, “Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles,” was published in the journal Nature Biomedical Engineering.

Extracellular vesicles, known as EVs, are tiny membrane-coated sacs, released by cells, that normally deliver proteins, fats, and genetic material to selected tissues. EVs also can be used as natural carriers of medicines, which makes them potential therapies for treating disease.

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TNF-alpha and interleukin 6 (IL-6) are pro-inflammatory immune signaling proteins that play a role in damaging the myelin sheath — the protective coating on nerve fibers — in MS. Therapies that block TNF-alpha and IL-6 can suppress inflammatory responses in MS as well as in other inflammatory conditions such as inflammatory bowel disease (IBD).

Now, scientists at the Karolinska Institutet have designed special vesicles — dubbed decoy EVs — that are coated with protein receptors that bind TNF-alpha and IL-6 and prevent them from activating immune responses in cells. In this study, the decoy EVs were evaluated as a potential anti-inflammatory therapy in an MS mouse model.

“We used different methods to optimize the expression [production] of receptors and tested the different variants of EVs in inflammatory cell models to identify which strategy gave the greatest anti-inflammatory effect,” Dhanu Gupta, a doctoral student at Karolinska Institutet and co-first author, said in a press release.

EV-producing cells were modified with DNA carrying instructions for the TNF-alpha and IL-6 protein receptors. The team added and screened various other elements to maximize their inhibitory potential.

Vesicles coated with either receptor showed inhibitory activity in a dose-dependent manner. The addition of the protein syntenin, which is implicated in the sorting of protein cargo into EVs, significantly showed the best inhibitory activity.

After establishing the elements with the best potency, the researchers determined that modified cells producing coated EVs retained normal biological processes, and that the engineered vesicles also were safe in mice.

EVs coated with TNF-alpha receptors were then evaluated against the approved anti-inflammatory therapy etanercept (sold under the brand name Enbrel), a biologic therapy designed to block TNF-alpha. In lab-grown cells, EVs were found to be 10 times more potent than etanercept.

Further testing using a mouse model with systemic inflammation showed that both anti-TNF-alpha and anti-IL-6 EVs resulted in significantly improved survival  — 100% at 60 hours after treatment — compared with mock-treated mice, which had 0% survival. Anti-TNF-alpha EVs also were more potent than etanercept at preventing mortality.

“These results collectively underpin the therapeutic potential of decoy EVs and led us to continue assessing the therapeutic anti-inflammatory potential of decoy EVs in an autoimmune MS disease model,” the team wrote.

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To examine the effects of decoy EVs on nerve-related inflammation, the experimental autoimmune encephalomyelitis (EAE) mouse model was used, which mimics MS in humans.

Injection with anti-TNF-alpha EVs significantly reduced disease progression over time, and lowered disease severity compared with mock treatment or control EVs — those lacking TNF-alpha or IL-6 receptors.

Mock-treated EAE mice showed gradual weight loss after symptom onset, indicating disease progression. Compared with mock-treated mice, those receiving decoy EVs — either anti-TNF-alpha and anti-IL-6 EVs — had sustained body weight over time, with increased weight by the end of the experiment. Decoy EVs also reduced the levels of TNF-alpha and IL-6 in the spinal cord.

Finally, the team engineered EVs that expressed both TNF-alpha and IL-6 receptors and evaluated them in a mouse model of IBD. A single dose of double-decoy EVs, given one day after symptom onset, showed a significant reduction in weight loss and improved survival compared with untreated mice. Double-decoy EVs also outperformed combined equivalent doses of etanercept and tocilizumab, a therapy that blocks IL-6.

“Collectively, this again confirmed the therapeutic potential of decoy EVs in inflammatory settings and further demonstrated the versatility of the engineering approach with the possibility of displaying multiple therapeutic receptors with improved efficacy,” the researchers wrote.

“By combining protein therapeutics and a natural delivery vehicle that can overcome tissue barriers, engineered EVs have great potential to be the next generation of biotherapeutics,” they concluded.

In the MS model, the therapy also led to a significant reduction in the neurological symptoms seen in MS flare-ups, the researchers said.

“Our findings are an important step in the right direction and demonstrate that EVs can be a promising treatment for inflammation, but the technique also has great potential for many other diseases,” said Samir EL Andaloussi, PhD, principal investigator at the Karolinska Institutet, and study co-lead.

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