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Zika virus injection treatment destroys brain tumor in rodent without causing neurological damage

Publicado em 27 outubro 2021

Search carried out in Center for the Study of the Human Genome and Stem Cells (CEGH-CEL) gives University of São Paulo (USP) showed that the systemic application of three injections with Zika virus in mice with brain tumors is capable of destroying the cancer without causing neurological damage or other organs, increasing the survival of the animals.

The scientists also injected Zika into an organ similar to the human brain created in vitro with stem cells, called cerebral organoid, and detected that the virus prevented the progression of the tumor, even reducing it.

In both models – in animals and in vitro -, after treatment, the cytokines (proteins that regulate the immune response) suppressed the progression of the tumor and there was an increase in the migration of defense cells to the brain affected by the cancer, awakening the immune system to the existence of the tumor.

These results, published in a special issue of Viruses scientific journal, confirmed the efficacy and safety of treatment with Zika in the models, opening perspectives for the use of virotherapy in central nervous system tumors. In Brazil, around 11 thousand new cases of the disease were registered last year, with approximately 5,200 in women, according to the National Cancer Institute (Inca).

“One of the important points, which confirms previous research, was the recruitment of the immune system, giving a good response to therapy. The two ways of action of the virus are very important, as they can allow it to act in a greater number of tumors than we initially thought”, he says Mayana Zatz, teacher of Institute of Biosciences (IB) from USP and coordinator of the CEGH-CEL – a Research, Innovation and Diffusion Center (Cepid) at FAPESP.

Zatz was the advisor of the article, together with the researcher Carolini Kaid, FAPESP scholarship holder, and the teacher Oswaldo Keith Okamoto, of the IB-USP.

Scientists at the center had already demonstrated Zika’s ability to infect and destroy central nervous system tumor cells in a study done with mice, released in 2018, and with dogs, published in 2020.

The group was also the first to discover that Brazilian Zika could be an effective agent to treat aggressive forms of embryonic tumors of the central nervous system, including medulloblastoma. The therapies currently available for these pediatric tumors are of low efficiency and cause serious adverse effects, affecting the quality of life of patients.

Now, researchers have pointed out the safety and effectiveness of the technique. “For any attempt at treatment, it is necessary to know the dosage and route of administration. We showed in this work that three doses of systemic intraperitoneal injections of Zika, with an interval of seven days, showed promising results in the models”, he said. Raiane Ferreira, PhD scholarship from FAPESP and first author of the article.

FAPESP also supported the work through the researcher’s grant Rodolfo Sanches Ferreira.

Between the end of 2015 and 2016, Brazil underwent a Zika epidemic, being, at the time, among the countries with the highest number of cases of the disease. In part, the explanation is linked to the presence of the virus transmission vector, the Aedes aegypti mosquito, which also transmits dengue.

Although Zika infection is usually asymptomatic, research has shown the link between the disease and the development of neurological syndromes in adults, such as that of Guillain-Barré, and congenital malformations in newborns, such as microcephaly.

The country registered a significant number of women infected with Zika who had babies with congenital syndrome, mainly in Northeastern States. Between 2015 and 2020, 3,423 children were born with congenital syndrome associated with the virus, according to data from the Ministry of Health.

Zatz says that he was in the Northeast region, where he collected genetic material right at the beginning of the group’s work. “In the formation of the brain there are neuroprogenitor cells. We collected samples from discordant twins, where one had microcephaly and the other did not. In the lab, we made strains of these neuroprogenitor cells and infected them with Zika to understand how the virus worked. Hence the idea of ??testing on brain tumors, rich in this type of cells.”

Study

The researchers worked with immunodeficient mice, a strain known as “nude”, that is, they have an immune system inhibited by having a reduced number of T lymphocytes. The viral load used was 2,000 Zika particles for each dose (2000 PFU / ZIKVBR).

To assess the safety of the treatment, first the application of the virus directly to the brain of animals with tumors was tested. The effect was positive, but after 21 days the cancer started to grow again.

were also made ventricular intracerebral injections (ICV) in infected animals with the same viral load, but these proved to be very aggressive and virulent. There was significant weight loss and survival of up to four weeks after Zika administration, while the control group remained alive and without clinical changes.

Scientists then performed systemic applications via intraperitoneal, with the three doses and the same time interval, obtaining positive effects – the animals continued eating, did not lose weight and maintained good clinical conditions.

In an experiment designed to analyze Zika’s tropism – whether it would target directly the brain or the tumor – the scientists injected the tumor into the thigh (flank) region of the mice and observed that the virus did not act on them. No tumor remission was observed in either group, suggesting that Zika tropism is indeed central nervous system-directed.

“After we were able to detect safety and that the tropism was for the brain, we started the three intraperitoneal injections of Zika every seven days and followed it up”, explains Ferreira.

When the tumor was located in the mouse brain, systemic serial injections showed efficient tumor destruction, without neurological or other organ damage, and increased the animals’ survival.

In the case of brain organoids, they were developed at an early stage (26 days) and also infected with 2,000 Zika particles seven days after the addition of tumor cells. Tumor cells quickly attached and began to spread into organoids after a week.

The result was that the virus-induced infection in the tumor cells hindered the progression of the disease, indicating an intensive oncolytic effect of Zika. For the first time, the group worked with embryonic tumors of the central nervous system in vitro, with similar results. The article, however, highlights the need for further investigation to confirm the selectivity of the virus in these cases.

New phase

According to Zatz, a new phase of the study is now beginning, with the recruitment of dogs affected by brain tumors. The proposal is to work with animals of different breeds and sizes.

“Dogs are extremely important models before we thought about testing in patients, as they have tumors very similar to humans and a preserved immune system. It will be possible to analyze different tumors”, completes the professor.

The researchers created a website with more information about this new step, which can be accessed on the website. The article Effect of Serial Systemic and Intratumoral Injections of Oncolytic ZIKVBR in Mice Bearing Embryonal CNS Tumors, by Raiane Oliveira Ferreira, Isabela Ganha, Rodolfo Sanches Ferreira, Heloisa by Siqueira Bueno, Oswaldo Keith Okamoto, Carolini Kaid and Mayana Zatz, can be read on the link.

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