New treatment for digestive fistulas proves effective

Researchers at Paris Diderot University in France propose the use of vesicles secreted by adipose stem cells as a biological therapeutic system. The methodology has been successfully tested in pigs.

By Maria Fernanda Ziegler  |  Agência FAPESP – Tiny vesicles released into the bloodstream by adipose stem cells are being tested as a therapeutic biological system by researchers at Paris Diderot University in France.

In this project, a group led by Franco-Brazilian scientist Amanda Andriola Silva Brun and physician Gabriel Rahmi evaluated the efficacy of the method in the treatment of digestive fistula, a pathology characterized by abnormal communication between the epithelium-lined surfaces that connect two organs in the digestive tract or the viscera and the skin.

This issue affects some 1.5 million patients in Europe and is hard to treat. Most cases result from surgical trauma, but fistulas can also appear as a consequence of cancer or Crohn’s disease, a chronic inflammatory bowel disorder that affects the lining of the digestive tract.

Under physiological conditions, extracellular vesicles secreted by stem cells (known as exosomes) are responsible for transporting DNA, RNA, lipids and proteins between cells, mediating information transfer between tissues.

The group developed a patented method to force cultured stem cells to produce extracellular vesicles ten times faster and in amounts ten times greater than normal. In collaboration with Brazilian researchers, they have also investigated the biodistribution of such vesicles in animal models.

Vesicles obtained in the laboratory were embedded in a heat-sensitive gel and injected directly into fistulas. “This method enabled us to close 100% of the digestive fistulas,” Brun said. “The combination of the fistulas with a heat-sensitive gel biomaterial ensures that cold administration in the liquid filled the entire fistula tract and retained the vesicles at the site.”

This novel strategy was tested in pigs for the treatment of esophageal fistula. The study is published in ACS Nano.

According to Brun, a high-cost treatment for perineal fistula using mesenchymal stem cells approved in Europe in 2018 has been effective in 51% of the patients concerned. “The advantage of extracellular nanovesicles is that because they aren’t cells, they don’t divide or differentiate,” she explained. “The risk of tumor formation after injection of the material is therefore much smaller.”

The researchers plan to evaluate the effects of extracellular vesicles in a Crohn’s perineal fistula model. Clinical trials are also an item on the group’s agenda. Funding for this research project has recently been approved by the European Research Council.

“A strong collaboration was established with the teams led by Carlos Buchpiguel and Roger Chammas, both affiliated with the University of São Paulo [USP],” Brun said. “A clinical study on the therapeutic effect of the gel is being prepared in Natal [capital of Rio Grande do Norte State in Northeast Brazil]. The collaboration also includes Professor Irami Araújo Filho [UFRN, the Federal University of Rio Grande do Norte], Professor Amália Rego [Liga contra o Câncer], and Dinalva Brito de Queiroz [a researcher at Evidence, a Brazilian compounding pharmacy].”

Bioinformatics

Brun presented the results of her research during the international symposium FAPESP Week France, held in Paris in late 2019. At the same event, Catherine Etchebest, also a researcher at Paris Diderot University, presented the results of a study investigating the mechanisms that govern important functions of red blood cell membrane proteins. She developed bioinformatics tools to predict the molecular structures of these proteins.

Since 2015, Etchebest has collaborated with Fernando Barroso Silva, a Brazilian researcher affiliated with the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP).

“Our collaboration began with a shared interest in the functional properties of a simple protein responsible for carrying water in red blood cells,” Etchebest recalled. “During the research, however, we discovered it wasn’t actually so simple.”

Red cell membrane proteins play a key role in several biological processes, she explained, such as signaling and transport. They are also involved in various diseases and are important targets for drugs.

“It can be easier to understand their functional properties if a 3D structure is available. However, only a few 3D structures of membrane proteins have been resolved to date. Bioinformatics and molecular modeling are powerful alternatives to fill this gap, and I have developed a database on these proteins at my laboratory,” she said.