2018-04-016 - EVsBioCD - Extracellular vesicles as a tool for the Identification of new biomarkers in Chagas disease.

EVsBioCD

2018-04-016

Able to detect parasite proteins present in EVs. Biomarkers detected by our product are highly dependent on the progression of the disease, being of high value for developing new drugs for Chagas disease.

The discovery and implementation of these new biomarkers would represent a game-changer in the diagnosis and treatment of Chagas disease. The research is very promising and the group was the first to describe the proteomic profile of VEs derived from the plasma of a cardiac transplant patient with CCD (Chronic Chagas Disease). VEs represent a cheap and minimally invasive method for the diagnosis and screening of diseases. Compared to other conventional biomarkers detected in biological samples such as serum or urine, VEs provide comparable or even superior specificity and sensitivity due to their excellent stability. In fact, the use of VEs as predictive biomarkers of progression in different pathologies have been described, such as ischemic heart injury, chronic liver diseases, various types of cancer and some parasitic diseases. The future implementation of this new biomarker in a future device would reduce the economic and social burden of this disease which affects disproportionately the most vulnerable population.

The epidemiology of Chagas disease has changed in recent decades, mainly due to international migration movements. An increase in cases of T. cruzi infection in non-endemic countries of North America, Europe and Asia is bringing new attention to this neglected disease and promoting the creation of global strategies for its detection, treatment and control. After the United States, which is the most common destination for Latin American migrants, Spain is the non-endemic country with the highest number of cases (80.000) in the developed world. The deficit of early markers of therapeutic response hinders the clinical monitoring of treated Chagas disease patients and clinical trials with new drugs. This gap represents one of the main priorities for research in Chagas disease. Therefore, biological biomarkers involved in the pathogenesis of this disease could be used as tools for early indicators of therapeutic response and/or disease outcome.

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Our aim is to develop the project until TRL 4-5 and then out-license the technology to a well-established IVD company. Our investigation is focused on the discovery of new biomarkers that could be incorporated into a biosensor to ease the implementation of a point-of-care medical device. Due to the high costs of development, the regulatory pathway and the need for clinical trials and CE marking, our objective is to advance until TRL 4-5 with competitive funds and look for potential licensees of the technology. They will be in charge to perform the rest of the development process until the market. Revenues will be received through royalties based on net sales under a license agreement with the industry partner.

Chagas disease is a very urgent global health problem. The disease is underdiagnosed affecting especially the most vulnerable population in rural areas of South America. People carrying the disease cannot have symptoms for years, and the current methods to detect it are inefficient and can trigger pharmacological actions that are not needed (false positives) Moreover, due to migration, there are a lot of cases in the USA and Spain mainly without being diagnosed affecting health inequality on these developing countries.

Our target market would be countries in South America where the disease is endemic affecting approximately 6 million people and with 70 million people at risk of becoming infected. The USA is also another important market for us due to the fact is the first non-endemic country on the list with the most cases of Chagas disease, followed by Spain, due mainly to the migrant population arriving at these countries.

We would need 500,000€ the following two years to complete the proof-of-concept in the laboratory and to perform the first validation of our technology through a Minimum Validated Product (MVP). The budget also includes the cost of patentability assessment of the new biomarkers, FTO studies (to be sure we are not going to infringe the rights of third parties) and a preliminary regulatory roadmap for our medical device.

Partnership with the industry (IVD companies) once scientific validation is high enough to show robustness to attract investors and potential licensees.

We hope to finish the laboratory proof of concept of our technology by mid of 2025. A deal with the industry will be expected in 2027 or 2028.

Extracellular vesicles (EVs) are small vesicles derived from cells and found in most biological fluids. Generally, they are classified into two groups, exosomes and microvesicles, according to their size, biogenesis and composition. In the last decade, research into the biology, function and potential applications of EVs has grown exponentially. An important part of the work carried out in this area has shown that the most relevant potential of EVs in the biomedical field is their usefulness as biomarkers in clinical diagnosis. EVs represent a cheap and minimally invasive method for disease diagnosis and screening. Compared to other conventional biomarkers detected in biological samples such as serum or urine, VEs provide comparable or even superior specificity and sensitivity due to their excellent stability. In fact, the use of VEs as predictive biomarkers of progression in different pathologies has been described, such as ischemic heart injury, chronic liver diseases, various types of cancer and some parasitic diseases. They can be released by different mammalian cells, and also by various pathological microorganisms, including parasites. VEs have also been found to play a role as modulators of host-parasite interactions in various diseases caused by protozoan parasites that infect humans. It has become clear that these vesicles serve as vehicles for the transfer of membrane and cytosolic proteins, lipids and RNA between cells. In chronic Chagas disease (CCD), several studies have shown that VEs are involved in the modulation of immune responses and interactions between the parasite and host cells. In addition, proteomic analyzes of EVs released by different T. cruzi parasite stages have revealed an enrichment in virulence factors essential for disease establishment and infection progression (Cortes-Serra et al., 2022 ). Until a few years ago, all these works had focused mainly on the analysis of the VEs released directly by the parasite in vitro culture. Therefore, we can hypothesize that proteins identified in VEs released by the host or parasite during infection could be potential biomarker candidates to assess therapeutic response, detect heart disease at very early stages, and to monitor treatment in more advanced cases of MCC. So far, the results have been very promising and have allowed the identification of 62 parasite proteins, some of which are present in several patients and with great potential to develop new biomarkers in the context of therapeutic response and disease progression.

Chagas disease is considered a Neglected Tropical Disease (NTD). Historically, NTDs have been ignored by the pharmaceutical industry and public health coverage in general. Most people infected with NTDs are confronted with poor sanitary conditions and have inadequate nutrition and healthcare. They are unable to pay for treatment, even if available. For the pharmaceutical industry, drugs or diagnosis methods to mitigate NTDs do not bring sufficient economic returns such that little incentive exists to spur its commercial interest in research and development (R&D). Additionally, the size of the market is very limited and there is not enough interaction between academia (in charge of the research for new solutions) and the industry.

The first patent was abandoned in 2021 due to the lack of scientific robustness in the biomarkers found. Now, when we validate new biomarkers in a higher number of samples, we will assess their patentability with more chances to be granted.

The PCT patent application was withdrawn in January 2021 because the biomarkers included in the priority application were not the strongest from the scientific perspective. The main reason was the study only had the evidence of one patient. The patent has also been withdrawn in Argentina beause of the low robustness of the current claims, only based on data from a single patient. In the past months, more samples have been studied and more proteins have been identified opening the door to the discovery of potential new biomarkers which patentability will be carefully analyzed.

Know-how in extracellular vesicles for the diagnosis of other parasitic diseases such as malaria

Patents: WO2020016402A1 ; PCT/EP2019/069478 - Date: Jan 23rd, 2020 Status: Granted URL: https://patents.google.com/patent/WO2014164472A1/pt

Our preliminary results, using 2D LC-MS/MS proteomic analysis, have demonstrated for the first time the presence of T. cruzi and human proteins specifically associated with EVs isolated from plasma of a chronic chagasic patient before treatment that are absent after treatment.