Parkinson's disease (PD) is the second most common neurodegenerative disease in industrialized countries after Alzheimer's disease. According to data from the Spanish Society of Neurology, more than seven million people suffer from Parkinson's disease worldwide. In the case of Spain, approximately 10,000 new cases are detected each year, with a total number of people exceeding 150,000. We are facing a growing public health problem, as pointed out by the World Health Organization (WHO), since its prevalence has doubled globally in the last 25 years. The WHO has warned that disability and mortality from Parkinson's disease are increasing at a much faster rate than any other neurological disease.

We are talking about a disease that, in its early stages, usually goes unnoticed since its manifestation consists of prodromal symptoms that include depression, sleep-related problems, cognitive deficits, olfactory dysfunction, constipation and other symptoms related to the autonomic nervous system. As the disease progresses, patients experience more specific motor symptoms leading to the definitive diagnosis: involuntary or uncontrollable movements, tremors, rigidity, and difficulty with balance and coordination. It is a complex disorder that requires a great deal of knowledge both in the diagnostic phase (to make a correct and early identification of symptoms, carry out the differential diagnosis and request the necessary complementary studies) and in the treatment phase (to decide the time of onset and treatment and to consider different therapies throughout the evolution in order to alleviate the symptoms).

Parkinson's is an extremely disabling disease that has a negative impact on the daily lives of those affected and their families. To date, despite the great effort made by the scientific community, there is no cure and we only have drugs to alleviate the symptoms once the diagnosis has been made, such as levodopa and carbidopa (considered the first-line drugs for the treatment of the motor symptoms of Parkinson's disease). A situation that poses important challenges in the context of public health since, as has been pointed out, its prevalence is expected to increase in the coming years as life expectancy increases, so it is likely that in the coming years the health system will have to face an economic burden in the order of billions of euros to deal with this disease.

Three biotech companies combine their capabilities in search of therapeutic targets

In this context, biotechnology is working to find solutions to tackle the public health problem of Parkinson's disease. A promising example is the project "Development of new drugs for the treatment of Parkinson's disease using Artificial Intelligence and mass screening of compounds", coordinated by AseBio with the participation of Celtarys Research,ZeClinicsand the Biofarma group of the University of Santiago de Compostela. This project brings together ZeClinics' capabilities in target validation and in vivo drug screening, Celtarys Research's scientific knowledge in design and synthesis of fluorescent tools, and USC-Biofarma's capabilities in the development of high-throughput in vitro screening assays.

The main objectives of this project are the identification of new therapeutic targets to treat Parkinson's disease and the establishment of an efficient protocol to identify drug candidates that can modulate these targets. The achievement of this objective represents the first milestone of a larger project aimed at identifying a molecule capable of interfering with the disease. With no cure currently available, it is of vital importance to contribute to the search for active molecules capable of acting on the pathology and improving the quality of life of patients.

"Our Biofarma group (USC) is leading a work package in which, taking advantage of our expertise in applied research in early drug discovery and our capabilities in the development of high-throughput in vitro screening assays, we will carry out the development of the activity assay on the selected targets, the validation of the developed ligands and the pharmacological evaluation of the agreed compounds, generating new candidates for the treatment of Parkinson's disease," explains Mabel Loza, PI of the project.

"We are at an early stage of the drug discovery process, in which we have identified a number of targets with therapeutic potential that we need to validate. For this, zebrafish as an animal model presents an advantage not only at an economic level, but also reduces time by allowing high-throughput pharmacological screening following all ethical guidelines. Our contribution is of vital importance because, as there is no cure, it is essential to find and validate new biomolecular targets", says Jessica García Fernandez, PostDoc Researcher at ZeClinics.

"Our project is based on previous results obtained in genetically modified animal models that have been analyzed (phenotypic and transcriptomic data) using artificial intelligence and vision tools to identify new targets and therapeutic molecules to treat Parkinson's disease," says Loza. "Subsequently, the targets are experimentally validated and chemical compounds are identified that can modulate their activity and, therefore, serve as potential pharmacological therapies. Thus, the main objectives of this project are the identification of new therapeutic targets for Parkinson's disease and the establishment of an effective protocol to identify drug candidates that can modulate these targets."

"We have obtained a number of targets that are downregulated in our animal models of Parkinson's disease. We hope that by repositioning drugs and testing a library of molecules, we will be able to obtain a lead compound with sufficient potential to ameliorate disease symptoms. We hope that in the future, Parkinson's patients will be able to benefit from this research," argues García Fernández ZeClinics.

"Celtarys Research, through its conjugation technology, will design an optimal fluorescent tool, which Biofarma will use in screening assays directed to the targets identified by Zeclinics. This collaborative and structured approach has the potential to significantly advance the project's objective, thus improving the treatment and quality of life of Parkinson's patients," said Maria Majellaro, Chief Scientific Officer of Celtarys Research.

The completion of this project will complete the initial stages of a new drug discovery program for Parkinson's disease. In this way, using artificial intelligence tools and genetic manipulation, new therapeutic targets will be experimentally validated whose inhibition will lead to the total or partial rescue of the pathological phenotype previously observed in models. In addition, the design and synthesis of fluorescent chemical tools for these new identified targets will be carried out. Finally, a high-throughput screening assay will be developed to screen compound libraries to identify new molecules for the treatment of Parkinson's disease. The potential positive results of this project will allow the identification of potential drug candidates and the establishment of a collaborative drug discovery methodology applicable to other diseases as well.

"The main objective is to fine-tune a robust biological assay for screening compounds in order to develop modulators for the targets previously identified using Zeclinics' Zebrafish model. This process will allow us to find promising initial compounds, which will serve as a starting point for the development of a drug candidate with optimal therapeutic properties," concludes Majellaro.

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