Claudia Villalobos
Having state-of-the-art infrastructure is an advantage for scientists from the Instituto Politécnico Nacional (IPN) to develop innovative frontier pharmacological products and position this university as an international benchmark in the generation of treatments based on gene silencing, as in the case of experts from the Escuela Superior de Medicina (ESM), who are creating drugs against idiopathic pulmonary arterial hypertension.
The road to developing drugs against different pathologies based on Ribonucleic Acid interference or small interfering RNA (siRNA) is usually long and winding, but thanks to the experience of Dr. Santiago Villafaña Rauda it is possible to turn it into a path full of hope for patients waiting for new treatments, as in this case, which already have encouraging results.
Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary arterial pressure.
"The first results have allowed us to corroborate that the drugs we designed significantly reverse in the animal model (Wistar rats) the damage to the right ventricle of the heart caused by pulmonary vasoconstriction," said the polytechnic specialist.
Reducing the vasoconstriction that occurs in arterial hypertension in the lungs is the key to avoid the enlargement of the heart's right ventricle. Therefore, the medium-term goal of the polytechnic research is to generate new treatments based on interfering Ribonucleic Acid or small interfering RNA, through which they will seek to increase the survival of patients and, by gradually reversing the damage, in the future allow their incorporation into normal life.
"These drugs were designed to prevent the translation of the messenger RNA of the polypeptide endothelin-1 (which favors vasoconstriction), as well as one of its receptors and the enzyme that participates in its biosynthesis," said Dr. Villafaña Rauda, who assured that an important part of the results are due to the participation of Master of Science Citlali Margarita Blancas Nápoles, who will obtain the degree of Doctor of Science with this work.
Dr. Villafaña Rauda pointed out that pulmonary arterial hypertension is a condition of diverse origin, characterized by a progressive increase in pulmonary arterial pressure, which, in the long term, by affecting circulation in the lungs, constitutes a potential condition for the development of hypertrophy of the right ventricle of the heart.
"It is an underdiagnosed disease. Although many people suffer from it, because of the symptomatology it can be confused with other conditions," he warned.
Because its symptoms include fatigue, shortness of breath and dizziness, among others, it is often confused with other conditions and is diagnosed late when the deterioration has advanced, which makes treatment difficult. Currently, treatments such as endothelin receptor antagonists and phosphodiesterase 5 inhibitors are prescribed, which help to prevent the disease from progressing so rapidly, but generate some side effects. There are others that are very expensive and therefore not very accessible to patients.
The design and development of siRNA drugs begin with a search on specific platforms and software for the drug sequences of approximately 21 nucleotides of RNA. "Subsequently, we use bioinformatics techniques to generate a hybridization of the siRNA sequence in the secondary structure of the messenger RNA, which allows us to interrupt translation and consequently decrease protein expression," explained Citlali Blancas.
He specified that the designs are human-rat. "This means that we consider the messenger RNA sequences of the endothelin-1 polypeptide, endothelin-converting enzyme, and endothelin receptor type A, both human and rat since the drug is tested in the animal model, but the therapy is aimed at humans," he clarified.
To corroborate that the drugs work according to the silencing carried out, an in silico simulation is performed with bioinformatics techniques and, once the scientists validate their correct activity, the sequences are synthesized in solid phase, purified and hybridized to administer them to the animal model.
After 15 days of applying siRNA to the rodents in the jugular vein, the organs (lungs and heart) are evaluated to measure, through the Fulton index, the effect of the treatment on right ventricular hypertrophy. "By performing these analyses we corroborated that the damage to the right ventricle was reversed in a very important percentage. Therefore, in the future, the drugs could be tested in human lung and heart cell lines to evaluate their effects," said the young researcher.
Through this line of research, focused on generating drugs to treat different diseases through gene silencing, graduate students have the opportunity to participate in the generation of new knowledge, acquire experience in the management of state-of-the-art infrastructure, attend various national and international congresses where the results of their research are presented, as well as participate in specialized competitions where their contributions are recognized.
The results achieved by this protocol are due to the hard work and dedication of the entire team of Dr. Villafaña Rauda, an expert who has the collaboration of scientists from the ESM, such as Dr. Rodrigo Romero Nava, who actively supports the projects of the Masters and Ph.D. students.
For its quality and contribution, the research on the creation of siRNAs to treat pulmonary arterial hypertension has received two awards. The Mexican Pharmaceutical Association awarded him the "Santiago Maza" national prize. Meanwhile, UMass Chan Medical School and the RNA Therapeutics Institute awarded him the international prize RNA Therapeutics: From Concept to Clinic Symposium.
To report on the progress of the project, scientific articles are being prepared for publication in prestigious international journals and the results will soon be presented at the fifth RNA Therapeutics: From Concept to Clinic 2023 conference at the University of Massachusetts, USA.
Dr. Santiago Villafaña Rauda emphasized that although there is still a need to deepen the studies of this pioneering line of research, the advances are progressing at a good pace and the results are very promising because they have equipment that facilitates the development of drugs, which motivates the students to strengthen their training and continue in the task of research to generate developments that have a favorable impact on health care and a better quality of life for the population.
Selección Gaceta Politécnica #163. 2023, June 30th. IPN Imagen Institucional: Read the full magazine in spanish here
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