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The coming revolution: synthetic DNA and RNA for therapeutic and diagnostic applications

The discovery of the mRNA vaccines for the treatment of coronavirus, as well as new medicines for the treatment of genetic diseases, has been important in the quest of solutions for undrugable diseases in an unexpected short-time.

Thus, the chemical modifications of nucleic acids with diagnostic and therapeutic purposes is now a reality, a revolution that promises to give hopes on unsolved medical problems or optimize previous approaches, largely due to the research push for the development of mRNA vaccines against SARS-CoV-2 infection.

Now, the prestigious “The Chemical Record” journal has invited the Nucleic Acids Chemistry group, of IQAC-CSIC and CIBER-BBN and belonging to the Global Health Platform of CSIC, to describe the advances and modificacions of the nucleic acids in the last decade. The article, authored by Dr. Carme Fàbrega, Dr. Anna Aviñó and Dr. Ramon Eritja (coordinator and director, respectively, of Unit 29 of ICTS NANBIOSIS), reports the development of synthetic DNA and RNA for therapeutic and diagnostic applications.

The article describes the most important results from the Nucleic Acid Chemistry group in this area covering the international context that surrounded these studies. These include the development of modifications in potentially therapeutic oligonucleotides to enhance nuclease resistance as well as improving cellular uptake and avoiding side effects, and the advances in the use of DNA nanostructures in the controlled deposition of matter in surfaces and their potential application as drug delivery systems is reported.

Moreover, the article has been selected to illustrate the front cover of The Chemical Record, a journal of the Chemical Society in Japan, with a suggestive image that shows the research activity in this area. The back image is the three dimensional reconstruction of a DNA array described by the group of Dr. Seeman obtained by A. Garibotti in Barcelona. On the top the crystal structure of the Argonaute protein from the Protein Data Bank is shown. This protein is a natural player that helps the therapeutic action of RNA molecules. 

Read the full article in this link.

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DNA nanotechnologists are in mourning

At the end of the XXth century Nanotechnology appeared as one of the more powerful technologies for the future. At that time material sciences were able to produce nanomaterials with exquisite size control and atomic force, microscopy was able to visualize objects in the nanoscale and photolithography arrived to their physical limits in the preparation of computer chips threatening Moore’s law. This empirical law saying that as transistor components shrank, the number per chip doubled about every 18 months, was acting from 1971  (Intel’s first chip) to billions in the present times. 

At these times, one crucial development was the discovery of the first self-assembling DNA structures, leaded by Ned Seeman, who died recently at age 75. Being a crystallographer interested in DNA-protein structures, Ned though that a good way to obtain crystals of DNA-protein complexes was to prepare crystal networks of DNA where proteins bind. (In the classical approach of obtaining protein crystals small oligonucleotides bind). In this way in 1982 he described the idea of making lattices from DNA junctions. In 1991 he obtained a DNA cube, the first tridimensional DNA nanostructure receiving the 1995 Feynman Prize in Nanotechnology. But the most impressive development was the so-called “DNA tile systems” published in 1998.

The figure shows a bidimensional array made by his former Ph.D. student Alejandra Garibotti in our laboratory in Barcelona. In the tile system two or more tiles (each one made out of 5 oligonucleotides) are designed to self-assemble one next to the other by their sticky ends making a large lattice or bidimensional crystal having a tunable shape and size defined by the tiles.

Later on in 2009, Ned was able to demonstrate the achievement of three-dimensional DNA crystals. These developments settle the foundations for the development of DNA origami, DNA computation, DNA nanoelectronics and DNA nanorobotics earning the Kavli Prize in Nanoscience in 2010. The immense creativity of Ned is not only an active value for mankind but also an example for old and new scientists.

By Ramón Eritja, Scientific Director of NANBIOSIS U29, January 10th, 2022

U29.-Oligonucleotide-Synthesis-Platform
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Two great scientists and excellent people pioneers on Nucleic Acids Chemistry

Nucleic Acid Chemistry is an interdisciplinary discipline that combines organic chemistry, biochemistry, pharmacology, materials chemistry and biophysics. It started soon after the Watson–Crick model of DNA with the synthesis of the first dinucleotide, published in 1955. However, in the last decade, this field has blossomed, with the demonstration that Nucleic Acid Chemistry can provide innovative solutions to health problems such as vaccination, pathogen detection, and the treatment of metabolic or genetic diseases as well as providing important tools for the interrogation of cellular mechanisms.

Profesor Ramon Eritja, Scientific director of the Oligonucleotides Synthesis Platform U29 from ICTS NANBIOSIS will chair next January 13 a webinar on Frontiers in Nucleic Acid Chemistry, organized by the Journal Molecules in which some examples of the recent developments in Nucleic Acid Chemistry will be explained.

This webinar is dedicated to the memory of Prof. Enrique Pedroso one of pioneering researchers and leading Spanish scientist in Oligonucleotide and Peptide Synthesis who passed away in September of 2020. His contributions on the synthesis of modified oligonucleotides and especially oligonucleotide conjugates and cyclic oligonucleotides have opened new avenues in the search for novel applications of oligonucleotides. In addition, Enrique was deeply involved in the research and promotion of nucleic acid chemistry, as an active member of the IRT Society as well as organizing the Spanish Nucleosides Nucleotides and Nucleic Acids meetings (RANN).

During the preparation of the webinar we received the sad news of the decease of Prof. Ned Seeman from New York University who pioneered the field of DNA nanobiotechnology demonstrating that DNA is an excellent tool for the assembly of complex two and three-dimensional DNA lattices with important applications in several fields. 

We remained sad for the loss of these great scientists and excellent persons. 

Program and free registry for the webinar here

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A project by NANBIOSIS researchers, focused on COVID-19 detection and therapy, selected in ‘La Marató’ research program

The Scientific Commission of ‘La Marató TV3’ has seleced the project entitled “Diagnosis and treatment of Sars-Cov-2 by triplex formation”, led by Ramon Eritja, Scientific Director of NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) from CIBER-BBN and IQAC_CSIC to be financed with € 398,750.00. Verónica Noé from the Fundació Bosch i Gimpera Universitat de Barcelona, ​​the CIBERESP researcher Enrique Calderón Sandubete, from the Virgen del Rocío University Hospital and María Valeria Grazú Bonavía, from the Institute of Nanoscience and Materials of Aragón, INMA (CSIC- UNIZE) also participate in this project.

The edition of this solidarity initiative promoted by the Corporació Catalana de Mitjans Audiovisuals, raised more than twelve million euros to finance research against COVID-19. The project was selected, among the 229 submitted, to receive funding for its development.
“Our project wants to solve two important problems in the fight against the COVID-19 pandemic: the first is how to quickly and specifically detect people infected by this virus; and the second is that right now we do not have a effective therapy specifically designed to be used against the virus that causes COVID-19 “explains Dr. Eritja.

The project will try to solve both problems using synthetic oligonucleotides with high and specific affinity for viral RNA. “In recent years, a dozen oligonucleotides have been approved by Health agencies (EMA and FDA) for the treatment of genetic diseases such as Duchene muscular dystrophy as well as metabolic diseases such as familial hypercholesterolemia. In the project we will use specific oligonucleotides, procuced at NANBIOSIS U29, to bind viral RNA that could be used in vitro for the selective capture and diagnosis of the SARS-.COV-2 virus, but also in vivo to inhibit the replication of viral RNA “adds Ramón Eritja.

The call for grants from ‘La Marató’ was carried out, exceptionally, between the months of December and January. Until May, the 229 candidate projects have been reviewed electronically, following a process of proven rigor and transparency, coordinated by the Catalan Agency for Quality and Health Evaluation, in which 95 international evaluators have participated. The assessment, among other aspects, of the quality, the methodology, the scientific, health and social relevance, the innovative value and the viability of the candidate works has determined which projects have been financed with the resources of La Marató 2020.

With this new edition from La Marató, the solidarity project of the Catalan Audiovisual Media Corporation and the Foundation since 1992 an amount of € 216 million have been awarded and a total of 949 research projects hve been promoted, with participation of 9,350 researchers have participated.

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A potential solution to decrease toxicity in colorectal cancer treatment

Cancer is one of the world’s leading causes of death, with over 18.1 million cases and 9.6 million deaths in 2018. One of the most successful drugs used in chemotherapy for the treatment of diverse severe cancers is 5-Fluorouracil (5-FU), however, one of the major problems described in clinical practice is 5-FU cell resistance.

Resarchers of the Nucleic Acids group and the Colloidal and interfacial Chemistry Group of CIBER-BBN at IQAC-CSIC have collaborated in a research to  inspect and test the ability of parallel G-quadruplexes to deliver floxuridine oligonucleotides into different types of cancer cells; finally, the internalization ability and the antiproliferative action of these oligoFdU-G-quadruplexes have been evaluated in FU-resistant cell lines.

Recently an article has been published with the research results by the Jorunal of Molecules entitled “Parallel G-quadruplex structures increase cellular uptake and cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil resistant cells”

The article describes a potential solution to decrease the toxicity of floxuridine, a known nucleoside antimetabolite used in the treatment of colorectal cancer, explains Ramón Eritja, Scientific Director of NANBIOSIS U29 from CIBER-BBN and IQAC-CSIC.

The authors used the NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) to prepare short oligonucleotides that form a tetrameric structure that is recognized by cancer cells facilitating the specific delivery to the tumor cells. Once inside of the cells, the oligonucleotides generate the active drug by nuclease degradation as a Trojan horse.

Article of reference:

Clua A, Fàbrega C, García-Chica J, Grijalvo S, Eritja R. Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil Resistant Cells. Molecules. 2021; 26(6):1741. [DOI] 

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NANBIOSIS Scientific Women in the International Day of Women and Girls in Science

Today February 11 is the International Day of Women and Girls in Science, a day to raise awareness of the gender gap in science and technology.

According to the United Nations, while yet women and girls continue to be excluded from participating fully in science, science and gender equality are vital to achieve the internationally agreed development goals, including the 2030 Agenda for Sustainable Development. Thus, in recent years, the international community has made a great effort to inspire and promote the participation of women and girls in science.

NANBIOSIS wants to acknowledge  the efforts made by scientific women who struggle every day to contribute their bit to Science and highlight their essential role in nowadays research. Especially we want to recognize the work of scientists women involved in NANBIOSIS, whatever is the nature of their contribution: technical, scientific development, management, coordination, direction, etc; just to mention some examples:
Neus Ferrer and Mercedes Márquez in the Scientific Direction and Coordination of Unit 1 Protein Production Platform (PPP)
Pilar Marco and Nuria Pascual in the Management and Scientific Coordination of U2 Custom Antibody Service (CAbS) 
Miriam Royo in the Scientific Direction of U3 Synthesis of Peptides Unit
Nora Ventosa and Nathaly Segovia in the Scientific Direction and Technical Coordination of U6 Biomaterial Processing and Nanostructuring Unit
Isabel Oliveira and Teresa Galán in the Coordination of U7 Nanotecnology Unit
Rosa Villa and Gemma Gabriel in the Management and Scientific Coordination of U8 Micro – Nano Technology Unit
Gema Martínez in the Scientific Coordination of U9 Synthesis of Nanoparticles Unit
Fany Peña in the Scientific Coordination of U13 Tissue & Scaffold Characterization Unit
Mª Luisa González Martín and Margarita Hierro in the of Direction and Scientific Coordination of U16 Tissue & Scaffold Characterization Unit
Gemma Pascual and Isabel Trabado in the Coordination of the U17 Confocal Microscopy Service
Isolda Casanova in the Scientific Coordination of U18 Nanotoxicology Unit
Beatriz Moreno in the Scientific Direction of Unit 19 Clinical tests lab
Ibane Abásolo in the Scientific Coordination of Unit 20 In Vivo Experimental Platformt
Verónica Crisóstomo in the Scientific Direction of Unit 24 Medical Imaging 
Ana Paula Candiota in the Scientific Coordination of Unit 25 Biomedical Applications I 
Maria Luisa García in the Scientific Direction of U28 NanoImaging Unit from Bionand, recently incorporated to NANBIOSIS, Anna Aviñó in the Scientific Coordination of U29 Oligonucleotide Synthesis Platform (OSP) – and

Nerea Argarate in the coordination of NANBIOSIS

Thanks to all of you and your teams!

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Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

In the frame of the collaboration of three units of NANBIOSIS, researchers of CIBER-BBN Groups proposed a strategy to simultaneously deliver anticancer drug pairs, composed by a tumor-targeted protein nanoparticle and an antiproliferative drug, with specific activ-ity for the same type of cancer.

These three units are:

The results on the investigation have been published in an article entitled “Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles”· by Acta Biomaterialia

The researchers have explored the possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respec- tively have been chemically coupled.

The resulting multifunctional hybrid nanoconjugates, with a hydro- dynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.

Thus, these results open a wide spectrum of opportunities in nanomedical oncology.

Article of reference:

Eric Voltà-Durán, Naroa Serna, Laura Sánchez-García, Anna Aviñó, Julieta M. Sánchez, Hèctor López-Laguna, Olivia Cano Garrido, Isolda Casanova, Ramón Mangues, Ramon Eritja, Esther Vázquez, Antonio Villaverde, Ugutz Unzueta Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles. Acta Biomaterialia, Volume 119, 1 January 2021, Pages 312-322), 57746-57756 https://doi.org/10.1016/j.actbio.2020.11.018 

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Nucleic Acids Chemistry, new book release by Ramon Eritja

Ramón Eritja, Scientific Director of NANBIOSIS Unit 29 Oligonucleotide Synthesis Platform (OSP) has just published a new book “Nucleic Acids Chemistry, modifications and conjugates for Biomedicine and Nanotechnology“, Anna Avinó, Scientific Coordinator of NANBIOSIS Unit 29 is also a writer of the book.

The book “Nucleic Acids Chemistry” takes the most important aspects of the methodology of oligonucleotides synthesis, that is currently expanding by the endorsement of a dozen of new medicines, such as the first medicine based on interfering RNA for the control of LDL and cholesterol in blood that will facilitate the decrease of cardiovascular illnesses.

The writing of the book has been directed by Dr. Ramon Eritja, of Centro de Investigación en Red de Nanomedicina (CIBER-BBN) and is Research Professor at Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), being its director between 2012-2017. The co-authors are Carme Fàbrega, Anna Aviñó, Santiago Grijalvo, Andreia F. Jorge, from IQAC-CSIC, Carlos González from Instituto de Química Física Rocasolano (IQFR-CSIC) and Raimundo Gargallo from University de Barcelona  The book began to be written in mid-2019, although most of the book was written during the lockdown.

In the last five years, an expansion of technologies based on DNA and RNA in diagnosis and therapeutic use has been produced, and it has been very important in the research of quick solutions to avoid the COVID pandemic and, predictably, the research group’s environment has led the development of several solutions, like biosensors for the direct detection of SARS-CoV-2.

A former PhD student of Ramon Eritja group, Dr. Ramón Güimil García, Head of Synthetic Oligonucleotides bei BioNTech, has participated in the development of the BioNTech-Pfizer mRNA vaccine. Another doctor, Brendan Manning, formed member of the group, has participated in the development of a diagnosis kit named Sherlock, which uses the CRISPR-Caspasa system for the detection of the virus that causes COVID.

Dr Erija completed his doctoral thesis at the University of Barcelona directed by Dr. Ernest Giralt on the subject of peptide synthesis. In 1984 he carried out his first postdoc with Dr. Itakura at the Beckman Research Institute of City of Hope in Los Angeles where the production of the first synthetic genes was carried out, highlighting the production of synthetic insulin that, with the name of humulin, solved the problems generated from the use of swine insulin. In 1986 she completed the second postdoc with Dr. Caruthers at the University of Colorado at Boulder. In this laboratory, phosphoramidites were developed, which are the reagents used today for the production of synthetic DNA and RNA. Upon his return to Barcelona, ​​he joined the CSIC Research and Development Center where he organized the first research group in our country focused on oligonucleotide synthesis. In 1984 he moved to the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany) to direct for 5 years one of the most prestigious groups in DNA and RNA Chemistry in Europe. Upon his return to Barcelona, ​​he was part of the Barcelona Institute for Biomedical Research (IRB Barcelona) and was recognized as a group of excellence by the CIBER-BBN. In 2012 he moved to the IQAC-CSIC to occupy the direction of the institute until 2017.

Refernce:

Nucleic Acids Chemistry – Modifications and Conjugates for Biomedicine and Nanotechnology Edited by: Ramon Eritja. De Gruyter | 2021 DOI: https://doi.org/10.1515/9783110639537

The book can be purchased here: link

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Non-viral mediated gene therapy in human cystic fibrosis airway epithelial cells recovers chloride channel functionality

Researchers of CIBER-BBN Units of NANBIOSIS: U29 Oligonucleotide Synthesis Platform (OSP) at IQAC_CSIC, led by Prof. Ramón Eritja and U10 Drug Formulation, at UPV-EHU, led by Prof José Luis Pedraz, are coauthors of an article published by International Journal of Pharmaceutics.

Gene therapy strategies based on non-viral vectors are currently considered as a promising therapeutic option for the treatment of cystic fibrosis (CF), being liposomes the most commonly used gene carriers. Niosomes offer a powerful alternative to liposomes due to their higher stability and lower cytotoxicity, provided by their non-ionic surfactant and helper components. In this work, a three-formulation screening is performed, in terms of physicochemical and biological behavior, in CF patient derived airway epithelial cells. The most efficient niosome formulation reaches 28% of EGFP expressing live cells and follows caveolae-mediated endocytosis. Transfection with therapeutic cystic fibrosis transmembrane conductance regulator (CFTR) gene results in 5-fold increase of CFTR protein expression in transfected versus non-transfected cells, which leads to 1.5-fold increment of the chloride channel functionality. These findings highlight the relevance of niosome-based systems as an encouraging non-viral gene therapy platform with potential therapeutic benefits for CF.

The article acknowledges U10 Drug Formulation, for the intellectual and technical assistance

Article or reference:

Non-viral mediated gene therapy in human cystic fibrosis airway epithelial cells recovers chloride channel functionality-Sainz-Ramos, M., Villate-Beitia, I., Gallego, I., A.L. Qtaish, N., Lopez-Mendez, T.B., Eritja, R., Grijalvo, S., Puras, G., Pedraz, J.L. International Journal of Pharmaceutics, 588, art. no. 119757, 2020. https://doi.org/10.1016/j.ijpharm.2020.119757

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Three Nanbiosis units work in the development of new sensors for the better detection of the fungus P. jirovecii, responsible for Pneumocystis pneumonia

Researchers from the CIBER-BBN have succeeded in developing detection systems for Pneumocystis jirovecii, an atypical fungus responsible for very serious pneumonia in immunosuppressed patients. These results, published in the journal Nanomaterials, are the result of collaboration between the CIBER-BBN groups led by Laura Lechuga, Ramon Eritja and Ramón Martínez Máñez, and the CIBERESP group led by Enrique J. Calderón.

The researchers acknowledge the paricipation of three NANBIOSIS units of CIBER-BBN:

The detection of the fungus in patients, who may be asymptomatic carriers until they develop pneumonia, is currently carried out using the PCR technique, requiring several hours, adequate facilities and qualified personnel to detect it. Now, the application of Nanotechnology has allowed the development of more sensitive and efficient biosensors to detect specific sequences corresponding to pathogens responsible for infectious diseases in a shorter time and without the need for large infrastructures.

In this case, a specific sequence corresponding to the gene belonging to the ribosomal subunit (mtLSU rRNA) of the P. jirovecii fungus has been detected using hairpin-shaped capture probes. These specific probes, as pointed out by Dr. Aviñó, a researcher at CIBER-BBN at the IQAC-CSIC, “are more efficient and are capable of recognizing a specific genomic sequence of the fungus and forming very stable triplex structures that can be detected on different platforms. biosensor “.

Laura Lechuga’s team at ICN2, through the use of an optical biosensor based on SPR technology, has detected in real time and without the use of markers, P. jirovecii in bronchoalveolar lavages and nasopharyngeal aspirates with a detection limit of nM level and in just a few minutes.

Likewise, the group led by Ramón Martínez-Máñez, scientific director of CIBER-BBN and principal investigator of the IQMA-IDM group at the Universitat Politècnica de València, has used the strategy of molecular gates composed of an anodic albumin matrix to develop a sensor capable of to efficiently detect real P. jirovecii samples without previous amplification steps in as little as one hour.

“These advances in the diagnosis of PCP have great potential for the development of highly sensitive point-of-care devices using direct patient samples and applicable in a wide variety of settings,” says the CIBERESP group leader. Enrique J. Calderón from the Virgen del Rocío University Hospital in Seville.

The researchers also emphasize that these techniques are very selective and can discriminate patients with other respiratory diseases derived from other microorganisms, thus allowing a more reliable diagnosis of infectious diseases.

Articles of reference:

Calvo-Lozano, O., Aviñó, A., Friaza, V., Medina-Escuela, A., S Huertas, C., Calderón, E. J., Eritja, E., Lechuga, L. M. (2020). Fast and accurate pneumocystis pneumonia diagnosis in human samples using a label-free plasmonic biosensor. Nanomaterials, 10(6), 1246. https://doi.org/10.3390/nano10061246

Pla, L., Santiago-Felipe, S., Aviñó, A., Eritja, R., Ruiz-Gaitán, A., Pemán, J., Friaza, V., Calderón, E.J. Martínez-Máñez, R., Aznar E. (2020). Triplex hybridization-based nanosystem for the rapid screening of Pneumocystis pneumonia in clinical samples. Journal of Fungi, 6(4), 292. https://doi.org/10.3390/jof6040292

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