Research lines<\/h2>\nFibrosis<\/h3>\nCancer<\/h3>\n
Cancer<\/h3>\n
Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide. This is a heterogeneous disease involving numerous genetic and epigenetic alterations, characterized by presenting wide-ranging clinical and pathological features. It is broadly classified as non-small cell lung cancer (NSCLC, 85% of total diagnoses) or small cell lung cancer (SCLC, 15% of total diagnoses). Lung cancer pathophysiology cannot be fully understood by enumeration of dysregulated pathways in the tumor cells but instead must encompass the contributions of the tumor microenvironment (TME). Host immune cells are a critical component of the TME, and it is well known that are present within it of nearly all premalignant and neoplastic lung lesions. Thus, host immune responses play a dichotomous role throughout the evolution of lung cancer, and can either facilitate the eradication of malignancy or promote an immunosuppressive TME favoring tumor progression. Most lung cancers escape host immune surveillance through a variety of mechanisms. Tumors can directly suppress effector cells by activating negative regulatory pathways (i.e. PD-1) or restrict the effector response through suppression of functional antigen presentation. Lung cancers can also alter TME composition to establish an immunosuppressive milieu characterized by abundant inhibitory molecules, such as TGF-b, and immunosuppressive cells accumulation, including regulatory T cell and myeloid-derived suppressor cells. Current first-line treatments and therapeutic protocols in clinical trials, which have relative efficacy in most cases, are associated with many adverse effects since these are in general systemic therapies. Synthetic biology, which offers innovative approaches for engineering new biological systems, is driving significant advances in biomedicine. Compared to drugs, nanoparticles, or viruses, bacteria provide several advantages when used as a vehicle to deliver therapies. Among others, they contain all biological machinery to synthesize therapeutics and complex regulatory circuits can be integrated to sense and respond specifically to injured tissue. For many years, we have deeply characterized the genome-reduced bacterium Mycoplasma pneumoniae<\/em> through systems biology analysis. Therefore, it is possible to take advantage of its natural tropism toward the human respiratory tract and solid lung tumours, to integrate genes encoding immunomodulatory molecules within this bacterial chassis. As a result, we will develop strains capable to deliver these specific immuno-active molecules locally, with high bioavailability and fewer systemic adverse effects.<\/p>\n In the western world, cancer is the second most common cause of death. The timely detection of micrometastasis is critical for effective treatment and is currently an unfulfilled clinical requirement in the case of lung cancer. To address this issue, our research aims to develop radically new biosensors that draw upon decades of microbial genetics, which have yielded versatile components for engineering bacterial gene expression. Lung diseases\u00a0are a leading cause of mortality worldwide.\u00a0Dysregulation of immunomodulatory molecules plays a key role in many pulmonary diseases, including lung\u00a0cancer,\u00a0idiopathic pulmonary fibrosis (IPF)\u00a0and infections. In IPF acute or chronic inflammation results in senescence of the alveolar cells with telomere shortening and\/or dysregulation of miRNAs. Modulating the immune response directly or its downstream repercussions could be a possible way to help treat lung diseases. Systemic treatment with immunomodulatory molecules however, can have several drawbacks and include toxic side effects in other organs, the need for continuous delivery and a high cost of production. Similarly, treating immunomodulatory repercussions such as telomere shortening or abnormal miRNA expression in target cells is not easy due to the lack of a technology that efficiently and specifically delivers RNA. Furthermore, viral transformation can result in toxicity and is associated with high costs. To circumvent these problems, we aim to engineer the genome-reduced lung bacterium\u00a0Mycoplasma pneumoniae<\/i>\u00a0as a vector to locally express immunomodulatory proteins, and\/or to deliver protein\u00ad\u2013RNA complexes into alveolar cells (Mycovector<\/i>).\u00a0MPN<\/i>\u00a0does not have a cell wall, it directly releases secreted biomolecules into the medium, it does not recombine, it has a unique genetic code that prevents the transfer of genes to other bacteria and we have a non-pathogenic engineered version of it. To design this\u00a0Mycovector<\/i>, we will combine our experience in this organism with our know-how in protein design (http:\/\/foldxsuite.crg.eu\/<\/a>). We will use our\u00a0Mycovector\u00a0<\/i>expressing different combinations of active biomolecules to treat bleomycin-induced IPF in mice.\u00a0<\/i>This project will not only offer new insights into the treatment of a currently incurable disease, but also\u00a0show that bacterial chassis can be used in other organs different from the gut paving the way to other applications in human health.<\/p>\n Funded by:<\/p>\n European Research Council, Advanced Grant<\/p>\n Cytokines are biomolecules of great potential interest for human therapy. They modulate the immune system and play an important role in cancer, inflammation, immune response and tissue regeneration. Despite their great potential, there are only a handful of cytokines approved for therapeutic purposes. This is because many of them can have adverse side effects as they usually target different cell types1, which adds to their low serum half-life, high production costs, or lack of physiological efficacy. Different methods have been proposed to improve the pharmacodynamics and pharmacokinetics of selected cytokines (e.g<\/i>. fusion to the IgG-Fc region2 or use of adjuvant polyethylene glycol3). However, other properties do also need improvement, such as achieving effective local concentration at the target site; promoting the right activity in cytokines with dual functionality and decreasing toxicity by removing binding to unwanted cell types.\u00a0 To help solving the issues above we have developed the concept of \u201cFoldikine\u201d, a protein design strategy that can be applied to all helix-bundle cytokines, many of which have been shown to be therapeutically relevant (e.g. IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, GM-CSF, IL6, IL11, IL12A, IL23A, IL27A, IL31, CLCF1, CNTF, CTF1, LIF, OSM, CSF3, IFN\uf0611, IFN\u03c9, IFN\u025b, IFN\u043a, IFN\u03b2, IFNg.<\/p>\n Funded by:<\/p>\n European Research Council, Proof of Concept<\/p>\n Official Website<\/a><\/p>\n Synthetic biology promises to enable researchers to design therapeutically and industrially valuable organisms. Achieving this promise requires new techniques for designing, synthesizing, and transplanting entire genomes. Here we propose to develop the first model-driven approach to synthetic biology, and use this approach to construct a bacterial chassis capable of synthesizing and delivering human lung therapies in situ. Specifically, we propose to develop a whole-cell model of the human lung pathogen M. pneumoniae<\/em>, and use this model to design and construct a reduced, non-pathogenic chassis capable of delivering human lung therapies and\/or vaccinations. This project will involve intimate integration of predictive modeling, genomic engineering, and systems and synthetic biology. Model predictions will provide direct input into genomic engineering, and the newly created strains will be characterized to refine the computational model. The project will produce the most accurate computational model of any organism to date, as well as produce the most reduced cell to date. In the future we anticipate this reduced chassis could be extended to synthesize and deliver small molecule and\/or protein therapies to diseased lungs in situ.<\/p>\n Funded by:<\/p>\n <\/a><\/p>\n Official Website<\/a> Annually, infections caused by Mycoplasma species in poultry, cows, and pigs result in multimillion Euro losses in USA and Europe.\u00a0 There is no effective vaccination against many Mycoplasmas that infect pets, humans and farm animals (e.g. Mycoplasma bovis<\/em> cow infection).\u00a0 Furthermore, most Mycoplasmas are difficult to grow in axenic culture,\u00a0requiring a complex media that includes animal serum. Consequently, even in those cases for which effective vaccines are available (namely, M. hyopneumoniae<\/em> in pigs and M. gallisepticum<\/em> and M. synoviae<\/em> in poultry), the production process of the vaccines is very irreproducible and prone to contamination by animal viruses. Funded by:<\/p>\n <\/a><\/p>\nSensing<\/h3>\n
\nSpecifically, we are working to develop and optimize Mycoplasma pneumoniae<\/em> as a switch-like sensor that can detect metabolites produced in tumour environment for a payload release. These sensors could potentially have a wide range of applications beyond tumour detection in the lung. Additionally, we are designing a sensor that can detect selected cancer-exposed specific antigens.<\/p>\nScreening<\/h3>\n
Current Grants<\/h2>\n
Lung-Biorepair<\/h3>\n
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Novel Engineered cytokines for human therapy – Cytodesign<\/h3>\n
<\/a><\/p>\nOld Grants<\/h2>\n
MiniCell<\/h3>\n
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Ref: PCIN-2015-125<\/strong><\/figcaption><\/figure>\nMYCOSYNVAC<\/h3>\n
\nReference number: 634942<\/strong><\/p>\n
\nHere we will capitalize on our extensive systems biology knowledge of M. pneumoniae<\/em> and on cutting-edge synthetic biology methodologies to design a universal Mycoplasma chassis that can be deployed as single- or multi-vaccine in a range of animal hosts. We envision an iterative workflow that is (whole-cell) model-driven and relies on a range of genome-editing and transplantation tools, circuit (re-)design and chassis plug-in as well as on assessment of vaccine performance pigs in an industrial setting.\u00a0 The chassis will be free of virulence determinants from M. pneumoniae<\/em> and will be optimized for fast growth in a serum-free medium. Using this chassis, we will express heterologous antigens from one or more pathogens (i.e. Mycoplasma and virus) and biological adjuvants to create a targeted vector vaccine. Specifically in this project, we will target the development of attenuated and\/or inactivated vaccine(s) against two Mycoplasma pathogens: M. hyopneumoniae<\/em> (pigs) and M. bovis<\/em> (cattle), and a combined one against M. hyopneumoniae <\/em>and PRSSV virus (pigs).\u00a0 We will ensure that foreseeable risks are avoided, all ethical issues are handled in a transparent manner, and that our results and their implications are disseminated effectively and communicated efficiently with the European public.<\/p>\n![\"\"](\"http:\/\/serranolab.crg.eu\/wp-content\/uploads\/2018\/06\/mycosyn.jpg\")
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Ref: 634942<\/strong><\/figcaption><\/figure>\nMycoChassis<\/h3>\n