Director Center for Genomic Regulation - CRG Barcelona, Spain
The direct use of recombinant bacteria, or indirectly using bacteriophages, producing and delivering in situ a therapeutic molecule of interest has been extensively described. Mycoplasma pneumoniae stands out as one of the most extensively studied microorganisms. This genome-reduced bacterium presents important advantages, primarily due to the absence of a cell wall, allowing for direct secretion of functional biomolecules into the surrounding medium. MPN limits horizontal gene transfer (HGT), by having a UGA triplet as a tryptophan codon rather than a STOP codon, some strains (i.e. MPN 129) have no recombination capacity and it divides every 8–12 h, being easily controlled. In the recent years, our group has focused on the engineering of the genome-reduced MPN as a live biotherapeutic (Mycochassis). We have demonstrated its potential application as a vector for the treatment of Staphylococcus aureus and Pseudomonas aeruginosa biofilms not only in vivo, but also ex vivo in endotracheal tubes of ventilator associated pneumonia patients. Using new genetic tools we have generated an attenuated chassis (Mycochassis) with the same colonization capacity of the wild-type strain in a murine and pig (collaboration with MD A. Torres, Hospital Clinic) lung models. Based on our results we incorporated a company that uses our engineered bacteria to treat human lung diseases (Pulmobiotics). One of the limitations of this bacteria is that it cannot secrete large amounts of a biological in the lung. To solve this issue and using proprietary protein design algorithms (FoldX and ModelX) engineered an anti-inflammatory cytokine, interleukin (IL)-10, that when Mycochassis expressed it in mouse and pig lungs it removes the inflammation induced by P. aeruginosa and mice death in an acute model of lung infection. Based on the technology developed to engineer more active cytokines we have recently incorporated another company, Orikine, whose objective is the design of improved cytokines for human therapy. Finally, we have shown that Mycochassis can express functional nanobodies, as well as scFVs antibodies and we are now using our protein design software to rationally engineer antibodies for human therapy.
