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NANO2021-Nanoteknologi og nye materiale

Gut-targeted RNA-based nanoparticles for fibrostenotic Crohn’s Disease: a novel therapeutic approach - RuNNINg

Awarded: NOK 3.9 mill.

RuNNINg is a transnational European project with partners from Italy, Greece, France and Norway. The consortium is composed of experts in nanocarrier development and formulation, characterization of nanomedicines, cell biology and clinicians, specialized in diseases in the gastro-intestinal tract, as for example inflammatory bowel disease (IBD) and Crohns disease. Intestinal fibrosis, the reaction of intestinal tissue to the damage inflicted by chronic inflammation, is a serious complication in patients with chronical inflammatory diseases in the intestine, e.g. Crohns disease. There is no treatment for intestinal fibrosis available. The main goal of the RuNNINg project is to develop a nanoparticle-based gene drug for the treatment of intestinal fibrosis. Novel nanocarriers loaded with a nucleic acid drug that controls a protein involved in the development of fibrosis will be developed. These nanoparticles must penetrate the mucus lining of the intestine to be delivered in a targeted way to the inflammatory cells of the intestinal wall. The particles will therefore be surface decorated with ligands that specifically recognize these cells in the intestinal wall. Finally, the nanoparticles must be embedded into a gel, so they can be administered to the patients either orally or rectal. All novel nanomedicines will be carefully characterized, and efficacy and toxicity tested in cell-based assays and in vivo in mouse models. At the end of the project, hopefully a novel nanomedicine product candidate will be ready for further preclinical assessment and clinical studies. Regulatory, ethical and market topics will be taken in consideration in all steps of the product development. The consortium had in January 2020 a kick-off video meeting for detailed planning of the work of the first year. Regular update video meetings were organized every 3rd month. Unfortunately, the COVID-19 pandemic reduced the project laboratory activity significantly during the first year. In 2021 the activity increased compared to 2021, but still some partners were not able to work at full scale and therefore the amount of material received was reduced. Due to the delays, the consortium applied for a cost neutral prolongation for the project, which was approved by all partner countries. The new end date of the project is 31/12/2023. In September the first face-to-face consortium meeting was held in Milan. This meeting was of high importance as it resulted in a lot of fruitful discussions which resulted in a concreate progress plan for the final 15 month of the project. During the last year we have performed a multilaboratory analysis of the nanoparticles that the Italian partner produces. Through this study we have been able to conclude the shelf life of empty nanoparticles by comparing the results from three different institutions. In addition, we have analysed tissue samples from the in vivo studies performed by the Greek partner. They administer a variant of the nanoparticles which have radioactive isotopes attached to the surface of the nanoparticle. When the radioactivity had disappeared, SINTEF received tissue samples for analysis by ICP-MS. The results from the in vivo measurements and ICP-MS will be used to elucidate the biodistribution of the particles. New tissue samples are expected in 2022 which will also include negative control animals and the feed and water for the animals, as some of the isotopes analysed are naturally abundant in the tissue of the animals. SINTEF has characterized particle suspensions supplied by the partners for sterility and endotoxin content, which are important indicators for the purity and quality of the samples. Further-more, SINTEF has worked on establishment and validation of model systems for uptake and transport of particles across the colon epithelial barriers. This includes establishment of a IBD model system based on cells isolated from patient samples cultured in three-dimensional cultures, which is expected to give more accurate data on uptake and effect of the particle suspensions evaluated than traditional cell line-based systems. In addition to low stability, it was detected during the first months that the Italian partner is not able to produce particle dispersions with high enough concentrations for use in later in vivo studies. SINTEF has therefore together with the Italian partner started to develop a suitable process for concentrating the dispersion. This activity is also more challenging than anticipated, primarily due to the low stability of the particles. At this point we are still in the development process for particles of high enough stability.

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RuNNINg er et transnasjonalt Europeisk prosjekt (Euronanomed III) med partnere fra Italia (koordinator), Hellas, Frankrike og Norge. Konsortiet består av eksperter innen nanobærerutvikling og formulering, karakterisering av nanomedisiner, cellebiologer og kliniske spesialister for tarmsykdommer, som for eksempel inflammatorisk tarmsykdom (IBD) og Crohns sykdom. Fibrose i tarm, en skade som oppstår i tarmvev som følge av kronisk betennelse, er en alvorlig komplikasjon hos pasienter med kroniske inflammatoriske tarmsykdomer, eks. Crohns sykdom. Det finnes i dag ingen behandling for fibrose i tarm. Prosjektets hovedmål er å utvikle en nanopartikkelbasert genmedisin for behandling av fibrose i tarm. Nye nanobærere fylt med et nukleinsyre-basert medikament, som kontrollerer et protein som har vist seg å være involvert i utviklingen av fibrose, vil bli utviklet. Slike nanopartikler må kunne penetrere tarmslimhinnen og bli levert målrettet til de inflammatoriske cellene i tarmveggen. Partiklene vil derfor overflatedekoreres med ligander som er spesifikk mot disse cellene i tarmveggen. Til slutt må nanopartiklene støpes i en gel, slik at de kan gis til pasientene enten oralt eller rektalt. Alle nye nanomedisiner vil bli nøye karakterisert og effekt og toksisitet testet i celle-baserte analyser og in vivo musestudier. Etter endt prosjekt håper man å ha utviklet et nytt nanomedisinprodukt for behandling av fibrose i tarm, klar for videreutvikling og kliniske studier. Regulatoriske, etiske og markedsmessige spørsmål vil bli inkludert på alle trinn av produktutviklingen.

Funding scheme:

NANO2021-Nanoteknologi og nye materiale