🔎 In this video, Milo Malanga from CarboHyde explains how cyclodextrins are being harnessed to support the safe and effective delivery of RNA-based therapies for Crohn’s disease within the GENEGUT project.
🔬 GENEGUT is developing a first-in-class oral RNA-based therapy to target intestinal inflammation at its source, and cyclodextrins are playing an essential role.
The RNA delivery will be enabled by a combination approach using novel Biomaterials, including patented amphiphilic cyclodextrins and amino polyesters, are designed to protect and carry RNA through the gastrointestinal tract by forming nanoparticles.
Today’s cyclodextrin was a little gift under CarboHyde’s and GENEGUT’s Christmas tree.
This study identified the structural modifications that enhance gene delivery activity of a range of cationic amphiphilic CDs, including both β- and γ-CD.
Each CDs incorporated a C12 lipid chain on the primary face of the CD. On the secondary rim, at positions C2 and C3, either primary or tertiary amine groups.
A comparative in vitro study was conducted to assess the gene silencing efficacy of these nanoparticles using the luciferase reporter gene in A549-luc cells.
Gene silencing levels for both β- and γ-CDs increased when modified with a primary amine compared to a tertiary amine group at position C2. Gene expression inhibition was further improved when the CDs were functionalized with amine functionalities at positions C2 and C3.
Modification of the secondary side of γ-cyclodextrins with two sets of primary amine functionalities via a thiopropyl linker, as compared to a triazole linker, achieved up to 80% gene knockdown, regardless of dose.
Check out the most recent paper of our collaborators in the GENEGUT Horizon Europe consortia presenting cyclodextrin-based nanoparticles for delivery of antisense oligonucleotides targeting huntingtin. Even if we were not part of this story, we are proud to get involved in the next chapter!
GENEGUT, a research project funded by Horizon Europe, is to develop the first oral RNA-based therapy for ileal Crohn’s Disease (CD) – a chronic inflammatory disease of the intestine. The work is set to start on 1st October 2022 and last for four years. The consortium is made up of nine partners from eight European countries, who are all leading experts in their field. CarboHyde will play a crucial role by kick-starting the project by developing custom-made cyclodextrin derivatives, which will help to deliver their RNA cargo to the small intestine.
Addressing the major medical need of Crohn’s Disease
Crohn’s disease (CD), one of the two major disorders under the umbrella term of IBD (Inflammatory Bowel Disease), is a highly prevalent and high-burden chronic inflammatory condition of the gastrointestinal tract (GIT). With up to 3 million people affected in Europe alone, the chronic disease has an accelerating incidence – leading to health costs of over 5 billion euros per year. Most significantly, however, there is no satisfactory treatment.
Role of CarboHyde
The challenging task of CarboHyde will be synthesizing amphiphilic cyclodextrins, which will be used to formulate nanoparticles containing the RNA cargo. CarboHyde will synthesize a library of amphiphilic cyclodextrins, including ones with different excipients, like polyethylene glycol or lipids. Chemically different variations of these excipients will be studied to select the best-performing ones. Nanoparticle formulations with the best working amphiphilic cyclodextrins will be tested to withstand the intestinal environment in different in vivo and in vitro models.
CarboHyde hired a Ph.D. student, Kristof Felegyi, to help the project progress.
Bringing together a multidisciplinary, European network
The expertise required to achieve this ambitious aim is as diverse as the nine partners from eight European countries that will collaborate in GENEGUT.
The project, coordinated by the School of Pharmacy of University College Cork, brings together the European Federation of Crohn’s & Ulcerative Colitis Associations with renowned researchers, expert clinical scientists, SMEs, and large pharma companies with expertise and patented technologies in global proteomics, nanotechnologies, cyclodextrin synthesis, multicellular models, drug delivery systems and production as well as innovation management, stakeholder involvement, and science communication.
A library of novel biomaterials will be synthesized and used to formulate nanoparticles containing therapeutic RNA (siRNA and mRNA). A quality-by-design approach will be applied to develop the nanoparticles for filling into capsules. The resulting nanoparticles will be assessed for safety and efficacy, including the mechanism of action, in a range of advanced in vitro and in vivo models of intestinal inflammation. The clinician, with expertise in diagnosing and treating CD patients based in UCC, will support and guide the overall project ensuring clinical relevance and providing advice on coherent plans for early clinical trials and regulatory submission, thus enabling rapid availability for patients.
Follow the progress of GENEGUT at www.genegut.eu and on Twitter and LinkedIn @GENEGUT_EU to learn about the project’s steps toward a better cure for Crohn’s Disease.
Network
University College Cork, Ireland
Bangor University, United Kingdom
Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Portugal
