Periodic Reporting for period 1 - GENEGUT (Oral delivery of encapsulated RNA nanotherapeutics for targeted treatment of ileal Crohn's disease)
Periodo di rendicontazione: 2022-10-01 al 2024-03-31
The main aim of GENEGUT is to develop an orally administered medicine containing RNA to treat ileal Crohn’s disease. The success of the Covid 19 vaccine which contained mRNA, a nucleic acid, as the active ingredient has given confidence to the public in general that medicinal products containing RNA are safe and effective. In the research world, this has opened up the opportunity of using this type of therapy to treat more complex diseases such as Crohn’s disease. Inflammatory bowel disease (IBD), including Crohn’s disease, affects over 3M people in Europe alone and this number is on the increase. It is a chronic debilitating condition which severely affects the quality of life of patients and their families. While medicines do exist for Crohn’s Disease they are largely unsatisfactory, many patients are frequently hospitalised and many ultimately undergo surgery to alleviate the condition. In addition to the significant stress on the patient, management of this disease imposes a major drain on healthcare budgets. Consequently, there is an urgent need to develop more effective medicines including those based on RNA. However, to achieve the maximum therapeutic benefit from RNA, a means of ensuring it is delivered to the site of disease is the main challenge to enabling the widespread use of this medicine.
While oral administration is more acceptable to patients, as it avoids injections and allows self-administration, it can be a hostile environment for certain medicines. To achieve successful oral delivery the RNA, which is a fragile molecule, must be protected from degradation by enzymes as it travels down the gastrointestinal tract to ensure it arrives intact at the site of the inflammation. The main objectives of GENEGUT are: (1) to design and synthesise packaging materials capable of making nanoparticles which contain and protect the RNA (WP1); (2) to test the stability and efficacy of the nanoparticles in cell culture models of the disease (WP2); (3) to prepare capsules, containing the nanoparticles, which can be taken orally and which will travel down the gastrointestinal tract (GIT) and release the nanoparticles at the Crohn’s disease site (WP3); (4) to evaluate the best nanoparticles in a pig model with Crohn’s disease; (WP4) to determine the willingness of stakeholders to prescribe this medicine; and (6) to estimate the cost and value for money of producing this RNA medicine (WP5). At the end of GENEGUT, we plan to have proof, from results obtained in the preclinical disease models, that the oral RNA medicine developed is safe and effective. This RNA medicine would then be suitable for testing in the clinic in a follow-up study. A successful innovative RNA medicine would revolutionise the treatment of Crohn’s disease thus improving the quality of life of millions of patients and reducing the drain on healthcare budgets.
While oral administration is more acceptable to patients, as it avoids injections and allows self-administration, it can be a hostile environment for certain medicines. To achieve successful oral delivery the RNA, which is a fragile molecule, must be protected from degradation by enzymes as it travels down the gastrointestinal tract to ensure it arrives intact at the site of the inflammation. The main objectives of GENEGUT are: (1) to design and synthesise packaging materials capable of making nanoparticles which contain and protect the RNA (WP1); (2) to test the stability and efficacy of the nanoparticles in cell culture models of the disease (WP2); (3) to prepare capsules, containing the nanoparticles, which can be taken orally and which will travel down the gastrointestinal tract (GIT) and release the nanoparticles at the Crohn’s disease site (WP3); (4) to evaluate the best nanoparticles in a pig model with Crohn’s disease; (WP4) to determine the willingness of stakeholders to prescribe this medicine; and (6) to estimate the cost and value for money of producing this RNA medicine (WP5). At the end of GENEGUT, we plan to have proof, from results obtained in the preclinical disease models, that the oral RNA medicine developed is safe and effective. This RNA medicine would then be suitable for testing in the clinic in a follow-up study. A successful innovative RNA medicine would revolutionise the treatment of Crohn’s disease thus improving the quality of life of millions of patients and reducing the drain on healthcare budgets.
In the first 18 months of the GENEGUT project implementation, two families of novel biomaterials have been synthesised as packaging materials to protect the RNA from degradation. Using these materials, nanoparticles containing RNA have been prepared and fully characterised for size, charge and loading capacity. Initial toxicity evaluations show they are safe. Studies to evaluate the stability of the nanoparticles in simulated intestinal fluids are also underway. A range of complex, innovative cell culture models of Crohn’s disease, including 3D cell models, have been established and validated. The ability of the RNA-containing nanoparticles to enter the cells and modulate gene expression has been monitored and based on these efficacy results, several ‘lead’ formulations have been identified for further investigation. The design of capsules, facilitating oral administration, is well advanced and test capsules have been fabricated which will facilitate travel down the GIT allowing site-specific release of the nanoparticles at the location of Crohn’s disease. Initial studies to determine the best capsule size for oral administration to pigs have taken place and planning is underway for a study in pigs with Crohn’s disease.
The current materials used for the oral delivery of RNA have to date been unsatisfactory. In GENEGUT, the design and synthesis of a library of novel biomaterials represent a notable achievement which will help to advance research in the oral delivery of therapeutic RNA. In addition, a range of cell culture models reproducing the disease microenvironment will help to more accurately monitor the efficacy of the formulations and help to predict outcomes in patients. The planned study in pigs with IBD will also be a first and comparisons of the results will indicate the ability of the cell culture models to predict the in vivo data. The health technology assessment (HTA) is ongoing, including a full review of the likely regulatory requirements for an oral RNA medicine, which will help to attract future investors capable of advancing the medicine into the clinic.