To meet the shortcomings of the current therapies, we designed MetraMorpheus. This mRNA-based therapy blocks the chemokine interleukin-8 (CXCL8), which has been proven to promote the progression of endometriosis.[9] It is blocked by the antibody O-1L8-15, produced inside the defective cells themselves upon receiving mRNA.
The mRNA is delivered by encapsulating inside lipid nanoparticles (LNPs) and injected through intravenous injections. Upon reaching the targeted tissue, the following pathway is activated:
However, IL-8 is an essential immunoregulator for the body. To ensure specificity to the disease process, we decorate an LNP with aptides – a peptide of 26 amino acids. It specifically targets the Extracellular Domain B of fibronectin [10], which is overexpressed in endometriotic tissue [11].
Proposed implementation
The proposed implementation of MetraMorpheus is shown here:
Essentially, this is an IV injection of an mRNA-LNP formulation. There are multiple methods of administration of drugs for endometriosis and other such reproductive disorders. In the next section, we explain the rationale behind this drug delivery option.
Rationale
The drug delivery systems that were open for use were:
- IUD’s,
- IM (Intramuscular)
- IV (Intravenous)
However, we chose IV, as though IUDs would be ideal and certainly preferrable to repeated IV injections given their excellent capacity for long-term drug delivery, considering the conventional mRNA’s thermostability, these would not be very effective in an IUD form. We decided against IM, as the distribution of I is very poor: As it is, due to First-Pass metabolism, the efficiency of an IV administration is greatly reduced.
Inspiration
To overcome the problems of existing methods, we looked at endometriosis from a fresh point of view: it is not hormone dependent only. Rather, it is also influenced heavily by immune dysregulation. While many theories remain to explain how the disease is established, we realised from our literature review that there is ectopic tissue in the peritoneum, and that it isn’t cleared up due to dysfunction of the immune system, leading to the chronic inflammation that is characteristic to endometriosis. We started collating literature to identify the targets of our treatment. The downregulation of chemokine IL-8 had the most favourable evidence in suppressing Endometriosis. We brainstormed various methods, including exosomes with miRNA, targeted fusion proteins, taking out cells and reinjecting them after genetic modification, etc. But the problem seemed to be that all of them were too expensive and had been tried without remarkable success. It was then that we were recommended to use LNPs for delivery of drug substance, which we later decided would be mRNA. Our Project, MetraMorpheus stems from the question “What if we make the defective tissue treat itself?” This can be an effective solution, eliminating the need for expensive therapies.
Now that we have learnt about the solution, let how we got inspired