Nagy Habib, Founder & Chair of the Scientific Advisory Board at MiNA Therapeutics discussed RNA activation and RNA delivery across a range of therapeutic areas including NASH, rare genetic diseases, and cancer. Habib began by explaining the key differences between siRNA and saRNA: “So saRNA and siRNA can be used really in most genes, but the saRNA are for diseases where there is low expression of the gene of protein. siRNA is a reverse of this, it's when you have a high expression of a toxic gene and you want to bring it down.”
In several autoimmune diseases, the IL-10 gene is repressed but saRNA can upregulate up to 20-fold. In fact, saRNA can upregulate other interleukin genes in autoimmune diseases including IL-19, IL-20, and IL-24 by targeting the enhancer that controls the promoters. Habib outlined how his team spent 20 months producing their first clinical saRNA called MTL-CEBPA which was used in three clinical trials. The main purpose of CEBP alpha is to prevent immunosuppression by tumour-associated macrophages. Habib explained CEBPA’s role as a master regulator: “It regulates more than 500 genes that's why it's called master regulator and it leads to the differentiation of the cell, the normal monocyte macrophage and dendritic cell.” However, in cancer and chronic inflammation, there is very little CEBPA leading to malformation of myeloid cells.
140 patients were injected with empty CEBPA, the first study was on liver cancer, and it was with thyroid kinase inhibitor while the second study was conducted on solid cancers. One example highlighted a patient with lung cancer, initially presenting with six metastases in the right lung and ten in the left lung, who achieved complete clearance following treatment with MTL-CEBPA and Sorafenib. Four years later, the patient remains recurrence-free.These promising results showed the ability of MTL-CEBPA to modulate immune responses by reprogramming macrophages to anti-tumoural states.
Habib also discussed the use of saRNA in other conditions, including brain inflammation, neurodegenerative diseases, and rare genetic disorders such as Hurler's disease. saRNA was shown to downregulate inflammatory markers in the brain, promote weight loss, and improve liver function in mouse models of fatty liver disease (NASH).
He argued that while most scientists would suggest that GalNAc technology is the optimal way of delivering siRNA to the liver, one should note that the FDA has approved 6 drugs for the liver based on GalNAc but none for NASH. He urged the audience to consider alternative options to GalNAC. In Hurler’s disease, saRNA increased enzyme production in donor cells, potentially improving outcomes for affected children.
RNA activation is highly versatile and its ability to precisely upregulate gene expression without long-term genetic alterations is particularly noteworthy. Habib aims to further investigate future applications of saRNA in rare genetic diseases and other unmet medical needs through collaboration. He concluded: “As people say, it takes a village. 140 patients, 20 hospitals, 7 countries, the MiNA therapeutic team that developed the RNA activation and so many people contributed, City of Hope with John Rossi and his team, especially their collaborations and another company called APTERNA.”