Nagy Habib discussed the subcutaneous delivery of siRNA, focusing on its potential to downregulate toxic proteins associated with diseases. He explained the differences between transcription in the nucleus and translation in the cytoplasm, emphasising the goal of silencing gene expression. Habib likened the process to a French accordion, where opening the chromatin allows RNA polymerase to express the gene. He provided an example with interleukin 10 (IL10), demonstrating a twenty-fold increase in polyadenylated mature mRNA expression in cells where IL10 was initially not expressed.
Habib highlighted the importance of bringing gene expression back to normal levels rather than achieving super-physiological levels, distinguishing their approach from gene therapy. He addressed concerns about off-target effects and toxicity, noting that their method aimed to restore normality. The presentation also covered the development of a drug targeting multiple genes, including IL10, IL19, IL20, and IL24, which are relevant for autoimmune diseases like multiple sclerosis and ulcerative colitis.
The development process involved bioinformatics to identify the best RNA activation sequences, followed by optimisation through nucleotide walks. Chemists played a crucial role in refining the sequences, sometimes testing hundreds of oligos to find the most effective one.
The presentation also touched on the use of saRNA for CEBP alpha, a master regulator in white blood cells, and its potential in treating cancer. Habib described how the drug could upregulate gene expression and downregulate inflammatory markers. He provided examples of successful treatments in patients with liver metastasis, highlighting the long-lasting effects and the potential for combination with immune checkpoint inhibitors.
Habib concluded by discussing the versatility of their approach, which could be applied to various genes and diseases. He emphasised the importance of selecting the right biomarkers for patient treatment and the potential for reducing the cost of gene therapy.
