Unlike siRNA, small activating RNA (saRNA) increases therapeutic protein expression by acting in the nucleus on transcription. Nagy Habib, Lead Clinician and Head of the Department at Imperial College London, discussed his latest work on small activating RNA and its application in cancer and rare genetic disease spaces. He also highlighted the delivery of RNA to the brain.
saRNA functions by opening chromatin, increasing acetylation, and forming strong RNA-DNA bonds. These bonds are much stronger than double-stranded DNA and upregulate genes to suitable physiological levels.
Habib mentioned that with his system called saCEBPA oligo, it only acted as an off-target in 1.6% of the total genes analysed. Habib and his team developed a drug called MTL-CEBPA and injected it into 140 patients. Typically, when T cells try to kill cancer cells, they cannot because there is a myeloid suppressive “gate” that prevents T cells from attacking cancer. However, saRNA can remove this gate, thus enhancing immunotherapy outcomes.
Habib presented a case study of a patient with six metastases in the lung. Usually, this patient would have three to six months to live, but when the patient was treated with a combination of sorafenib and MTL-CEBPA, they lived 5 more years without recurrence. Habib noted that before receiving MTL-CEBPA, CD163 + M2 macrophages were abundant. But after six doses of MTL-CEBPA, the tumour biopsy showed no detectable CD163 + M2 macrophages.
From a rare disease angle, Habib is developing a small activating RNA to increase foetal haemoglobin. Although there are approved gene therapies for rare diseases, they cost around £3 million, meaning only a very small minority of patients can access these treatments. So, Habib has developed an alternative technology that costs around £500 per month, which is still expensive but more economically reasonable than the alternative options.
To deliver saRNA, Habib developed a transferrin receptor aptamer. This enables subcutaneous administration to reach the central brain regions relevant to neuroinflammation and Alzheimer’s. Overall, this extensive work on saRNA could have broad implications across multiple therapeutic areas and improve patient quality of life.
