Aro Biotherapeutics, a clinical-stage biotechnology company developing potent and tissue-targeted short-interfering RNA (siRNA) medicines, has announced preclinical data highlighting the therapeutic potential of its proprietary CD71 Centyrin – IFIH1 siRNA conjugate for the treatment of Type 1 diabetes.
IFIH1/MDA5 is a genetically validated but historically intractable target in autoimmune diseases, including type 1 diabetes (T1D). Small molecule inhibitors have been unsuccessful, and monoclonal antibody strategies are not viable due to the intracellular localisation of the MDA5 protein.
Systemically delivered oligonucleotides are largely restricted to the liver, significantly limiting extrahepatic targeting. Aro’s clinically validated CD71 targeting Centyrin is conjugated to an siRNA against IFIH1 mRNA (which encodes for the MDA5 protein) for delivery to CD71 receptor-expressing cells, including immune cells and the pancreas. The conjugate was tested on primary human immune cells in vitro and tested systemically in a murine model of T1D for efficacy.
In vitro, the conjugate demonstrated efficient uptake and robust target knock down in primary human dendritic cells, resulting in attenuation of type 1 interferon production, a known driver of T1D pathogenesis. In the hallmark non-obese diabetic T1D disease model in mice, the conjugate dramatically reduced blood glucose levels, resulting in suppression of overall T1D incidence as well as improved survival when compared to untreated controls. RNA sequencing of pancreatic tissue confirmed preservation of insulin production and genes associated with beta cell health in the conjugate treated animals.
