Professor Radboud University - RIMLS & Radboud University Medical Center, Gelderland, Netherlands
Therapeutic targeting of lncRNAs to treat inflammatory disease
Stephanie Fanucchi Msc.Ph.D 1 & Musa M. Mhlanga Msc., Ph.D 2,3,4
1Lemba Therapeutics, Jonkerbosplein 52, 6534 AB Nijmegen, The Netherlands; 2Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Epigenomics & Single Cell Biophysics Group, 3Department of Cell Biology, Radboud University, 6525 GA Nijmegen, the Netherlands; 4Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
Human innate immune cells exposed to pathogenic infections or pro-inflammatory stimuli develop enhanced immune responses upon re-infection or repeated pro-inflammatory stimuli with a secondary stimulus; a process termed trained immunity or innate immune memory. Trained immune responses have been shown to be dysregulated in inflammatory disease states such as sepsis, cancer and even autoimmune conditions such as rheumatoid arthritis. These innate immune memory responses are most noticeable in the myeloid compartment of the innate immune system. Accumulation of H3K4me3 epigenetic marks on multiple immune gene promoters are the basis of innate immune memory and underlie robust transcriptional responses during trained immune responses. Mechanistically, a newly identified subset of long non coding RNAs (lncRNAs), referred to as immune-gene priming lncRNAs (IPLs), regulate the acquisition of H3K4me3 epigenetic marks. This primes immune genes for rapid transcriptional responses during innate immune responses. Silencing of these IPLs abrogates the accumulation of H3K4me3 epigenetic marks at the promoters of these genes. Therefore, altering the activity of these lncRNAs using antisense oligonucleotide (ASO) GapMER technology represents a novel therapeutic approach to achieve discrete immunomodulation in inflammatory disease states. Using the proprietary MOSAICTM machine learning AI-engine we identified ASO candidates targeting IPLs with the highest potency and lowest toxicity. High scoring ASO candidates were tested in high-throughput, cell-based and phenotypic screens to assay IPL target inhibition and toxicity. Experimentally validated lead ASOs were therapeutically introduced in multiple relevant preclinical models. Lead ASOs significantly reduced systemic inflammation and mortality in a humanized mouse model of acute inflammation, attenuated tumour growth in a xenograft murine model of cancer and reduced inflammation-mediated choroidal neovascularization in a porcine model of wet age-related macular degeneration (AMD). Lead ASOs were also shown to reduce inflammatory gene expression and biomarkers in an explant model of synovial tissue obtained from human arthritic joints. Taken together, these data demonstrate that targeting lncRNAs with ASOs represents a promising new therapeutic strategy and drug class in achieving tailored immunomodulation in a wide range of inflammatory and oncogenic diseases.