Leonard Lipovich, PhD

Professor (Research), Department of Biology, Wenzhou-Kean University, China

“Fat Monkey to Flat Monkey in a Week: The Power of Primate-Specific Long Non-Coding RNA (LncRNA)-Targeted Therapeutics from the GWAS-Transcriptome Interface in T2D, Obesity, Cancer, and Beyond”

Abstract

Over two decades ago, the Human Genome Project revealed that over 98% of the human genome sequence resided outside of protein-coding genes. In the FANTOM (Functional Annotation of Mammalian cDNA) and ENCODE (Encyclopedia of DNA Elements) Consortia, we laid the foundation for the current knowledge that two-thirds of the ~75,000 human genes do not encode proteins, and that most human long non-coding RNA (lncRNA) genes lack evolutionary conservation beyond primates. LncRNA genes are the most abundant class of human non-coding RNA genes. An order of magnitude more numerous than microRNAs, lncRNAs are versatile, both positive and negative, epigenetic and post-transcriptional, regulators of protein-coding genes. However, big pharma remains obsessed with protein-based pathways, even though only < 5,000 of the 20,000 protein-coding human genes are druggable and just < 1,000 of those have been drugged. We previously described primate-specific lncRNAs in epilepsy and cancer. Interrogating the genomewide intersection of significant disease-associated genetic variants from Genome-Wide Association Studies (GWAS) with promoters and exons of all lncRNA genes, we identified 475 lncRNAs as putative causal contributors to common diseases, including type 2 diabetes. We manually annotated, and functionally validated in the laboratory, the primate-specific lncRNA LOC157273, which - when carrying the disease-risk allele of the exon 2 SNP rs4841132 - causes high fasting glucose levels by suppressing its neighbor gene PPP1R3B (which converts blood glucose into liver glycogen), as a direct T2D causal candidate. We described gene structure differences of the human and Macaca fascicularis orthologs of LOC157273 and tested 2 siRNA-based drug candidates for safety and non-toxicity in this animal model, demonstrating that LOC157273 is a suitable liver-specific target for RNAi-based T2D treatments. Its knockdown in vivo reduces fasting glucose levels and rescues liver glycogen storage, concomitant with decreasing HbA1c, in healthy animals. A 10% reduction of body weight and abdominal circumference within a week of initial drug administration in a high-fat diet-induced T2D/obesity model was observed as well. These innovative therapeutics demonstrate early potential to replace insulin and GLP-1 receptor agonists in managing diabetes and obesity, respectively, within a nonhuman primate model. In parallel, we have shown dozens of primate-specific lncRNAs to be oncogenic in triple-negative breast cancer and AML. Evidently, human lncRNA genes with recent evolutionary origins in primates contribute to diverse disease etiologies and represent an important new class of druggable targets.