Over two decades ago, the Human Genome Project revealed that 98% of the human genome sequence resides outside of protein-coding genes. In the FANTOM (FunctionalAnnotation of Mammalian cDNA) and ENCODE (Encyclopedia of DNA Elements) Consortia, we demonstrated that two-thirds of human genes do not encode proteins, and that most human long non-coding RNA (lncRNA) genes lack evolutionary conservation beyond primates [1-3]. The current GENCODE catalog of 75,000 human genes remains fully consistent with those early conclusions. LncRNA genes are now recognized as the most abundant class of human non-coding RNA genes. An order of magnitude more abundant than microRNAs, lncRNAs exhibit protean versatility as positive and negative, epigenetic and post-transcriptional, global as well as gene-specific regulators. We previously described certain primate-specific lncRNAs as contributors to the etiology of human pediatric neocortical epilepsy [4] and as estrogen-induced oncogenes as well as estrogen-repressed tumor suppressors in estrogen receptor positive human breast cancer [5]. Our group’s other current initiatives explore disease-causative lncRNAs in female reproductive biology, including preterm birth and the polycystic ovary syndrome. However, here we focus on an lncRNA contributor to metabolic disease. Interrogating the genomewide overlap of all significant disease-associated genetic variants from Genome-Wide Association Studies (GWAS) with all promoters and exons of lncRNA genes, we identified 475 primate-specific lncRNAs implicated by genetic evidence as causal contributors to common diseases, including type 2 diabetes. We manually annotated, and functionally validated in the laboratory, the primate-specific lncRNA LOC157273 [6], which - when it contains the disease-risk allele of the exon 2 SNP rs4841132 - leads to high fasting
glucose levels by suppressing its neighbor gene PPP1R3B (responsible for converting blood glucose into liver glycogen), as a direct T2D causal candidate. We confirmed the safety and non-toxicity of multiple siRNA-based, LOC157273-suppressing drug candidates in Macaca
fascicularis, demonstrating that LOC157273 is a liver-specific target for RNAi-based T2D treatments. Its knockdown in vivo in this cynomolgus monkey model reduces fasting glucose levels and rescues liver glycogen storage, concomitant with decreased HbA1c and
cholesterol levels. We subsequently tested the egicacy of our top-lead LOC157273- suppressing siRNA in a spontaneous diet-induced T2D and obesity model in the cynomolgus monkey. We showed that our siRNA drug against this primate-specific target is well-tolerated, and leads to a 10% weight loss and 10% BMI reduction within 1 week of a single-dose administration. Weight is not regained after 1 month, despite continuation of a high-fat Western diet. We conclude that anti-LOC157273 siRNA drugs may replace insulin for T2D treatment and may also replace GLP1 receptor agonists (e.g. Ozempic) for the treatment of obesity, and more generally, that – despite their recent evolutionary origins – primate-specific lncRNAs directly contribute to common human diseases where they can be targeted by sequence-based therapeutics.