Antisense Oligonucleotide-Based Technology to Fight the Global Obesity Crisis

Baker Heart and Diabetes Institute Background
According to the World Health Organization, obesity is a key risk factor for “premature deaths from non-communicable diseases – the world’s leading cause of death” and therefore requires “urgent and targeted intervention”. Obesity affects more than 650 million adults worldwide and an estimated 40 million children will suffer from obesity or overweight in the next decade; leading to a rise in cardiovascular disease, type 2 diabetes, various forms of cancer, as well as mental health issues in the coming years.
Recently, a dual GLP-1/GIP receptor agonist and a GLP-1/GIP/GCG receptor triagonist attracted a lot of attention as potential treatments for diabetes and obesity. The interest in the development of therapeutic molecules in this area is therefore raising, with a market expected to reach US$27.1 billion by 2028 (CAGR 16.7%).
Technology Overview
The Baker Institute researchers have identified proteasome modulator 9 (PSMD9) as a therapeutic target for obesity. In one of the world’s most in-depth examinations into proteome and lipidome variation published in Nature, the researchers demonstrated that PSMD9 protein expression is correlated with the plasma and liver levels of several lipid species. Using the UK Biobank database (500k participants), the researchers recently showed that the liver expression of PSMD9 is highly correlated with lipid metabolism and adiposity in humans, supporting previous genome-wide association studies (GWAS) linking PSMD9 to obesity and diabetes. 
In mice, induced overexpression of PSMD9 increased liver and circulating lipids, while its silencing decreased the expression of genes and proteins involved in de novo lipogenesis as well as lipid levels . In this context, anti-sense oligonucleotides (ASOs) with a favorable toxicity profile have been selected to silence PSMD9 expression (PSMD9-ASO) in mice fed with a western diet. A first long-acting ASO, inclisiran (Novartis), has recently been approved by the FDA/EMA and is expected to be a “game-changer” in hypercholesterolemia management in patients, with only 2 administrations a year, assuring better treatment compliance. 
The data shows that PSMD9-ASO administration once weekly over 28 days reduces fat mass and body weight gains in mice fed with a high-fat diet compared to the animals treated with control . In addition, PSMD9-ASO treatment improves blood glucose as well as hepatic steatosis, fibrosis and inflammation. The researchers are confident that transitioning in humans, a unique dose twice per year should be sufficient to significantly reduce patients’ body weight, constituting a competitive advantage compared to current anti-obesity strategies.
Stage of Development

Proof of concept: preclinical data available (in vivo).
Extensive in vitro profiling available. 

Further Detail
Mini-Review: Keating MF, Drew BG, Calkin AC. Antisense oligonucleotide technologies to combat obesity and fatty liver disease. Front. Physiol. (2022).
Benefits

Potential durability of pharmacological action, assuring patient compliance (2 doses/year). Once weekly administration in mice reduces body weight gain, fat mass gain and improves blood glucose, hepatic steatosis, fibrosis and inflammation
Well-tolerated, low toxicity, ASO already tested in humans 
Privileged access to various established animal models, metabolomic core facility and an internationally recognized team successful in the generation of IP leading to commercial and clinical outcomes

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