Non-Alcoholic Fatty Liver Disease: Groundbreaking work using an RNA inhibitor approach gives hope for a future cure

Non-Alcoholic Fatty Liver Disease: Groundbreaking work using an RNA inhibitor approach gives hope for a future cure

Non-Alcoholic Fatty Liver Disease (NAFLD) is a major health problem affecting approximately 30 percent of the population in western countries and in sharp increase over the last three decades. Despite several attempts and ongoing clinical trials, there is currently no approved treatment for this serious and potentially life-threatening disease. In one out of five cases, steatosis leads to cirrhosis, which may require a liver transplant. 
In the past, some human genetics studies have linked PCSK7 variants to lipid metabolism. But in this groundbreaking work,  Dr. Nabil G. Seidah’s team at the Montreal Clinical Research Institute (IRCM) found that the PCSK7 gene produces a chaperone PCSK7 protein that regulates apoB, the main protein of LDL cholesterol particles. Dr. Seidah, who is also Full Professor at Université de Montréal’s Faculty of Medicine, also found that removing PCSK7 leads to a 50% degradation of apoB and prevents hepatic steatosis. Moreover, it leads to effective recovery of the liver from diet-induced NAFLD (decreased lipids, inflammation, hepatocyte ballooning and fibrosis in the liver).

A Fruitful Collaboration Around an RNA-Based Therapeutic Approach
For this research, Dr. Seidah’s team joined forces with Dr. Martin Sauvageau's lab to develop an RNA-based therapeutic approach to silence PCSK7, using antisense oligonucleotides (ASO) that have galactose (GalNAc) moieties attached to it, to specifically bring the ASO to liver hepatocytes and induce the degradation of PCSK7 mRNA.

Why This Research Matters
Injecting this ASO in mice reversed the diet-induced NAFLD, indicating that this may serve as a promising new target for NAFLD. The team already has ASO to target the human PCSK7 gene. Tests are ongoing to determine if their effect is recapitulated in human cells and soon in humanized PCSK7 mice, which would then open the door to clinical trials.

The Brand-New Sidney-Altman RNA Therapeutic Hub
The development of this ASO-based therapeutic approach is part of the new Sidney-Altman RNA Therapeutic Hub at IRCM, which will allow the development (design, synthesis, screening, and pre-clinical) testing of RNA therapies to help bring the discoveries from labs across a network of hospital and research centers closer to the clinic. 

The team wants to thank Vatsal Sachan, Mailys Le Dévéhat and many members of the Seidah lab, as well as Jean-François Laurendeau from the Sauvageau lab. This work was supported in part by a CIHR Foundation grant (NGS: # 148363), a Canada Research Chairs in Precursor Proteolysis (NGS: # 950-231335), a CIHR operating grant (MF: # 93581) for the human data, and a Leducq Foundation grant (NGS: # 13 CVD 03). We also thank Univalor/Liphorus Inc: Économie, Sciences et Innovation Québec (PSO3) for supporting this work.

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