Development of a mRNA based tretment to enahnce albumin production in experimental models of liver cirrhosis 

PI:

Salvatore Piano

Email:

salvatore.piano@unipd.it

Affiliation:

Dipartimento di Medicina - DIMED, Università degli Studi di Padova

ORCID:

0000-0002-9356-5830

The Unit of Internal Medicine and Hepatology of the University-Hospital of Padua deals with all diseases of internal interest, including disorders of the cognitive sphere, but in particular with liver diseases. The clinic is equipped for the diagnosis and treatment of all liver diseases, in particular viral hepatitis, liver cirrhosis and liver cancer. The selection for liver transplantation and the follow-up of the transplanted patient are carried out too. The main lines of research include studies on the progression of liver damage and complications of cirrhosis, liver carcinogenesis and development of new tumor markers, molecular characterization of hepatitis viruses and of resistance to antiviral therapy, as well as of splanchnic hemodynamics and renal physiopathology.

Albumin is the most abundant protein in human blood and has a wide range of biological activities including the capability to counteract inflammation and oxidative stress. Patients with cirrhosis, the 8th cause of death worldwide, suffer from hypoalbuminemia due to hepatocytes dysfunction and systemic inflammation. Hypoalbuminemia is a strong predictor of mortality and complication of cirrhosis. So far, liver transplantation is the only definitive treatment of cirrhosis. However, long-term administration of human albumin solution (HAS) is effective in reducing mortality and the occurrence of complications of cirrhosis. However, HAS is a blood derived product, is costly, has limited availability and requires weekly infusions.

We aim to develop a liver targeted polymeric nanoparticles (NPs) encapsulating human codon-optimized albumin mRNA (ALB), to improve albumin production in the liver of cirrhotic patients.

The project includes 3 main steps.

Step 1. In vitro study

Immortalized hepatocytes (HepG2) will be transfected with polyplexes made up of eGFP-mRNA and NPs (GFP-NPs) or albumin-mRNA and NPs (ALB-NPs).  GFP and Albumin localization and production in transfected cells at different time point will be assess.

Step 2. In vivo study in analbuminemic rat model

The next step involves the administration of ALB-NPs in analbuminemic rats to verify the ability of the polyplexes to induce albumin production and evaluate possible medium-term side effects. Rats will be followed in a 1-month time-course to prove the extent and the durability of the treatment.

Step 3. In vivo study in two cirrhotic rat models

Cirrhosis will be induced in Sprague-Dawley rats by bile duct ligation and thioacetamide using a standardized protocol. Rats will be treated weekly for a month. Weight and blood samples will be collected daily during the first week and then twice a week until the end of the treatment. The following parameters will be monitored in serum: albumin concentration, AST, ALT, bilirubin, creatinine, TNF-alpha, IL-6, IL-1beta, IL-10 and MDA. Rats survival will be recorded. Livers will be collected at the time of death or after 1 month at the time of the sacrifice (1 day after last dose of ALB-NPs). Albumin mRNA expression will be measured and compared to control rats and untreated rats.

This strategy would be the first one worldwide to provide a gene therapy to improve albumin production in experimental cirrhosis and can pave the way for a new treatment of liver cirrhosis.

Relevant Publications

  1. Gagliardi R, Zeni N, Piano S. Intravenous albumin in cirrhosis: Updated clinical uses and novel perspectives. Ann Hepatol. 2023 Sep 1;28(6):101150. doi: 10.1016/j.aohep.2023.101150. Epub ahead of print. PMID: 37659473.

  2. Piano S, Mahmud N, Caraceni P, Tonon M, Mookerjee RP. Mechanisms and treatment approaches for ACLF. Liver Int. 2023 Sep 16. doi: 10.1111/liv.15733. Epub ahead of print. PMID: 37715608.

  3. Tonon M, Piano S. Cirrhosis and Portal Hypertension: How Do We Deal with Ascites and Its Consequences. Med Clin North Am. 2023 May;107(3):505-516. doi: 10.1016/j.mcna.2022.12.004. Epub 2023 Feb 20. PMID: 37001950.

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