Oligonucleotide therapies for nonalcoholic steatohepatitis

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Abstract

Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.

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Abstract

Wang and colleagues summarize pre-clinical and clinical studies that are undertaken by utilizing various types of delivery approaches to testify promising oligonucleotide-related therapeutic strategies for nonalcoholic steatohepatitis.

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Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

Zobair Younossi, Aaron Koenig, Dinan Abdelatif … (2016)

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver-related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random-effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (95% CI: 22.10-28.65) with highest prevalence in the Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity (51.34%; 95% CI: 41.38-61.20), type 2 diabetes (22.51%; 95% CI: 17.92-27.89), hyperlipidemia (69.16%; 95% CI: 49.91-83.46%), hypertension (39.34%; 95% CI: 33.15-45.88), and metabolic syndrome (42.54%; 95% CI: 30.06-56.05). Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69-47.13) and 0.09 (95% CI: 0.06-0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person-years (range, 0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33-1.77) and 11.77 per 1,000 person-years (range, 7.10-19.53) and 15.44 per 1,000 (range, 11.72-20.34) and 25.56 per 1,000 person-years (range, 6.29-103.80). Incidence risk ratios for liver-specific and overall mortality for NAFLD were 1.94 (range, 1.28-2.92) and 1.05 (range, 0.70-1.56).

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The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.

Naga Chalasani, Zobair Younossi, Joel E Lavine … (2018)

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Design and validation of a histological scoring system for nonalcoholic fatty liver disease.

David Kleiner, Elizabeth Brunt, Mark Van Natta … (2005)

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

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Author and article information

Contributors

Jun Xie

Yi Wang

Journal

Journal ID (nlm-ta): Mol Ther Nucleic Acids

Journal ID (iso-abbrev): Mol Ther Nucleic Acids

Title: Molecular Therapy. Nucleic Acids

Publisher: American Society of Gene & Cell Therapy

ISSN (Electronic): 2162-2531

Publication date PMC-release: 30 March 2024

Publication date Collection: 11 June 2024

Publication date (Electronic): 30 March 2024

Volume: 35

Issue: 2

Electronic Location Identifier: 102184

Affiliations

[1 ]Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China

[2 ]Department of Cardiology, The Third People’s Hospital of Chengdu, Chengdu 610031, China

[3 ]Department of Breast Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China

[4 ]Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA

[5 ]Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA

[6 ]Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA

[7 ]Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA

Author notes

[∗ ]Corresponding author: Jun Xie, PhD, Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. jun.xie@ 123456umassmed.edu

[∗∗ ]Corresponding author: Yi Wang, PhD, Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China. wangyi83@ 123456scu.edu.cn

[8]

These authors contributed equally

Article

Publisher Item ID: S2162-2531(24)00071-4 Publisher ID: 102184

DOI: 10.1016/j.omtn.2024.102184

PMC ID: 11044058

PubMed ID: 38665220

SO-VID: 2464c9a2-173e-43f2-b2ae-68f89ea7c909

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Oligonucleotide therapies for nonalcoholic steatohepatitis

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Most cited references 404

Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.

Design and validation of a histological scoring system for nonalcoholic fatty liver disease.

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