Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Novel therapeutic approaches to cure chronic HBV infection

25.04.2013
Exciting new data presented today at the International Liver Congress™ 2013 include results from early in vitro and in vivo studies targeting covalently closed circular DNA (cccDNA), which may form the basis of a cure for chronic hepatitis B virus (HBV) infection.

HBV cccDNA is organized into mini-chromosomes within the nucleus of infected cells by histone and non-histone proteins. Despite the availability of efficient therapies against HBV, long-term persistence of cccDNA necessitates life-long treatments to suppress the virus. The following three experimental studies demonstrate effective HBV-cccDNA targeting/depletion using novel therapeutic approaches which offer the potential of a cure.

Liver regeneration induces strong reduction of viral replication and cccDNA levels, but not complete cccDNA eradication; without antiviral treatment, de novo HBV infection can be re-established.

Key findings of research in HBV-infected human hepatocytes using the uPA/SCID chimeric mouse system show that liver regeneration induces strong reduction of viral replication and cccDNA levels, with rapid formation of cccDNA-free hepatocytes. However, because complete cccDNA eradication is not achieved, in the absence of antiviral treatment, de novo HBV infection could be re-established in quiescent (non-dividing) human hepatocytes. This suggests that induction of hepatocyte turn-over together with antiviral drugs inducing viral suppression, such as nucleoside analogues and IFN, or blocking cell entry, may accelerate the clearance of the viral minichromosome.

Targeting epigenetic control of nuclear cccDNA minichromosome to suppress HBV transcription and replication may form basis for other therapeutic approaches to curing chronic HBV infection.

In the infected liver cell the rate of replication of HBV is regulated by the acetylation or methylation of histone proteins which surround the cccDNA minichromosome – so called epigenetic regulation. In a separate innovative study, the suppression of HBV transcription and replication by small molecules that target the epigenetic control of nuclear cccDNA minichromosome was investigated. The different classes of small molecules studied included: Class I, II and III histone deacetylase inhibitors (HDACi); p300 and PCAF histone acetyltransferases (HAT) inhibitors; hSirt1 activators; JMJD3 histone demethylase inhibitors.

The combined inhibition of p300 and PCAF HATs resulted in an evident reduction of HBV replication which mirrored the decrease of pgRNA transcription. The hSirt1/2 activator MC2791 and the JMJD3 inhibitor MC3119, albeit with different efficiency, inhibited both HBV replication and cccDNA transcription. Results represent a proof of concept that activation of hSirt1 and Ezh2 (through the inhibition of its functional antagonist JMJD3) by small molecules can induce an active epigenetic suppression of HBV cccDNA minichromosome similar to that observed with IFNá, and lead to persistent cccDNA silencing.

Lymphtoxin beta receptor (LTbR) agonisation represents basis for novel alternative therapeutic approach to curing chronic HBV infection.

The final study demonstrated that stimulating the lymphtoxin beta receptor (LTbR) provides an effective, long lasting and non-cytopathic mechanism for achieving effective HBV-cccDNA depletion in infected hepatocytes. Cell culture models including HBV-infected HepaRG cells and primary human hepatocytes were used to test the effect of antibodies stimulating human LTbR (BS1 or CBE11). Results show that a strong and dose-dependent anti-HBV effect was achieved by activation of the LTbR. All HBV replication markers were decreased with this treatment, including cccDNA in cells where HBV infection was already established.

Hepatitis B is the most prevalent cause of chronic viral hepatitis and a major global health problem. Prof. Fabien Zoulim, EASL Educational Councillor commented on the exciting new data: "In chronic hepatitis B infection, the viral genome forms a stable minichromosome - the covalently closed circular DNA (cccDNA) - which can persist throughout the lifespan of the hepatocyte."

"Current treatments focus on suppression of HBV and discovery of compounds directly targeting cccDNA has been one of the major challenges to curing HBV infection; but these preliminary data show novel therapeutic approaches can be applied to successfully target cccDNA with the long-term aspiration of finding a cure" added Prof. Fabien Zoulim.

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL's main focus on education and research is delivered through numerous events and initiatives, including:

The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide

Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year

Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology

Journal of Hepatology published monthly
Participation in a number of policy initiatives at European level
About The International Liver CongressTM 2013
The International Liver Congress™ 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 – 28, 2013. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

References:

1 Allweiss L et al, PROLIFERATION OF HEPATITIS B VIRUS INFECTED HUMAN HEPATOCYTES INDUCES SUPPRESSION OF VIRAL REPLICATION AND RAPID CCCDNA DECREASE IN HUMANIZED MICE. Presented at the International Liver Congress™ 2013

2 Palumbo GA et al, SUPPRESSION OF HEPATITIS B VIRUS (HBV) TRANSCRIPTION AND REPLICATION BY SMALL

3 MOLECULES THAT TARGET THE EPIGENETIC CONTROL OF NUCLEAR CCCDNA MINICHROMOSOME. Presented at the International Liver Congress™ 2013 4 Lucifora J et al, LYMPHOTOXIN BETA RECEPTOR ACTIVATION LEADS TO DEGRADATION OF HBV CCCDNA FROM INFECTED HEPATOCYTES. Presented at the International Liver Congress™ 2013

Dimple Natali | EurekAlert!
Further information:
http://www.easl.eu/

More articles from Health and Medicine:

nachricht The cytoskeleton of neurons has been found to be involved in Alzheimer's disease
18.01.2019 | University of the Basque Country

nachricht Bioinspired nanoscale drug delivery method developed by WSU, PNNL researchers
10.01.2019 | Washington State University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Ten-year anniversary of the Neumayer Station III

The scientific and political community alike stress the importance of German Antarctic research

Joint Press Release from the BMBF and AWI

The Antarctic is a frigid continent south of the Antarctic Circle, where researchers are the only inhabitants. Despite the hostile conditions, here the Alfred...

Im Focus: Ultra ultrasound to transform new tech

World first experiments on sensor that may revolutionise everything from medical devices to unmanned vehicles

The new sensor - capable of detecting vibrations of living cells - may revolutionise everything from medical devices to unmanned vehicles.

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Additive manufacturing reflects fundamental metallurgical principles to create materials

18.01.2019 | Materials Sciences

How molecules teeter in a laser field

18.01.2019 | Life Sciences

The cytoskeleton of neurons has been found to be involved in Alzheimer's disease

18.01.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>