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Editing genes to treat liver disease

- Deborah Minors

Gene silencing and gene editing are trail-blazing technologies against the hepatitis B virus, which infects 240 million people worldwide and kills thousands.


Patrick Arbuthnot delivered the 11th James HS Gear Memorial Lecture, entitled Advancing gene therapy to counter the global impact of infection with hepatitis B virus hosted by the Poliomyelitis Research Foundation on Monday, 14 November 2016.

Arbuthnot is a Personal Professor and the Director of the Wits/SAMRC Antiviral Gene Therapy Research Unit in the School of Pathology, Faculty of Health Sciences at Wits University. He was a James Gear postdoctoral Fellow in Necker, France, from 1992 to 1994 and has filed six patents on research topics that relate to gene therapies for treating viral infections.

Fifty years of Hepatitis B virus

The first marker of the hepatitis B virus (HBV) was discovered in 1963 by mathematician-turned-geneticist, Baruch S. Blumberg (1925–2011). He collected blood samples from diverse parts of the world to investigate what made humans more or less susceptible to infection. By chance, a research assistant, Barbara Walton, who donated blood suddenly tested positive for HBV. Blumberg subsequently discovered the ‘Australian antigen’ from an Aborigine. Blumberg won the Nobel Prize in Physiology or Medicine 1976 for “discoveries concerning new mechanisms for the origin and dissemination of infectious diseases”.

After discovering HBV, Blumberg was able to:

  • identify asymptomatic carriers of HBV (those who carried the virus but did become sick from it)
  • establish the link between HBV and liver cancer
  • improve the safety of blood transfusions
  • develop a vaccine

The year 2015 marked the 50th anniversary of the discovery of HBV which remains a global healthcare challenge in the 21st century.

“Hepatitis B virus is a very important global health problem at the moment. People don’t realise how significant infection with HBV actually is. HBV and hepatitis C virus (HCV) infection are significant in the number of deaths they cause in the world,” says Arbuthnot.

A persistent and perilous pathogen

HBV today chronically affects an estimated 240 million people.

“This puts people at very high risk for liver cancer. About 25 percent of chronic carriers will develop liver cancer,” says Arbuthnot.

A study published in Lancet in September 2016,  The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013 cites an increase in the number of deaths from HBV and HCV from 0.89 million in 1990 to 1.45 million in 2013. Although the increase in mortality is mainly ascribed to the increase in population sizes in the areas where the virus most commonly occurs, the numbers remain staggering.   

“This was a study that was carried out on all forms of hepatitis viruses – A, B, C and D – and HBV and HCV account for more than 96% of deaths; higher than in 1996, which was 92%. That’s 700 000 people who die per year as a result of HBV infection,” says Arbuthnot.

In 1997 HBV ranked tenth among global causes of death and advanced to seventh place in 2014 – higher than Tuberculosis, malaria and AIDS.

HBV is common in Africa and Asia. In Asia, transmission mainly occurs perinatally, i.e., from mother to baby during childbirth. In Africa, however, transmission is horizontal; children spread the infection amongst each other.

Challenges in new HBV drug development

Although the vaccine against HBV is very effective and prevents infection, HBV treatments have had modest efficacy. New drug development is expensive (US$500 million), slow (12–15 years from concept to clinical application), and usually has a high failure rate (only one or two out of 10 000 will reach market and patients).

This scenario has paved the way for new treatments such as gene therapy.

“The available treatments for HBV are largely inadequate. Very few people get cured from the infection and part of the reason is that it’s quite difficult to identify suitable targets to inhibit or disable the HBV completely. Some approaches, which I believe show a lot of promise, use gene therapy to disable the HB virus,” says Arbuthnot.

Rogue genes, rational design and gene therapy

Genes underlie all biological processes. Human beings each have around 20 000 genes located on three billion nucleotides, which are the ‘building blocks’ of DNA. We have two copies of those three billion – one copy from our father and one copy from our mother.

Derangements of gene functions are also responsible for diseases. People who have mutations sometimes develop Cancer, or if they have a defect in a gene, such as a blood clotting factor, they may develop hemophilia. In the case of hepatitis, the virus introduces ‘rogues’ into the liver cell of a person who is infected.

“The aim of gene therapy is to inactivate these genes and render the virus disabled so that it cannot proliferate,” explains Arbuthnot.

Gene therapy is an approach that employs ‘rational design’. This refers to understanding the sequence information in a pathogenic organism (HBV or HIV) or the mutation that might be occurring in a deficient gene.

Rational design is important to gene therapy because this detailed knowledge about gene sequences enables the efficient and economical development of a therapeutic.

“You can design a gene therapy which you have a reasonably good idea will work and the failure rate is obviously mitigated,” says Arbuthnot.

Gene therapy entails using DNA or messenger RNA to encode a protein that has the functional effect of a gene. Gene therapy in HBV uses gene editing or gene silencing technologies to disable the HBV.

Gene editing

Gene editing is the targeted mutation of a gene. Gene editing in the treatment of HBV aims to introduce mutations. Gene editors, called TALENs (transcription activator-like effector nucleases) slice the HPV until a mutation is introduced. The TALENs effectively inhibit HBV replication and, ultimately, should permanently disable HBV replication. The therapy effectively edits out the cccDNA (covalently closed circular DNA) gene in the virus itself that causes infection.  

“If you mutate the cccDNA the virus can no longer replicate because its genes are basically inactive as a result of the mutation. cccDNA is the main reason other treatments are ineffective, because you can knock down the virus but the available treatments have no effect on the cccDNA. So as soon as you withdraw the treatment the virus replication rebounds and you’re back to square one.”

Gene silencing

Gene silencing uses one virus to disable another virus using a vector (carrier). Gene silencing acts on the RNA interference pathways that occur naturally in cells responsible for controlling gene expression. This RNA usually exerts its control by suppression.

“So it’s very powerful, very specific, and it inhibits the expression of genes,” says Arbuthnot. However, because gene silencing acts on the messenger RNA, the cccDNA remains intact. “It’s not got such a permanent effect as the gene editing approach.”

In future, gene therapy will be part of a combination regimen of treatment of HBV.

  • In April 2016, Arbuthnot co-authored a paper, entitled: Progress With Developing Use of Gene Editing To Cure Chronic Infection With Hepatitis B Virus, to advance gene therapy.