Hepatitis A

There’s some exciting news coming out of Chapel Hill, NC. 

It looks as though scientists have discovered a drug that may hold the key to curing Hepatitis A

A team from the UNC School of Medicine found that the virus needs specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases to replicate. They successfully tested the oral drug RG7834 on mice. The treatment stopped the hepatitis A virus (HAV) from replicating and made it impossible for HAV to infect liver cells.

They say this is the first drug to deliver effective results in animals with HAV. Although a vaccine against the virus has been available for several years, there is currently no way of treating hepatitis A once someone has it.

In a university release, senior author Stanley M. Lemon, MD, professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, said:

“Our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts viral replication and reverses liver inflammation in a mouse model of hepatitis A, providing proof of principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreak settings.”

Dr. Lemon has been working on a treatment for hepatitis for decades. In the 1970-80s, he was part of the Walter Reed Army Medical Center team, which created the first inactivated HAV vaccine for humans.

By the 90s, cases of the virus dropped off because the vaccine was so widely available. By the 2000s, cases of HAV dramatically plummeted even further. 

Because of their success, researchers turned to treating hepatitis B and C, but Lemon says these viruses are extremely different from HAV — even though they share the same name. 

Actually, Hepatitis A isn’t even part of the same virus family, according to researchers.

“It’s like comparing apples to turnips,” the study author explains. “The only similarity is that they all cause inflammation of the liver.”

Unfortunately, the team says hepatitis A has been making a comeback in recent years. Although the vaccine continues to be effective, cases have been rising since 2016, with the CDC recording more than 44,000 cases, 27,000 hospitalizations, and 400 deaths in the U.S. alone during that time.

Part of the problem is that not everyone gets vaccinated, and the virus can live in the environment for a long time — on people’s hands, food, and water.

Globally, doctors diagnose millions of HAV infections each year. The virus causes fever, abdominal pain, jaundice, nausea, and a loss of appetite and sense of taste.

In 2013, Lemon and other researchers discovered that hepatitis A undergoes an extreme transformation once it reaches the liver. The virus hijacks parts of the cell membrane when it leaves the organ, making it invisible to antibodies that would usually attack and quarantine hepatitis A before it spreads through the blood.

A few years later, scientists discovered that hepatitis B needed TENT4A/B to replicate in patients. That discovery led other scientists to look for the human proteins HAV needs to replicate. This new study found ZCCHC14, a protein that interacts with zinc and binds to a person’s RNA.

“This was the tipping point for this current study,” Lemon explains. “We found ZCCHC14 binds very specifically to a certain part of HAV’s RNA, the molecule that contains the virus’s genetic information. And as a result of that binding, the virus is able to recruit TENT4 from the human cell.”

The study author adds that, in a healthy person, TENT4 plays a role in RNA modification during cell growth. In people with hepatitis A, the virus hijacks TENT4 and uses it to reproduce. Researchers theorized that stopping the virus from hijacking TENT4 could limit HAV’s spread.

Previous studies showed that RG7834 could block hepatitis B from targeting TENT4, so the team tested this compound on mice genetically engineered to have HAV. Results show oral treatments of RG7834 “dramatically diminished” liver injury in the animals. The dosage researchers used was also safe for the mice, but study authors add that they’re still far off from human trials.

“This compound is a long way from human use,” Lemon cautions, “but it points the path to an effective way to treat a disease for which we have no treatment at all.”

Previous animal studies testing RG7834 for use against chronic cases of hepatitis B suggested that the drug may be too toxic to use over a long period. However, Lemon suggests the short timeframe patients would need the drug for to treat HAV could avoid this side effect.

He concludes, “The treatment for Hepatitis A would be short-term, and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.”

The study is published in the Proceedings of the National Academy of Sciences.

Sources:

https://www.mayoclinic.org/diseases-conditions/hepatitis-a/symptoms-causes/syc-20367007
https://www.proteinatlas.org/ENSG00000140948-ZCCHC14
https://www.mdpi.com/1422-0067/22/13/6957
https://www.mayoclinic.org/diseases-conditions/hepatitis-b/symptoms-causes/syc-20366802
https://www.mayoclinic.org/diseases-conditions/hepatitis-c/symptoms-causes/syc-20354278
https://www.cdc.gov/hepatitis/statistics/index.htm
https://www.technologynetworks.com/immunology/news/key-to-hepatitis-a-replication-discovered-363330

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