��Ѹ��Դ��߿�Ƭ of Lethbridge and ��Ѹ��Դ��߿�Ƭ of Calgary researchers explore avenues for novel treatments of Hepatitis B Virus

trevor.kenney — Wed, 24 Mar 2021 20:34:44 +0000

Researchers at the Universities of Lethbridge and Calgary have reported a unique structure in the genome of the Hepatitis B virus (HBV), furthering the knowledge and understanding about how human proteins interact with the viral genome.

Dr. Trushar Patel

HBV is one of the leading causes of liver diseases and cancer. Despite the availability of effective vaccines, approximately 250 million individuals are chronically infected worldwide. According to the Canadian Liver Foundation, approximately 250,000 to 460,000 Canadians may be chronically infected with HBV. The current treatment regimen for HBV comprises drugs that suppress the virus but when treatment is stopped, the infection usually relapses owing to the presence of the covalently closed compact DNA (cccDNA) genome of HBV in infected patients.

The study is jointly led by Dr. Trushar Patel, a Canada Research Chair in RNA and Protein Biophysics at the U of L, and Dr. Carla Coffin from U of C (coordinating site of the Canadian Hepatitis B Network). The study, entitled Identification and characterization of a G-quadruplex structure in the pre-core promoter region of hepatitis B virus covalently closed circular DNA, is published in the prestigious Journal of Biological Chemistry (JBC).

The JBC article by co-first authors Dr. Vanessa Meier-Stephenson and Dr. Maulik Badmalia reports the presence of a unique fold in the virus genome which is critical for binding to a human protein called Sp1 that helps the virus proliferate. An earlier study published by the same group first reported a conserved Guanine-rich stretch in the HBV genome indicating that this region may be able to form the unique DNA fold known as a G-quadruplex (G4). This sequence is further important as it is known to interact with the human protein Sp1. The group also investigated where or how these G4 quadruplexes bind, using hepatitis B positive liver samples from patients. Finally, using HBV infected cell lines, the group found that the sequence has a considerable effect on the production of virus proteins. The article published in JBC identifies a novel strategy for combatting HBV infection by targeting the HBV cccDNA which hides in the infected cells.

With this newfound knowledge, the group plans to investigate and study novel compounds for combatting the HBV infection, including those that specifically affect the interaction of cccDNA and human proteins. They have developed and patented a class of compounds to do just this and many of these compounds are already showing promising results in cell culture assays. Further pre-clinical work is underway.

This work was supported by Alberta Innovates, the Canadian Network on Hepatitis C Fellowship, the Canada Foundation for Innovation and Diamond Light Source (UK).

The full JBC article can be found here.

Research collaboration between ��Ѹ��Դ��߿�Ƭ of Lethbridge and ��Ѹ��Դ��߿�Ƭ of Calgary takes aim at hepatitis C virus

trevor.kenney — Wed, 04 Jul 2018 16:12:34 +0000

A unique research partnership between the ��Ѹ��Դ��߿�Ƭ of Lethbridge and the ��Ѹ��Դ��߿�Ƭ of Calgary has Dr. Vanessa Meier-Stephenson using Highway 2 as a pathway to developing a greater understanding of the hepatitis C virus, and potential new therapeutics to combat the infectious disease.

Supported by a CanHepC Network Post-doctoral Fellowship, Vanessa Meier-Stephenson is utilizing the laboratory expertise of the U of L’s Dr. Trushar Patel in collaboration with UCalgary’s Dr. Carla Coffin.

Supported by a CanHepC Network Post-doctoral Fellowship, Meier-Stephenson is utilizing the laboratory expertise of the U of L’s Dr. Trushar Patel in collaboration with UCalgary’s Dr. Carla Coffin as she explores how the Hepatitis C virus hijacks one of our cell’s proteins responsible for the virus’s replication, liver disease and cancer-causing pathways.

The hepatitis C virus affects more than 71 million people worldwide and is linked to liver diseases and liver cancers.

“We actually have a lot of great drug therapies for people who are affected by hepatitis C but there are still a lot of unanswered questions about this virus in terms of how it causes liver diseases and how it leads to some of the different cancers that we see,” says Meier-Stephenson. “I will be analyzing the interaction between the virus and the cell protein using various biochemical, biophysical and cell culture techniques in order to determine the specifics of the interaction, including its 3D-structural basis.”

To attack this problem, a collaborative effort is being employed through a combined post-doctoral study, mining the expertise of two of the province’s most advanced research programs.

“There’s no single lab in Alberta that would have all the components we’re using to approach this problem, but by combining the strengths of the two labs, we can accomplish so much more with our research,” says Meier-Stephenson. “They’re completely different labs in terms of what they bring to the table but they fit together so nicely for this project.”

A Newfoundland native, Meier-Stephenson did her undergraduate work at Mount Allison ��Ѹ��Դ��߿�Ƭ and completed her PhD at Dalhousie ��Ѹ��Դ��߿�Ƭ in Halifax. While she pursued medicine and currently practices as an infectious diseases physician, she’s still fascinated by lab work and research into drug design and discovery. As a clinician, she says it can be difficult treating patients with gaps in knowledge and lack of effective treatments.

“There are so many viruses we have absolutely no treatment for,” says Meier-Stephenson. “At least for hepatitis B and C, and HIV, we have some treatments, but they’re more just to suppress the virus rather than get rid of it. It can be disheartening that there are instances when you can’t do anything other than support a patient. I’d like to be able to take it beyond the diagnosis and say, “Yes, we’ve now figured out a way to treat this and this is how I can help you.” Having some of those skill sets that can lead to treatment, I feel I should at least try.”

Working with viruses related to hepatitis C and similar mechanisms they use to hijack cell proteins, Meier-Stephenson says it was natural to branch off into this study when funding from the CanHepC Network became available. Her first conversation with Coffin revealed how she had collaborated with the U of L’s Patel and it opened up new opportunities.

“Dr. Patel has the capacity for the biophysical studies, digging down to the very structural nature of all these compounds. He brings that expertise where he’s able to study the interactions between various cellular components, not just for viruses, but for all sorts of systems,” says Meier-Stephenson. “Dr. Coffin brings all the clinical aspects that link these together. She has a strong basic science lab as well, but from a different perspective using sequencing methods and DNA-specific approaches to study mechanistic and immunologic phenomena in clinically-relevant samples.”

Meier-Stephenson says the cooperative approach adds greater perspective to the work and opens further windows for collaboration when the respective research networks of Patel and Coffin are also in the picture.

“To really advance research, we have to collaborate and work together, because it makes for stronger, more relevant results,” she says. “It helps move things forward, where if we tried to do it all on our own, we just wouldn’t get that same breadth of what we’re doing now.”

The fellowship is a two-year award, after which Meier-Stephenson would like to have her own lab established.

“By the end of the award term, I’m hoping to have my own independent research program, with the goal of doing something similar to what I’m doing now, a mix between the two disciplines that both Drs. Coffin and Patel are doing, ultimately working towards viral treatments.”

Meier-Stephenson is inspired by the considerable contributions other Canadian researchers have brought to the study of infectious diseases, citing Winnipeg’s National Microbiology Laboratory’s development of an Ebola vaccine, Mike Houghton’s isolation/co-discovery of the hepatitis C virus and Lorne Tyrell’s work on the mainstay treatment of hepatitis B and HIV (Lamivudine).

“Canada has really been showing itself as a major player in the virology field and there’s no reason to think we can’t be part of something similar.”

UNews - Vanessa Meier-Stephenson

��Ѹ�����Դ���߿�Ƭ of Lethbridge and ��Ѹ�����Դ���߿�Ƭ of Calgary researchers explore avenues for novel treatments of Hepatitis B Virus

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