UNews - Carla Coffin

��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.

Alberta Innovates grant facilitates joint research project on the hepatitis B virus

trevor.kenney — Tue, 30 Apr 2019 19:58:21 +0000

Dr. Trushar Patel at the ��Ѹ��Դ��߿�Ƭ of Lethbridge and Dr. Carla Coffin at the ��Ѹ��Դ��߿�Ƭ of Calgary have secured Alberta Innovates funding worth $639,000 to further research aimed at developing innovative strategies to combat hepatitis B virus (HBV) infection.

HBV is a global public health problem responsible for a million deaths every year, according to the Hepatitis B Foundation.

The ��Ѹ��Դ��߿�Ƭ of Lethbridge's Dr. Trushar Patel.

“Although we have a very effective vaccine against hepatitis B, there have been over two billion people worldwide infected with the hepatitis B virus,” says Patel. “The vaccine is not useful for people who have already been infected. Globally, over 250 million are chronically infected and at risk of developing liver cancer.”

HBV is transmitted through blood or other body fluids. The most common methods of transmission are from mother to child at birth or in early childhood from close contact with body fluids of an infected individual. Children born to HBV-infected mothers are at high risk of lifelong infection and developing serious liver disease like cirrhosis and liver cancer. Hotspots for HBV infection include Africa, Asia and the Middle East, largely due to sporadic vaccination programs in those areas. In Canada, HBV vaccination in childhood or early adolescence began in the mid-1990s. Most adults born before 1985 have not been vaccinated.

“Despite the significant public health impact, research on hepatitis B has been severely underfunded. We are grateful for this funding as it allows us to continue to contribute to the global efforts to achieve a cure by understanding how to prevent HBV multiplication,” say Patel and Coffin. “Our preliminary results from earlier research show we are already on a positive track.”

Current treatments for HBV include long-term, often lifelong, use of oral antiviral medications or interferon injections. Although interferon is given for one year, treatment has severe side effects and limitations. Patel and Coffin want to help pave the way for new treatments in the future and are pursuing a two-pronged approach.

They first want to identify new targets for treatment on the hepatitis B genome. Secondly, because viruses cannot survive on their own and require proteins from the body to help them replicate, Patel wants to understand how the body and the virus communicate and then block the communication so replication doesn’t occur.

“We have already designed some therapeutic molecules based on our work that was done here in Lethbridge. Dr. Coffin’s lab is currently testing if these molecules can inhibit HBV replication,” says Patel.

Part of the project was supported by Patel’s Canada Research Chair program through the Canadian Institutes of Health Research and the Cumming School of Medicine Clinical Research Fund. The preliminary results from that research were included in the Alberta Innovates grant application.

“Because the results are still preliminary, we can’t make any promises until we have the fully developed story. But clearly the reviewers at Alberta Innovates liked our idea and approaches,” says Coffin. “We hope to have pre-clinical work done at the end of the three years. Then we will move to the next phase of the research, which would mean applying for more funding to improve the molecules we are designing for animal studies.”

“We take this opportunity to thank our collaborators, the U of L and the U of C, as well as Alberta Innovates for their encouragement, support and motivation for our interdisciplinary research work on understanding host-viral communications,” says Patel.

Patel is an assistant professor and a Canada Research Chair (RNA & Protein Biophysics) in the U of L’s Department of Chemistry and Biochemistry and an adjunct assistant professor at the U of C’s Cumming School of Medicine. Coffin is an associate professor of Medicine and a hepatologist (liver specialist) at the U of C.

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.”

��Ѹ��Դ��߿�Ƭ of Lethbridge and ��Ѹ��Դ��߿�Ƭ of Calgary researchers collaborate to tackle hepatitis B virus

trevor.kenney — Thu, 01 Mar 2018 21:38:24 +0000

For Lethbridge residents suffering from the effects of chronic HBV and its resulting health problems, treatment options in Lethbridge are limited, sending most patients to the Calgary Liver Unit. On Thursday, Mar. 8, Calgary Liver Unit Medical Director Dr. Carla Coffin will present her work at the ��Ѹ��Դ��߿�Ƭ of Lethbridge as part of the U of L’s Alberta RNA Research and Training Institute (ARRTI) Speaker Series.

The hepatitis B virus (HBV) is a human pathogen that causes both acute and chronic infection, affecting millions of people worldwide. Hundreds of people in Lethbridge are likely suffering from chronic HBV. Coffin, in collaboration with the U of L’s Dr. Trushar Patel is working to combat the disease.

“Our work integrates Dr. Coffin’s expertise in molecular virology with my expertise in structural biophysics tools,” says Patel, an assistant professor in the Department of Chemistry & Biochemistry and member of ARRTI. “When viruses infect cells, they use the cell’s own machinery to produce more copies of themselves. Our research is focused on investigating the mechanisms by which host proteins aid HBV replication, for example the transcription of the HBV DNA genome into RNA. Understanding such mechanisms could result in identification of target proteins, against which novel therapeutic molecules can be developed to treat HBV infection.”

The likelihood of developing chronic hepatitis after an acute infection depends on the age of the patient; 1-5 per cent in adults, 5-10 per cent in adolescents, 25-50 per cent in children aged one to five years, and 90 per cent for infants. After several decades, which are usually asymptomatic, 20-25 per cent of HBV carriers will develop cirrhosis of the liver, and 5-6 per cent will develop liver cancer (hepatocellular carcinoma, or HCC). Although there are good treatments to control the infection, there is no cure and many patients often require lifelong, expensive therapy.

Coffin has been an associate professor in the Cumming School of Medicine at the ��Ѹ��Դ��߿�Ƭ of Calgary since 2009. She was co-chair of the 2018 Canadian Association for the Study of the Liver Management of HBV Guidelines Committee and served on the World Health Organization Expert Advisory Committee for Essential Medicines (HBV and HCV). Her clinical and bench laboratory research aims to help better identify hepatitis B patients who would benefit from therapy, as well as developing better HBV therapeutics. Through her collaboration with Patel, the Canadian Institute for Health Research funded a fellowship through the Canadian Hepatitis C Network for Dr. Vanessa Meier-Stephenson to also participate in the work.

Her talk, Hepatitis B Virus Persistence, takes place Thursday, Mar. 8 at 3 p.m. in room C756 at the ��Ѹ��Դ��߿�Ƭ of Lethbridge, and is open to the public. ARRTI has been holding the ARRTI Speaker Series since 2014, in which researchers, both local and external, are invited to speak about their current research in RNA and related topics. This year, in recognition of its influence, the ARRTI Speaker Series is sponsored by the International RNA Society as part of its RNA Salon initiative to promote RNA-related research.

For more information about Coffin, Patel or ARRTI, visit these websites:

https://www.ucalgary.ca/girg/membership/coffinc

http://trpatel.com/

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