‘Silver bullet’ solutions in NZ antibiotic research
28 August 2017
Amidst the burgeoning threats of a global “antibiotic apocalypse” and a major New Zealand health crisis hospitalising more than 100 children every year, two leading researchers from Victoria University of Wellington are breaking new ground in the fight against pathogens and will introduce their work at an upcoming Spotlight Lecture focusing on antibiotics, drug discovery and penicillin prevention of rheumatic fever.
Silver has been used for centuries to kill germs and bacteria, and even ward off or destroy evil, so its beneficial properties are widely accepted. But what Day and his team are working on is a ‘silver bullet’ in the form of an innovative method of using aptamers (synthetic antibodies) to deliver medicines to specific targets – in this case Pseudomonas aeruginosa, an “opportunistic bacterium” commonly infecting those with compromised immune systems that is ranked by the World Health Organisation in 2017 as the second greatest microbial threat to human health and in dire need of new antibiotics to treat it.
“Aptamers are essentially chemical antibodies which are selected to target specific pathogens. We have joined these aptamers targeted at P. aeruginosa to medicinal silver – which has been known since 4000 BC to be incredibly effective in treating infections,” says Day.
“In larger doses silver can be toxic, but what we have done with the aptamers is ensure specific delivery to the bacteria and not to the surrounding cells. These ‘aptabiotics’ are quick to produce compared to antibodies, drug molecules, including nanomaterials, can easily be incorporated into their structure to target specific cells, and they kill bacteria incredibly rapidly.”
Initial testing by Day and his team has proven highly successful, and the team is expanding trials with the cutting-edge process they have now patented.
“We’re the only ones doing this at the moment, and it’s a little bit out there. People never thought about delivering silver directly to the cells themselves. What we’re trying to do now is tailor these aptamers to other pathogens,” Day says.
Although the need for a new range of antibiotics to combat the ever-growing number of resistant bugs is essential, for diseases like rheumatic fever, penicillin is still the best response and preventative measure we have.
Considered an illness of developing countries, acute rheumatic fever (ARF) is an autoimmune condition caused by untreated group A streptococcal (GAS) bacterial infections of the throat (and possibly skin) which causes the heart, joints, brain and skin to become inflamed and swollen. Multiple or severe attacks of ARF can cause permanent heart damage known as rheumatic heart disease (RHD).
Painful monthly injections of the antibiotic Benzathine Penicillin G (BPG) are given for at least 10 years to prevent further GAS infections that can lead to ARF and cause RHD. New Zealand has high rates of ARF, with Māori and Pacific children and young people aged 5-14 years most affected.
Together with collaborators, Sika-Paotonu’s work is concerned with the ongoing prevention of ARF by reformulating the monthly penicillin injections required to prevent further GAS infections that could cause another bout of the condition.
“These monthly injections are needed for at least a decade and sometimes a lifetime, and by all accounts each injection is very painful. A new penicillin for ARF/RHD is urgently needed,” says Sika-Paotonu.
“A vaccine against GAS is on its way, but will take time, so we are looking at how to better manage this disease in the interim. Penicillin works great, but the injections are horrible. We are part of a global effort to reformulate BPG to make it less painful to give and hopefully last longer.”
Another important component of Sika-Paotonu’s research is finding out how BPG actually works in the bodies of those most affected.
“The initial studies were carried out in the 1950s to determine how BPG would work, but they gave injections to soldiers in the US who were all fit, healthy European men aged 18-24. The data was then used to determine how we use penicillin today on very different groups of people, including sick young people. Clearly there’s a huge gap in the research around this which we are also looking to fill,” Sika-Paotonu says.
“This is a major health issue in New Zealand, and globally, that we need to continue raising awareness about while we work to address it.”
A tiny device to instantly detect pathogens that is being developed by researchers at Victoria University of Wellington could save the seafood industry millions of dollars a year and help reduce overfishing.
Professor Thomas Nann and Dr Renee Goreham, from Victoria’s School of Chemical and Physical Sciences, are working on a device that will use state-of-the-art aptamer technology to detect hazardous levels of food pathogens, specifically E. coli.
Professor Nann, who is also Director of the MacDiarmid Institute for Advanced Materials and Nanotechnology, says the device will target the extracellular vesicles (EVs) excreted by E.coli. These vesicles are nanometre-sized structures consisting of fluid enclosed by two layers of lipid molecules, which are released by cells.
“Once we’ve isolated the vesicles that are given off by E.coli bacteria—which is relatively easy to do with the nanotechnology we work with—we will then develop an aptamer [a molecule that binds to a specific compound] that will target them,” he says.
“It’s difficult to chase one single bacteria, because we cannot see it—at the moment we have to grow a sample in a lab over several days before we can actually identify if it contains bacteria. But bacteria excrete these vesicles all the time in great numbers, so if we chase the vesicles rather than the bacteria itself we can gather enough to detect it much more easily.”
He says the technique can be compared to finding a needle in a haystack. “The easiest way to find the needle is to take a magnet and run it over the haystack—we would be doing a similar thing, but instead of magnets we’d be using aptamers, which are a bit like chemical magnets. The vesicles we’ve identified would stick selectively to these aptamers.”
Dr Goreham says pathogen contamination is a huge problem in the food industry and can be costly—latest figures estimate the cost to New Zealand to be around $161.9 million a year.
“Fisheries are crying out for a fast, reliable and highly targeted sensor for foodborne pathogens. Currently, they have to monitor their whole manufacturing systems, which is very costly and not very reliable. Culturing a sample can take three days, so if that result comes three days after the initial contamination it could have spread throughout the entire factory in that time, meaning they have to shut down the whole operation,” she says. “We think that by detecting extracellular vesicles instead of the bacteria cells themselves, we will be able to identify pathogens on-site, which will make the process not only faster but much cheaper too.”
Dr Goreham says there will be other benefits too.
“Fisheries will save money by not having to dispose of a contaminated catch, recall the product or clean the entire processing plant, which they would otherwise have had to do after waiting several days for the presence of bacteria to be confirmed from a cultured sample,” says Dr Goreham. “As a consequence of not having to dispose of so much of the catch, more seafood will make it to market—that would mean larger profits for the fisheries as well as a likely reduction in overfishing.”
She says the technology has the potential to be applied to other food industries. “We are starting with fisheries, but once the prototype’s been developed and commercialised then the idea could be applied to industries such as milk or meat.”
Professor Nann and Dr Goreham are working with seafood company Sanford Ltd to test the technology. The pair is also hoping to work with AuramerBio, a specialist aptamer-producing company based in Wellington that was co-founded by Victoria University Associate Professor Justin Hodgkiss.
Professor Nann says the device could have a huge impact on the New Zealand economy. “We think it could enable the creation of high-value manufacturing jobs here, and also help lessen routine testing costs for the food industry, allow early in-house testing and reduce the large-scale wastage that comes with product recalls.”
‘We’ve reached peak antibiotics’
17 July 2017
Superbugs are one of the greatest threats to human health, and Kiwi researchers are using several pioneering methods to find new ways to help. Naomi Arnold reports.
When antibiotics entered widespread use 200 years ago, they changed our lives, giving us a weapon against common bacterial infections that can kill.
Since then, some bacteria have developed resistance to certain antibiotics, leading to the rise of superbugs, which are becoming a major problem in New Zealand hospitals.
A 2016 report by the Institute of Environmental Science and Research (ESR) for the Ministry of Health found New Zealand was one of the highest users of antibiotics in the developed world.
Many antibiotics can no longer be used, and on the horizon is the possibility that infections once thought conquered may kill again.
Contributing to the problem is the historical misuse of antibiotics: prescriptions for viruses, people failing to complete their courses of medication (thereby allowing bacteria to evolve to resist the antibiotics), their use in food and meat production, and antibacterial soaps in home and industrial cleaning products, which go straight into our waterways.
The World Health Organisation recently described humanity as being in “a race against time” to develop antibiotics against multi-drug resistant superbugs. According to one estimate, annual deaths from superbugs will reach 10 million by 2050.
But despite the threat of widespread resistance, research into new antibiotics has been declining since a golden age of discovery in the 1940s-1960s. However, several New Zealand scientists are searching for answers.
We simply need more money for research, says Dr Siouxsie Wiles, who Newsroom featured in May when she and CureKids launched a crowd-funding effort to pay for her testing of 1000 soil and fungi samples for their potential to kill superbugs. So far, the effort has raised 111 per cent of her $250,000 goal: nearly $280,000.
That’s a sentiment repeated by Massey University microbiologist and senior lecturer Dr Heather Hendrickson, who has been working in the field for 17 years.
“I would love to see more interest from funding agencies in this sort of work,” she says.
An age where humans die of common infections isn’t far off. “We’ve reached peak antibiotics.”
Hendrickson investigates a range of issues, including how bacteria evolve and the discovery of viruses which infect them, called bacteriophages.
“These are the ancient enemies of bacteria and they have huge potential as a tool to kill bacteria,” she says. “But we have barely scratched the surface of their diversity; they are still largely unknown.”
One of the processes she studies is horizontal gene transfer, where even distantly-related bacteria exchange DNA, including genes that are resistant to antibiotics. It can also result in new pathogens.
She says the work is of “critical importance”. New Zealand is seeing increased instances of antibiotic resistance in many of the same pathogens noted by the World Health Organisation.
She was recently part of the Royal Society of New Zealand review on the topic, which collected data that suggested New Zealand is witnessing increases in methicillin-resistant Staphylococcus aureus (a common cause of skin infections, sinusitis, and food poisoning); further resistances in some gut bacteria, like E. coli; and also those that cause sexually transmitted infections, like Neisseria gonnoroheae, responsible for gonorrhea.
With one of the issues in antibiotic resistance the use of the bacteria-killers in animal feed, Hendrickson says we need to start demanding meat be labelled with whether or not antibiotics are used during production.
“This is a step that is being considered in legislation elsewhere and I think it would make consumers more aware of the actual costs of the cheap meat that they are eating.”
Consumers can help by not buying antibacterial soaps, by not using antibiotics unnecessarily (e.g. for a virus). “We can all play a part in ensuring that antibiotics last for as long as possible.”
As for a solution, she says she’s interested in scientific projects that involve looking for new antibiotics. “I also think we need to consider approaches like phage therapy and phage therapeutics, where we use the natural enemies of phages and their products to fight bacterial infections where possible.”
At Victoria University of Wellington’s School of Biological Sciences, senior lecturer Jeremy Owen and associate professor and biotechnology programme director David Ackerley are searching for new antibiotics from bacteria that live in soil and other complex environments.
They are at the forefront of this particular type of synthetic biology approach to discovering new drugs.
“If we cannot find effective new antibiotics soon, we may be faced with a return to the 1920s pre-antibiotic era, where people routinely died of the most mundane things, like a scratch from a rose thorn while gardening,” David Ackerley says.
“The good news is, we have learned a lot over the past 70 years about how to better use antibiotics to slow the development of resistant bacteria. The bad news is that in that time we have burned our way through nearly all of the antibiotics discovered to date. We are trying to refill our pharmacies with new antibiotic options.”
The majority of antibiotics in use today were discovered by growing bacteria isolated from different soils around the globe, testing the different molecules they naturally secrete.
The pair say this was a highly productive approach between the 1940s and 1960s, but researchers have struggled to find anything new since.
“The same sets of molecules just kept cropping up time and time again,” Ackerley says. “In recent times we have realised that only a very small proportion of soil bacteria – under 1 percent – can be grown effectively outside of their natural environment. It is a certainty that the remaining 99 percent produce some very effective antibiotics that we have previously been unable to access.”
Because most soil bacteria can’t be grown in a lab, the team are going straight to the bacteria’s DNA, purified from the soil. They’ve developed several different strategies to ‘fish out’ clusters of gene that encode antibiotic-synthesising cellular machinery.
“These genes effectively act as blueprints that tell a cell how to make one particular antibiotic,” he says. “Taking advantage of the fact that bacteria are so good at swapping bits of DNA, we and others have shown that you can employ ‘synthetic biology’ approaches to transfer these blueprints to a new host – a bacterium that we can grow in the lab – and a surprising amount of the time it will gain the ability to produce a new antibiotic.
“Luckily for us, most antibiotic gene clusters not only encode the assembly line needed to make an antibiotic, but also a means for defending the host cell against any toxic effects, so the new bacterial host is usually immune to the new drug it is making.”
He says big pharma companies seem to be increasingly interested in this space, which bodes well for downstream development of promising new drug candidates.
Four questions for Victoria University of Wellington's David Ackerley
Are we doing enough to tackle this global problem?
No. Not yet. Until very recently there has been little incentive for large pharmaceutical companies to develop new alternatives to current antibiotics, as any new antibiotics to hit the clinic will likely be reserved to treat only the cases where the current frontline drugs fail.
Because antibiotics work so well in curing disease then patients don’t need to keep taking them for years on end (in fact, good clinical practice will do what it can to discourage unnecessary use). All of this reduces profit margins for the pharmaceutical companies.
However, there are starting to be “prize-type” financial incentives implemented by governments to encourage discovery, moreover the fact is the situation is starting to get really dire, so the market for new antibiotics that are effective against drug-resistant superbugs is unfortunately growing all the time.
How is your work funded?
Our main source of funding at present is a $1.2m grant from the Health Research Council of NZ, specifically for discovery of new antibiotics. But one of our key methods for finding promising gene clusters came out of an unrelated ‘blue skies’ Marsden project, which really emphasises the importance of funding basic research to enable unexpected discoveries.
We have also received supporting funding from the Maurice Wilkins Centre for Molecular Biodiscovery and the Cancer Society of NZ, to try and find promising anti-cancer drugs in a similar manner.
Coming back to the basic discovery level, it’s really hard to get funding for a project that wants to search for new drugs – the fight for scientific research funding is so competitive that grant review panels tend to strongly favour projects with a logical and clear progression of goals and a high likelihood of success.
They usually don’t like projects where the first aim is to find new compounds, as all the remaining aims will be 100 percent dependent on the first one, and if that is not successful the whole project falls over. The phrase commonly used to dismiss such projects is “that’s just a fishing expedition”, and to get past that criticism you usually have to convince the panel your methods are incredibly new and exciting, and have a high likelihood of success.
Otherwise, you are faced with the chicken-and-egg scenario that you can’t get the funding without having already found the new drug candidates, after which you no longer need the funding for the discovery work.
Given the severity of the problem, it does seem that having a few decent-sized grants reserved to specifically target discovery of new antibiotics might be warranted.
Who needs to make changes to ensure we are looking at ways to solve this issue?
At an academic or small company discovery level, government policy decisions can have a big impact on priority areas for funding. For drug development, governments can again play a key role in incentivising companies to develop new antibiotic drugs even if they will be reserved only to treat the most severe drug-resistant cases.
Large philanthropic organisations like the Gates Foundation can also potentially help provide incentives in the form of prizes etc for new clinically-approved antibiotics that won’t have a large patient pool, so that companies have a way of recouping the many hundreds of millions of dollars of investment it takes to bring a new drug the whole way from discovery to large and very expensive clinical trials, and ultimately to market.
How far off is a “solution” to the problem of antibiotic resistance, and what might that look like?
The preclinical and clinical trials needed to ensure new drugs are both safe and effective are not only super-expensive, they also consume large amounts of time. The problem is getting so severe that it is possible the next generation of antibiotics will be rushed through expedited trials in only a few years rather than the more usual decade or so – however, that kind of approach of course brings risks in that any side-effects or possible longer-term consequences of any approved drug will be less fully understood.
At any rate, the good news is that there are new types of antibiotics starting to come through the pipelines again. But we are nevertheless going to be faced, at least for a while, with increasing numbers of infectious diseases that are not safely treatable if they are even treatable at all.
Professor Furneaux, Director of Victoria’s Ferrier Research Institute, was presented with the award for overall excellence in all core areas of research commercialisation at a ceremony in Auckland.
He also took home the Baldwins Researcher Entrepreneur Award, which recognises a researcher who has made outstanding contributions to business innovation or has created innovative businesses in New Zealand through technology licencing, start-up creation or by providing expertise to support business innovation.
Professor Furneaux has been recognised for entrepreneurial endeavours that have generated tens of millions of dollars of economic activity for New Zealand over the past 25 years.
Starting out as a synthetic chemist, today Professor Furneaux leads a team of 40 scientists at the Ferrier Institute, whose innovative medical drug compounds have been licensed to international pharmaceutical and agrochemical companies, and an exciting new start-up.
The judges described Professor Furneaux as “a world class research entrepreneur”, and his story as “one of enormous achievement”.
“It’s a real honour to receive these awards for myself and our talented team of scientists and collaborators,” says Professor Furneaux. “Also, a big shout out to the commercial partners who successfully applied our science.”
The Institute’s most successful commercial deal, in conjunction with Albert Einstein College of Medicine in New York, is its 16-year relationship with United States-based, NASDAQ-listed company BioCryst Pharmaceuticals, Inc.
Under this licensing deal, four generations of novel compounds, covered by over 160 granted patents, have yielded six lead drug candidates with applications as diverse as cancer, gout, psoriasis, transplant rejection and malaria.
One of these candidates is an active ingredient behind a new oral drug, Mundesine®, which treats patients with a specific type of non-Hodgkin lymphoma. In March this year, Japan became the first country to approve Mundesine®, licensed by BioCryst Pharmaceuticals Inc. under an exclusive licence with Albert Einstein College of Medicine and Viclink, Victoria University’s commercialisation office.
Professor Furneaux says he’s thrilled that his team’s successes with BioCryst spurred significant commercial benefit to New Zealand through the establishment of GlycoSyn, a Wellington-based manufacturer of pharmaceutical ingredients.
“We are always looking for areas where we can apply our chemistry in ways that differentiate us so that we can patent the intellectual property we create for the future benefit of both Victoria University and New Zealand as a whole.”
Collaborations key in Victoria’s commercial success
22 May 2017
Victoria University of Wellington is celebrating its success in science and innovation with two finalists in the 2017 KiwiNet Research Commercialisation Awards.
Professor Richard Furneaux, director of Victoria’s Ferrier Research Institute, has been named a Researcher Entrepreneur finalist, and Viclink, Victoria’s commercialisation office, is a finalist in the Commercial Deal category.
Professor Furneaux has been recognised for his entrepreneurial endeavours which have generated tens of millions of dollars of economic activity for New Zealand over the past 25 years.
Starting out as a synthetic chemist, today Professor Furneaux leads a team of 40 scientists at the Ferrier Institute, whose innovations include the synthesis of an active ingredient in anti-lymphoma drug Mundesine®. Last month, Japan became the first country to approve Mundesine®, licensed by BioCryst Pharmaceuticals Inc. under an exclusive licence with Albert Einstein College of Medicine and Viclink.
Research by the Ferrier team has also led to a breakthrough synthetic vaccine to treat cancer, allergies and autoimmune diseases. The Institute recently announced a five-year, $500,000 research partnership with the Breast Cancer Foundation New Zealand, which will see Ferrier scientists progress a potential breast cancer vaccine.
The Baldwins Researcher Entrepreneur Award recognises an entrepreneurial researcher who has made outstanding contributions to business innovation or has created innovative businesses in New Zealand through technology licencing, start-up creation or by providing expertise to support business innovation.
Viclink has also been named as a finalist for KiwiNet’s PwC Commercial Deal Award.
Viclink and the University’s Ferrier Institute have maintained a successful, 16-year relationship with United-States based NASDAQ-listed company BioCryst.
In conjunction with partners at Albert Einstein College of Medicine in New York, the licensing deal with BioCryst has resulted in more than 160 patents and six lead drug candidates with applications as diverse as cancer, gout, psoriasis, transplant rejection and malaria.
The relationship with BioCryst has yielded significant commercial benefit to New Zealand, the flow on creation of research jobs, and the establishment of GlycoSyn, a Wellington-based manufacturer of pharmaceutical ingredients.
Viclink has played a key role in the relationship between Victoria University and BioCryst.
The PwC Commercial Deal Award celebrates excellence in research commercialisation delivering outstanding innovation performance and the potential for generating significant economic impact for New Zealand.
KiwiNet is a consortium of fifteen universities, crown research institutes and a crown entity established to boost commercial outcomes from publicly-funded research.
The winners will be announced on Thursday 13 July in Auckland.
® MUNDESINE is a registered trade mark (in Japan) of Mundipharma AG.
Is mitochondrial transfer a player in bone marrow transplantation?
04 May 2017
Our Cancer Cell Biology researchers are undertaking a study that Group Leader, Professor Mike Berridge describes as “a world-first”. They are investigating whether DNA can transfer between cells damaged in bone marrow transplants.
“Using our cancer model, we showed that a damaged cell could collect fresh mitochondria from the host organism – there was a transfer of DNA,” said Dr Melanie McConnell, Malaghan Institute Research Associate and Senior Lecturer at Victoria University. The team soon realised that a similar situation occurred in bone marrow transplants. There, a patient is given therapies to suppress the growth of abnormally proliferating cells, before receiving replacement bone marrow from a donor. The result is that a transplant recipient could be left with two different types of mitochondrial DNA – their own, and that of the donor.
Using the differences between these mitochondrial DNA–there are about 40 base differences between any two humans – Prof Berridge and his research group aim to investigate whether genes travel between cells in order to replace those damaged in bone marrow transplants that include cancer. Eight donor-recipient pairs will be involved in this ground-breaking study: Samples of each participant’s bone marrow will be taken before, and again three months after transplantation. The aim of this is to examine whether any donor mitochondrial DNA markers are present in the recipient’s bone marrow.
In parallel, the team will investigate mitochondrial transfer in mice that have been treated with radiation – similar to that used in cancer treatment – which induces damage in the bone marrow. “We work with mouse models as it allows us to carefully design our experiments,” explains Prof Berridge, “…and to probe for genetic differences, we are using DNA sequencing and bioinformatics.”
Combined, these studies will provide a unique insight into the mechanism behind DNA transfer, and may have an impact on future treatment choices.
The Great New Zealand Trek: 9 Years and more than NZ$250,000 of support for our Multiple Sclerosis research
4 May 2017
With an impressive 238 participants taking part this year, it’s been another successful stage of the Great New Zealand Trek (GNZT): This year’s Stage 12 held earlier in March 2017, from Burkes Pass area just west of Fairlie to Becks in the heart of Central Otago, raised another $36,000, bringing the total support from the charitable trust to over $250,000.
Professor Anne La Flamme, who leads our Multiple Sclerosis (MS) research programme also participated in the trek, having done so since 2010. Her 12-year-old daughter Josie joined her this year for the first time.
Thanks to the generosity of the GNZT we are able to pursue novel and cutting-edge ideas. Professor Anne La Flamme says: “Most times these ideas are risky and they might not work, but they could prove enormous beneficial if they do. Because of the risk, it is incredibly difficult to find the funds to start this research, but having funds from the GNZT gives us that ability.”
The key achievements in our MS research have been in identifying several new therapeutic strategies to treat progressive MS and seeing them undergo clinical trials.
Kitty Johnson, a trustee and the organiser of the GNZT supports our MS research. “Professor Anne La Flamme’s engagement and the research team’s ability to think outside the box and probe new never-before- seen scientific discoveries is what it makes exciting and fundamentally important at the same time.”, she summaries.
For more information on The Great New Zealand Trek and to find out how you can get involved in Stage 13 in March 2018, please visit the GNZT’s website.
Driving the next generation of cancer immunotherapy treatments in New Zealand
4 May 2017
Professor Ian Hermans, Vaccine Therapy Programme Leader, and Dr Robert Weinkove, Wade Thompson Clinical Research Fellow and Clinical Director of the Human Immunology Lab, are establishing a research group that will bring cutting-edge new cellular therapies into New Zealand. This research involves a breakthrough area of oncology called CAR-T cell immunotherapy.
In this transfusion-like therapy, some of the patient’s own immune cells, the ‘T cells’, are modified to express a specific receptor – a chimeric antigen receptor (CAR) – in order to redirect them against cancer cells. “The approach works differently to vaccines, which aim to boost someone’s own immune response,” explains Dr Weinkove. “Here, we’re directly altering the immune cells themselves to target them.”
Central to the success of this new translational research is the expertise and knowledge of our team in good manufacturing practice (GMP) – international regulations for the production of medicinal products. “Our collaborators have developed an exciting pipeline of CAR-T cell therapies, our role is to make changes to the way they are manufactured and trialled, so that it fits with what’s regarded in the Western regulatory environment as ‘best practise’,” Prof Hermans explained.
For us at the Malaghan Institute, the driving motivation behind this project is the impact that it could have on the lives of New Zealanders. “For some leukaemias, more than half of people treated with CAR-T cell therapies have remained in remission for years without any other treatment,” Dr Weinkove said. “This is preliminary data, and we still have questions about the longer term effects, but as a clinician, I am extremely excited about the potential of CAR-T cell therapies.”
Victoria research leads to new drug for hard-to-treat lymphomas
19 April 2017
Japan has become the first country to approve an anti-lymphoma drug developed following initial research from Victoria University of Wellington.
The new oral drug, called Mundesine®, treats patients with a type of lymphoma called peripheral T-cell lymphoma (PTCL) — a group of aggressive diseases that accounts for 10 to 15 percent of all cases of non-Hodgkin lymphomas.
The active ingredient in the drug Mundesine®, forodesine hydrochloride, was first synthesised by Professors Peter Tyler and Richard Furneaux at Victoria’s Ferrier Research Institute, and first conceived by long-time collaborator Professor Vern Schramm from the Albert Einstein College of Medicine in New York.
The drug has been approved by Japan’s Ministry of Health, Labour and Welfare following 19 clinical trials.
“I’m very proud,” says Professor Tyler. “We’ve been working on this science for 20 years, and used a rational approach to design this drug. We resolved some complex chemistry and it’s great that, following this approval, the drug is now a step closer to being available.
“In some cancers, like lymphoma, T-cells, a type of white blood cell, replicate uncontrollably. This drug inhibits the enzyme PNP (purine nucleoside phosphorylase), causing a metabolic imbalance in the T-cells that triggers cell death. The approval of Mundesine® provides further treatment options for patients with PTCL.”
Mundesine® was licensed by BioCryst Pharmaceuticals Inc., under an exclusive licence with Albert Einstein College of Medicine and Viclink, Victoria University’s commercialisation office. BioCryst subsequently entered into an exclusive sub-licensing agreement with Mundipharma to develop and commercialise forodesine in the field of oncology.
The drug has been specifically approved for patients whose PTCL has relapsed (recurred) or is refractory (resistant to treatment). Few effective treatments have been available for these conditions. Those PTCL patients who relapse following chemotherapy currently live an average of only six more months.
The research to identify the active ingredient (forodesine hydrochloride) of the Mundesine® drug product was carried out with funding support for the Ferrier Research Institute from New Zealand government agencies, and for the Albert Einstein College of Medicine from the United States General Medical Institute of the National Institutes of Health.
® MUNDESINE is a registered trade mark (in Japan) of Mundipharma AG.
Five-year research partnership targets breast cancer vaccine
21 March 2017
A vaccine for breast cancer is on the horizon, thanks to a new partnership between Victoria University of Wellington’s Ferrier Research Institute and the Breast Cancer Foundation New Zealand (BCFNZ).
The five-year research partnership will see BCFNZ give the Ferrier Institute $500,000 to progress a significant breakthrough made by chemists at the Institute to create a life-saving breast cancer vaccine.
Ferrier Research Institute chemists are making gains in the area of cancer immunotherapy—described by leading journal Science as the ‘Breakthrough of the Year’ in 2013.
The Institute is developing a synthetic cancer vaccine technology that can activate tumour-specific T cells, producing a targeted immune response. This synthetic cancer vaccine causes rejection of cancer in several types of animal models.
Ferrier Institute director Professor Richard Furneaux says the technology is almost there. “We just need to get it to the next level of testing—human clinical trials.”
Professor Gavin Painter, who leads the chemistry team at Ferrier, says the support of BCFNZ is crucial.
“Getting a new therapy to human clinical trials requires significant investment, and an intensive campaign of chemistry, biology and regulatory compliance.
“Our success to date has been made possible because we work with the exceptional immunology research group led by Professor Ian Hermans at the Malaghan Institute of Medical Research here in Wellington, a relationship built up in a seven-year strategic collaboration.”
Evangelia Henderson, chief executive at BCFNZ says: “We went looking for a research partner who would give us the best shot of moving toward our vision of zero deaths from breast cancer. We were blown away by the calibre of the Ferrier team, the work they’d already done in the exciting field of immunotherapy and vaccines, and the strength of their international partnerships. It was a no-brainer for us.”
Cancer immunotherapy has caused a paradigm shift in cancer treatment, with a focus on targeting the body’s own immune system to fight cancer cells rather than introducing toxic agents to attack tumours directly. This line of research has led to the production of cancer vaccines which are showing promising results when used in certain situations; they are well tolerated by the body, have fewer side effects than current chemotherapy treatments and may be more effective in the long-term.
The successful immunotherapy treatment platform pioneered at Ferrier in collaboration with the Malaghan Insitute of Medical Research, has led to the establishment of biotechnology company Avalia Immunotherapies, which aims to commercialise the vaccine technology to help patients. Avalia’s chief executive officer is Victoria alumna Dr Shivali Gulab, a former NZBIO Young Bioscientist of the Year who is based in New York driving the progress of the vaccine technology towards human clinical trials.
For 20 years the Ferrier Research Institute has had an extensive working relationship with the Albert Einstein College of Medicine in New York which has resulted in successful drug trials. These include some of the most powerful enzyme inhibitors ever reported including Forodesine as a targeted therapy for a variety of haematological cancers, and Ulodesine as an orally available drug to treat severe gout.
Mimicking evolution to treat cancer
8 March 2017
Artificial forms of evolution are being used by a Victoria University of Wellington scientist to improve the ability of microbes to attack tumours.
Research led by Associate Professor David Ackerley, director of Victoria’s Biotechnology programme, has underpinned the development of a new form of chemotherapy that exclusively targets cancer cells.
A key goal of this chemotherapy is a more targeted treatment method that results in fewer side effects for cancer patients.
To achieve this goal, Associate Professor Ackerley and his team engineered enzymes that can transform a relatively safe and non-toxic compound (a “pro-drug”) into a drug that is highly toxic to cancer cells.
The genes encoding these enzymes are delivered to cancer cells using viruses or bacteria that are only able to replicate in tumours.
The pro-drug the team worked with is called PR-104A, and was developed by scientists at the University of Auckland, including Associate Professor Ackerley’s collaborators on this study, Associate Professor Adam Patterson and Dr Jeff Smaill.
“The enzyme we started with was moderately active with PR-104A,” says Associate Professor Ackerley. “However, this was purely by chance—nature has never evolved enzymes to recognise these very artificial types of molecules.
“We reasoned that by mimicking evolution in the laboratory—by introducing random mutations into the gene encoding our target enzyme, then selecting the tiny minority of variants where chance mutations had improved activity—we might eventually achieve a more specialised enzyme that could more effectively activate PR-104A.”
Not only is the team’s artificially evolved enzyme significantly better at activating PR-104A within living cells, it also addresses another major problem—how to keep track of the microbes in patients to make sure they are only infecting cancerous cells.
“A unique aspect of our work is that our enzymes can also trap radioactive molecules called ‘positron emission tomography (PET) probes’,” says Associate Professor Ackerley. “We hope that this will allow a clinician to put a patient in a full body PET scanner to safely identify the regions where the microbes are replicating.”
The team’s research has been published in this month’s edition of high-profile research journal Cell Chemical Biology, and has been supported by several New Zealand funding agencies including the Marsden Fund managed by the Royal Society of New Zealand, the Health Research Council of New Zealand and the New Zealand Cancer Society.
In ongoing work, Dr Smaill and Associate Professor Patterson have been developing more effective pro-drugs to partner with Associate Professor Ackerley’s enzymes. The team has been collaborating with groups at the University of Nottingham in the United Kingdom and Maastricht University in the Netherlands, aiming to progress the therapy into clinical trials in cancer patients.
Harnessing hope to treat rare disease in children
24 January 2017
New research from Victoria University of Wellington has provided insight into the effectiveness of a potential drug to treat a rare, fatal disease in children.
ometimes referred to as childhood Alzheimer’s, Niemann-Pick Type C (NPC) disease is a genetic disorder characterised by an inability of the body to transport cholesterol and other fatty substances (lipids) inside cells in the brain and liver. Lipids consequently accumulate in the liver, spleen and brain.
The disease causes quick and progressive mental and physical deterioration with typical loss of life prior to adolescence. Though rare, an estimated 500 children currently suffer from NPC disease worldwide.
An international team, led by Dr Andrew Munkacsi from Victoria’s School of Biological Sciences and Dr Stephen Sturley at Columbia University Medical Center, investigated the therapeutic efficacy of Vorinostat—a drug approved to treat cancer—to treat NPC disease.
“As no cure exists, finding drug therapy is crucial,” explains Dr Munkacsi. “Given that it takes more time to develop a new drug than the average lifespan of an NPC patient, identifying an existing drug treatment is the goal.”
“Vorinostat is currently in a clinical trial for NPC disease. This clinical trial was approved without some therapeutic efficacy testing because the drug was already approved to treat cutaneous T-cell lymphoma and potential drugs to treat NPC disease are in very high demand.”
In 2011, Drs Munkacsi and Sturley published a paper that identified the potential of Vorinostat to treat NPC disease. The study involved experiments using yeast as a model of NPC disease and then translating these experiments to cultures of human cells.
A new paper, published online last month in The Journal of Biological Chemistry, builds upon the 2011 study.
It found Vorinostat has the ability to correct multiple pathophysiological defects in the liver of an animal model that closely mimics human patients. The accumulation of lipids in liver cells was reduced and liver health was improved.
“By measuring the expression of approximately 14,000 genes in the liver, we were able to determine that Vorinostat normalised expression of key genes in the biosynthesis and transport of cholesterol in the liver,” says Victoria University Master’s graduate Natalie Hammond, a co-author on the new paper.
“It’s an exciting result that shows the potential of Vorinostat to treat NPC disease in the clinical trial”, says Dr Munkacsi.
“While it helped reduce lipids in the liver, it is unable to cross the blood-brain barrier and so may not address the build-up of lipids in the brain.”
Other contributing authors to the paper were from Callaghan Innovation in Lower Hutt, Tottori University in Japan and various research institutions in the United States (Mount Sinai School of Medicine, Washington University School of Medicine, Giesel School of Medicine at Dartmouth and University of Texas Southwestern Medical Center).
The study was primarily supported by the National Niemann-Pick Disease Foundation, the Ara Parseghian Medical Research Foundation and Dana’s Angels Research Trust.
“These parent-patient funded foundations are critical to investigations in rare diseases like NPC disease,” says Dr Munkacsi.