Dr. Paola Marignani is searching for new treatments. More precisely, the Dalhousie Medical School researcher wants a new combination of drugs to target cancer in a new and different way.…
Dr. Paola Marignani is searching for new treatments. More precisely, the Dalhousie Medical School researcher wants a new combination of drugs to target cancer in a new and different way.
“Many of the drugs we have in the clinic today block oncogenes that were discovered 15 or 20 years ago,” says Dr. Marignani, pictured at right. “We can’t just keep using the same drugs over and over again in different combinations. We need to find new targets and new drugs.”
Her key target is LKB1, a protein that has multiple functions throughout the body, including tumour suppression. LKB1 is often found to be missing or mutated in breast cancer, lung cancer, pancreatic cancer and other forms of the disease. “If you lose LKB1 or its mutated, it sets up protein signalling pathways for disaster,” says Dr. Marignani. “It would be like an intersection that once had stop signs and is now without any. Eventually an accident is going to happen.”
To understand what happens when LKB1 is lost and mutated, her team used re-engineered mice without the ability to express the protein. That led them to finding a combination of compounds that shuts down aggressive, metabolically active HER2-positive breast cancers — a common form of the disease — in the rodents.
Dr. Marignani is using a two-pronged approach by testing the new compounds in combination with Herceptin®, which has become the standard of care for HER2-positive breast cancer. “We know Herceptin® is effective,” says Dr. Marignani. “We can use the discovery we made in mice to strategically attack the cancers from multiple branches using new drugs in combination with the standard treatment of care, and see what happens.”
So far, she is cautiously optimistic. “The animals tolerate the drug combination, which is very important, and early data suggests the tumours are not progressing.”
Beyond shutting down tumour growth, Dr. Marignani and her team want to find ways to stop cancer from recurring by killing off the cancer stem cells that resist the original treatment.
“There is always the possibility that there are some cancer stem cells hiding out, just waiting, that have developed resistance to the treatment that killed off the bulk of the cancer,” she explains. “We have seen that our drug combination reduced the proteins that drive recurrence. We did not anticipate this would happen because there was no evidence in the literature. In our current study, we need to consider whether stem cells play a role in cancer recurrence in our model and look for pathways that are active in those cells. We don’t know yet. We’re working on it.”
With fine tuning of her animal-model preclinical work done, Dr. Marignani hopes to move into a Phase 1 clinical trial, testing the safety of the drug combination in humans. But she emphasizes that the work is in the early stages.
“It is important that we look for new treatment possibilities even though the current treatments are reasonably good. Targeting oncogenes has served us well, however it is time we expand our toolbox. We can do better.”
Two Federal Government departments — Innovation, Science and Economic Development Canada and Health Canada — have asked the Council of Canadian Academies (CCA) to study and report back on the state of regenerative medicine in Canada.…
Two Federal Government departments — Innovation, Science and Economic Development Canada and Health Canada — have asked the Council of Canadian Academies (CCA) to study and report back on the state of regenerative medicine in Canada.
“We are very pleased to receive this request from the Government,” says Dr. Eric M. Meslin, President and CEO of the CCA, in a media release. “Canada is a global leader in regenerative medicine and we look forward to contributing to the evidence base for making decisions about how this country can continue to excel in this incredibly important field of medicine.”
The council will conduct an “expert panel workshop” to address two key questions:
- What are Canada’s strengths in regenerative medicine (and why are they strengths)?
- What are the opportunities that exist and barriers that must be overcome for Canada to ensure that it can excel in regenerative medicine in the international arena?
“This is good news for advancing stem cell R&D,” says James Price President & CEO of the Canadian Stem Cell Foundation, adding that the move shows that regenerative medicine is a priority for the Government.
“As the champion of the Canadian Stem Cell Strategy, which would see more stem cell research leap the hurdle to clinical trials and new treatments, we applaud the Government for commissioning the workshop. We look forward to helping the CCA in any way possible.”
The CCA, a not-for-profit organization that undertakes independent, authoritative, evidence-based assessments to inform public policy, is assembling a multidisciplinary, multi-sectoral, group of experts to participate in the two-day workshop expected to take place in the coming weeks. The results will be published in early 2017.
Summer isn’t really summer without a local fair or carnival to enjoy — a place you can have a variety of experiences, from riding bumper cars and tasting weird food treats to seeing expertly executed home crafts.…
Summer isn’t really summer without a local fair or carnival to enjoy — a place you can have a variety of experiences, from riding bumper cars and tasting weird food treats to seeing expertly executed home crafts.
Next week we will be adopting the carnival concept to discussing stem cells. Organized by Stacey Johnson at the Canadian Centre for the Commercialization of Regenerative Medicine (CCRM), the Thursday, Aug. 25 blog carnival will feature blogs from across the stem cell research community — including this one — posting different perspectives on a single subject. Here’s what everyone will be blogging about:
It’s been 10 years since scientists Shinya Yamanaka and Kazutoshi Takahashi announced their discovery on Aug. 25, 2006 that adult cells could be reprogrammed into induced pluripotent stem (iPS) cells to look and function like embryonic stem cells. In the decade since their discovery, converting this science into useful treatments for diseases like heart failure or diabetes has yet to be fully realized. When do you think this technology will result in commercial products or new revolutionary medical treatments, and why?
It all happens in one week’s time. You can find out more about the blog carnival at CCRM’s highly informative Signals blog. Signals will be the site where, on Aug. 25, you can link to other writers’ unique insights on the subject. Watch for it!
Dr. Valerie Wallace is realistic about finding cell-based cures for blindness.
“It’s a long road,” says the Dr. Wallace, Chair of the Vision Science Research Program at University Health Network’s Krembil Research Institute in Toronto.…
Dr. Valerie Wallace is realistic about finding cell-based cures for blindness.
“It’s a long road,” says the Dr. Wallace, Chair of the Vision Science Research Program at University Health Network’s Krembil Research Institute in Toronto. “Cell transplantation is tremendously complicated, difficult, and painstaking.”
But she is also optimistic about what the future holds for gaining a better understanding of the underlying causes of macular degeneration, which is triggered by deterioration of the cone photoreceptors (cones) in the centre of the eye that mediate reading and seeing fine detail. (In contrast, rod photoreceptors are concentrated along the edges of the retina to facilitate peripheral vision.)
“We are learning a lot about the biology that underpins photo cones, says Dr. Wallace. “They are a rare cell type and understanding their development has been difficult. Now we have tools to do that. That’s what I’m excited about.”
Her lab has developed a new mouse strain with fluorescently tagged cones to allow the researchers to track the progress of the cells to see if they can rescue visual function when transplanted into blind mice.
“We’re looking directly at this. Can cone cells transplant? Can they rescue vision? And if they can, what stage of cone development is the best for transplantation?”
The work she is doing feeds into a larger team effort dedicated to optimizing how to make photo receptors from human stem cells. What she learns from trying to engraft mouse cells will be applied to people. It also has implications for finding therapies for other neural degenerative diseases, such as Parkinson’s disease, Alzheimer’s and stroke.
“The eye has always been thought of as very different from the brain,” she says, “but it is part of the brain. Our work on identifying novel approaches to promote the survival of these cells could extend to promote neuron survival in other parts of the central nervous system.”
And the eye, aside from being the window to the soul, can also be a window into a person’s health. Says Dr. Wallace: “People are now using non-invasive imaging of the eye to look at markers of disease. There is a large study in Alzheimer’s that is imaging the eye to identify people at early stages of the disease. That’s happening more and more. People are appreciating that some aspects of eye health might inform the progression or even the diagnosis of other diseases.”
Dr. Wallace, who calls herself “a developmental biologist at heart,” doesn’t forget who she’s working for: people struggling with vision loss. Her past work with the Foundation Fighting Blindness, which helps fund her research, guarantees that. “I hear a lot about what’s important to patients.”
While progress is taking time, the science is steadily moving forward. “A lot of the things we’re doing now were not even being talked about 10 years ago.”
A 73-year-old man from Hawkesbury, Ontario, survived a deadly infection after receiving millions of mesenchymal stem cells in a world-first trial at The Ottawa Hospital.…
A 73-year-old man from Hawkesbury, Ontario, survived a deadly infection after receiving millions of mesenchymal stem cells in a world-first trial at The Ottawa Hospital.
Charles Berniqué developed severe septic shock in June of last year after his esophagus burst, likely from food poisoning. Septic shock is a deadly condition in which rampant infection triggers hyper-activation of the immune system, causing the cardiovascular system and organs to fail.
Mr. Berniqué was first treated by thoracic surgeons, who restored his fluids, repaired his esophagus and started antibiotic therapy. He was placed into a coma in the intensive care unit where mechanical ventilation and dialysis supported his heart, lungs and kidneys.
During this time, his wife Maureen consented to his participation in the clinical trial led by Drs. Duncan Stewart and Lauralyn McIntyre.
Within 24 hours, Mr. Berniqué received an intravenous infusion of 30 million mesenchymal stem cells originally extracted from the bone marrow of a healthy Ottawa volunteer.
“Our laboratory studies that showed that mesenchymal stem cell therapy tripled survival in a mouse model of septic shock,” Dr. Stewart, Executive Vice-President of Research and senior scientist at The Ottawa Hospital, said in a media release. “The cells also reduced damaging inflammation and helped the mice eliminate the bacteria.”
Dr. McIntyre, an intensive care physician and senior scientist at The Ottawa Hospital, was impressed by the results. “Researchers around the world have spent decades trying to find a therapy that will treat the root causes of septic shock rather than just the symptoms, but so far, none of these therapies have improved survival,” she said. “We don’t know whether the cell therapy played any role in Mr. Berniqué’ s remarkable recovery, but the cells were very well tolerated and we are excited to continue to study this promising therapy in more patients.”
Mesenchymal stem cells have been studied extensively in human clinical trials for other conditions, but The Ottawa Hospital trial is the first in the world to evaluate the cells specifically for the treatment of septic shock. The main goal of the Phase I trial is to evaluate the tolerability and feasibility of the cells. However, the researchers have already received funding from the Ontario Institute for Regenerative Medicine to begin scaling up their cell bank for a larger Phase II trial, which will help determine if the therapy is effective against septic shock.
As for Mr. Berniqué, he’s grateful to be alive and happy that the care he received may do the same for others. “It is tremendous what The Ottawa Hospital did for me,” he said. “I was so close to death, but I received the best care in the world and got to participate in this study which could help many people.”
It can take millions of cells to do the most simple stem cell transplant. Coming up with ways to produce huge volumes of pure, safe cells is a challenge.…
It can take millions of cells to do the most simple stem cell transplant. Coming up with ways to produce huge volumes of pure, safe cells is a challenge. In mid-January, Prime Minister Justin Trudeau made an appearance at the MaRS Discovery District building in downtown Toronto to announce $20 million in federal funding for advanced therapeutic cell manufacturing to be managed by the Centre for Commercialization of Regenerative Medicine (CCRM), with GE Healthcare also committing $20 million. CCRM’s CEO Dr. Michael May talks about plans for the centre.
Q: How did this come about?
A: This has been evolving over five years as we developed very strong relationships with industry leaders, of which GE HealthcCare is one. As the industry evolves, manufacturing issues are maybe the most talked about bottleneck in cell and gene therapy.
Q: What is your centre going to do?
A: This centre is a business unit of the overall CCRM operation. It has two main activities. One is targeting particular bottlenecks — strategic gaps in the industry — around particular cell types and specific operations and then inventing solutions that can be commercialized as tools and devices. The second thing is the centre will utilize the expertise in the team and the new solutions that will be invented, or technologies that will be integrated, to tackle company problems on a fee-for-service basis.
Q: Can you give a hypothetical example?
A: Any company, large or small, or an academic who is making cells likely has not addressed scale-up and manufacturing in an appropriate way. They are a potential client for not only the solutions we will come up with but also the fee-for-service optimization and scale-up that we will do.
Q: So, if I’m a scientist and I want to do some testing using a particular cell type, but I need millions and millions of cells, I come to you?
A: Yes. We might help in lots of different ways. If there is scale-up that’s needed, we would advise on what needs to get done and create a project around that. And we could hopefully help fund it. It could be fee-for-service or a co-development or any combination.
Q: The space that you have, will scientists be using it themselves or will they be hiring your team to do something for them?
A: It’s not that we would advise them what to do and they would go off to their labs and do it. This will be an advanced manufacturing centre. Our focus with this funding will be our new Good Manufacturing Practice (GMP) facility to make cells for clinical trials. We are going to hire 30 to 40 people to conduct these projects and do this fee-for-service work.
Q: You’ve got GE Healthcare as a major partner, but do you want more businesses to come in?
A: This is a consortium model. GE Healthcare is an anchor partner but we want to bring together and integrate technologies from other sources as well. So, we’re looking for technology partners. But we’re also looking for clients — cell therapy companies that need these solutions. An advantage of the site is it is in such a rich clinical environment in Toronto and, more broadly, Canada. That was a great attraction for GE because it enables them to engage with their customers in clinical trials and projects where the technologies can be stress-tested. This is real-time engagement of the community and the market.
Q: What’s the facility itself?
A: The facility is in MaRS (a not-for-profit corporation founded in downtown Toronto in 2000). It’s going to be part of an entire floor of activities focused on regenerative medicine. There will be the GMP facility there. Our CCRM employees will be there. It will also be the headquarters for the Ontario Institute for Regenerative Medicine and the University of Toronto’s new Medicine by Design project. So when people enter the 10th floor of MaRS, they are going to see a very integrated, co-ordinated ecosystem in and around cell therapy and regenerative medicine.
Q: Will you be working with other cell manufacturing centres like the one opening in Edmonton, and centres in Laval, Montreal and Ottawa?
A: We’re working with those through CellCAN, that’s one point of contact. I was just in Montreal and promoting the idea of the centre being the process development arm. If we need to optimize or scale up manufacturing we can do it in our centre and transfer those solutions back to manufacturing facilities as needed across the country.
Q: So it’s the Canadian model of working collaboratively, not competitively?
A: Absolutely. Although this will be, within MaRS, a very unique ecosystem, it has to be integrated with other activities across the country. It has to be integrated with other activities across the globe. Trying to achieve the proper scale is impossible with one centre or even one country.
Q: What are the anticipated outcomes?
A: The outcomes will be new technologies and tools to enable clinical- and commercial-scale manufacturing of cells — so there will be very tangible widgets that come out. Over the medium term, there will be a blueprint for cell manufacturing of the future,with integration of a number of technologies. We believe this centre will attract clinical trials to Canada and accelerate the development of technologies and clinical translation so more patients will be receiving cell therapies. It will support companies created in Canada but, as I mentioned, attract companies to Canada. We can’t just talk about scientific leadership anymore. We have to be leading commercialization. We need to be leading translation, through clinical trials. And this piece is manufacturing. Because with manufacturing comes stickiness and companies that are sustainable in Canada.
Q: What do you mean by ‘stickiness?’
A: This is advanced manufacturing; it’s not like making a car that you can diffuse production to the cheapest site in the world. This is an area where the leading edge is still being developed. If we are the leaders in manufacturing cells and those cells get manufactured here, then the companies that are here and the jobs we create here will be sticky.
Federal regulators in the United States are about to crack down on hundreds of clinics peddling pricey stem cell therapies to treat a laundry list of diseases and conditions without scientific evidence to back them up.…
Federal regulators in the United States are about to crack down on hundreds of clinics peddling pricey stem cell therapies to treat a laundry list of diseases and conditions without scientific evidence to back them up.
According to a report by STAT, an online health and medicine news service, some 200 stem cell clinics have cropped up in recent years, selling injections, facelifts, and treatments that have not undergone clinical trials.
Many of the clinics use a procedure called stromal vascular fraction (SVF) in which cells are extracted from a patient by liposuction, run through a centrifuge to collect the adipose (fat) stem cells and returned to the patient intravenously or injected at the site of the condition. Clinics promote the SVF procedure to treat a variety of conditions such as arthritis, Parkinson’s disease, pulmonary fibrosis, chronic obstructive pulmonary disease, multiple sclerosis, cerebral palsy, and amyotrophic lateral sclerosis. Treatments can cost anywhere from $5,000 to $25,000.
The American Food and Drug Administration (FDA) recently issued draft guidelines on the use of human cells, tissues, or cellular or tissue-based products and will hold a public hearing on April 13 at Silver Spring, Maryland to help finalize its stand on such treatments.
As STAT reported, the FDA already sent a warning letter to a network of stem cell clinics in California, New York, and Florida advising the owner that he needed FDA approval to sell and use stem cells, which the agency classified as biological drugs.
FDA approval requires evidence that stem cell treatments are safe and effective, which, as the article points out, “takes drug companies many years of clinical trials to obtain, at a cost of millions of dollars.”
Canadian bioethicist Dr. Leigh Turner of the University of Minnesota has long criticized the FDA for failing to crack down on the clinics as the mushroomed across the U.S. “If it’s not safe and it’s not going to help patients,” Dr. Turner told STAT. “It’s just predatory behavior.”
Young scientists who have done something remarkable in stem cell research recently have until March 1 to tell the world about it and win a $25,000 award.…
Young scientists who have done something remarkable in stem cell research recently have until March 1 to tell the world about it and win a $25,000 award.
Early career scientists — younger than 45 as of Jan. 1 2016 — working in the field of stem cells and/or regenerative medicine are eligible for the annual Stem Cells and Regenerative Medicine Award. Entrants must submit an essay describing the implications of work they have done in the past three years in developing cell-based treatments for cancer, degenerative disorders and immunological conditions.
Sponsored by China-based Boyalife, the largest stem cell bank in Asia, and the American Association for the Advancement of Science, publisher of Science, Science Translational Medicine, Science Signaling and Science Advances, the award recognizes significant contributions in advancing basic science to clinical applications in the field.
The winning essay will be published in Science. The runner-up will receive $5,000. Find out more here.
When most of us think about using stem cells to cure disease, we picture these building block cells being injected into damaged tissues or organs to help repair and rebuild them.…
When most of us think about using stem cells to cure disease, we picture these building block cells being injected into damaged tissues or organs to help repair and rebuild them.
According to a recent Wall Street Journal article, there are more than 300 clinical trials underway around the world to test stem cells’ ability to treat diseases such as heart attack (read about a Canadian study here), stroke and amyotrophic lateral sclerosis — among others. The general idea is to get the stem cells to where the disease is doing damage so they can affect healing.
But, as the WSJ article points out, there is another approach in which stem cells are used to create models of disease outside the human body, in a Petri dish. These models not only provide researchers with a closer look at the molecular makeup of a disease, they offer the opportunity to test drugs that might be effective against it. The article highlights research at the University of California, San Diego where stem cells are being used to make Alzheimer’s neurons to test the safety and effectiveness of potential drug therapies.
There are real benefits to this approach. For one, it’s a supplement to using animals as disease models. Sometimes animals aren’t susceptible to the same diseases as people. In Alzheimer’s, for example, researchers use mice that have been altered to carry different genes or combinations of genes associated with the dementia.
The stem cell model approach also can save time and money. If scientists can rule out a compound as ineffective before moving to clinical trials, it can prevent years of work being done and millions of dollars being spent to travel down a research road that ultimately is a dead end.
Also, advances in technology mean scientists can use high-throughput screening to test hundreds, even thousands, of compounds against model tissue or organs to find a good candidate to shut down the disease — the research equivalent to finding a therapeutic needle in a haystack.
Dr. Eva Feldman devoted 12 years to working on a drug-based cure for amyotrophic lateral sclerosis (ALS). It was, she says, “a very big endeavour.” It failed.…
Dr. Eva Feldman devoted 12 years to working on a drug-based cure for amyotrophic lateral sclerosis (ALS). It was, she says, “a very big endeavour.” It failed.
So, in 2006 the University of Michigan clinician/researcher took a sabbatical to rethink her approach to fighting ALS, the cruel, fatal condition that attacks the nerve cells (neurons) that control muscle movement. “I wanted a break,” she says. In California, Dr. Feldman found scientists doing interesting animal studies on treating spinal cord injury with stem cells. It changed her perspective entirely.
Today, with two early-stage human studies behind her, Dr. Feldman hopes to soon begin a large-scale clinical trial to test whether human neural stem cells injected into the spinal columns of ALS patients can stop the disease from stealing their ability to walk, talk, eat and breathe.
“We inject the cells into the high part of the spinal cord of patients with ALS with the goal of protecting the large motor neurons that are necessary to maintain normal breathing. Our goal is for the stem cells to go into that area, surround the neurons that are starting to get ill and nurse them back to health. We do very similar injections in the lumbar area of the spine to preserve the neurons that go to the muscles that allow patients to walk.”
Preclinical studies she and her team conducted on rats and pigs showed that the stem cells “take a really bad environment and clean it up.” Inflammation is ameliorated and the stem cells surround the large, ailing motor neurons and nurse them back to health. “The cells go from looking like they are about to die to being quite healthy and robust,” says Dr. Feldman.
Phase I and II clinical trials involving 30 patients went “extremely well,” she says, with the procedure proven to be safe and the patients able to tolerate the accompanying immuno-suppressant therapy. “We have good preliminary data,” she says.
Neuralstem Inc., Dr. Feldman’s industry partner in the project, is organizing a large, multi-centre trial in 2016 to test whether the procedure truly works. Richard Garr, the company’s Chief Executive Office, is understandably guarded about the details, saying via email that his company is working with the U.S. Food and Drug Administration and that “all of the issues with respect to the scope and nature of the trial are still being determined.”
Dr. Feldman, who has been down this road before with the failed ALS drug, is cautiously optimistic. “As enthusiastic as I am about the therapy, until we do a very large trial we simply won’t know with certainty that this is the hopeful home run that we want it to be.”
For Ted Harada, a 43-year-old former FedEx manager in Atlanta, Dr. Feldman’s stem cell therapy has been a life-saver. The recipient of two stem cell implant surgeries, he has seen his decline from ALS virtually stopped. The normal survival period for ALS, which is sometimes called Lou Gehrig’s disease after the New York Yankee slugger who succumbed to it, is about 36 months. He is now five years out and feeling good, although he still has the disease.
“I put my cane down two or three weeks after the (second) surgery and I haven’t picked it back up,” he says. “When I had my fifth year anniversary, my doctor said ‘Ted, I would have guaranteed you’d be dead within two or three years when I first met you.’ I like to say that the surgeries set the clock back to what I call onset.”
Dr. Feldman says other patients in the studies also have done well but “the numbers are small … until our numbers are larger we can’t say with certainty.”
While criteria haven’t been set, participants in the larger trial likely will need to be in the early stages of the disease, with the ability to breathe reasonably well and speak and swallow without difficulty. Dr. Feldman says Canadian patients might be eligible if they can travel to a surgical site — but, again, details are still being worked out.
Dr. Feldman is also excited about the possibility of using the same kinds of stem cells to treat the dementia disease.
“I have beautiful preclinical data in animal models of Alzheimer’s. We’ve shown that the injection of stem cells into the selected areas of the brain that are required to form new memories rescues the animals and they are able to function normally. We see the accumulation of amyloid, which is the build-up of plaque that patients get, gone. The stem cells go in and they are just like garbage disposals, cleaning up all the garbage. It’s remarkable.”