Patients who have used stem cell therapy to reverse the effects of multiple sclerosis are lobbying the Federal Government to provide the treatment in Australia.
A European trial has achieved a 95 per cent success rate, but Australian hospitals are reluctant to use it.
The treatment involves using haematopoietic stem cell therapy, where a patient’s stem cells are harvested from their blood, then an intense chemotherapy regime kills off the MS-ridden immune system, before the harvested stem cells are reinjected.
Neurologist Dr Colin Andrews was one of the first in Australia to use the treatmen, which is only suitable for patients with aggressive MS that existing medication cannot treat.
“We're rebooting the immune system and moving the cells we don’t want,” Dr Andrews said.
“Within a week to 10 days you've got a whole new immune system.”
Recent overseas studies have had a 95 percent success rate of stopping the disease.
The first eight patients in Australia had the treatment done at Canberra Hospital, but the hospital shut down the program half way through the ninth patient on the grounds it was unethical.
“What we’re doing here is harvesting the patient’s own cells, it’s not cells from elsewhere or any other source, so I can’t see there's an ethical issue,” Dr Andrews said. It leaves only one doctor in Australia offering the treatment, yet there are about 4000 sufferers, leaving many heading overseas for help.
But it is at huge cost.
“I had no choice, I was on a ticking time bomb, I didn’t know what to expect next, my health and my child is far more important so I had to go,” Melinda Beattie said.
She spent $65,000 to go to India for the treatment, while Andrew Price flew to the US spending $130,000.
Both their treatments were successful.
They've now formed an organisation to lobby the Federal Government, but MS Australia is refusing to support it at the current time.
“The procedure itself is still in a very experimental stage very much only works with a very small number of people,” Deb Cerasa from MS Australia said.
But Dr Andrews has defended the treatment.
“It’s a procedure, it’s not an experiment, something that’s been around for 10 years, it’s widely practiced throughout the rest of the world we don’t regard it as experimental,” he said.
Source: Yahoo! 7 News (26/02/14)
Extensive renewal of the T cell repertoire following autologous stem cell transplant in MS(18/02/14)
A new study describes the complexity of the new T cell repertoire following immune-depleting therapy to treat multiple sclerosis, improving our understanding of immune tolerance and clinical outcomes.
In the Immune Tolerance Network's (ITN) HALT-MS study, 24 patients with relapsing, remitting multiple sclerosis received high-dose immunosuppression followed by a transplant of their own stem cells, called an autologous stem cell transplant, to potentially reprogram the immune system so that it stops attacking the brain and spinal cord. Data published today in the Journal of Clinical Investigation quantified and characterized T cell populations following this aggressive regimen to understand how the reconstituting immune system is related to patient outcomes.
ITN investigators used a high-throughput, deep-sequencing technology (Adaptive Biotechnologies, ImmunoSEQTM Platform) to analyze the T cell receptor (TCR) sequences in CD4+ and CD8+ cells to compare the repertoire at baseline pre-transplant, two months post-transplant and 12 months post-transplant.
Using this approach, alongside conventional flow cytometry, the investigators found that CD4+ and CD8+ lymphocytes exhibit different reconstitution patterns following transplantation. The scientists observed that the dominant CD8+ T cell clones present at baseline were expanded at 12 months post-transplant, suggesting these clones were not effectively eradicated during treatment. In contrast, the dominant CD4+ T cell clones present at baseline were undetectable at 12 months, and the reconstituted CD4+ T cell repertoire was predominantly comprised of new clones.
The results also suggest the possibility that differences in repertoire diversity early in the reconstitution process might be associated with clinical outcomes. Nineteen patients who responded to treatment had a more diverse repertoire two months following transplant compared to four patients who did not respond. Despite the low number of non-responders, these comparisons approached statistical significance and point to the possibility that complexity in the T cell compartment may be important for establishing immune tolerance.
This is one of the first studies to quantitatively compare the baseline T cell repertoire with the reconstituted repertoire following autologous stem cell transplant, and provides a previously unseen in-depth analysis of how the immune system reconstitutes itself following immune-depleting therapy.
Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (18/02/14)
Stem cell 'major discovery' claimed(31/01/14)
Stem cell researchers are heralding a "major scientific discovery", with the potential to start a new age of personalised medicine.
Scientists in Japan showed stem cells can now be made quickly just by dipping blood cells into acid.
Stem cells can transform into any tissue and are already being trialled for healing the eye, heart and brain.
The latest development, published in the journal Nature, could make the technology cheaper, faster and safer.
The human body is built of cells with a specific role - nerve cells, liver cells, muscle cells - and that role is fixed.
However, stem cells can become any other type of cell, and they have become a major field of research in medicine for their potential to regenerate the body.
Embryos are one, ethically charged, source of stem cells. Nobel prize winning research also showed that skin cells could be "genetically reprogrammed" to become stem cells (termed induced pluripotent stem cells).
Now a study shows that shocking blood cells with acid could also trigger the transformation into stem cells - this time termed STAP (stimulus-triggered acquisition of pluripotency) cells.
Dr Haruko Obokata, from the Riken Centre for Developmental Biology in Japan, said she was "really surprised" that cells could respond to their environment in this way.
She added: "It's exciting to think about the new possibilities these findings offer us, not only in regenerative medicine, but cancer as well."
The breakthrough was achieved in mouse blood cells, but research is now taking place to achieve the same results with human blood.
Chris Mason, professor of regenerative medicine at University College London, said if it also works in humans then "the age of personalised medicine would have finally arrived."
He told the BBC: "I thought - 'my God that's a game changer!' It's a very exciting, but surprise, finding.
"It looks a bit too good to be true, but the number of experts who have reviewed and checked this, I'm sure that it is.
"If this works in people as well as it does in mice, it looks faster, cheaper and possibly safer than other cell reprogramming technologies - personalised reprogrammed cell therapies may now be viable."
For age-related macular degeneration, which causes sight loss, it takes 10 months to go from a patient's skin sample to a therapy that could be injected into their eye -and at huge cost.
Prof Mason said weeks could be knocked off that time which would save money, as would cheaper components.
The finding has been described as "remarkable" by the Medical Research Council's Prof Robin Lovell-Badge and as "a major scientific discovery" by Dr Dusko Ilic, a reader in stem cell science at Kings College London.
Dr Ilic added: "The approach is indeed revolutionary.
"It will make a fundamental change in how scientists perceive the interplay of environment and genome."
But he added: "It does not bring stem cell-based therapy closer. We will need to use the same precautions for the cells generated in this way as for the cells isolated from embryos or reprogrammed with a standard method."
And Prof Lovell-Badge said: "It is going to be a while before the nature of these cells are understood, and whether they might prove to be useful for developing therapies, but the really intriguing thing to discover will be the mechanism underlying how a low pH shock triggers reprogramming - and why it does not happen when we eat lemon or vinegar or drink cola?"
Source: BBC News © British Broadcasting Corporation 2014 (31/01/14)
New targeted stem cell therapy looks to improve MS patients dealing with incontinence complications.
StemGenex®, the leading resource for adult adipose stem cell therapy in the US aimed at improving the lives of patients dealing with degenerative diseases today announced the newest therapy to assist patients diagnosed with Multiple Sclerosis.
According to the National MS Society, at least 80% of people with MS experience bladder dysfunction. StemGenex believes a new therapy delivering adipose derived mesenchymal cells directly to the bladder may reduce the inflammation that is causing the patient’s incontinence.
Direct bladder targeting is the latest in a series of targeted therapies StemGenex® plans to announce in the next few months for patients dealing with degenerative diseases such as Parkinson’s, Alzheimer’s, COPD and of course Multiple Sclerosis. Earlier this month StemGenex announced a new intranasal stem cell therapy. The goal of this new technique is to encourage more stem cells to travel through the blood brain barrier to target the damage caused by MS.
Stem cell treatment studies are currently being offered by StemGenex to patients diagnosed with Multiple Sclerosis and other degenerative neurological diseases. StemGenex takes a unique approach of compassion and empowerment while providing access to the latest stem cell therapies for degenerative neurological diseases including Parkinson’s and Alzheimer’s disease, stroke recovery and others. Rita Alexander, founder of StemGenex and the company’s first stem cell patient, insists that all patients be treated like they are one of our loved ones. "Hope, compassion, and the relentless pursuit for an end to these diseases are our primary focus."
Source: © Copyright 1997-2013, Vocus PRW Holdings, LLC. Vocus, PRWeb (03/12/13)
A team of Ottawa doctors is preparing to publish a full report on its breakthrough multiple sclerosis treatment study that has so far eliminated the disease in those treated.
The experimental study began about 13 years ago as a last resort for patients who fail to improve on drug therapy and who suffer severe symptoms of MS. Snippets of the results have been published “here and there,” said, neurologist Dr. Mark Freedman, one of the leads of the program at The Ottawa Hospital, but its never been published in its entirety.
No specific date has been set for its release, but the team’s findings are far from secret. With MS not returning in any of the 24 participants, patient success stories appear in news media across the country. Since the original study’s completion, about another dozen patients have been treated with all of them showing the same results.
Eliminating MS completely and watching patients improve surprised both Freedman and Dr. Harold Atkins, a bone-marrow transplant expert, who started the study. The two originally set out to monitor the development of the disease and find a way to treat it. Their theory was this: Wipe out the entire immune system, reboot it with a transplant of the patient’s own bone marrow and wait for MS to regenerate.
“We thought we might be able to intercept one of the signals that initiates the disease and that would then give us a clue on how to treat it,” Freedman said. He jokes that they “had, in effect, failed because the disease never came back. No one expected to see zero disease activity after the transplant.”
Patients from Vancouver to Newfoundland, who had given up hope, became part of the original 24, including third-year medical student Alex Normandin from Montreal.
The aspiring doctor noticed alarming symptoms of fatigue, numbness and problems with balance and co-ordination. Researchers at the Montreal Neurological Institute confirmed he has a particularly aggressive form of MS, an unpredictable and degenerative disease that affects the central nervous system.
Most patients do not become severely disabled because the illness moves slowly. But in Normandin’s case, the destruction was so fast that doctors expected him to need a wheelchair within months.
Normandin, however, learned of the cutting-edge treatment run by Freedman and Atkins. He became patient No. 19 in the experiment and had his transplant in Ottawa in December 2008.
The procedure has its risks. One patient died in an earlier phase of the trial. It was in 2001 or 2002, Freedman recalled, saying the death was due to the pill form of the drug Busulphan. Used early on in the experiment, the drug attacks the liver twice, both when it enters the body and again when it leaves. But within a year, the team had found that a new intravenous version of the drug improved patient safety tremendously.
Freedman had the task of trying to scare patients by telling them the risks.
“My job was to talk everybody out of it,” he said. “It really is the hardest thing they’ll have to do in their lives. It is a bit of a gamble, but with the fantastic team we have in Ottawa, it’s less of a gamble.”
All participants showed dramatic improvement, and none reported relapses, according to a study on the Freedman-Atkins treatment by a team of MS researchers at the Neuro and the Université de Montréal.
Plus, magnetic resonance imaging (MRI) showed no new lesions in the brain, “no new MS disease activity,” according to findings published in the latest issue of Annals of Neurology.
For Normandin, he’s now a family physician in private practice on the West Island and no longer takes medication for the illness. His fatigue and balance problems continue to diminish daily.
But despite such dramatic results, none of the MS researchers in this study is calling the procedure a cure.
For one thing, it is not known whether the treatment is good at stopping other kinds of MS, explained neurologist Amit Bar-Or of the Montreal Neurological Institute and McGill University and the study’s principal investigator.
Also, bone-marrow stem-cell transplants to treat MS are not approved outside of clinical trials because while the disease itself is not deadly, the procedure is fatal in as much as five per cent of patients.
But Freedman questions the risk rate. He says the five-per-cent figure was from data collected in the 1990s as the team prepared for the experiment. That number has since dropped to about one per cent, he said.
In addition to medical advancements, by comparing the immune responses in patients before and after the treatment, researchers discovered a key biological target for new therapies that might be able to provide similar benefits without the risks associated with knocking out someone’s immune system to facilitate a bone-marrow transplant.
Several studies have already noted that in MS patients, the body’s immune system attacks its own cells. Overactive T cells (a type of white blood cells called lymphocytes) — that are responsible for defending the body against bacteria, viruses and other parasites — can also damage myelin, the protective insulation covering nerves.
The concept is straightforward, Bar-Or explained. To fight an infection, different types of T cells mount a quick response, then other T cells quickly ratchet back that response, he said. But in auto-immune conditions, including MS, this regulation goes awry and the body attacks itself.
Researchers have zeroed in on a particular subset of T cells, called TH17 cells, that have a substantially diminished function following the experimental transplant. The discovery could help researchers target treatment in MS patients generally.
“We are cautious in not claiming we have figured out all cells responsible for all relapses in all MS patients,” Bar-Or noted. “Keep in mind these patients have very aggressive MS, so maybe TH17 are particularly important in these patients.”
Emerging treatments, however, are already attempting to target TH17 cells, but the story is even more complicated, Bar-Or said.
“We don’t know everything about them (TH17 cells) even in terms of basic immunology. It’s likely that within the TH17 subset there may be particular bad guys ... It would be nice to know which because we need to have these cells some of the time. Getting rid of all of them all of the time, may not be completely safe.”
Both the clinical study at the Ottawa Hospital Multiple Sclerosis Research Unit and biological study in Montreal were funded by the Research Foundation of the Multiple Sclerosis Society of Canada.
Canada has one of the highest rates of MS in the world — affecting about 55,000 to 75,000 people.
Normandin says his illness has been a blessing in disguise, giving him a unique perspective not found in medical text books.
“It changed my whole outlook on life. It definitely affects the way I see patients. I’m more sensitive in how to talk to them and more empathetic dealing with chronic diseases.”
He was once on a career track where the focus was work, but now “life balance” is everything and he is grateful for the treatment that gave him his life back and allowed him to work in a clinic where he can spend as much time as necessary talking to patients.
“Life is great,” he said. “I love to say it.”
Source: The Ottawa Citizen © Copyright (c) The Ottawa Citizen 2013 (18/11/13)
Researchers in Milan, Italy reported that stem cells derived from mouse skin tissue were able to reduce nervous system damage in mice with a disease similar to multiple sclerosis, offering further evidence for the possibility that stem cells from patients might in the future be used for cell therapy to treat MS. The study, by Cecilia Laterza, Ph.D., Gianvito Martino, MD and colleagues at the San Raffaele Scientific Institute, Milan, and the University of Milan, was published today in Nature Communications.
The study was co-funded by the National Multiple Sclerosis Society, Multiple Sclerosis Italian Foundation (FISM), MIUR Lombardy Region (NetLips Project), ELA Foundation, BMW Italy and NEUROKINE network (EU Framework 7 ITNproject).
Current therapies for MS reduce the immune system attacks that damage the brain and spinal cord, but they are not effective in progressive phases of the disease, when damage to the protective myelin coating on nerve fibers and the nerve fibers themselves may be widespread. Finding ways to repair the nervous system to restore function is a major research priority.
For this study the team used mouse skin stem cells and forced them through "cell reprogramming" to become myelin-making cells. This technique allows differentiated (specialized) cells, such as skin cells, to become embryonic-like stem cells which can become any kind of cell, including neural stem cells, the stem cells of the brain.
As in previous studies of this type, after the cells were infused into the spinal cord, they promoted recovery in mice with the MS-like disease EAE (experimental autoimmune encephalomyelitis). Transplanted cells were able to reduce inflammation and protect the intact myelin from further damage, and were also able to foster the production of new myelin by the brain's own cells. The team further showed that the protective effect was mediated by a soluble factor released by the transplanted cells, called "leukemia inhibitory factor."
"Our discovery opens new therapeutic possibilities for multiple sclerosis patients because it might target the damage to myelin and nerves itself," stated study leader Dr. Gianvito Martino.
"This is an important step for stem cell therapeutics," noted Dr. Timothy Coetzee, Chief Research Officer of the National MS Society. "The hope is that skin or other cells from individuals with MS could one day be used as a source for reparative stem cells, which could then be transplanted back into the patient without the complications of graft rejection," he added.
More work is needed, but this type of research gives hope that this strategy may eventually help restore lost function. Read more about research to repair the nervous system.
"There is still a long way to go before reaching clinical applications but we are getting there," said Dr. Martino. "We hope that our work will contribute to widen the therapeutic opportunities stem cells can offer to patients with multiple sclerosis."
"This is an important result for people with MS: rigorous basic science providing insights into the mechanisms involved in myelin and nerve damage is the only way to foster the discovery of new therapies for progressive forms of the disease," noted Paola Zaratin, Ph.D., Director of Scientific Research at the Italian MS Society/Italian MS Foundation.
Source: The Sacramento Bee Copyright © The Sacramento Bee 2013 (30/10/13)
Jason McIntyre's autoimmune system is dead. The rest of him isn't feeling much better. Eleven days ago he underwent an aggressive chemotherapy, not for the sake of killing cancer - but to knock out every skerrick of protection his body has against infection.
Sitting in a freezer were 35 million stem cells that were shaken from Mr McIntyre's bone marrow by a combination of drugs. These were filtered from his blood about three weeks ago. That process, he says, left him with aching bones. It was his birthday.
If he survives long enough - that is, if a piece of dust doesn't get in his eye and spark a fatal infection - the stem cells will this week be returned to his body, as building blocks for a brand new autoimmune system.
Mr McIntyre, 37, is only the sixth patient with multiple sclerosis to undergo this experimental therapy - known as an autologous haematopoietic stem cell transplant - in a small trial being conducted by St Vincent's Hospital in Sydney.
Thousands of stem cell transplants are performed worldwide to treat certain blood cancers in patients who have become resistant to regular therapies - but the numbers of MS sufferers treated with a stem cell transplant are in the hundreds.
It's a strategy reserved for people like Jason McIntyre whose form of MS is very aggressive and resistant to drug therapy.
About three years ago, the Melbourne truck driver arrived home with blurry vision. He told his wife, Kym, that he couldn't read the number plates on cars. Soon after, following a session at the gym, he was ''boiling hot and his vision went blurry again''.
Kym McIntyre says it all happened pretty quickly. He started dragging his left foot. He couldn't unscrew bottle tops and lost his co-ordination.
An eye doctor recognised the problem as multiple sclerosis, but Mr McIntyre was told by a specialist that he'd have to wait for another attack - another lesion on the brain to develop - for the diagnosis to be confirmed.
Meanwhile, the trucking company Mr McIntyre ran with his father, Peter, had to stay in business. Peter was meant to be retiring, but went back on the road. The McIntyres have two small children, and the medical bills aren't going away.
When the diagnosis was confirmed, Mr McIntyre underwent a series of injections to alleviate symptoms and slow the attacks. It didn't work. He was put on a more aggressive drug therapy. That didn't work either, and his body went into further decline. His specialist said he had run out of options.
''Jason's sister Stacey didn't cop that,'' says Ms McIntyre. ''She went online and found a transplant trial was happening in Canberra.'' However, that project collapsed because of lack of funding.
Then came word that the haematopoietic stem cell transplant team at St Vincent's Hospital in Sydney - where patients with blood cancers are routinely treated - were trialling the treatment with MS sufferers who weren't responding to traditional therapies.
Speaking from his hospital bed, Mr McIntyre said the chemotherapy was ''knocking me about a bit. Feeling tired. See how we go.''
His wife was upbeat - or perhaps driven is a better word. ''I'm sick of chasing the kids. I need him back in action.''
The children, Pyper, 6, and Ryder, 3, were at an apartment with Ms McIntyre's mother. They were anxious and rowdy. ''They just want everything to get back to normal.'' Stem cell transplants have a claimed 70 per cent success rate at halting some types of MS. However, researchers here and abroad can't get sufficient funding such that a randomised trial can be undertaken that would bring the treatment into the mainstream.
''There have been many attempts in Europe to mount good clinical studies to demonstrate definitively that the transplants are effective, but [the studies] weren't successful … each time they ran out of money,'' says Professor David Ma, the head of the St Vincent's haematopoietic stem cell transplant team, which is caring for Mr McIntyre.
The St Vincent's small-scale trial is part of an international effort to get enough runs on the board - and secure funding.
Multiple sclerosis, says Professor Ma, is a good fit for stem cell transplant therapy because it's an autoimmune disease.
The brain and spinal cord become inflamed with lesions - and these are then attacked and damaged by the autoimmune system. If the immune system can be effectively killed off, and replaced with a new system, then the brain has an opportunity to recover from the inflammation that caused the problem in the first place.
''It's a radical strategy, for sure,'' says Professor Ma. ''We're trying to get it past the experimental stage.''
Lisa Melton, research development manager with MS Research Australia, said about 40 patients in Australia were known to have undergone the therapy, with mixed results. Most of the treatments were carried out at the discretion of treating doctors on compassionate grounds at different centres around the country.
''It's a dangerous procedure, highly aggressive, and carries considerable risks,'' says Dr Melton.
MS Research Australia is funding a database to record outcomes in Australian cases.
Source: The Age National Copyright © 2013 Fairfax Media (28/10/13)
As stem cell clinical trials for multiple sclerosis (MS) patients become more common, it is crucial for researchers to understand the biologic changes and therapeutic effects of older donor stem cells. A new study appearing in the latest issue of STEM CELLS Translational Medicine is the first to demonstrate that, in fact, adipose-derived stem cells donated by older people are less effective than cells from their younger counterparts.
MS is a neurodegenerative disease characterized by inflammation and scar-like lesions throughout the central nervous system (CNS). There is no cure and no treatment eases the severe forms of MS. But previous studies on animals have shown that transplantation of mesenchymal stem cells (MSCs) holds promise as a therapy for all forms of MS. The MSCs migrate to areas of damage, release trophic (cell growth) factors and exert neuroprotective and immunomodulatory effects to inhibit T cell proliferation.
MS-related clinical trials have all confirmed the safety of autologous MSC therapy. However what is unclear is whether MSCs derived from older donors have the same therapeutic potential as those from younger ones.
"Aging is known to have a negative impact on the regenerative capacity of most tissues, and human MSCs are susceptible to biologic aging including changes in differentiation potential, proliferation ability and gene expression. These age-related differences may affect the ability of older donor cells to migrate extensively, provide trophic support, persist long-term and promote repair mechanisms," said Bruce Bunnell, Ph.D., of Tulane University’s Center for Stem Cell Research and Regenerative Medicine. He served as lead author of the study, conducted by a team composed of his colleagues at Tulane.
In their study, mice were induced with chronic experimental autoimmune encephalomyelitis (EAE) and treated before disease onset with human adipose-derived MSCs derived from younger (less than 35 years) or older (over age 60) donors. The results corroborated previous studies suggesting that older donors are less effective than their younger counterparts.
"We found that, in vitro, the stem cells from the older donors failed to ameliorate the neurodegeneration associated with EAE. Mice treated with older donor cells had increased inflammation of the central nervous system, demyelination leading to an impairment in movement, cognition and other functions dependent on nerves, and a proliferation of splenocytes [white blood cells in the spleen], compared to the mice receiving cells from younger donors," Dr. Bunnell noted.
In fact, the T cell proliferation assay results in the study indicated that older MSCs might actually stimulate the proliferation of the T cells, while younger stem cells are capable of inhibiting the proliferation of T cells. (T cells are a type of white blood cell in the body’s immune system that help fight off disease and harmful substances.)
As such, Dr. Bunnell said, "A decrease in T cell proliferation would result in a decreased number of T cells available to attack the CNS in the mice, which directly supports the results showing that the CNS damage and inflammation is less severe in the young MSC-treated mice than in the old MSC-treated mice."
"This study in an animal model of MS is the first to demonstrate that fat-derived stem cells from older human donors have less therapeutic effectiveness than cells from young donors," said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "The results point to a potential need to evaluate cell therapy protocols for late-onset multiple sclerosis patients."
The full article, "Age of the donor reduces the ability of human adipose-derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model," can be accessed at: http://www.stemcellstm.com/content/ .
Source: Digital Journal copyright © 2013 digitaljournal.com (09/09/13)
The Tisch MS Research Center of New York announced today that it has received Investigational New Drug (IND) approval from the Food and Drug Administration (FDA) to commence a Phase 1 trial using autologous neural stem cells in the treatment of multiple sclerosis (MS). MS is a chronic human autoimmune disease of the central nervous system that leads to myelin damage and neurodegeneration and affects approximately 2.5 million people worldwide.
"To my knowledge, this is the first FDA-approved stem cell trial in the United States to investigate direct injection of stem cells into the cerebrospinal fluid of MS patients, and represents an exciting advance in MS research and treatment," said Dr. Saud A. Sadiq, Senior Research Scientist at Tisch MS Research Center of New York and the study's principal investigator.
The groundbreaking study will investigate a regenerative strategy using stem cells harvested from the patient's own bone marrow. These stem cells will be injected intrathecally (into the cerebrospinal fluid surrounding the spinal cord) in 20 participants who meet the inclusion criteria for the trial. This will be an open label safety and tolerability study. All study activities will be conducted at the Tisch MS Research Center and affiliated International Multiple Sclerosis Management Practice (IMSMP).
The clinical application of autologous neural progenitors in MS is the culmination of a decade of stem cell research conducted by a dedicated team of scientists headed by Dr. Sadiq and by Dr. Violaine Harris, Research Scientist at Tisch MS Research Center.
Preclinical testing found that the injection of these cells may decrease brain inflammation and promote myelin repair and/or neuroprotection. "This study exemplifies the Tisch MS Research Center's dedication to translational research and provides a hope that established disability may be reversed in MS," Dr. Sadiq noted.
Participants will undergo a single bone marrow collection procedure, from which mesenchymal stem cell-derived neural progenitor cells (MSC-NPs) will be isolated, expanded and tested prior to injection. Participants will receive three rounds of injections at three month intervals. Safety and efficacy parameters will be evaluated in all participants through regular follow-up visits.
ABOUT TISCH MS RESEARCH CENTER OF NEW YORK For over twenty years, Dr. Saud A. Sadiq has believed that combining excellence in clinical care with innovative research targeted at finding the cure for multiple sclerosis would set an exemplary standard in the treatment of MS patients. Today, the Tisch MS Research Center of New York embodies this new model of healthcare, in which your doctor is also your researcher. Dr. Sadiq helps those with MS by conducting cutting-edge, patient-based research to ensure unparalleled care. The close relationship of the non-profit research center and its affiliated clinical practice (International Multiple Sclerosis Management Practice) enables the testing of new MS treatments and accelerates the pace at which research discoveries move from lab bench to bedside. The Tisch MS Research Center of New York aims to identify the disease trigger, optimize treatments for patients, and repair the damage caused by multiple sclerosis.
Source: Digital Journal copyright © 2013 digitaljournal.com (14/08/13)
T cell responses after hematopoietic stem cell transplantation for aggressive relapsing-remitting MS(04/06/13)
Autologous hematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission.
However, the mode of action is not yet fully understood. The aim of the study was to evaluate similarities and differences of the CD4+ T cell populations between HSCT-treated patients (n=12) and healthy controls (n=9). More specifically, we performed phenotyping of memory T cells, Tregs, T helper type 1 (Th1) and T helper type 17 (Th17) cells. Further, T cell reactivity to a tentative antigen: myelin oligodendrocyte glycoprotein was investigated in these patient populations.
Patients treated with natalizumab (n=15) were included as a comparative group. White blood cells were analyzed with flow cytometry and T cell culture supernatants were analyzed with magnetic bead panel immunoassays.
HSCT-treated patients had similar levels of Tregs, Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated patients had lower frequencies of Tregs, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated patients cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more TGF-β1 than natalizumab-treated patients suggestive of a suppressive response.
Conversely, T cells from natalizumab-treated patients cultured with those peptides produced more IL-17, IL-1 and IL-10 indicating a Th17 response.
In conclusion, we demonstrate circumstantial evidence for the removal of auto-reactive T cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen post HSCT.
Burman J, Fransson M, Tötterman TH, Fagius J, Mangsbo SM, Loskog AS.
Source Department of Neurosciences, Uppsala University, Uppsala, Sweden; Department of Neurology, Uppsala University Hospital, Uppsala, Sweden; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Source: Immunology. 2013 May 30. doi: 10.1111/imm.12129. and Pubmed PMID: 23721329 (04/06/13)
High-dose immunosuppressant therapy and autologous hematopoietic stem cell transplant (HSCT) induced durable freedom from relapses and MRI lesions in patients with multiple sclerosis, researchers reported here.
At evaluations performed 1 and 2 years after the procedure, patients showed no gadolinium-enhancing lesions on MRI scans, and only six of the 24 patients receiving the transplants experienced relapses, reported Richard A. Nash, MD, of Colorado Blood Cancer Institute in Denver, and colleagues.
In a poster presented at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, the investigators indicated that overall functional ability and quality of life were improved as well with the transplant procedure.
Immunosuppressant therapy with drugs and dosages high enough to be severely myelosuppressive, followed by HSCT, had been tested previously in patients with advanced, progressive MS, for which there is currently no broadly effective treatment. The results were disappointing, Nash and colleagues indicated, as "many patients continued to lose neurological function."
But it was unclear whether the lack of effect was because the treatment failed to suppress MS autoimmune activity or because the process of neurodegeneration had become independent of autoimmune mechanisms.
Since the latter seemed like the more likely explanation, Nash and colleagues tested a similar regimen in patients with relapsing-remitting MS, in which autoimmunity is widely believed to be the chief pathological process.
The 25 patients enrolled in the study had a median age of 38 and median duration of disease of 6.4 years. Median score on the Expanded Disability Status Scale (EDSS) was 4.5, indicating moderate disability. About 40% had gadolinium-enhancing lesions at baseline, including five patients with two or more each.
Participants first underwent stem cell mobilization with granulocyte colony-stimulating factor (along with cyclophosphamide in one patient who did not mobilize enough cells with G-GSF alone), with CD34 stem cells then collected.
Patients then received a high-dose immunosuppressant regimen similar to those used in cancer patients undergoing HSCT. Drugs included carmustine, etoposide, melphalan, and cytarabine given over a 6-day period. The collected stem cells (median 4.6 million/kg) were then reinfused.
One patient did not complete the procedure because of pulmonary embolism occurring during the mobilization phase.
In the remaining 24 patients, all but one had no gadolinium-enhancing lesions at the 6-month mark after the procedure, and no patients had such lesions after 1 and 2 years.
Mean T1 lesion volume remained unchanged through the 2-year evaluation. Mean T2 lesion volume declined by more than 0.5 mL at 6 months and by 0.9 mL at 2 years, relative to baseline.
Disability progression as well as relapses were rare through the first 2 years. About 90% were free of both clinical manifestations of MS. MRI disease activity was also seen in only two patients.
Overall event-free survival at 2 years -- taking into account both clinical and MRI disease activity -- was 82.8% (90% CI 65.0%-92.0%), the researchers indicated.
MS Functional Composite scores increased from a median of -0.21 at baseline to 0.22 after 2 years (P=0.012). Similarly, MS Impact Scale scores decreased by a median of 8.93 points from baseline at the 2-year evaluation (P=0.016).
Examination of circulating immune cells indicated that, 1 year after transplant, CD8-positive T-cell counts had returned to normal levels, whereas CD4-positive naive and memory T-cell counts remained depressed.
Nash and colleagues indicated that they planned to follow the cohort for 5 years. Preliminary data collected in this effort suggested a resumption of MRI disease activity in some patients after the 42-month mark. One patient died from MS-related causes after reaching 2 years in the study.
Serious adverse events during the HSCT procedure were common -- a total of 94 grade 4 events were recorded, although all but seven were either hematologic or gastrointestinal. Those seven events included depression, suicide attempt, hypokalemia, respiratory failure, and severely elevated alanine aminotransferase.
The study was funded by the National Institutes of Health.
Study authors reported relationships with Acorda, Roche, Avanir, Bayer, EMD Serono, Pfizer, Teva, Biogen Idec, Novartis, Sanofi, Lilly, GlaxoSmithKline, NeuroRx Research, Opexa, and Coronado Biosciences.
Primary source: CMSC-ACTRIMS
Source reference: Nash R, et al "Two-year follow-up of the HALT MS clinical trial: interim analysis" CMSC-ACTRIMS 2013; Abstract P20.
Source: MedPage Today © 2013 MedPage Today, LLC. (04/06/13)
A potential new treatment for multiple sclerosis lies within modified adult stem cells, University of Adelaide researchers say.
The researchers are embarking on a new project which uses stem cells from fat tissue to send cells with special anti-inflammatory properties directly to the damaged site in the central nervous system.
MS is a progressive disease where the body attacks the central nervous system, causing nerve inflammation and scarring. It results in the impairment of motor, sensory and cognitive function.
Director of the Centre for Molecular Pathology, Professor Shaun McColl, said treatments for MS need to control the immune response and repair the damage caused to the fatty myelin sheaths which protect the nerves.
"We've already shown that adult stem cells have great potential to both control the immune response and promote repair of the central nervous system. It also prevents further damage," he said.
"But the trick is getting the stem cells to the right location where they can perform this function."
When stem cells are injected into the blood system, very few cross the blood/brain barrier into the central nervous system.
Lead investigator Dr Iain Comerford said it was hoped the manipulated adult stem cells could cross that barrier, targeting the inflammation site and repairing the damaged myelin.
"It involves promoting stem cell migration to the central nervous system by manipulating receptors on the surface of the stem cells that control cell movement," Dr Comerford said.
"We're also modifying the stem cells to suppress the immune response by introducing molecules that regulate inflammation."
At the end of the three-year project, the researchers aim to show they can successfully modify the stem cells to effectively reach the central nervous system and inhibit inflammation.
"If it works, there is great potential for a new therapy for this debilitating disease," Dr Comerford said.
Source: news.com.au Copyright 2013 News Limited (10/05/13)
Scientists have discovered an antibody that can turn stem cells from a patient's bone marrow directly into brain cells, a potential breakthrough in the treatment of neurological diseases and injuries.
Richard Lerner, of the Scripps Research Institute in California, says that when a specific antibody is injected into stem cells from bone marrow—which normally turn into white blood cells—the cells can be triggered to turn into brain cells.
"There's been a lot of research activity where people would like to repair brain and spinal cord injuries," Lerner says. "With this method, you can go to a person's own stem cells and turn them into brain cells that can repair nerve injuries."
Antibodies are Y-shaped proteins that the immune system uses to help identify foreign threats to the body. They bind to foreign invaders in the body in order to alert white blood cells to attack harmful bacteria and viruses. There are millions of known antibodies.
Lerner and his team were working to find an antibody that would activate what is known as the GCSF receptor in bone marrow stem cells, in order to stimulate their growth. When they found one that worked, the researchers were surprised: Instead of inducing the stem cells to grow, they began to form into neural cells.
"The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish," which is reminiscent of behaviour of neural cells, Jia Xie, a research associate on Lerner's team, said in a released statement. Further tests confirmed that they were neural progenitor cells, which are very similar to mature brain cells.
Lerner says that scientists have "an awful lot of experience injecting antibodies" into stem cells and that the process is not "inherently dangerous." The team plans to start animal tests of the technology soon.
"We're going to collaborate with people who are trying to regenerate nerves in the eye," Lerner says. "We will team up with a couple people strong in that area of research."
Source: US News © 2013 U.S.News & World Report LP (24/04/13)
Ordinary skin cells have been directly converted into the myelinating cells destroyed in multiple sclerosis, according to two new papers in Nature Biotechnology.
Using a process they call "cellular reprogramming," researchers at Stanford University School of Medicine and Case Western Reserve School of Medicine, in two very similar papers, described how they turned the fibroblasts into what appear to be oligodendrocyte precursor cells, in mice. Oligodendrocytes produce myelin, the fatty insulation necessary to allow nerve signal conduction. It is caused by an autoimmune reaction attacking the oligodendrocytes.
" We propose direct lineage reprogramming as a viable alternative approach for the generation of OPCs for use in disease modeling and regenerative medicine," the Stanford team stated in their paper.
In multiple sclerosis, the destruction of oligodendrocytes and myelin results in symptoms such as loss of balance, problems moving arms and legs, loss of coordination and weakness, according to the National Institues of Health. Other problems include loss of bladder control, impaired vision, depression, and memory loss.
To fix these problems, not only must the autoimmune reaction be brought under control, but the myelin must be repaired. That implies producing new oligodendrocytes. Hence, the OPCs, which researchers think could become effective sources of the olgodendrocytes when transplanted. (Transplantion of fully mature cells doesn't seem to work in such studies; the cells seem to need to complete the last step of maturation in their new enviroment to wire into the nervous system.)
But until very recently, making OPCs has extremely difficult. In February, a team led by University of Rochester scientists created oligodendrocytes from induced pluripotent stem cells, which themselves were derived from fibroblasts. These cells were transplanted into animal models of multiple sclerosis, where they produced myelin.
The University of Rochester team's approach added IPS cells to other sources of oligodendrocytes, including stem cells committed to producing neural lineage-committed stem cells and embryonic stem cells. However, all of these sources require the cells to be taken through intermediate steps to get to the desired cell. By contrast, direct conversion offers a less complicated route, and avoids the troublesome pluripotent stage, in which cells are prone to form tumors.
If the Case Western or Stanford technology turns out to be useful for MS patients, it will help confirm the prediction of Ian Wilmut not long ago that direct conversion would become feasible and ultimately supplant the use of stem cells. The Case Western team spelled out this vision in their paper:
"With further optimization, this approach could provide a source of functional OPCs that will complement, and possibly obviate, the use of pluripotent stem cells and fetal cells in cell-based remyelinating therapies," the Case Western paper stated.
The induced oligodendrocyte precursor cells, or iOPCs, just produce oligodendrocytes, the paper said, while neural stem cells and induced neural stem cells are inefficient in producing them, and they produce other unwanted cells such as neurons and astrocytes.
"We have shown that iOPCs integrate into the CNS and myelinate axons of congenitally dysmyelinated mice in vivo after transplantation," the Case Western paper concluded. "However, for iOPCs to have clinical relevance, future studies will have to extend this reprogramming strategy to human somatic cells and demonstrate extensive CNS myelination and long-term functional benefit to transplant recipients."
Source: U-T San Diego © 1995-2013 The San Diego Union-Tribune, LLC (15/04/13)
A new study by multiple sclerosis researchers at three Canadian centres addresses why bone marrow transplantation (BMT) has positive results in patients with particularly aggressive forms of MS. The transplantation treatment, which is performed as part of a clinical trial and carries potentially serious risks, virtually stops all new relapsing activity as observed upon clinical examination and brain MRI scans. The study reveals how the immune system changes as a result of the transplantation. Specifically, a sub-set of T cells in the immune system known as Th17 cells, have a substantially diminished function following the treatment.
The finding to be published in the upcoming issue of Annals of Neurology and currently in the early online version, provides important insight into how and why BMT treatment works as well as how relapses may develop in MS.
"Our study examined why patients essentially stop having relapses and new brain lesions after the bone marrow transplant treatment, which involves ablative chemotherapy followed by stem cell transplantation using the patient's own cells," said Prof. Amit Bar-Or, the principle investigator of the study, who is a neurologist and MS researcher at The Montreal Neurological Institute and Hospital -The Neuro, McGill University, and Director of The Neuro's Experimental Therapeutics Program. "We discovered differences between the immune responses of these patients before and after treatment, which point to a particular type of immune response as the potential perpetrator of relapses in MS."
"Although the immune system that re-emerges in these patients from their stem cells is generally intact, we identified a selectively diminished capacity of their Th17 immune responses following therapy -- which could explain the lack of new MS disease activity. In untreated patients, these Th17 cells may be particularly important in breaching the blood-brain-barrier, which normally protects the central nervous system. This interaction of Th17 cells with the blood-brain barrier can facilitate subsequent invasion of other immune cells such as Th1 cells, which are thought to also contribute to brain cell injury.
Twenty-four patients participated in the overall clinical trial as part of the 'Canadian MS BMT' clinical trial, coordinated by Drs. Mark Freedman and Harry Atkins at the Ottawa General Hospital. The new discovery, made in a subset of patients participating in the clinical trial, was based on immunological studies carried out jointly in laboratories at The Neuro and the Université de Montréal. Results of this study not only show the clinical benefits of BMT treatment, but also open a unique window into the immunological mechanisms underlying relapses in MS. Th17 cells could be the immune cells associated with the initiation of new relapsing disease activity in this group of patients with aggressive MS. This finding deepens our understanding of MS and could guide the development of personalized medicine with a more favourable risk/benefit profile.
Among the patients treated in the Canadian MS BMT clinical trial, was Dr. Alexander Normandin, a family doctor, who was a third- year McGill medical student getting ready for his surgery exams when he first learned he had MS, "I was so engrossed in my studies that I didn't pay attention to the first sign but within a few days of waking up with a numb temple, my face felt frozen. I learned that I had a very aggressive form of MS and would probably be in a wheelchair within a year. It was a brutal blow. I became patient #19 -- of only 24 for this experimental treatment. My immune system was knocked out and then rebooted with my stem cells. Today, my MS has stabilized. I now have this disease under control and I take it one day at a time."
Both the clinical and biological studies were supported by the Research Foundation of the Multiple Sclerosis Society of Canada.
Journal Reference: Peter J. Darlington, Tarik Touil, Jean-Sebastien Doucet, Denis Gaucher, Joumana Zeidan, Dominique Gauchat, Rachel Corsini, Ho Jin Kim, Martin Duddy, Farzaneh Jalili, Nathalie Arbour, Hania Kebir, Jacqueline Chen, Douglas L. Arnold, Marjorie Bowman, Jack Antel, Alexandre Prat, Mark S. Freedman, Harold Atkins, Rafick Sekaly, Remi Cheynier, Amit Bar-Or. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Annals of Neurology, 2013; DOI: 10.1002/ana.23784
Source: Science Daily Copyright © 1995-2012 ScienceDaily LLC (28/03/13)
A study out February 7 in the journal Cell Stem Cell shows that human brain cells created by reprogramming skin cells are highly effective in treating myelin disorders, a family of diseases that includes multiple sclerosis and rare childhood disorders called pediatric leukodystrophies.
The study is the first successful attempt to employ human induced pluripotent stem cells (hiPSC) to produce a population of cells that are critical to neural signaling in the brain. In this instance, the researchers utilized cells crafted from human skin and transplanted them into animal models of myelin disease.
"This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., lead author of the study. "In fact, it appears that cells derived from this source are at least as effective as those created using embryonic or tissue-specific stem cells."
The discovery opens the door to potential new treatments using hiPSC-derived cells for a range of neurological diseases characterized by the loss of a specific cell population in the central nervous system called myelin. Like the insulation found on electrical wires, myelin is a fatty tissue that ensheathes the connections between nerve cells and ensures the crisp transmission of signals from one cell to another. When myelin tissue is damaged, communication between cells can be disrupted or even lost.
The most common myelin disorder is multiple sclerosis, a condition in which the body's own immune system attacks and destroys myelin. The loss of myelin is also the hallmark of a family of serious and often fatal diseases known as pediatric leukodystrophies. While individually very rare, collectively several thousand children are born in the U.S. with some form of leukodystrophy every year.
The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.
However, several obstacles have thwarted scientists. One of the key challenges is that OPCs are a mature cell in the central nervous system and appear late in development. "Compared to neurons, which are among the first cells formed in human development, there are more stages and many more steps required to create glial cells such as OPCs," said Goldman. "This process requires that we understand the basic biology and the normal development of these cells and then reproduce this precise sequence in the lab."
Another challenge has been identifying the ideal source of these cells. Much of the research in the field has focused on cells derived from tissue-specific and embryonic stem cells. While research using these cells has yielded critical insight into the biology of stem cells, these sources are not considered ideal to meet demand once stem cell-based therapies become more common.
The discovery in 2007 that human skin cells could be "reprogrammed" to the point where they returned to a biological state equivalent of an embryonic stem cell, called induced pluripotent stem cells, represented a new path forward for scientists. Because these cells -- created by using the recipient's own skin -- would be a genetic match, the likelihood of rejection upon transplantation is significantly diminished. These cells also promised an abundant source of material from which to fashion the cells necessary for therapies.
Goldman's team was the first to successfully master the complex process of using hiPSCs to create OPCs. This process proved time consuming. It took Goldman's lab four years to establish the exact chemical signaling required to reprogram, produce, and ultimately purify OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.
Once they succeeded in identifying and purifying OPCs from hiPSCs, they then assessed the ability of the cells to make new myelin when transplanted into mice with a hereditary leukodystrophy that rendered them genetically incapable of producing myelin.
They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice.
"The new population of OPCs and oligodendrocytes was dense, abundant, and complete," said Goldman. "In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."
The next stage in evaluating these cells -- clinical studies -- may not be long in the offing. Goldman, along with a team of researchers and clinicians from Rochester, Syracuse, and Buffalo, are preparing to launch a clinical trial using OPCs to treat multiple sclerosis. This group, titled the Upstate MS Consortium, has been approved for funding by New York State Stem Cell Science (NYSTEM). While the consortia's initial study -- the early stages of which are scheduled to begin in 2015 -- will focus cells derived from tissue sources, Goldman anticipates that hiPSC-derived OPCs will eventually be included in this project.
Source: ScienceDaily Copyright © 1995-2012 ScienceDaily LLC (08/02/13)
Scientists in recent years have found a way to infuse stem cells into the brains of animals to repair damage to the central nervous system, offering some of the most encouraging news yet for multiple sclerosis patients.
Now, a key $12.1 million study soon will be under way in Buffalo and two other upstate medical centers that will for the first time begin to test the procedure in people.
The hope is that the stem cells will generate new myelin, the fatty substance that surrounds nerves like the insulation on a wire. Myelin is damaged in MS, leading to weak or lost signals between nerves. Eventually, the painful disease spreads in a slow, unpredictable path toward paralysis.
“This is a promising strategy. It has been extraordinarily effective in mice, and there is great hope the technique will be successful in people,” said Dr. Steven Goldman, co-principal investigator and co-director of the University of Rochester Center for Translational Neuromedicine.
The study by researchers in Rochester, the University at Buffalo and Upstate Medical University in Syracuse has far-ranging implications. It potentially could be applied to millions of patients with a host of other conditions, including Alzheimer’s and Parkinson’s disease.
Although stem cells show great promise, the approach is a ways from reality.
What works in mice does not always work in humans. In addition, scientists don’t know what causes MS, so they can’t exactly replicate MS in animals, complicating tests of the potential new treatment.
“Expectations have to be kept under control. You’re not going to implant stem cells in people and suddenly see them running around,” said Dr. Bianca Guttman-Weinstock, co-principal investigator at UB.
Stem cells are often referred to as master cells because they develop into the many different types of cells in the body that form organs and tissue. Stem cells also have the potential to repair or replace damaged cells.
Other scientists are looking at whether it may be possible to use certain stem cells to prevent the body’s immune system from attacking nerves.
“There is a lot happening in stem cell research, and it’s exciting because five years ago, these were just ideas. Now, they are reality,” said Dr. Timothy Coetzee, chief research officer at the National MS Society.
Until recently, scientists didn’t know exactly which master stem cells ultimately developed into cells that make myelin in a complicated process. They now know that cells called oligodendrocytes produce myelin. They also learned how to turn stem cells into a type of cell called glial progenitor cells. Glial progenitor cells are the cells that make oligodendrocytes.
These findings allowed scientists to transplant oligodendrocytes into the brains of mice that had no myelin. The result: The cells began to repair damaged areas.
“It was an extraordinarily effective strategy,” said Goldman.
All this progress has occurred in the last few years, including a study published late last year using stem cells transplanted into the brains of children with a rare genetic brain disease known as Pelizaeus-Merzbacher disease, in which myelin is lacking.
The significance of the research is that it indicates stem cells can be safely transplanted and may be effective at making myelin.
Children are different than adults, but Goldman and others say there is great hope the technique will succeed in adults.
The first step
The upstate consortium study for MS, which is funded by the Empire State Stem Cell Board, is the first step in a typical research process, which occurs in phases and usually takes many years to complete.
In the first two phases, scientists test the safety and effectiveness of an experimental treatment, and that’s what will happen with this stem cell trial for MS.
Patients enrolled in the study will be those with secondary progressive MS. These individuals no longer have periods of remission and, instead, experience a slow but steady worsening of symptoms with no approved therapy. Small holes will be drilled into their skulls and stem cells injected through catheters inserted in the holes.
The original proposal for the study recommended obtaining stem cells from discarded fetal brains. Technology has progressed enough that the current plan, dependent on government approval, is to start with stem cells from the patient’s own skin cells and reprogram them into cells useful for making myelin.
Before the first patients can receive the treatment in 2016, researchers must spend the next few years preparing for the trial. Among other things, they need to refine how they will measure the repair of myelin, as well as improvements in the patients. It’s a tricky issue because improvements are likely to occur slowly and will vary from person to person, said Guttman-Weinstock.
A key role
It seems fitting that the study will include Buffalo.
Research by the late Dr. Lawrence D. Jacobs, a Buffalo neurologist, played a key role in the development of Avonex, the drug most widely prescribed to treat relapsing MS.
Population studies show that higher rates of MS exist in temperate climates, in particular a geographic band in North America across the northern United States and southern Canada that includes Western New York.
If stem cells work, it could change the lives of millions of people worldwide who suffer from a disease that can be unbearable as patients decline in function and health.
That’s why many individuals like Shelly Boyle track research on potential MS treatments with a laser-like focus.
“I read everything I can read,” said Boyle, a 48-year-old Cheektowaga resident who was diagnosed with MS in 1990.
She stopped working as a chiropractor in 2004 as her symptoms worsened. She has trouble walking and coordinating the small muscles in her fingers. The medication she has been taking is no longer effective.
“The idea of drilling into my brain would scare me if I was in the trial, but the prospect of something new on the horizon is exciting,” she said. “I’m running out of options.”
Source: The Buffalo News Copyright 1999 - 2013 - The Buffalo News (14/01/13)
In a new study appearing this month in the Journal of Neuroscience, researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases.
"One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells," said University of Rochester Medical Center (URMC) neurologist Steve Goldman, M.D., Ph.D., lead author of the study.
"This study demonstrates that – in the case of certain populations of brain cells – we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells."
The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons. Damage to myelin lies at the root of a long list of diseases, such as multiple sclerosis, cerebral palsy, and a family of deadly childhood diseases called pediatric leukodystrophies. The scientific community believes that regenerative medicine – in the form of cell transplantation – holds great promise for treating myelin disorders.
Goldman and his colleagues, for example, have demonstrated in numerous animal model studies that transplanted GPCs can proliferate in the brain and repair damaged myelin. However, one of the barriers to moving forward with human treatments for myelin disease has been the difficulty of creating a plentiful supply of necessary cells, in this case GPCs. Scientists have been successful at getting these cells to divide and multiply in the lab, but only for limited periods of time, resulting in the generation of limited numbers of usable cells.
"After a period of time, the cells stop dividing or, more typically, begin to specialize and form astrocytes which are not useful for myelin repair," said Goldman. "These cells could go either way but they essentially choose the wrong direction."
Overcoming this problem required that Goldman's lab master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes. One of the key players in cell division is a protein called beta-catenin. Beta-catenin is regulated by another protein in the cell called glycogen synthase kinase 3 beta (GSK3B). GSK3B is responsible for altering beta-catenin by adding an additional phosphate molecule to its structure, essentially giving it a barcode that the cell then uses to sort the protein and send it off to be destroyed. During development, when cell division is necessary, this process is interrupted by another signal that blocks GSK3B. When this occurs, the beta-catenin protein is spared destruction and eventually makes its way to the cell's nucleus where it starts a chemical chain reaction that ultimately instructs the cell to divide.
However, after a period of time this process slows and, instead of replicating, the cells begin to then commit to becoming one type or another.
The challenge for scientists was to find another way to essentially trick these cells into continuing to divide, and to do so without risking the uncontrolled growth that could otherwise result in tumor formation.
The new discovery hinges on a receptor called protein tyrosine phosphatase beta/zeta (PTPRZ1). Goldman and his team long suspected that PTPRZ1 played an important role in cell division; the receptor shows up prominently in molecular profiles of GPCs. After a six-year effort to discern the receptor's function, they found that it works in concert with GSK3B and helps "label" beta-catenin protein for either destruction or nuclear activity. The breakthrough was the identification of a molecule – called pleiotrophin – that essentially blocks the function of the PTPRZ1 receptor. They found that by regulating the levels of pleiotrophin, they were able to essentially "short circuit" PTPRZ1's normal influence on cell division, allowing the cells to continue dividing.
While the experiments were performed on cells derived from human brain tissue, the authors contend that the same process could also be applied to GPCs derived from embryos or from "reprogrammed" skin cells. This would greatly expand the number of cells potentially derived from single patient samples, whether for transplantation back to those same individuals or for use in other patients.
Source: Medical Xpress © Medical Xpress 2011-2012 (01/11/12)
When the era of regenerative medicine dawned more than three decades ago, the potential to replenish populations of cells destroyed by disease was seen by many as the next medical revolution. However, what followed turned out not to be a sprint to the clinic, but rather a long tedious slog carried out in labs across the globe required to master the complexity of stem cells and then pair their capabilities and attributes with specific diseases.
In a review article appearing in the journal Science, University of Rochester Medical Center scientists Steve Goldman, M.D., Ph.D., Maiken Nedergaard, Ph.D., and Martha Windrem, Ph.D., contend that researchers are now on the threshold of human application of stem cell therapies for a class of neurological diseases known as myelin disorders - a long list of diseases that include conditions such as multiple sclerosis, white matter stroke, cerebral palsy, certain dementias, and rare but fatal childhood disorders called pediatric leukodystrophies.
"Stem cell biology has progressed in many ways over the last decade, and many potential opportunities for clinical translation have arisen," said Goldman. "In particular, for diseases of the central nervous system, which have proven difficult to treat because of the brain's great cellular complexity, we postulated that the simplest cell types might provide us the best opportunities for cell therapy."
The common factor in myelin disorders is a cell called the oligodendrocyte. These cells arise, or are created, by another cell found in the central nervous system called the glial progenitor cell. Both oligodendrocytes and their "sister cells" - called astrocytes - share this same parent and serve critical support functions in the central nervous systems.
Oligodendrocytes produce myelin, a fatty substance that insulates the fibrous connections between nerve cells that are responsible for transmitting signals throughout the body. When myelin-producing cells are lost or damaged in conditions such as multiple sclerosis and spinal cord injury, signals traveling between nerves are weakened or even lost. Astrocytes also play an essential role in the brain. Long overlooked and underappreciated, it is now understood that astrocytes are critical to the health and signaling function of oligodendrocytes as well as neurons.
Glial progenitor cells and their offspring represent a promising target for stem cell therapies, because - unlike other cells in the central nervous system - they are relatively homogeneous and more readily manipulated and transplanted. In the case of oligodendrocytes, multiple animal studies have shown that, once transplanted, these cells will disperse and begin to repair or "remyelinate" damaged areas.
"Glial cell dysfunction accounts for a broad spectrum of diseases, some of which - like the white matter degeneration of aging - are far more prevalent than we previously realized," said Goldman. "Yet glial progenitor cells are relatively easy to work with, especially since we don't have to worry about re-establishing precise point to point connections as we must with neurons. This gives us hope that we may begin to treat diseases of glia by direct transplantation of competent progenitor cells."
Scientists have reached this point, according to the authors, because of a number of key advances. Better imaging technologies - namely advanced MRI scanners - now provide greater insight and clarity into the specific damage caused in the central nervous system by myelin disorders. These technologies also enable scientists to precisely follow the results of their work.
Even more importantly, researchers have overcome numerous obstacles and made significant strides in their ability to manipulate and handle these cells. Goldman's lab in particular has been a pioneer in understanding the precise chemical signals necessary to coax stem cells into making glial progenitor cells, as well as those needed to "instruct" these cells to make oligodendrocytes or astrocytes. His lab has been able to produce these cells from a number of different sources - including "reprogramming" skin cells, a technology that has the advantage of genetically matching transplanted cells to the donor. They have also developed techniques to sort these cells based on unique identifying markers, a critical step that ensures the purity of the cells used in transplantation, lowering the risk for tumor formation.
Nedergaard's lab has studied the integration of these cells into existing neural networks, and well as in imaging their structure and function in the adult nervous system. Together, the two labs have developed models of both human neural activity and disease based on animals transplanted with glial progenitor cells, which will enable human neural cells to be evaluated in the context of the live adult brain - as opposed to a test tube. This work has already opened new avenues in both modeling and potentially treating human glial disease.
All of these advances, contend the authors, have accelerated research to the point where human studies for myelin disorders are close at hand. For instance, diseases such as multiple sclerosis, which benefit from a new generation of stabilizing anti-inflammatory drugs, may be an especially appealing target for progenitor-based cell therapies which could repair the now permanent and untreatable damage to the central nervous system that occurs in the disease. Similarly, the authors point to a number of the childhood diseases of white matter that now appear ripe for cell-based treatment.
"We have developed a tremendous amount of information about these cells and how to produce them," said Goldman. "We understand the different cell populations, their genetic profiles, and how they behave in culture and in a variety of animal models. We also have better understanding of the disease target environments than ever before, and have the radiographic technologies to follow how patients do after transplantation. Moving into clinical trials for myelin disorders is really just a question of resources at this point."
Source: Medical News Today © MediLexicon International Ltd 2004-2012 (29/10/12)
New research suggests that stem cell transplants to treat certain brain and nervous system diseases such as multiple sclerosis may be moving closer to reality.
One study found that experimental stem cell transplants are safe and possibly effective in children with a rare genetic brain disease. Another study in mice showed that these cells are capable of transforming into, and functioning as, the healthy cell type. The stem cells used in the two studies were developed by study sponsor StemCells, Inc.
Both papers appear online in Science Translational Research.
The work, while still in its infancy, may have far-reaching implications for the treatment of many more common diseases that affect the brain and nervous system.
Researchers out of the University of California, San Francisco (UCSF), looked at the how neural stem cells behaved when transplanted into the brains of four young children with an early-onset, fatal form of Pelizaeus-Merzbacher disease (PMD).
Can Stem Cell Transplants Help Treat MS?
PMD is a very rare genetic disorder in which brain cells called oligodendrocytes can’t make myelin. Myelin is a fatty substance that insulates the nerve fibers of the brain, spinal cord, and optic nerves (central nervous system), and is essential for transmission of nerve signals so that the nervous system can function properly.
In multiple sclerosis, the myelin surrounding the nerve is targeted and damaged by the body’s immune system.
The new study found that the neural stem cell transplants were safe. What’s more, brain scans showed that the implanted cells seem to be doing what is expected of them -- i.e. making myelin.
Researchers compared treated areas of participants' brains with untreated areas. "The study goes beyond safety and we see some effects in the transplanted region that are consistent with the appearance of myelin, at one year,” says study author David H. Rowitch, MD, PhD. “It is not definitive, but it is suggestive.” He is a professor of pediatrics and neurological surgery at UCSF, and is the chief of neonatology at UCSF Benioff Children’s Hospital.
PMD is rare, but other diseases that affect the myelin, such as MS, are more common.
So is it possible that these same stem cell transplants could also benefit these other diseases? Although the possibility exists, Rowitch is noncommittal at this point. “We don’t have data that this could work in MS or other diseases,” he says.
With PMD, the cells that produce myelin are not doing their job. Other diseases involve multiple causes or pathways. If further research in treating PMD pans out, the next step will be to look at MS and other diseases that affect myelin, Rowitch says.
Nancy L. Sicotte, MD, is the director of the Multiple Sclerosis Program at Cedars-Sinai Medical Center in Los Angeles. She says that MS may be more complicated to treat with stem cell therapy.
“With MS, we would be trying to introduce stem cells into an inflamed nervous system,” she says. "To be effective, we have to stop the inflammation process, which we haven’t fully been able to do yet.”
Still, “stem-cell based therapies hold a lot of promise and potential,” Sicotte says. “You always have to temper that with the fact that it takes time to bring a great idea in the lab to humans.”
A Big Deal
A related study by researchers at Oregon Health & Science University's (OHSU) Doernbecher Children’s Hospital in Portland showed that banked brain stem cells can survive and make myelin in mice with symptoms of myelin loss. This work served as one of the building blocks for the study in children with PMD.
This mouse study also gives scientists a glimpse into how these cells behave once they are transplanted, says researcher Stephen A. Back, MD, PhD. He is a clinician-scientist in the Papé Family Pediatric Research Institute at OHSU Doernbecher. “When implanted, they preferentially make myelin-forming cell.”
This is a big deal.
“Stem cells are capable of making new myelin in a brain showing deterioration, and that is very exciting,” he says. “We were surprised to see how well the new myelin was able to form in symptomatic animals.”
The implications are far-reaching. For example, “if we show in a rare disorder like PMD that patients benefit from the transplants, then we will want to do newborn screening to pick up babies with the disorders and get them transplanted as soon as possible,” Back says. “The sooner you get to these kids, the better, [since] the disease can progress like gangbusters once it starts.”
Source: WebMD ©2005-2012 WebMD, LLC. (11/10/12)
Athersys, Inc. announced today it is presenting new research results at the Second Midwest Conference on Stem Cell Biology & Therapy at Oakland University in Rochester, Michigan, that highlight the potential for MultiStem®, its proprietary adult stem cell therapy, to treat multiple sclerosis (MS).
The work conducted by Athersys scientists, in collaboration with Robert Miller, Ph.D. and other scientists from Case Western Reserve University School of Medicine, and with the support of Fast Forward, a subsidiary of the National Multiple Sclerosis Society, demonstrates the potential benefits of MultiStem therapy for treating MS. In standard preclinical models of MS, researchers observed that MultiStem administration results in sustained behavioral improvements, arrests the demyelination process that is central to the pathology of MS, and supports remyelination of affected axons.
"MultiStem therapy has shown promise in treating multiple disease indications in the neurological and inflammatory and immune disease areas," said Robert Mays, Ph.D., Head of Neuroscience at Athersys. "Multiple sclerosis presents as a neurological disorder, but a central component underlying the disease is immune system dysfunction. The results of our latest preclinical studies confirm that the immunomodulatory and regenerative properties of MultiStem therapy could have relevance for treatment of this disease."
In preclinical experiments, rodents were given either an intravenous injection of MultiStem cells or placebo after the onset of symptoms in an MS model. The rodents treated with MultiStem displayed sustained and statistically significant improvement in functional testing compared to placebo treated animals. This functional improvement correlated with a statistical decrease in demyelinated lesions in the nervous system of cell treated animals compared to placebo as well as increased remyelination in cell treated animals, and this result has been confirmed in a second animal model of MS, suggesting that MultiStem treatment may accelerate the process of axonal remyelination.
"Long-term successful treatment of demyelinating diseases, such as MS, will likely require both the regulation of the immune system and the promotion of remyelination to protect axonal integrity," said Robert Miller, Ph.D., Vice President for Research and Technology Management at Case Western Reserve University. Miller also serves as Director of the Center for Translational Neuroscience at the university's School of Medicine. "I am pleased that the most recent studies suggest that MultiStem treatment influences both aspects of the disease, which means it has great potential as an attractive therapeutic option."
In 2011, Athersys and Fast Forward, LLC, a nonprofit subsidiary of the National Multiple Sclerosis Society, announced an alliance to fund the development of MultiStem for the treatment of MS, including treatment of chronic progressive forms of the disease. Fast Forward committed up to $640,000 to fund the advancement of the program to the clinical development stage.
MS is a chronic, unpredictable neurological disease that affects the central nervous system. It is thought to be an autoimmune disorder, meaning the immune system incorrectly attacks healthy tissue. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. These problems may be permanent or may come and go. According to the National MS Society, at least 400,000 Americans have MS, and every hour someone is newly diagnosed. MS affects about 2.5 million people worldwide.
MultiStem® cell therapy is a patented product that has shown the ability to promote tissue repair and healing in a variety of ways, such as through the production of multiple therapeutic factors produced in response to signals of inflammation and tissue damage. MultiStem has demonstrated therapeutic potential for the treatment of inflammatory and immune disorders, neurological conditions, and cardiovascular disease, as well as other areas, and represents a unique "off-the-shelf" stem cell product that can be manufactured in a scalable manner, may be stored for years in frozen form, and is administered without tissue matching or the need for immune suppression. The product is extensively characterized for safety, consistency and potency. Athersys has forged strategic partnerships with Pfizer Inc. to develop MultiStem for inflammatory bowel disease and with RTI Biologics, Inc. to develop cell therapy for use with a bone allograft product in the orthopedic market.
Athersys is a clinical stage biotechnology company engaged in the discovery and development of therapeutic product candidates designed to extend and enhance the quality of human life. The Company is developing its MultiStem® cell therapy product, a patented, adult-derived "off-the-shelf" stem cell product platform for disease indications in the cardiovascular, neurological, inflammatory and immune disease areas. The Company currently has several clinical stage programs involving MultiStem, including for treating inflammatory bowel disease, ischemic stroke, damage caused by myocardial infarction, and for the prevention of graft versus host disease. Athersys has also developed a diverse portfolio that includes other technologies and product development opportunities, and has forged strategic partnerships and collaborations with leading pharmaceutical and biotechnology companies, as well as world-renowned research institutions in the United States and Europe to further develop its platform and products.
About Fast Forward, LLC
Fast Forward, LLC is a nonprofit organization established by the National Multiple Sclerosis Society in order to accelerate the development of treatments for MS. Fast Forward accomplishes its mission by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS.
Source: Athersys, Inc. (05/10/12)
One of the most promising and exciting treatment avenues for multiple sclerosis is the use of a patient's own stem cells to try to stop -- or even repair -- some of the disease's brain tissue damage.
But injecting a patient with a dose of his or her own bone-marrow stem cells was actually a pretty crude method of treating the disease, because no one was quite sure how or why it worked. Last year, doctors at the Cleveland Clinic, University Hospitals Seidman Cancer Center and Case Western Reserve University began trying this for MS patients in a Phase 1 clinical trial after positive results were seen in mice.
Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheaths that surround and protect nerve cells. When myelin is damaged, the nerve cells are exposed and unable to do their job, which is sending signals to the brain and back. This results in the loss of motor skills, coordination and cognitive abilities.
Like many other researchers using stem cells, the local group didn't know exactly how their treatment worked, but they knew that when they gave these human mesenchymal stem cells, or MSCs, to mice with a mouse version of the disease, the mice got better.
Figuring out why the mice improved could help researchers see if the MSC injection will work well in a particular patient before the patient is injected, and possibly augment or improve the treatment as well.
In May, the research group at CWRU, headed up by neurosciences professor Robert Miller, discovered exactly what it is in the stem-cell soup that has a healing effect: a large molecule called hepatocyte growth factor, or HGF. The team published their results in Nature Neuroscience.
Miller's group knew that it could be the stem cells themselves, by coming in physical contact with the myelin damage, that were having a healing effect. Or it could be something the stem cells secreted into the surrounding liquid culture, or media, they were grown in, that was key. HGF is secreted by the stem cells, Miller said.
The team identified the HGF by first injecting only the liquid the stem cells were grown in, but not the stem cells themselves, into the mice they were studying. The mice got better, so the team knew whatever was helping was in the media.
Next, they isolated the small, medium and large molecules from the media and tried each size on the mice. Only the large-molecule treatment had the healing effect, meaning that whatever was helping was somewhere in that mix, Miller said.
"The molecule that jumped out at us was HGF," he said, because it is the right size, is made by MSCs, and in a couple of studies had been shown to be involved in myelin repair.
So the scientists took a purified sample of HGF and injected it into the sick mice. They got better. When they blocked the receptor for HGF in the mice, they stayed sick. It was pretty compelling evidence that they'd found what they'd been looking for, Miller said.
"We went on to show that HGF, like the MSCs, is regulating both the immune response, and it is independently promoting myelin repair in the brain," he said.
MSCs, taken from the bone marrow, are currently being tested in more than 150 clinical trials in the United States and around the world to treat conditions such as osteoarthritis, diabetes, emphysema and stroke.
The local Phase 1 trial has enrolled 16 of 24 total patients, and eight of them have completed the trial protocol, said Dr. Jeffrey Cohen, Cleveland Clinic neurologist and lead investigator of the trial.
So far, the treatment seems to be working, Cohen said.
"It's a little early to be saying it, but things have looked encouraging."
And there have been no safety concerns and almost no side effects. There has also been no activation -- an aggravation or return of symptoms -- of this relapsing disease in the patients involved, which has happened unexpectedly with other types of MS treatments.
Miller's discovery won't change the course of the trial currently under way at the Clinic and UH, but it may change the future of MSC treatment.
While they don't know yet what the outcome of that trial will be, it's possible that if a patient doesn't respond to the treatment, it could mean that his stem cells aren't producing enough HGF to be effective at healing, Miller said. Miller will be studying MSC samples from all the patients in the trial to find out if those who are better at producing HGF fare better.
He'll also be trying to see if they can predict how well a patient will do based on his HGF levels in the MSC sample.
"Finally, though we're a long way from this, maybe we could augment the expression of HGF in patients whose stem cells aren't that effective to enhance their effectiveness," he said.
But why not just inject the HGF alone? Miller said there are two reasons. First, the receptor for HGF in the cells, called c-MET, has been implicated in liver and breast cancer. Injecting HGF by itself into the body may stimulate the c-MET pathway, he said, and the research team is not willing to risk that.
"The stem cells have the advantage that they tend to home to the area of insult, so they don't stick around in other parts of the body," he said. "They target the treatment where it's needed."
Miller said his group is experimenting with a way of delivering HGF directly into the area of injury in the brain to minimize its contact with the rest of the body. HGF and c-MET are not associated with brain tumors.
They are also trying to test small fragments of the growth factor as a treatment, to see if they can eliminate some of the cancer concerns.
Cohen's group hopes to have results from the Phase 1 trial available in the spring and has already started planning a larger study based on those results.
Source: North East Ohio © 2012 Cleveland Live LLC (05/09/12)