Hematopoietic Stem Cells: a New Transplant Paradigm for Multiple Sclerosis?

Expert Contributor: Harold L. Atkins, MD<br />
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<p>For years now, bone marrow transplants have been used to treat patients with leukemia and other blood disorders. The hematopoietic (blood-forming) stem cells present in bone marrow can restore a patient&rsquo;s blood system after it has been devastated by chemotherapy or radiation. This same approach is now being tested in clinical trials for people with multiple sclerosis (MS) and other autoimmune diseases in the hope that providing brand new blood cells will reset the immune system to a healthy state.</p>
<p>Dr. Harry Atkins, from the Ottawa Hospital Research Institute (OHRI), is one of the scientists working in this field. Previously, he had been exploring ways to manipulate the immune system in leukemia patients to be able to give them highly mismatched donor stem cell transplants, and one of his colleagues wondered if the approach might also work for autoimmune diseases. At about the same time, he met Dr. Mark Freedman, also at the OHRI, and together they discussed which autoimmune disease to focus on. They chose MS.&nbsp;</p>
<p>There is still no cure for MS. When the body&rsquo;s own immune system attacks parts of<img src="757024a1-49dd-416f-bffa-72773ab4fb8f" title="Myelin Sheath_28May2014_mc copy" width="240" style="float: right;" /> the&nbsp;central nervous system (brain and spinal cord), two crucial elements are damaged: myelin and nerve axons. Myelin is layered in a protective sheath made by specialized brain cells, the &nbsp;oligodendrocytes (Oligo) that wind around nerves much the same way that insulation winds around electrical wires (as shown in the figure). Without myelin, nerve impulses are too slow to be useful. Axons are the long nerve extensions that transmit electrical impulses from one nerve cell to the next. During MS, the pockets of damage (lesions) to myelin and nerve axons inevitably lead to slower and slower nerve conduction, short circuits, and irreversible nerve damage. The resulting disabilities may be fleeting at first, but repeated attacks render the central nervous system incapable of long-lasting repair, and individuals are left with permanent nerve damage and chronic disabilities.</p>
<p>But is there any reason to think that hematopoietic stem cell transplants (HSCT) could &lsquo;reset&rsquo; the immune system in MS? Keep in mind that these are the stem cells that power the blood and immune systems, churning out billions of blood cells every day.</p>
<p>Dr. Atkins explains some of the main pillars of scientific evidence. Scientists first tested the approach in animals with an MS-like disease and showed that radiation or chemotherapy followed by a bone marrow stem cell transplant could help to control the immune system. At the same time, there were reports that patients who had received bone marrow transplants for leukemia, who also had MS, had some improvements in their MS. And when clinicians started to do autologous (using the patient&rsquo;s own cells) bone marrow transplants in people with other autoimmune diseases, such as rheumatoid arthritis, and those patients improved, that was enough evidence for researchers to start thinking about whether the same approach could reset the immune system in patients with MS. After rigorous pre-clinical testing, the approach was cautiously introduced into clinical trials in the late 1990s.</p>
<p>Since then, people with certain forms of MS have received autologous hematopoietic stem cell transplants in clinical trials worldwide, and many lessons have been learned along the way. For example, in their phase II trial with 24 patients who failed conventional therapy, Drs. Atkins and Freeman found that a very high dose of chemotherapy followed by purified autologous hematopoietic stem cell transplants appeared to have the most impact on preventing ongoing inflammatory activity and progression in these patients. In some cases, disabilities even improved, suggesting that parts of the brain were being repaired. In fact, one patient who received the treatment twelve years ago is still in remission.</p>
<p>But this treatment is not for everyone with MS, and most patients will benefit more from conventional drug therapies. There are very significant risks and side effects of the chemotherapy and transplant regime, including long hospitalization and serious toxicity.</p>
<p>Dr. Atkins highlights a few priorities for better understanding how to use hematopoietic stem cells transplants for MS. The first is finding the minimal dose of chemotherapy that will effectively destroy the immune system without being too toxic, and the second is to understand which patients could benefit most from this therapy and whether it would be better to start the therapy earlier during the treatment pathway. It is also necessary to benchmark this approach against conventional therapies.</p>
<p>This is the next step for Drs. Atkins and Freeman who are organizing a phase III randomized clinical trial to compare the hematopoietic stem cell transplant approach in people with MS who have highly active disease, and who have failed one or two conventional drugs, against individuals with MS who are treated with the best available, approved drug therapy.&nbsp;</p>
<p>In the future, Dr. Atkins suggests that it might also be worthwhile to combine multiple hematopoietic stem cell treatments to replace the immune system, along with stem cells that can make the brain cell types that repair damaged myelin. His dream is to someday find a way to identify and knock out just the autoimmune cells in MS and encourage the patient&rsquo;s own stem cells to repopulate the immune system, without actually having to do a transplant. This could become a new treatment paradigm for MS &ndash; one where the immune system is repaired rather than suppressed &ndash; and it could offer real hope for patients who suffer from the most aggressive forms of the disease.</p>

Bringing Focus to Stem Cell Treatment for Eye Disease

<p style="text-align: justify;"><span style="text-align: left;">Several eye diseases are considered excellent candidates for stem cell therapy. In particular, widespread ocular diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), as well as a genetic condition called Stargardt&rsquo;s macular dystrophy (STGD) that afflicts young people, are all potential disease targets for therapeutic approaches.</span></p>
<p style="text-align: justify;">The eye is an ideal system to test cellular therapies. The human eye is an immune-privileged site, and therefore less likely to reject transplanted cells than other areas of the body. It is also a relatively self-contained area, with barriers that keep cells from migrating to other parts of the body. The nature of the eye and the imaging tools used by ophthalmologists to examine it allow clinicians to watch what is happening in real time as they put the cells in, seeing how the cells interact within the eye.</p>
<p style="text-align: justify;">Research has already led to successful stem cell therapy in the eye. Injuries or diseases affecting the cornea, the outer part of the eye, have been successfully treated by transplanting stem cells in the supportive tissue called the corneal limbus. Many patients have recovered clarity of vision in the cornea and the restoration of other vision benefits that have lasted more than ten years. However, treatments for diseases of the retina, which is in the back of the eye, are not as far along, with interventions just now being tested.</p>
<p style="text-align: justify;">The retina is a layer of tissue in the back of the eye that senses light and sends images to the brain. The macula lies at the center of this nerve tissue and is responsible for central vision&mdash;it is essential for tasks such as reading, driving, and facial recognition. The photoreceptor cells in the macula (called &ldquo;cones&rdquo; and &ldquo;rods&rdquo;) react to light and send signals to the optic nerve and the brain. Supporting these cells is a layer of cells called the retinal pigment epithelium, or RPE, tissue that plays a critical supporting role in keeping the retina functioning well, including helping it get nutrients and balance fluids in the eye, facilitating the blood retina barrier, helping control bacteria in the eye, and even playing a role in immunity protection. Over the years, stem cell researchers have learned a lot about retinal cells and their roles in eye function. </p>
<p style="text-align: justify;">While the RPE layer of tissue is a relatively simple structure, it is vitally important to the eye; if it dies, the retina dies, and vision is lost.</p>
<p> </p>
<p style="text-align: justify;">The retinal diseases mentioned above, AMD, RP, and STGD, result in the gradual deterioration of photoreceptors in the macula. As the rods and cones die off, eyesight deteriorates, eventually leading to blindness. There are currently no cures for these diseases.</p>
<p> </p>
<p style="text-align: justify;">Over the last decade, stem cell researchers have been studying ways to replace the RPE layer of the eye. Approaches using embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have shown some success in generating RPE-like cells (<a href="https://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells">read more about stem cell types here</a>). These stem cell-derived RPE cells are good candidates for transplantation into diseased retinae for potential AMD, RP, and STGD treatments, and research and clinical trials are underway using these approaches. </p>
<p style="text-align: justify;">In addition, researchers are finding that adult RPE cells have retained the potential to divide. By exploiting this potential in the laboratory, scientists may be able to successfully make the hundreds and thousands of RPE cells necessary to develop treatments for many retinal diseases.</p>
<p style="text-align: justify;">Although clinical trials are ongoing, research into stem cell therapy for retinal disease continues. Scientists are analyzing the development of the retina in different species in hopes of gaining insight into how the retina forms and whether this knowledge can be applied therapeutically. A recent study in Stem Cell Reports focusing on the <a href="http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(17)30074-7">regenerative properties of glial cells in the retina of zebrafish</a> will add to the body of research on how cells function within the retina.</p>
<p> </p>
<p style="text-align: justify;">If RPE replacement works, it may help pave the way for replacement of other retinal cells, and other central nervous system cells. </p>
<p> </p>
<p style="text-align: justify;">Learn more about research into Macular Degeneration at <a href="https://www.closerlookatstemcells.org/stem-cells-and-medicine/macular-degeneration">A Closer Look at Stem Cells</a>. </p>
<p> </p>
<p style="text-align: justify;">Research timeline and additional resources:</p>
<li><em>16 February, 2017</em> -Japan is supporting a clinical trial using an <a href="http://asia.nikkei.com/magazine/20170216/Tech-Science/Japan-greenlights-clinical-tests-using-donor-iPS-cells">induced pluripotent stem cell RPE product</a> to treat degenerative eye disorders.<em> October, 2015</em> – A California company begins a clinical trial using <a href="http://www.medscape.com/viewarticle/848280">human embryonic stem cell derived RPE</a> delivered as a patch.</li>
<li><em>October, 2015</em> – A California company begins a clinical trial using <a href="http://www.medscape.com/viewarticle/848280">human embryonic stem cell derived RPE</a> delivered as a patch.</li>
<li><em>6 November, 2014</em> – An Israeli company begins a clinical trial using a <a href="http://www.hadassah.org/news-stories/clinical-trial-of.html?referrer=https://www.google.com/">human embryonic stem cell derived RPE product</a> as a cell suspension, injected sub-retinally.&nbsp;</li>

Stem Cell Therapies: Are We Blinded by Perception or Focused on Reality?

<p>Is there a stem cell therapy for [insert disease here]? The question arises nearly every day and it is not surprising given the abundance of articles and advertisements promoting the use of &ldquo;stem cell treatments&rdquo; for a staggering number of diseases and injuries. A quick search of the internet brings up a long list of clinics offering what appear to be stem cell solutions for a wide variety of medical problems. </p>
<p>The sheer number of clinics offering these solutions fosters the perception that medically-accepted stem cell-based treatments are available for nearly every disease or injury. However, the reality is that there are currently only a few stem cell-based treatments that have been rigorously tested and scientifically proven to be safe and effective. </p>
<p>The rigorous testing of emerging potential therapies takes time, including testing in formal clinical trials, as well as a formal regulatory review process. This time-tested process is necessary to ensure that cellular products are safe and effective before they are marketed to consumers. </p>
<p>Clinics offering unproven therapies are perpetuating a myth that autologous treatments&mdash;those that use cells from one&rsquo;s own body, such as body fat don&rsquo;t need to go through this process because they are naturally safe since the cells are from one&rsquo;s own body and they are effective because stem cells have an innate ability to sense, locate and treat cell and tissue damage. </p>
<p>This is not true. In fact, all treatments need to be proven safe and effective and have associated risks. Cellular therapies have a unique set of risks as compared to more traditional drug-based treatments.</p>
<p>Cellular therapies use living cells that are biologically active: they have the potential to migrate through the body, they can secrete other biologically active molecules, and they may live indefinitely, even in tissues where they are not normally found. These factors and others can impact the safety and efficacy of any cell-based treatment.</p>
<p>There are several factors to consider when evaluating whether a cell therapy will be effective. One of the most essential is the need to characterize the cells being used. How are these cells identified and isolated? How reproducible is this process? How are the cells exerting an effect &ndash; are they secreting something in the body or are they replacing dead or damaged cells in the area of the injury or disease?</p>
<p>Additionally, how many cells are needed for the treatment to be effective? In many systems, as stem cells age they decline in number and function, making standardization of treatment between younger and older patients difficult. These questions must be part of the evaluation process. </p>
<p>Several stem cell-based interventions are currently working their way through the formal clinical trial process. <a href="http://www.nejm.org/doi/full/10.1056/NEJMe1701379">In at least one example</a>, the methodical process of testing a potential therapy for age-related macular degeneration (AMD) uncovered a potential safety risk which temporarily suspended the trial until the potential risks could be assessed. </p>
<p>While critics may contend the testing and approval time unfairly delays or blocks the availability of life-saving treatments, the risks of using cell-based products that have not been tested can be high, even for those who believe they have nothing to lose.</p>
<p>A recent tragic report of three people being blinded or nearly-blinded by a &ldquo;stem cell treatment&rdquo; is just one example. The process used cells from each patient&rsquo;s own fat, manipulated in some way and then injected into both eyes. Rather than treating the underlying AMD, the procedure worsened the vision of all three patients. This is only one of many examples of autologous cell &ldquo;treatments&rdquo; that have given rise to significant adverse effects. While not all patients will have serious side effects, the risks (and benefits) of untested &ldquo;treatments&rdquo; are not always fully understood.</p>
<p>As with many medicines, cell-based treatments, even those that have been reviewed, approved, and rigorously tested, have risks. However, the clinical trial process is designed to assess those risks and to mitigate and minimize them for the patient. Unproven therapies are just that&mdash;unknown, untested, and risky.</p>

Connecting Genetics and Heart Disease

By Maya Chaddah | August 5, 2014
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Expert Contributor: Chad Cowan, PhD
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<p>Scientists and clinicians have long suspected and recently confirmed that a person&rsquo;s genetic makeup contributes to the likelihood of their having a heart attack. However, there has remained a gap between our knowledge of genetic indicators and medicine; a gap that Dr. Chad Cowan, of Harvard University, is trying to bridge with stem cell research.</p>
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<h3 style=”font-size: 14px;”>Chad Cowan, Harvard University, USA</h3>
<td><img width=”145″ height=”218″ src=”https://www.closerlookatstemcells.org/wp-content/uploads/2014/08/2014-07-31-cowan-photo_crop.png” alt=”2014-07-31 Cowan Photo_crop” /></td>
<h3 class=”talktitle”></strong></p>
<p>According to Dr. Cowan,what we know about genetics is not the full picture. We do not yet fully understand how a given gene functions within a cell or how it affects other genes. He believes the study of induced pluripotent stem cells (iPS cells) &ndash; adult stem cells that are reprogrammed in such a way that they can generate most other cell types found within the body &ndash; will result in better and more personalized approaches to treat &nbsp;heart attacks. </p>
<p>The foundation of Dr. Cowan&rsquo;s research began over 60 years ago, with the Framingham Heart Study. The death rates from heart disease and heart attacks had been increasing steadily since the beginning of the century, but not much was known about the general causes. The objective of the study was to identify contributing factors by following the development of the disease over a long period of time in a large group of participants. </p>
<p>The study began in 1948 with 5,209 citizens, aged 30-62, from Framingham, Massachusetts, USA, who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke. They each had an initial physical examination and lifestyle interview, and then returned every two years thereafter for physical examinations, medical histories and laboratory tests.&nbsp; In 1971, the study was expanded to include a second generation, the original participants&rsquo; adult children and their spouses. The study continues to enroll a third generation of participants and to increase its diversity.</p>
<p>Three years ago, Dr. Cowan&rsquo;s group teamed up the Framingham Heart Study to learn more about how different genetic factors influence cholesterol levels in the blood, and to look for&mdash;and test&mdash;drugs that might help lower blood cholesterol. Using a technique called cellular reprogramming, his group made iPS cells from over 60 second generation study participants, which were then used to create patient-specific liver cells and heart cells.</p>
<p>Dr. Cowan&rsquo;s team had earlier identified a variant of the SORT1 gene that influences cholesterol levels in the blood and, thus, risk of heart disease. They have since proposed that the variant increases the amount of the SORT1 gene product (called Sortilin 1) in the liver, and that increasing Sortilin 1 levels reduces the cholesterol secreted into the blood, decreasing the likelihood of a heart attack. In bearing out this hypothesis, they are studying iPS cell-derived liver cells with and without the gene variant to determine whether there is a difference in cholesterol levels. </p>
<p>Dr. Cowan believes his iPS cells, and the liver and heart cells made from them, together with study participants&rsquo; medical histories, will continue to improve our understanding of heart disease, inform the development of new drugs and enable us to screen drugs for safety and efficacy against individual patients. &nbsp;</p>

Exploring Endogenous Heart Repair and Regeneration

By Maya Chaddah | February 13, 2014<br />
Expert Contributor: Deepak Srivastava, MD<br />
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<p>For the millions of people who suffer from heart attacks every year, the aftereffects are literally scarring. When the heart muscle dies from lack of blood, it is replaced by scar tissue, since the heart has very little regenerative capacity. While better medical care and timely management of heart attacks have decreased the number of early deaths, survivors face an increased risk of chronic heart failure as they develop even more scarring. This grim prospect is what stem cell scientists, like Dr. Deepak Srivastava, Director of Cardiovascular Disease and the Stem Cell Center at the Gladstone Institutes in San Francisco, are hoping to change.<span style="line-height: 1.5;"></span></p>
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<h3 style="font-size: 14px;">Stem Cells in Focus Webcast</h3>
<td style="width: 110px;"><img width="100" title="2014-02_Srivastava_Photo" src="5505d1eb-ee32-4fdc-8a40-b722afbea36a" /></td>
<h3 class="talktitle">An Introduction to Endogenous Heart Repair</h3>
<p><strong>Deepak Srivastava, MD,&nbsp;</strong><em>Gladstone Institutes, USA</em></p>
<p>Learn more about the research and its potential, and pose your questions directly to Dr. Srivastava, during a&nbsp;<a href="6f543347-74f7-428f-87e9-5c0539b925b2" target="_blank">live public webcast</a>, <strong>Thursday, February 20 at 2 pm ET (USA).</strong></p>
<p>They plan to fix the heart from the inside &ndash; a strategy called endogenous (self) repair &ndash; by stimulating resident heart cells to generate new cardiomyocytes, the specialized heart muscle cells that keep our hearts beating.</p>
<p>But why does the heart need help regenerating in the first place? Well, scientists used to think that our heart muscle cells were with us for life. It turns out, by the time we reach the age of 50, approximately half of all the cells in the heart aren&rsquo;t the ones we were born with. While this is welcome proof that the heart can regenerate enough to maintain itself, the slow rate of turnover &ndash; about 0.5 to 1% per year &ndash; is far too low to repair damaged heart muscle.<span style="line-height: 1.5;"></span></p>
<p>The source for new muscle cells for heart turnover is still a black box. There might be a pool of heart stem cells that slowly churn out new muscle cells. Or that might be the role of stem cells circulating in the blood that set up shop in the heart. Or there may be unknown factors that trigger existing heart muscle cells to multiply. These theories are all being explored. </p>
<p>&nbsp;<span style="line-height: 1.5;">One of the reasons that scientists have turned to endogenous repair for answers, is that clinical trials transplanting adult stem cells from a variety of sources have not panned out as hoped. While the safety profiles have been encouraging, the level of heart recovery has been minimal at best. Scientists are not yet sure why, but they are exploring the possibilities around increasing stem cell survival, expanding the numbers of patient-derived stem cells, and finding agents that can attract stem cells to damaged heart tissue for future trials.&nbsp;</span></p>
<p>But is there any evidence for endogenous repair of the heart? This area of research is in early days, but the answer seems to be yes: there are internal switches that can kick start heart muscle cells in newborn mice; there are heart cells in newly born mammals that look like they might be able to make new heart muscle; and there are experiments showing how non-muscle cells in the heart can be coopted to become heart muscle cells.</p>
<div style="font-size: 10px; float: right; padding-bottom: 5px; padding-top: 5px; padding-left: 5px; line-height: 1em; padding-right: 5px; width: 250px; background-color: #e9ecef;"><img width="240" title="Fibroblast cell reprogrammed into heart muscle" style="padding-bottom: 5px; padding-top: 5px; padding-left: 5px; padding-right: 5px;" src="b4ca0f83-d3b6-425c-bf75-08724e428d26" />An example of a heart muscle cell that was created from a reprogrammed fibroblast. A protein specific to heart muscles is visualized by the green fluorescence.</div>
<p>The last example brings us back to Dr. Srivastava&rsquo;s approach. His team is the first to show that fibroblasts, structural support cells found throughout the body, can be directly converted, or reprogrammed, into heart muscle cells. Figuring out the conversion process was no simple task. First, they identified a pool of 14 different factors known to be used by nature to make a heart in an embryo. Then they painstakingly whittled the number down to three essential factors. Finally, they introduced the factors into fibroblasts by way of a virus delivery system and found that the three factors were enough to convert the fibroblasts into cells that looked very much like heart muscle. In mice with heart damage similar to a heart attack in humans, the three factors not only created new muscle, but also improved the pumping of the heart. This reprogramming process is novel because it triggers the conversion of one specialized cell directly into another specialized cell, without first being forced to become a stem cell.</p>
<p>Having shown that it&rsquo;s possible to directly reprogram mouse fibroblasts (in a dish and in adult hearts) and also human heart fibroblasts in a dish, Dr. Srivastava&rsquo;s group is testing the recipe in pigs, whose heart size and physiology is closer to our own.</p>
<p>So what are some of the pros and cons of direct reprogramming? A big plus is that this represents a new way to fix damaged heart tissue – and since the heart is over 50% fibroblasts, there are ample cells to reprogram. The major issue is safety: there is always the chance of causing tumors when using virus delivery systems. Many researchers are trying to find ways around this; one possibility is identifying small drug-like molecules that could replace the reprogramming-factor / virus delivery combination. Dr. Srivastava&rsquo;s main concern is the risk of irregular heartbeats that could happen if the newly made heart muscle cells, located in patchy, scarred areas of the heart, start beating out of sync because they are not able to connect with existing heart muscle cells.</p>
<p>In the best of all worlds, Dr. Srivastava estimates the direct reprogramming approach might reach clinical trials within five years. The first trials would primarily assess safety but would also begin to probe what really happens inside a human heart, perhaps through testing in patients scheduled for heart transplantation, allowing scientists to study their old hearts post-transplant. While such trials are well into the future, the possibility of repairing the heart via direct reprogramming does offer some much needed hope for all those who face the prospect of heart failure.</p>

Introducing “Stem Cells in Focus”

By Janet Rossant, ISSCR President | January 16, 2014

Happy New Year from the International Society for Stem Cell Research (ISSCR) and welcome to our very first “Stem Cells in Focus” post.

The ISSCR is an independent nonprofit organization with over 4,100 members in 55+ countries. Our community is composed of researchers, clinicians and industry professionals working to advance stem cell research with the goal of finding or improving treatments for blood disorders, cancers, eye diseases, heart failure, multiple sclerosis, Parkinson’s disease, spinal cord injury, stroke and other currently intractable diseases and injuries.

As we welcome 2014, the ISSCR is deepening its commitment to public education and outreach through a broad-based effort to share our science. We look forward to bringing you regular updates from the front lines of stem cell research and to sharing our excitement in the progress being made. Many of you have questions about what stem cell research is, the timeline and potential for treatments, specific diseases impacting you or loved ones and the validity of certain therapies. We will do our best to provide answers and guidance.

This blog is just one part of our commitment to you. Each month, we will work with our members and experts to highlight different advancements in stem cell research, such as heart repair and regeneration, disease modeling and drug discovery and personalized stem cell medicine. We will explain the importance of each topic and discuss its potential to improve human health.

If you have questions about topics, you may pose them directly to our experts via another new feature – regular and live public webcasts. Additional information from the ISSCR will be available to you 24/7 via ISSCR.org and A Closer Look at Stem Cells, both of which will be expanded in the months ahead.

Please visit “Stem Cells in Focus” each month and follow our more regular updates on the ISSCR Facebook page. Thank you in advance for your feedback and engagement, and we hope we can count on your interest in and support of stem cell research for years to come.