Personalized Stem Cells for Curing Parkinson’s Disease

Stem cell treatments for curing Parkinson’s disease have been one of the dreams of stem cell scientists ever since the first embryonic stem cells were derived from mouse embryos in 1981. Unfortunately, this proved to be one of the harder therapeutic nuts to crack. Several experiments have shown that while feasible, getting the recipe right has required a fair amount of tweaking.


Parkinson’s disease (PD) results from the progressive death of neurons in the midbrain that release a neurotransmitter called dopamine, To review briefly, the brain consists of the forebrain, midbrain and hindbrain. The forebrain consists of the two large cerebral hemispheres that occupy the vast majority of the space within your skull. In addition to the left and right cerebral hemispheres is the diencephalon that consists of the thalamus, subthalamus, hypothalamus, and epithalamus. The thalamus serves as a relay station for a whole variety of nerve fiber tracts, the hypothalamus regulates visceral activities by way of other brain regions and the autonomic nervous system. and the epithalamus connects the limbic system to the rest of the brain. The midbrain, which lies below the diencephalon, is part of the brain stem and dopamine produced in two regions of the midbrain, the substantia nigra and ventral tegmental area play roles in motivation and habituation, and refinement of the control of voluntary movement, The hindbrain consists of the metencephalon and the myelencephalon, both of which contain mutiple fiber tracts and nuclei for vital functions.

Midbrain 2

The death of dopamine-producing neurons in the pars compacta region of the substantia nigra region of the midbrain causes PD. The par compacta sends nerve fibers to the cerebral hemispheres, in particular to cluster of neurons called the basal ganglia. The basal ganglia do not initiate movement, but they refine movement and stabilize the limbs and other body parts while moving. Thus the basal ganglia normally exert a constant inhibitory influence on a wide range of movements. preventing movement at inappropriate times. When someone decides to move, this inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine releases this inhibition, and therefore high levels of dopamine tend to promote movement and low levels of dopamine demand greater exertion to generate any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, or less overall movement.

Basal ganglia

Now that we have some knowledge of PD and what causes it, we can examine how to cure it. Since the death of dopamine-secreting neurons causes PD, replacing death or moribund neurons should be possible. Several preclinical studies in laboratory animals and clinical studies with human patients has shown that this is possible.

Rodents can contract a synthetic form of PD if they are treated with a drug called 6-hydroxydopamine. This drug kills off their dopamine-secreting neurons and creates a PD-like disease. Embryonic stem cells can be differentiated in the laboratory into dopamine-secreting neurons, which can then be transplanted into the midbrain. In PD rats, this strategy has reversed the symptoms of PD, but tumor growth has been a nagging problem. The biggest problem is that isolating fully differentiated dopamine-secreting cells has proven difficult because of a lack of good, solid indicators that say to the scientists, “This one is a dopamine-secreting neuron and this one is not.” Thus, isolating nice, clean cultures of only dopamine-secreting cells has been kind of tough to do.

Fortunately, Doi and others in the Takahashi lab at the University of Kyoto showed that prolonged maturation culture system (42 days long) can eliminate most of the tumor-making cells. However, this culture system is laboriously long. Now, Takahashi and Doi and others have struck again in a paper published in Stem Cell Reports in which they used induced pluripotent stem cells to derive dopamine-secreting neurons to treat PD rats.  Because induced pluripotent stem cells are made from a patient’s own adult cells and are converted into embryonic-like stem cells by means of a combination of genetic engineering and cell culture techniques, they are patient-specific and do not require the dismembering of human embryos.

The novelty of this paper is that Doi and others used a protein that acts as an earmark for dopamine-secreting midbrain neurons and this protein is called CORIN. CORIN is a protease, which simply means that it clips other proteins into small pieces. Nevertheless, by using the CORIN protein, Takahashi, Doi and others successfully and efficiently isolated dopamine-secreting midbrain neurons from other cells in their cultures.  Additionally, Doi and the gang were able to differentiate the induced pluripotent stem cells into dopamine-secreting progenitor cells.  This means that the cells were poised to differentiate into dopamine-secreting neurons, but were not quite there yet.  This way, the cells would grow in culture, but upon transplantation, they would differentiate into dopamine-secreting neurons rather than form tumors.  High numbers of cells are required for clinical purposes and this technique allows the for production of large number of cells.

The technique used in this paper also produced the cells under conditions that were safe, scalable and potentially usable for clinical use. These high-quality cells never produced any tumors and produced definitive behavioral improvements in the implanted laboratory animals. The problems that remain are one of scale. The grafts of dopamine-secreting cells that survived in the midbrains of these mice were relatively small (about 1 square millimeter in size or the thickness of a dime).  This is probably due to the fact that the cells differentiate when transplanted rather than growing.  Therefore, this technique will need to be adapted to somehow increase the size of the graphs of dopamine-secreting neurons.  In some PD patients such small graphs will probably work just fine, but in others, probably not.  The other issue is that these implanted cells might be subjected to the same bad intracerebral environment as the original cells and die off quickly, thus abrogating any positive clinical effect they might have.  This is another issue that will need to be examined.

The work goes on, without the need to destroy any embryos.

See Daisuke Doi at al., Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation. Stem Cell Reports 2014, 2: 337-350.

Controlling Transplanted Stem Cells from the Inside Out

Scientists have worked very hard to understand how to control stem cell differentiation.  However, despite how well you direct stem cell behavior in culture, once those stem cells have been transplanted, they will often do as they wish.  Sometimes, transplanted stem cells surprise people.

Several publications describe stem cells that, once transplanted undergo “heterotropic differentiation.” Heterotropic differentiation refers to tissues that form in the wrong place. For example, one lab found that transplantation of mesenchymal stem cells into mouse hearts after a heart attack produced bone (don’t believe me – see Martin Breitbach and others, “Potential risks of bone marrow cell transplantation into infarcted hearts.” Blood 2007 110:1362-1369).  Bone in the heart – that can’t be good. Therefore, new ways to control the differentiation of cells once they have been transplanted are a desirable goal for stem cell research.

From this motivation comes a weird but wonderful paper from Jeffrey Karp and James Ankrum of Brigham and Women’s Hospital and MIT, respectively, that loads stem cells with microparticles that give the transplanted stem cell continuous cues that tell them how to behave over the course of days or weeks as the particles degrade.

“Regardless of where the cell in the body, it’s going to be receiving its cues from the inside,” said Karp. “This is a completely different strategy than the current method of placing cells onto drug-doped microcarriers or scaffolds, which is limiting because the cells need to remain in close proximity to those materials in order to function. Also these types of materials are too large to be infused into the bloodstream.”

Controlling cells in culture is relatively easy. If cells take up the right molecules, they will change their behavior. This level of control, however, is lost after the cell is transplanted. Sometimes implanted cells readily respond to the environment within the body,. but other times, their behavior is erratic and unpredictable. Karp’s strategy, which her called “particle engineering,” corrects this problem by turning cells into pre-programmable units. The internalized particles stably remain inside the transplanted cell and instruct it precisely how to act. It can direct cells to release anti-inflammatory factors, or regenerate lost tissue and heal lesions or wounds.

“Once those particles are internalized into the cells, which can take on the order of 6-24 hours, we can deliver the transplant immediately or even cryopreserve the cells,” said Karp. “When the cells are thawed at the patient’s bedside, they can be administrated and the agents will start to be released inside the cells to control differentiation, immune modulation or matrix production, for example.”

It could take more than a decade for this type of cell therapy to be a common medical practice, but to speed up the pace of this research, Karp published the study to encourage others in the scientific community to apply the technique to their various fields. Karp’s paper also illustrates the range of different cell types that can be controlled by particle engineering, including stem cells, cells of the immune system, and pancreatic cells.

“With this versatile platform, which leveraged Harvard and MIT experts in drug delivery, cell engineering, and biology, we’ve demonstrated the ability to track cells in the body, control stem cell differentiation, and even change the way cells interact with immune cells, said Ankrum, who is a former graduate student in Karp’s laboratory. “We’re excited to see what applications other researchers will imagine using this platform.”

Stem Cell-Based Gene Therapy Restores Normal Skin Function

Michele De Luca from the University of Modena, Italy and his collaborator Reggio Emilia have used a stem cell-based gene therapy to treat an inherited skin disorder.

Epidermolysis bullosa is a painful skin disorder that causes the skin to be very fragile and blister easily. These blisters can lead to life-threatening infections. Unfortunately, no cure exists for this condition and most treatments try to alleviate the symptoms and infections.

Stem cell-based therapy seems to be one of the best ways to treat this disease, there are no clinical studies that have examined the long-term outcomes of such a treatment.

However, De Luca and his colleagues have examined a particular patients with epidermolysis bullosa who was treated with a stem cell-based gene therapy nearly seven years ago as part of a clinical trial.

The treatment of this patient has established that transplantation of a small quantity of stem cells into the skin on this patient’s legs restored normal skin function without causing any adverse side effects.

“These findings pave the way for the future safe use of epidermal stem cells for combined cell and gene therapy of epidermolysis bullosa and other genetic skin diseases,” said Michele De Luca.

De Luca and his research team found that their treatment of their patient, named Claudio, caused the skin covering his upper legs to looker normal and show no signs of blisters. To treat Claudio, De Luca and his colleague extracted skin cells from Claudio’s palm, used genetic engineering techniques to correct the genetic defect in the cells, and then transplanted these cells back into the skin of his upper legs. This was part of a clinical trial conducted at the University of Modena.

Claudio’s legs also showed no signs of tumors and the small number of transplanted cells sufficiently repaired Claudio’s skin long-term. Keep in mind that Claudio’s skin cells had undergone approximately 80 cycles of cell division and still had many of the features of palm skin cells, they show proper elasticity and strength and did not blister.

“This finding suggests that adult stem cell primarily regenerate the tissue in which they normally reside, with little plasticity to regenerate other tissues,” De Luca said. “This calls into question the supposed plasticity of adult stem cells and highlights the need to carefully chose the right type of stem cell for therapeutic tissue regeneration.”

I think De Luca slightly overstates his case here. Certainly choosing the right stem cells is crucial for successful stem cell treatments, but to take stem cells from skin, which are dedicated to making skin and expect them to form other tissues is unreasonable. However, several experiments have shown that stem cells from hair follicles and form neural tissues and several other cell types as well (see Jaks V, Kasper M, Toftgård R. The hair follicle-a stem cell zoo. Exp Cell Res. 2010 May 1;316(8):1422-8).

Adult stem cells have limited plasticity to be sure, but their plasticity is far greater than originally thought and a wealth of experiments have established that.

Despite these quibbles, this is a remarkable experiment that illustrates the feasibility and safety of such a treatment.  A larger problem is that large quantities of cells will be required to treat a person.  It is doubtful that small skin biopsies around the body can provide enough cells to treat the whole person.  Therefore, this might a case for induced pluripotent skin cells, which seriously complicates this treatment strategy.

Biphasic Electrical Stimulation Increases Stem Cell Survival

One of the challenges of stem cell-based therapies is cell survival. Once stem cells are implanted into a foreign site, many of them tend to pack up and die before they can do any good. For this reason, many scientists have examined strategies to improve stem cell survival.

A new technique that improves stem cells survival have been discovered by Yubo Fan and his colleagues at Beihang University School of Biological Science and Medical Engineering. This non-chemical technique, biphasic electrical stimulation (BES) might become important for spinal cord injury patients in the near future.

The BES incubation system. (a) Schematic diagram of a longitudinal section of the incubation chamber including: the upper and lower electric conductive glass plates (FTO glass), a closed silicone gasket, the incubation chamber, and a pair of electrode wires; (b) Schematic diagram of a longitudinal section of the entire BES incubation system including the incubation chamber, the fluid inflow-outflow system, the air filter system, a pair of electrode wires, and a fixed cover and base. Conditions of BES: the NPCs were exposed to 12 h of BES at 25mV/mm and 50mV/mm electric field strengths with a pulse-burst pattern and 8ms pulses (20% duty cycle). Cells that were not exposed to BES served as controls. (A color version of this figure is available in the online journal)
The BES incubation system. (a) Schematic diagram of a longitudinal
section of the incubation chamber including: the upper and lower electric  conductive glass plates (FTO glass), a closed silicone gasket, the incubation
chamber, and a pair of electrode wires; (b) Schematic diagram of a longitudinal
section of the entire BES incubation system including the incubation chamber,
the fluid inflow-outflow system, the air filter system, a pair of electrode wires, and
a fixed cover and base. Conditions of BES: the NPCs were exposed to 12 h of
BES at 25mV/mm and 50mV/mm electric field strengths with a pulse-burst
pattern and 8ms pulses (20% duty cycle). Cells that were not exposed to BES
served as controls. 

Spinal cord injury affects approximately 250,000 Americans, with 52% being paraplegic and 47% quadriplegic. There are 11,000 new spinal cord injuries each year and 82% are male.

Stem cell transplantions into the spinal cord to regenerate severed neurons and associated cells provides a potentially powerful treatment. However, once stem cells are implanted into the injured spinal cord, many of them die. Cell death is probably a consequence of several factors such as a local immune response, hypoxia (lack of oxygen), and probably most importantly, limited quantities of growth factors.

Fan said of his work, “We’ve shown for the very first time that BES may provide insight into preventing growth factor deprivation-triggered apoptosis in olfactory bulb precursor cells. These findings suggest that BES may thus be used as a strategy to improve cell survival and prevent cell apoptosis (programmed cell death) in stem cell-based transplantation therapies.”

The olfactory bulb is in green in this mouse brain.
The olfactory bulb is in green in this mouse brain.

Since electrical stimulation dramatically accelerates the speed of axonal regeneration and target innervation and positively modulates the functional recovery of injured nerves, Fan decided to test BES. His results showed that BES upregulated all the sorts of responses in stem cells that you would normally see with growth factors. Thus BES can increase stem cell survival without exogenous chemicals or genetic engineering.

Fan and his team examined the effects of BES on olfactory bulb neural precursor cells and they found that 12 hours of BES exposure protected cells from dying after growth factor deprivation. How did BES do this? Fan and other showed that BES stimulated a growth factor pathway called the PI3K/Akt signaling cascade. BES also increase the output of brain-derived neurotrophic factor.

“What was especially surprising and exciting,” said Fan, “was that a non-chemical procedure can prevent apoptosis in stem cell therapy for spinal cord patients.” Fan continued: “How BES precisely regulates the survival of exogenous stem cells is still unknown but will be an extremely novel area of research on spinal cord injury in the future.”

BES alters the ultrastructure of NPCs. The ultrastructural morphological changes of cells were investigated by TEM. In the control group (unstimulated), cells had a necrotic appearance: most cells lost the normal cellular structure with a consequent release of cell contents. In the 25mV/mm and 50mV/mm BES groups, the NPCs showed an apoptotic morphology with nuclear fragmentation and condensation
BES alters the ultrastructure of NPCs. The ultrastructural morphological changes of cells were investigated by TEM. In the control group (unstimulated), cells had a necrotic appearance: most cells lost the normal cellular structure with a consequent release of cell contents. In the 25mV/mm and 50mV/mm BES groups, the NPCs showed an apoptotic morphology with nuclear fragmentation and condensation

BES can improve the survival of neural precursor cells and will provide the survival of neural precursor cells and will provide the basis or future studies that could lead to novel therapies for patients with spinal cord injury.

Some Induced Pluripotent Stem Cell Lines Cause Tumors When Transplanted into Mouse Cochleas

Japanese researchers have been carefully evaluating the safety of different stem cell lines to determine the tendency of these cells to form tumors when transplanted into mice. Such studies have made it abundantly clear that the tendency for cell lines to form tumors depends upon the cell line and where it is transplanted (see Blum & Benvenisty, The Tumorigenicity of Human Embryonic Stem Cells. Advances in Cancer Research, Volume 100, 2008, Pages 133–158). However, little is known about the cochlea and the tendency of stem cells to cause tumors when transplanted into the cochlea. Therefore, Takayuki Nakagawa of Kyoto University and his group examined the results of stem cell transplantation into mouse cochlea.

Nakagawa made it clear that his motivation for this work is to achieve successful stem cell transplantation into the cochlea to treat hearing loss. He said: “Hearing loss affect millions of people world-wide. Recent studies have indicated the potential of stem cell-based approaches for the regeneration of hair cells and associated auditory primary neurons. These structures are essential for hearing and defects result in profound hearing loss and deafness.”

In this study, Nakagawa’s group transplanted embryonic stem cells and three distinct clones of mouse induced pluripotent stem cells into the cochlea of adult mice. According to Nakagawa; “Our study examined using induced-pluripotent stem cells generated from the patient source to determine if they offer a promising alternative to ES (embryonic stem) cells. In addition, the potential for tumor risk from iPS cells needed clarification.”

Upon transplantation into the cochlea, each cell line showed a distinct ability to form neural structures and integrate into the adult cochlea four weeks after transplantation. Some cells showed poor survival in the cochlea and one induced pluripotent stem cell line formed tumors in the cochlea. “To our knowledge, this is the first documentation of teratoma formation in cochleae after cell transplantation,” said Nakagawa.

These data demonstrate the necessity of screen individual iPS cell lines before their use, since some lines have greater tumor-causing potential than others.  Furthermore, it essential for researchers to design and develop screens to eliminate tumorigenic iPS cell lines.

John Sladek from the University of Colorado School of Medicine said: “While this study do not look at the ability of the transplanted cells to repair hearing loss, it does provide insight into the survival and fate of transplanted cells.  It highlights the importance of factors such as knowing the original source of the cells and their degree of differentiation to enable the cells to be ranked in order of their likelihood of forming tumors.”

Clinical Trial shows that Stem Cell Injections In Lou Gehrig’s Disease Can Be Given Safely

The journal Stem Cells has released an online version of a paper ahead of the print version that describes an important experiment in the treatment of amyotrophic lateral sclerosis (ALS), otherwise known as Lou Gehring’s disease. This paper describes an experiment that resulted from collaboration between the University of Michigan, Emory University and NeuralStem, Inc., which sponsored the study.

In this clinical trial, 12 patients were transplanted with spinal cord stem cells. All transplantations were done at Emory University. The early results of this trial show that spinal stem cells can be safely delivered into the spinal cords of ALS patients. This study might certainly open the door to further research on stem cell-based treatments for ALS.

All 12 patients had ALS and none experienced any long-term complications from this stem cell transplantation procedure. Additionally, none of the patients showed any signs of rejecting the implanted cells. Because inflammation in the spinal cord accelerates the progression of the disease, there were concerns that the implantation could increase the disease in these patients. However, in the months following the surgery that was used to inject the stem cells, none of the patients showed evidence that their ALS progression was accelerating.

Eva Feldman, M.D., Ph.D. is the principal investigator at the University of Michigan Medical School for this trial and serves as a consultant to NeuralStem. She is also the director of the A. Alfred Taubman Medical Research Institute and the U-M Health System’s ALS Clinic. Dr. Feldman stated, “This important publication reinforces our belief that we have demonstrated a safe, reproducible and robust route of administration into the spine for these spinal cord neural stem cells. The publication covers data up to 18 months out from the original surgery. However, we must be cautious in interpreting this data, as this trial was neither designed nor statistically powered to study efficacy.”

The trial began in January 2010 at Emory University. The first 12 patients received neural stem cell transplants in the lumbar, or lower, region of the spinal cord. After reviewing safety data from these patients, the Food and Drug Administration granted approval for the trial to advance to the final two groups of patients (three in each group), all of whom will be transplanted in the cervical, or upper, region of the spinal cord.

Nicholas Boulis, M.D., associate professor of neurosurgery at Emory School of Medicine, performs the surgery that implant the neural stem cells. Boulis also developed the device he used inject the stem cells into the spinal cord. This same device received a notice of patent allowance from U.S. Patent and Trademark Office in October. NeuralStem has purchased an exclusive license to this technology. Boulis trained in neurosurgery at University of Michigan and collaborated on research with Feldman during his seven years of residency. He holds an adjunct associate professor of neurology position at University of Michigan and is one of the Taubman Scholars at the U-M Taubman Institute.

This clinical trial is one of the first U.S. clinical trials of stem cell injections into the spinal cord for the treatment of ALS. NeuralStem, Inc., a Maryland-based company, is funding the clinical trial and has also provided the human neural stem cells for transplantation. NeuralStem’s cells have the ability to mature into various types of cells in the nervous system, including the motor neurons that are specifically lost in ALS. However, scientists say the goal of stem cell transplantation is not to generate new motor neurons, but to protect the still-functioning motor neurons by nurturing them with the stem cells, and therefore, potentially slowing the progression of the disease.

HIV Drug Maraviroc Reduces Graft-Versus-Host Disease In Stem Cell Transplant Patients

A drug called maraviroc is normally used to treat Human Immunodeficiency Virus (HIV) infections, but work at the University of Pennsylvania suggests that maraviroc redirects the trafficking of immune cells. The significance of these results are profound for transplant patients, since a drug like maraviroc can potentially reduce the incidence of graft-versus-host disease in cancer patients who have received allogeneic (from someone else) stem cell transplantation (ASCT). This research, which was conducted at the Perelman School of Medicine at the University of Pennsylvania, was presented at the 53rd American Society of Hematology Annual Meeting.

Graft-versus-host disease or GvHD occurs as complication after a stem cell or bone marrow transplant. During GvHD, the newly transplanted cells recognize the recipient’s body as foreign and mount an attack against it. Acute cases of GvHD usually occur within the first 3 months after the transplant. Chronic GvHD usually starts more than 3 months after the transplant. GvHD rates vary from 30 – 40% among related bone marrow or stem cells donors and from 60 – 80% between unrelated donors and recipients. The greater the degree of immunological mismatches between the donor and the recipient, the greater the risk of GvHD. After a transplant, the recipient usually takes a battery of drugs that suppress the immune system. These drug treatments help reduce the chances or severity of GvHD.

Standard treatments for GvHD suppress the immune system. Commonly used medicines include methotrexate, cyclosporine, tacrolimus, sirolimus, ATG (Antithymocyte globulin), and alemtuzumab either alone or in combination. High-dose corticosteroids are the most effective treatment for acute GVHD. Antibodies to T cells and other medicines are given to patients who do not respond to steroids. Chronic GvHD treatments include prednisone, (a steroid) with or without cyclosporine. Other treatments include mycophenolate mofetil (CellCept), sirolimus (Rapamycin), and tacrolimus (Prograf). These treatments, if given during the course of the stem cell or bone marrow transplant, reduce but do not eliminate the risk of developing GvHD.

In the current trial, treatment with maraviroc dramatically reduced the incidence of GvHD in organs where it is most dangerous (liver, GI tract, lung, skin — without compromising the immune system and leaving patients more vulnerable to severe infections.

Assistant professor in the division of Hematology-Oncology and a member of the Hematologic Malignancies Research Program at Penn’s Abramson Cancer Center, Ran Reshef, commented: “There hasn’t been a change to the standard of care for GvHD since the late 1980s, so we’re very excited about these results, which exceeded our expectations. Until now, we thought that only extreme suppression of the immune system can get rid of GvHD, but in this approach we are not killing immune cells or suppressing their activity, we are just preventing them from moving into certain sensitive organs that they could harm.”

Reshef and colleagues presented results showing that maraviroc is safe and feasible in stem cell transplant patients who have received stem cells from a healthy donor. A brief course of the drug led to a 73% reduction in severe GvHD in the first six months after transplant, compared with a matched control group treated at Penn during the same time period (6% who received maraviroc developed severe GvHD vs. 22% of other patients receiving standard drug regimens).

Reshef explained, “Just like in real estate, immune responses are all about location, location, location. Cells of the immune system don’t move around the body in a random way. There is a very distinct and well-orchestrated process whereby cells express particular receptors on their surface that allows them to respond to small proteins called chemokines. The chemokines direct the immune cells to specific organs, where they are needed, or in the case of GvHD, to where they cause damage.”

Thirty-eight patients with blood cancers, including acute myeloid leukemia, myelodysplastic syndrome, lymphoma, myelofibrosis, and others, enrolled in the phase I/II trial. All patients received the standard GvHD prevention drugs tacrolimus and methotrexate, plus a 33-day course of maraviroc that began two days before transplant. In the first 100 days after transplant, none of the patients treated with maraviroc developed GvHD in the gut or liver. By contrast, 12.5% of patients in the control group developed GvHD in the gut and 8.3 percent developed it in the liver within 100 days of their transplant.

The differential impact of maraviroc on those organs indicates that the drug is working as expected, by limiting the movement of T lymphocytes to specific organs in the body. Maraviroc works by blocking the CCR5 receptor on the surfaces of lymphocytes. This prevents the lymphocytes from trafficking to certain organs. Maraviroc did not affect GvHD rates in the skin, which might mean that the CCR5 receptor is more important for sending lymphocytes into the liver and the gut than the skin.

After 180 days, the benefit of maraviroc appeared to be partially sustained in patients and the cumulative incidence of gut GvHD rose to 8.8% and the rates of liver GvHD rose only to 2.9%. The cumulative incidence of GvHD in the control group, however, remained higher, at 28.4% for gut and 14.8% for liver GvHD. Based on these data, the research team plans to try a longer treatment regimen with maraviroc to see if longer exposures to maraviroc can its protective effect.

Additionally, maraviroc treatment appeared to neither increase treatment-related toxicities nor alter the relapse rate of their underlying disease. Clearly this drug shows promise for limiting the devastating effects of GvHD in stem transplant patients.