ScienceDaily (May 2, 2012) HIV patients treated with genetically modified T cells remain healthy up to 11 years after initial therapy, researchers from the Perelman School of Medicine at the University of Pennsylvania report in the new issue of Science Translational Medicine. The results provide a framework for the use of this type of gene therapy as a powerful weapon in the treatment of HIV, cancer, and a wide variety of other diseases.

"We have 43 patients and they are all healthy," says senior author Carl June, MD, a professor of Pathology and Laboratory Medicine at Penn Medicine. "And out of those, 41 patients show long term persistence of the modified T cells in their bodies."

Early gene therapy studies raised concern that gene transfer to cells via retroviruses might lead to leukemia in a substantial proportion of patients, due to mutations that may arise in genes when new DNA is inserted. The new long-term data, however, allay that concern in T cells, further buoying the hope generated by work June's team published in 2011 showing the eradication of tumors in patients with chronic lymphocytic leukemia using a similar strategy.

"If you have a safe way to modify cells in patients with HIV, you can potentially develop curative approaches," June says. "Patients now have to take medicine for their whole lives to keep their virus under control, but there are a number of gene therapy approaches that might be curative." A lifetime of anti-HIV drug therapy, by contrast, is expensive and can be accompanied by significant side effects.

They also note that the approach the Penn Medicine team studied may allow patients with cancers and other diseases to avoid the complications and mortality risks associated with more conventional treatments, since patients treated with the modified T cells did not require drugs to weaken their own immune systems in order for the modified cells to proliferate in their bodies after infusion, as is customary for cancer patients who receive stem cell transplants.

To demonstrate the long-term safety of genetically modified T cells, June and colleagues have followed HIV-positive patients who enrolled in three trials between 1998 and 2002. Each patient received one or more infusions of their own T cells that had been genetically modified in the laboratory using a retroviral vector. The vector encoded a chimeric antigen receptor that recognizes the HIV envelope protein and directs the modified T cell to kill any HIV-infected cells it encounters.

As is standard for any trial, the researchers carefully monitored patients for any serious adverse events immediately after infusion -- none of which were seen. Additionally, because of the earlier concerns about long-term side effects, the U.S. Food and Drug Administration also asked the team to follow the patients for up to 15 years to ensure that the modified T cells were not causing blood cancers or other late effects. Therefore, each patient underwent an exam and provided blood samples during each of the subsequent years.

Now, with more than 500 years of combined patient safety data, June and colleagues are confident that the retroviral vector system is safe for modifying T cells. By contrast, June notes, the earlier, worrying side effects were seen when viral vectors were used to modify blood stem cells. The new results show that the target cell for gene modification plays an important role in long-term safety for patients treated. "T cells appear to be a safe haven for gene modification," June says.

The multi-year blood samples also show that the gene-modified T cell population persists in the patients' blood for more than a decade. In fact, models suggest that more than half of the T cells or their progeny are still alive 16 years after infusion, which means one treatment might be able to kill off HIV-infected cells for decades. The prolonged safety data means that it might be possible to test T cell-based gene therapy for the treatment of non-life threatening diseases, like arthritis.

"Until now, we've focused on cancer and HIV-infection, but these data provide a rationale for starting to focus on other disease types," June says. "What we have demonstrated in this study and recent studies is that gene transfer to T cells can endow these cells with enhanced and novel functions. We view this as a personalized medicine platform to target disease using a patient's own cells."

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Genetically modified T cell therapy appears to be safe, lasting in decade-long study of HIV patients

ScienceDaily (May 2, 2012) UC Davis Health System researchers are a step closer to launching human clinical trials involving the use of an innovative stem cell therapy to fight the virus that causes AIDS.

In a paper published in the May issue of the Journal of Virology, the UC Davis HIV team demonstrated both the safety and efficacy of transplanting anti-HIV stem cells into mice that represent models of infected patients. The technique, which involves replacing the immune system with stem cells engineered with a triple combination of HIV-resistant genes, proved capable of replicating a normally functioning human immune system by protecting and expanding HIV-resistant immune cells. The cells thrived and self-renewed even when challenged with an HIV viral load.

"We envision this as a potential functional cure for patients infected with HIV, giving them the ability to maintain a normal immune system through genetic resistance," said lead author Joseph Anderson, an assistant adjunct professor of internal medicine and a stem cell researcher at the UC Davis Institute for Regenerative Cures. "Ideally, it would be a one-time treatment through which stem cells express HIV-resistant genes, which in turn generate an entire HIV-resistant immune system."

To establish immunity in mice whose immune systems paralleled those of patients with HIV, Anderson and his team genetically modified human blood stem cells, which are responsible for producing the various types of immune cells in the body.

Building on work that members of the team have pursued over the last decade, they developed several anti-HIV genes that were inserted into blood stem cells using standard gene-therapy techniques and viral vectors (viruses that efficiently insert the genes they carry into host cells). The resulting combination vector contained:

These engineered blood stem cells, which could be differentiated into normal and functional human immune cells, were introduced into the mice. The goal was to validate whether this experimental treatment would result in an immune system that remained functional, even in the face of an HIV infection, and would halt or slow the progression toward AIDS.

The results were successful on all counts.

"After we challenged transplanted mice with live HIV, we demonstrated that the cells with HIV-resistant genes were protected from infection and survived in the face of a viral challenge, maintaining normal human CD4 levels," said Anderson. CD4+ T-cells are a type of specialized immune cell that HIV attacks and uses to make more copies of HIV.

"We actually saw an expansion of resistant cells after the viral challenge, because other cells which were not resistant were being killed off, and only the resistant cells remained, which took over the immune system and maintained normal CD4 levels," added Anderson.

The data provided from the study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validated its potential application in future human clinical trials. The team has submitted a grant application for human clinical trials and is currently seeking regulatory approval, which is necessary to move on to clinical trials.

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Stem cell therapy shows promise in fight against HIV

ScienceDaily (Apr. 24, 2012) Although people generally talk about cancer, it is clear that the disease occurs in a bewildering variety of forms. Even single groups of cancers, such as those of the white blood cells, may show widely differing properties. How do the various cancers arise and what factors determine their progression? Clues to these two issues, at least for leukemias, have now been provided by Boris Kovacic and colleagues at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna). The results are published in the current issue of the journal EMBO Molecular Medicine and have extremely important consequences for the treatment of a particularly aggressive type of leukemia.

It is well known that many types of cancer arise as a result of a mutation within a cell and prevailing wisdom has held that the stage of differentiation of this cell determines exactly what form of cancer develops. For example, it was believed that so-called chronic myeloid leukemia or CML arises from bone marrow stem cells, while a different type of leukemia, known as B-cell acute lymphoid leukemia or B-ALL, results from B-cell precursors. This belief has been spectacularly refuted by the latest results from Boris Kovacic and colleagues in the Vetmeduni Viennas institutes of Animal Breeding and Genetics and of Pharmacology and Toxicology.

The researchers have now shown that both CML and B-ALL arise from the most primordial kind of blood cell (long-term haematopoietic stem cells), although the pathways by which the diseases progress are different. The usual causes of CML and B-ALL are two highly related versions of the same oncogene, BCR/ABL. If the primordial blood cells are transformed or made potentially cancerous by a particular version of BCR/ABL, for technical reasons termed BCR/ABLp210, the result is chronic myeloid leukemia or CML. The long-term haematopoietic stem cells remain and act as the dreaded cancer stem cells, or CSCs, which ensure that the disease persists. Curing chronic myeloid leukemia requires the complete elimination of the CSCs. However, if the long-term haematopoietic stem cells are transformed by a related version of BCR/ABL, BCR/ABLp185, the result is a highly aggressive form of leukemia, B-ALL. The finding that B-ALL actually originates from the same stem cells as CML was both unexpected and highly provocative.

Kovacic and colleagues have shown further that B-ALL only develops if the transformed stem cell is exposed to a particular growth factor, interleukin-7. If interleukin-7 is present (it usually is), the transformed long-term haematopoietic stem cells undergo a differentiation step to CSCs, which in this case correspond to pro-B cells. If interleukin-7 is absent during the initial phase of transformation, B-ALL cannot develop.

In other words, two distinct types of cell are involved in leukemia development, the primordial cells (also termed the cells of origin of cancer) and the cancer stem cells that cause the disease to progress. Unless the CSCs are eliminated, fresh cancer cells can arise at any time and the leukemia will recur. The problem is that current leukemia therapies are not designed to target CSCs. The primordial CSCs in CML are highly quiescent and thus difficult to target. In contrast, the CSCs in B-ALL are abundant and have a high turnover rate, which makes them susceptible to treatment. Treatment of B-ALL may thus succeed in eliminating most CSCs but if even a single cell remains intact it is likely that the patient will relapse, possibly with an even more aggressive form of leukemia. A therapy that targets the bulk of tumour cells will not work, as Kovacic succinctly summarizes his results. To treat B-ALL successfully it will be necessary for us to learn much more about the development of the disease. A combined therapy is required, so future work should aim at developing drugs that target the long-term haematopoietic stem cells from which B-ALL is derived.

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Leukemia cells have a remembrance of things past

Public release date: 25-Apr-2012 [ | E-mail | Share ]

Contact: Kim Irwin kirwin@mednet.ucla.edu 310-206-2805 University of California - Los Angeles Health Sciences

Can one feel too attached? Does one need to let go to mature? Neural stem cells have this problem, too.

As immature cells, neural stem cells must stick together in a protected environment called a niche in order to divide so they can make all of the cells that populate the nervous system. But when it's time to mature, or differentiate, the neural stem cells must stop dividing, detach from their neighbors and migrate to where they are needed to form the circuits necessary for humans to think, feel and interact with the world.

Now, stem cell researchers at UCLA have identified new components of the genetic pathway that controls the adhesive properties and proliferation of neural stem cells and the formation of neurons in early development.

The finding by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA could be important because errors in this pathway can lead to a variety of birth defects that affect the structure of the nervous system, as well as more subtle changes that impair cognitive and motor functions associated with disorders such as autism.

The results of the four-year study are published April 26, 2012 in the peer-reviewed journal Neuron.

The UCLA team found that a delicate balance of gene expression enables the pool of neural stem and progenitor cells in early development to initially increase and then quickly stop dividing to form neurons at defined times.

"One of the greatest mysteries in developmental biology is what constitutes the switch between stem cell proliferation and differentiation. In our studies of the formation of motor neurons, the cells that are essential for movement, we were able to uncover what controls the early expansion of neural stem and progenitor cells, and more importantly what stops their proliferation when there are enough precursors built up," said Bennett G. Novitch, an assistant professor of neurobiology, a Broad Stem Cell Research Center scientist and senior author of the study. "If the neurons don't form at the proper time, it could lead to deficits in their numbers and to catastrophic, potentially fatal neurological defects."

During the first trimester of development, the neural stem and progenitor cells form a niche, or safe zone, within the nervous system. The neural stem and precursor cells adhere to each other in a way that allows them to expand their numbers and keep from differentiating. A protein called N-cadherin facilitates this adhesion, Novitch said.

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Growing up as a neural stem cell: The importance of clinging together and then letting go

Despite decades of cancer research, cancer remains a leading cause of death worldwide, accounting for 7.6 million deaths in 2008, and breast cancer is one of the most common causes of cancer deaths each year . In Singapore, more than 1,400 women are diagnosed with breast cancer and more than 300 die as a result of breast cancer each year . The high fatality rate of cancer is partially attributed to the invasive ability of malignant tumors to spread throughout the human body, and the ineffectiveness of conventional therapies to eradicate the cancer cells.

A team of researchers led by IBN Group Leader, Dr Shu Wang, has made a landmark discovery that neural stem cells (NSCs) derived from human induced pluripotent stem (iPS) cells could be used to treat breast cancer. The effectiveness of using NSCs, which originate from the central nervous system, to treat brain tumors has been investigated in previous studies. This is the first study that demonstrates that iPS cell-derived NSCs could also target tumors outside the central nervous system, to treat both primary and secondary tumors.

To test the efficiency of NSCs in targeting and treating breast cancer, the researchers injected NSCs loaded with a suicide gene (herpes simplex virus thymidine) into mice bearing breast tumors. They did this using baculoviral vectors or gene carriers engineered from an insect virus (baculovirus), which does not replicate in human cells, making the carriers less harmful for clinical use. A prodrug (ganciclovir), which would activate the suicide gene to kill the cancerous cells upon contact, was subsequently injected into the mice. A dual-colored whole body imaging technology was then used to track the distribution and migration of the iPS-NSCs.

The imaging results revealed that the iPS-NSCs homed in on the breast tumors in the mice, and also accumulated in various organs infiltrated by the cancer cells such as the lung, stomach and bone. The survival of the tumor-bearing mice was prolonged from 34 days to 39 days. This data supports and explains how engineered iPS-NSCs are able to effectively seek out and inhibit tumor growth and proliferation.

Dr Shu Wang shared, "We have demonstrated that tumor-targeting neural stem cells may be derived from human iPS cells, and that these cells may be used in combination with a therapeutic gene to cripple tumor growth. This is a significant finding for stem cell-based cancer therapy, and we will continue to improve and optimize our neural stem cell system by preventing any unwanted activation of the therapeutic gene in non-tumor regions and minimizing possible side effects."

"IBN's expertise in generating human stem cells from iPS cells and our novel use of insect virus carriers for gene delivery have paved the way for the development of innovative stem cell-based therapies. With their two-pronged attack on tumors using genetically engineered neural stem cells, our researchers have discovered a promising alternative to conventional cancer treatment," added Professor Jackie. Y. Ying, IBN Executive Director.

Compared to collecting and expanding primary cells from individual patients, IBN's approach of using iPS cells to derive NSCs is less laborious and suitable for large-scale manufacture of uniform batches of cellular products for repeated patient treatments. Importantly, this approach will help eliminate variability in the quality of the cellular products, thus facilitating reliable comparative analysis of clinical outcomes.

Additionally, these iPS cell-derived NSCs are derived from adult cells, which bypass the sensitive ethical issue surrounding the use of human embryos, and since iPS cells are developed from a patient's own cells, the likelihood of immune rejection would be reduced.

References: 1. J. Yang, D. H. Lam, S. S. Goh, E. X. L. Lee, Y. Zhao, F. Chang Tay, C. Chen, S. Du, G. Balasundaram, M. Shahbazi, C. K. Tham, W. H. Ng, H. C. Toh and S. Wang, "Tumor Tropism of Intravenously Injected Human Induced Pluripotent Stem Cell-derived Neural Stem Cells and their Gene Therapy Application in a Metastatic Breast Cancer Model," Stem Cells, (2012) DOI: 10.1002/stem.1051.

2. E. X. Lee, D. H. Lam, C. Wu, J. Yang, C. K. Tham and S. Wang, "Glioma Gene Therapy Using Induced Pluripotent Stem Cell-Derived Neural Stem Cells," Molecular Pharmaceutics, 8 (2011) 1515-1524.

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IBN Discovers Human Neural Stem Cells with Tumor Targeting Ability - A Promising Discovery for Breast Cancer Therapy

The Catholic Church has never had a particularly easy relationship with science. After all, this is the institution that sentenced Galileo Galilei as a heretic for his theories on the universe during the Roman Inquisition. Two thousand years later, the church forgave Galileo and called the whole misunderstanding a tragic mutual incomprehension but it remains safe to say the Vatican doesnt have a great track record when it comes to empirical open-mindedness.

So onlookers were surprised when the Vatican announced it would be hosting a global conference on the highly controversial issue of stem-cell research in Rome over four days in late April. The church held a similar conference in 2010 and 2011, which focused on its recommendation that stem-cell research should be limited to adult cells that can be harvested from live donors, not embryonic cells that destroy the source. But this years conference schedule featured some of the worlds foremost experts in embryonic research as keynote speakersleading some scientists to think that the Vatican might actually be looking for enlightenment on the topic.

That was not exactly case. Instead, the Vatican seems to have hoped that by including embryonic researchers in the program, it would appear that these scientists actually endorsed the Vaticans stance.

It might have worked to some extent, but after some of the speakers declined to censor their speeches, the Vatican abruptly canceled the conference altogether. According to the conference website, the event was canceled due to serious economic and logistic-organizational reasons that have completely jeopardized the success of the 3rd International Congress on Responsible Stem Cell Research. The scientists who were planning to attend say they are being stifled instead. I think the only interpretation is that we are being censored, Alan Trounson, president of the California Institute for Regenerative Medicine in San Francisco, said in a statement. It is very disappointing that they are unwilling to hear the truth.

Just what was the Vatican thinking? Inviting embryonic stem-cell researchers to a conference and then denying them the right to talk about their field of expertise was a major gamble. Had the speakers agreed to avoid reference to embryonic research, it would have given the disingenuous impression that they endorse the Holy Sees recommendation on adult stem-cell research only. Did the Vatican really think they could control the scientific community? Apparently so. Father Scott Borgman of the Pontifical Academy for Life, which co-organized the conference, had reportedly asked the speakers to limit their discussions to adult stem-cell research only. George Daly, a leading embryonic researcher with the Childrens Hospital in Boston, says he was actually told not to make embryonic researchhis field of expertisea focal point of his talk. When he told Borgman that he would still be touching on the topic in a historical context, higher-ups in the Vatican reportedly panicked. I had been encouraged to think that the Congress would be a forum for discussion of many areas of common interest to the Vatican and stem cell scientists, regardless of the disagreements over embryonic stem cells, Daly told The Daily Beast. We should all agree that clinical trials of new medical treatments based on stem cells should proceed according to rigorous principles to ensure patients are kept as safe as possible and free from exploitation. And we should all agree that premature claims of therapeutic efficacy and direct marketing of unproven interventions to vulnerable patients is a threat to legitimate attempts to develop experimental stem cell medicines.

Pope Benedict looks on during the mass in solemnity of the chair of St. Peter with new Cardinals in St. Peter's basilica at the Vatican on February 19, 2012. The Vatican stands by its decision to cancel the controversial conference as having a purely business motive. , Alberto Pizzoli, AFP / Getty Images

With the cancelation of the event, discourse between the two diverse entities will not have a venue. One Vatican official told the Catholic News Service that many of the Vaticans leaders were secretly glad the conference failed. I am infinitely relieved that the church has avoided a major blunder which would have confused the faithful for decades to come, the unnamed source said. The Holy Spirit has certainly shown to be present through those faithful members who drew attention to the ambiguity of the choice of speakers. I hope and pray that a review will be affected of the basis on which these congresses are planned.

Some stem-cell researchers are also relieved the conference wont go on. I personally am very uncomfortable with a scientific meeting run by a church, and one at which only certain types of science and scientists are allowed to attend, blogged Paul Knoepfler, an associate professor of Cell Biology and Human Anatomy at UC Davis School of Medicine who blogs about stem cell research at IPCell.com. Also I cant help but wonder, what would be the reaction if someone like Daley spent a few minutes of his talk discussing his embryonic cell research in a very nonconfrontational way? Would he be tasered or drop through some trap door straight to Hell?

Still, Knoepfler was hopeful. I view the canceled Vatican stem-cell meeting as a missed opportunity for a very much needed, open dialogue about stem cells, he told The Daily Beast. More specifically, I believe the reasons for the cancellation reflect an anti-scientific attitude by the highest level of Vatican leaders. More simply put, the attitude might be summed up by the phrase If you do not think like us, you are not welcome at our meeting, and well go so far as to cancel the whole thing to avoid your presence.

Inviting embryonic stem-cell researchers to a conference and then denying them the right to talk about their field of expertise was a major gamble.

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Vatican’s Stem-Cell Censorship Sham

MADISON, Wis., March 28, 2012 /PRNewswire/ --Cellular Dynamics International, Inc. (CDI) today announced an expansion of its existing distribution agreement with iPS Academia Japan, Inc. to include iCell Neurons and iCell Endothelial Cells. The original distribution agreement, announced on June 8, 2011, covered the distribution of CDI's iCell Cardiomyocytes, the first commercially available product based on induced pluripotent stem cells (iPSCs), in Japan.

CDI is the world's largest manufacturer of human cellular tools for drug discovery and safety derived from iPSCs. The company currently manufactures iCell Cardiomyocytes, iCell Neurons and iCell Endothelial Cells with several other cell types, including liver cells, in development.

iPS Academia Japan was originally established to manage the patents and technology arising from the work of Shinya Yamanaka, MD, PhD of Kyoto University. CDI was the first foreign company granted a license to Yamanaka's iPSC patent portfolio by iPS Academia Japan, announced in May 2010.

"The reliability and consistent quality of CDI's cardiomyocytes have proven to be a valuable product offering to our academic and pharmaceutical customers," said Shosaku Murayama, President and CEO of iPS Academia Japan. "We're already seeing demand for additional human cell types manufactured by CDI by our Japanese customers."

Robert Palay, CEO and chairman of the board of CDI, noted, "We view the expansion of our distribution agreement with iPS Academia Japan as a vote of confidence in our ability to provide human iPSC-derived cells in the quantity, quality and purity required for scientists to realize the full potential of their experiments. We look forward to future growth of our relationship with iPS Academia Japan as we launch new human cell types and in vitro human disease models."

About Cellular Dynamics International Cellular Dynamics International, Inc. (CDI) is a leading developer of next-generation stem cell technologies for drug development, cell therapy, tissue engineering and organ regeneration. CDI harnesses its unique manufacturing technology to produce differentiated tissue cells from any individual's stem cell line in industrial quality, quantity and purity. CDI is accelerating the adoption of pluripotent stem cell technology, adapting its methods to fit into standard clinical practice by the creation of individual stem cell lines from a standard blood draw. CDI was founded in 2004 by Dr. James Thomson, a pioneer in human pluripotent stem cell research at the University of Wisconsin-Madison. CDI's facilities are located in Madison, Wisconsin. See http://www.cellulardynamics.com.

About iPS Academia Japan, Inc. iPS Academia Japan, Inc. (AJ) is an affiliate of Kyoto University, and its main role is, among other activities, to manage and utilize the patents and other intellectual properties held/controlled by Kyoto University and other universities in the field of iPSC technologies so that the research results contribute to health and welfare worldwide.

AJ was established in Kyoto in June 2008. AJ's patent portfolio consists of about 60 patent families (the total number of patent applications is about 220 cases) in the iPSC technology as of March 2012, and about 50 license arrangements have been executed with domestic or international enterprises. See http://ips-cell.net.

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Cellular Dynamics Expands Distribution Agreement with iPS Academia Japan, Inc. to Include Distribution of iCell ...

March 27, 2012

According to a new study, using a patients own bone marrow may help repair damaged areas of the heart caused by heart failure.

Researchers found that left ventricular ejection fraction increased by 2.7 percent in patients who received stem cell therapy.

The study, which was presented at the American College of Cardiologys 61st Annual Scientific Session, revealed that the improvement in ejection fraction correlated with the number of CD34+ and CD133+ cells in the bone marrow.

This is the kind of information we need in order to move forward with the clinical use of stem cell therapy, Emerson Perin, MD, PhD, director of clinical research for cardiovascular medicine at the Texas Heart Institute and the studys lead investigator, said at the event.

The study included 92 patients who were randomly selected to receive stem cell treatment or placebo. The patients all had chronic ischemic heart disease and an ejection fraction of less than 45 percent along with heart failure.

Doctors placed a catheter in the hearts left ventricle to inject 3 ccs, or 100 million stem cells, into an average of 15 sites of the stem cell patients hearts.

The doctors used electromechanical mapping of the heart to measure the voltage in areas of the heart muscle and create a real-time image of the heart.

With this mapping procedure, we have a roadmap to the heart muscle, said Dr. Perin. Were very careful about where we inject the cells; electromechanical mapping allows us to target the cell injections to viable areas of the heart.

The trial was designed to determine whether left ventricular end systolic volume and myocardial oxygen consumption improved in patients who received stem cell treatment.

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Cell Therapy Improves Damaged Heart In Study

Public release date: 24-Mar-2012 [ | E-mail | Share ]

Contact: Traci Klein newsbureau@mayo.edu 507-284-5005 Mayo Clinic

CHICAGO -- A research network led by a Mayo Clinic physician found that stem cells derived from heart failure patients' own bone marrow and injected into their hearts improved the function of the left ventricle, the heart's pumping chamber. Researchers also found that certain types of the stem cells were associated with the largest improvement and warrant further study.

The results were presented today at the 2012 American College of Cardiology Meeting in Chicago. They will also be published online in the Journal of the American Medical Association.

This Phase II clinical trial, designed to test this strategy to improve cardiac function, is an extension of earlier efforts in Brazil in which a smaller number of patients received fewer stem cells. For this new network study, 92 patients received a placebo or 100 million stem cells derived from the bone marrow in their hips in a one-time injection. This was the first study in humans to deliver that many bone marrow stem cells.

"We found that the bone marrow cells did not have a significant impact on the original end points that we chose, which involved reversibility of a lack of blood supply to the heart, the volume of the left ventricle of the heart at the end of a contraction, and maximal oxygen consumption derived through a treadmill test," says Robert Simari, M.D., a cardiologist at Mayo Clinic in Rochester, Minn. He is chairman of the Cardiovascular Cell Therapy Research Network (CCTRN), the network of five academic centers and associated satellite sites that conducted the study. The CCTRN is supported by the National Heart, Lung, and Blood Institute, which also funded the study.

"But interestingly, we did find that the very simple measure of ejection fraction was improved in the group that received the cells compared to the placebo group by 2.7 percent," Dr. Simari says. Ejection fraction is the percentage of blood pumped out of the left ventricle during each contraction.

Study principal investigators Emerson Perin, M.D., Ph.D., and James Willerson, M.D., of the Texas Heart Institute, explain that even though 2.7 percent does not seem like a large number, it is statistically significant and means an improvement in heart function for chronic heart failure patients who have no other options.

"This was a pretty sick population," Dr. Perin says. "They had already had heart attacks, undergone bypass surgery, and had stents placed. However, they weren't at the level of needing a heart transplant yet. In some patients, particularly those who were younger or whose bone marrows were enriched in certain stem cell populations, had even greater improvements in their ejection fractions."

The average age of study participants was 63. The researchers found that patients younger than 62 improved more. Their ejection fraction improved by 4.7 percent. The researchers looked at the makeup of these patients' stem cells from a supply stored at a biorepository established by the CCTRN. They found these patients had more CD34+ and CD133+ type of stem cells in their mixture.

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Bone marrow stem cells improve heart function, study finds

By Prue Salasky

3:48 p.m. EDT, March 23, 2012

UVA recently performed the first two stem cell transplants in Virginia, using non-embryonic stem cells from umbilical cord blood. The Stem Cell Transplant Program offers both bone marrow and stem cell transplants, with a focus on cord blood, to treat leukemia, lymphoma, Hodkin's disease and other blood diseases.

The outcome isn't known yet, but in both patients the stem cells began producing new cells 14 days after the transplant instead of the 24 to 28 days it usually takes.

The cord blood comes from placentas that otherwise would be discarded following childbirth; its benefits include sidestepping ethical issues of embryonic stem cells; they're easier and faster to collect than stem cells from other sources; and they are immune tolerant (this means that they won't attack other cells in the body and match doesn't have to be exact).

Speed is important because there is a narrow window of opportunity to perform a transplant when a patient's disease is in remission.

The program is led by Mary Laughlin, who heads up a team of 29, including 4 other transplant physicians who started seeing patients in September. The program had anticipated doing 15 transplants in first year; now expects to do 100.

Link:
Health Notes: UVA performs first stem cell transplants in Virginia

SATURDAY, March 24 (HealthDay News) -- An innovative approach using patients' own bone marrow cells to treat chronic heart failure came up short in terms of effectiveness, researchers report.

Use of stem cell therapy to repair the slow, steady damage done to heart muscle and improve heart function is safe, but has not been shown to improve most measures of heart function, the study authors said.

"For the measures we paid most attention to, we saw no effect, there is no question about that," said researcher Dr. Lemuel Moye, a professor of biostatistics at the University of Texas School of Public Health in Houston.

"Ultimately, this is going to pay off handsomely for individuals and for public health in general, but it's going to take years of work," Moye said. "We are the vanguard looking for new promising lines of research."

While the hoped-for results didn't materialize, there appeared to be a small improvement in some patients, he said. "When we looked at another commonly used measure of heart function called ejection fraction, or the strength of the heart's pumping, that's where all the action was," Moye noted.

It's hard to know which measures of heart function to look at, Moye explained. "We have had some difficulty with that," he said.

Future research will look at other measures of heart function, pay more attention to the characteristics of the cells that are injected and determine which cells are best, he added.

Cardiac cells and other types of specially prepared cells are available now that were not accessible when this study started in 2009, Moye pointed out.

The results of the trial, which was sponsored by the U.S. National Heart, Lung, and Blood Institute, were to be presented Saturday at the American College of Cardiology's annual meeting in Chicago. The report was also published online March 24 in the Journal of the American Medical Association.

For the study, Moye and colleagues worked with 92 patients, average age 63 and mostly male, who had heart failure with and without chest pain. They were randomly assigned to receive either an injection of 100 million bone marrow cells from their own bone marrow, or an inactive placebo. Patients in both groups also received aggressive medical therapy.

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Stem-Cell Trial Failed to Treat Heart Failure

Public release date: 22-Mar-2012 [ | E-mail | Share ]

Contact: Dr. Frank Edenhofer f.edenhofer@uni-bonn.de 49-228-688-5529 University of Bonn

These stem cells can reproduce and be converted into various types of brain cells. To date, only reprogramming in brain cells that were already fully developed or which had only a limited ability to divide was possible. The new reprogramming method presented by the Bonn scientists and submitted for publication in July 2011 now enables derivation of brain stem cells that are still immature and able to undergo practically unlimited division to be extracted from conventional body cells. The results have now been published in the current edition of the prestigious journal Cell Stem Cell.

The Japanese stem cell researcher Professor Shinya Yamanaka and his team produced stem cells from the connective tissue cells of mice for the first time in 2006; these cells can differentiate into all types of body cells. These induced pluripotent stem cells (iPS cells) develop via reprogramming into a type of embryonic stage. This result made the scientific community sit up and take notice. If as many stem cells as desired can be produced from conventional body cells, this holds great potential for medical developments and drug research. "Now a team of scientists from the University of Bonn has proven a variant for this method in a mouse model," report Dr. Frank Edenhofer and his team at the Institute of Reconstructive Neurobiology (Director: Dr. Oliver Brstle) of the University of Bonn. Also involved were the epileptologists and the Institute of Human Genetics of the University of Bonn, led by Dr. Markus Nthen, who is also a member of the German Center for Neurodegenerative Diseases.

Edenhofer and his co-workers Marc Thier, Philipp Wrsdrfer and Yenal B. Lakes used connective tissue cells from mice as a starting material. Just as Yamanaka did, they initiated the conversion with a combination of four genes. "We however deliberately targeted the production of neural stem cells or brain stem cells, not pluripotent iPS multipurpose cells," says Edenhofer. These cells are known as somatic or adult stem cells, which can develop into the cells typical of the nervous system, neurons, oligodendrocytes and astrocytes.

The gene "Oct4" is the central control factor

The gene "Oct4" is a crucial control factor. "First, it prepares the connective tissue cell for reprogramming, later, however, Oct4 appears to prevent destabilized cells from becoming brain stem cells" reports the Bonn stem cell researcher. While this factor is switched on during reprogramming of iPS cells over a longer period of time, the Bonn researchers activate the factor with special techniques for only a few days. "If this molecular switch is toggled over a limited period of time, the brain stem cells, which we refer to as induced neural stem cells (iNS cells), can be reached directly," said Edenhofer. "Oct4 activates the process, destabilizes the cells and clears them for the direct reprogramming. However, we still need to analyze the exact mechanism of the cellular conversion."

The scientists at the University of Bonn have thus found a new way to reprogram cells, which is considerably faster and also safer in comparison to the iPS cells and embryonic stem cells. "Since we cut down on the reprogramming of the cells via the embryonic stage, our method is about two to three times faster than the method used to produce iPS cells," stresses Edenhofer. Thus the work involved and the costs are also much lower. In addition, the novel Bonn method is associated with a dramatically lower risk of tumors. As compared to other approaches, the Bonn scientists' method stands out due to the production of neural cells that can be multiplied to a nearly unlimited degree.

Low risk of tumor and unlimited self renewal

A low risk of tumor formation is important because in the distant future, neural cells will replace defective cells of the nervous system. A vision of the various international scientific teams is to eventually create adult stem cells for example from skin or hair root cells, differentiate these further for therapeutic purposes, and then implant them in damaged areas. "But that is still a long way off," says Edenhofer. However, the scientists have a rather urgent need today for a simple way to obtain brain stem cells from the patient to use them to study various neurodegenerative diseases and test drugs in a Petri dish. "Our work could form the basis for providing practically unlimited quantities of the patient's own cells." The current study was initially conducted on mice. "We are now extremely eager to see whether these results can also be applied to humans," says the Bonn scientist.

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A new shortcut for stem cell programming

The Stem Cell Transplant Program at the University of Virginia Health System recently performed the first two stem cell transplants in Virginia, using non-embryonic stem cells from umbilical cord blood.

The program offers both bone marrow and stem cell transplants, with a focus on cord blood, to treat leukemia, lymphoma, Hodgkins disease and other blood diseases.

While it will take several months to know how effective the cord blood transplants were, the initial results are promising, says Mary Laughlin, MD, an internationally known stem cell expert recruited to UVA to head the program. In both patients, the stem cells began engrafting producing new cells 14 days after the transplant instead of the 24 to 28 days it normally takes.

Why cord blood stem cells? As an obstetrician once told Laughlin: Something thrown away in my OB suite saves a life in your cancer suite.

The cord blood used for these stem cell transplants comes from placentas that otherwise would be discarded following childbirth, Laughlin says. The cord blood is used with the permission of the new parents, she says. By using cord blood stem cells instead of embryonic stem cells, UVAs program sidesteps the ethical, religious and political concerns commonly associated with stem cells, she says.

Other benefits: Cord blood stem cells are also faster and easier to collect than stem cells from other sources; they are also immune tolerant.

Speed is important because there is a narrow window of opportunity to perform a transplant when a patients disease is in remission. And because the cord blood stem cells are immune tolerant meaning they will not attack other cells in the body the chances of a successful transplant are higher and the donor match doesnt have to be as exact, giving more patients the opportunity to receive a transplant.

Stem cell transplants: Part of a fast-growing program Laughlin heads up a team of 29 staff members, including four additional transplant physicians, who began seeing patients in September. The demand for transplants has already been greater than Laughlin and her team expected. The program had initially planned to do 15 transplants in its first year. Instead, it expects to do 100.

Its reflective of this unmet need, Laughlin says. Patients who otherwise would have to travel many states away to have these same procedures, now they can do a fairly short drive from Roanoke, or down from Winchester. Because of our central location, its ideal for them.

What are stem cells? Learn more about how they work.

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First Stem Cell Transplants in Virginia Performed at UVA

ScienceDaily (Mar. 19, 2012) Research from a Kansas State University professor may make it easier to recover after spinal cord injury or to study neurological disorders.

Mark Weiss, professor of anatomy and physiology, is researching genetic models for spinal cord injury or diseases such as Parkinson's disease. He is developing technology that can advance cellular therapy and regenerative medicine -- a type of research that can greatly improve animal and human health.

"We're trying to build tools, trying to build models that will have broad applications," Weiss said. "So if you're interested in neural differentiation or if you're interested in response after an injury, we're trying to come up with cell lines that will teach us, help us to solve a medical mystery."

Weiss' research team has perfected a technique to use stem cells to study targeted genetic modifications. They are among a handful of laboratories in the world using these types of models for disease. The research is an important step in the field of functional genomics, which focuses on understanding the functions and roles of these genes in disease.

The researchers are creating several tools to study functional genomics. One such tool involves developing new ways to use fluorescent transporters, which make it easier to study proteins and their functions. These fluorescent transporters can be especially helpful when studying neurological disorders such as Parkinson's disease, stroke and spinal cord injury.

"People who have spinal cord injury do not experience a lot of regeneration," Weiss said. "It is one of the problems of the nervous system -- it is not great at regenerating itself like other tissues."

The researchers want to discover a way to help this regenerative process kick in. By studying signals from fluorescing cells, they can understand how neural stem cells are reactivated.

"We want to try and make these genetic markers, and then we can test different kinds of treatment to see how they assist in the regenerative process," Weiss said.

Weiss' stem cell research has appeared in two recent journals: Stem Cells and Development and the Journal of Assisted Reproduction and Genetics. His research has been funded by the National Institutes of Health and university funds, including the Johnson Cancer Research Center.

Weiss' seven-member research team includes a visiting professor, two full-time researchers, a graduate student and three undergraduates. He has also been collaborating with researchers from the University of Kansas Medical Center.

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Genetic research develops tools for studying diseases, improving regenerative treatment

Pluristem Therapeutics Ltd. (Nasdaq:PSTI; DAX: PJT: PLTR) today announced that its PLacental eXpanded (PLX) cells improve several parameters in acute myocardial infarction (heart attacks) in animals. The preclinical trial was conducted at the Center for Regenerative Therapies in Germany.

The trial included 20 mice, which were given induced heart attacks. Half the mice were then given either PLX cells, and the other half were given a cell-free medium as a control. Five other mice underwent a sham (placebo) operation. After four weeks, the mice underwent an ECG, and were then killed for a physical examination of their hearts. The mice which received PLX had improved cardiac muscle function compared with the control group.

Study leader Prof. Christof Stamm said, "As a cardiac surgeon, the unique ability demonstrated by Pluristem's PLX cells for the treatment of heart disease is very exciting." He added, "PLX cells showed promising results in the AMI studies."

Pluristem chairman and CEO Zami Aberman said, "These results demonstrate the potential benefits of our cells for use in the treatment of ischemic heart disease, a multi-billion dollar annual market, and one in which many pharmaceutical companies are constantly looking to provide patients with innovative and effective solutions. In addition to moving ahead with our AMI trial, we look forward to continuing to work on finding cell therapy solutions for numerous debilitating diseases."

An article in the New England Journal of Medicine states that 624,000 patients suffer an acute myocardial infarction annually in the US, a number that will most likely increase with the rising prevalence of obesity, diabetes and the aging of the population.

Pluristem's share price rose 5.1% by mid-afternoon on the TASE today to NIS 8.50, after closing at $2.15 on Nasdaq yesterday, giving a market cap of $95 million. The share is up 6.5% in premarket trading on Nasdaq today.

Published by Globes [online], Israel business news - http://www.globes-online.com - on March 20, 2012

Copyright of Globes Publisher Itonut (1983) Ltd. 2012

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Pluristem reports success in stem cell heart attack treatment

EDMONDS, Wash., March 14, 2012 /PRNewswire/ --Washington Center for Pain Management is participating in a nationwide FDA-cleared adult stem cell study testing novel treatment for chronic low back pain and has enrolled its first patient. The study will test the use of Mesenchymal Precursor Cells (MPCs) adult stem cells derived from bone marrow that will be directly injected into the lumbar disc. The minimally invasive procedure may offer an alternative to back surgery for eligible patients with chronic pain from degenerative discs.

An estimated 30 million people in the United States suffer from back pain. Degenerative disc disease is the most common cause of low-back pain, which develops with the gradual loss of a material called proteoglycan, which cushions the bones of the spine and enables normal motion.

Most patients with low-back pain respond to physical therapy and medications, but in advanced cases, artificial disc replacement or spinal fusion -- removal of the degenerated discs and the fusion of the bones of the spine -- is necessary. However, these surgeries often are not entirely effective.

"Millions of Americans are debilitated by chronic low back pain," says Dr Hyun Joong Hong MD, the lead investigator at The Washington Center for Pain Management. "This promising therapy is at the cutting edge of medical science and has the potential to create a paradigm shift in our approach to minimally invasive solutions to this disease."

Researchers will enroll approximately 100 study participants. About fifteen participants will be enrolled at The Washington Center for Pain Management and the rest at 11 other medical centers throughout the United States. The trial is scheduled to last for three years.

Washington Center for Pain Management is enrolling study participants suffering from moderate low-back pain for a minimum of six months and whose condition has not responded to other, conventional treatments.

Once enrolled, patients are randomly assigned to one of four treatment groups:

Patients will receive a single injection of their assigned test agent directly into the center of the target discs within their spine and will be monitored for safety. Patients will also be monitored using imaging to identify any changes in their disease condition or disease progression. Use of pain medications, self-reports of pain, subsequent surgical interventions and assessments of disability, quality of life, productivity and activity will be evaluated. Repair of the disc and reduction of chronic back pain will be assessed in each patient.

Promising results have been observed in prior research using animal models when stem cells were investigated for the repair of damaged spine discs. The cells were well tolerated in these study animals.

This study is sponsored by Mesoblast Limited, a world leader in the development of biologic products for the broad field of regenerative medicine. Mesoblast has the worldwide exclusive rights to a series of patents and technologies developed over more than 10 years relating to the identification, extraction, culture and uses of adult Mesenchymal Precursor Cells (MPCs). The MPCs are derived from young adult donors' bone marrow and are immune tolerant.

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Washington Center for Pain Management Begins Enrollment in United States Stem Cell Therapy Study in Subjects With ...

ScienceDaily (Mar. 13, 2012) For the first time, scientists at the University of Wisconsin-Madison have made early retina structures containing proliferating neuroretinal progenitor cells using induced pluripotent stem (iPS) cells derived from human blood.

And in another advance, the retina structures showed the capacity to form layers of cells as the retina does in normal human development and these cells possessed the machinery that could allow them to communicate information. (Light-sensitive photoreceptor cells in the retina along the back wall of the eye produce impulses that are ultimately transmitted through the optic nerve and then to the brain, allowing you to see.) Put together, these findings suggest that it is possible to assemble human retinal cells into more complex retinal tissues, all starting from a routine patient blood sample.

Many applications of laboratory-built human retinal tissues can be envisioned, including using them to test drugs and study degenerative diseases of the retina such as retinitis pigmentosa, a prominent cause of blindness in children and young adults. One day, it may also be possible replace multiple layers of the retina in order to help patients with more widespread retinal damage.

We dont know how far this technology will take us, but the fact that we are able to grow a rudimentary retina structure from a patients blood cells is encouraging, not only because it confirms our earlier work using human skin cells, but also because blood as a starting source is convenient to obtain, says Dr. David Gamm, pediatric ophthalmologist and senior author of the study. This is a solid step forward.

In 2011, the Gamm lab at the UW Waisman Center created structures from the most primitive stage of retinal development using embryonic stem cells and stem cells derived from human skin. While those structures generated the major types of retinal cells, including photoreceptors, they lacked the organization found in more mature retina.

This time, the team, led by Gamm, Assistant Professor of Ophthalmology and Visual Sciences in the UW School of Medicine and Public Health, and postdoctoral researcher and lead author Dr. Joseph Phillips, used their method to grow retina-like tissue from iPS cells derived from human blood gathered via standard blood draw techniques.

In their study, about 16 percent of the initial retinal structures developed distinct layers. The outermost layer primarily contained photoreceptors, whereas the middle and inner layers harbored intermediary retinal neurons and ganglion cells, respectively. This particular arrangement of cells is reminiscent of what is found in the back of the eye. Further, work by Dr. Phillips showed that these retinal cells were capable of making synapses, a prerequisite for them to communicate with one another.

The iPS cells used in the study were generated through collaboration with Cellular Dynamics International (CDI) of Madison, Wis., who pioneered the technique to convert blood cells into iPS cells. CDI scientists extracted a type of blood cell called a T-lymphocyte from the donor sample, and reprogrammed the cells into iPS cells. CDI was founded by UW stem cell pioneer Dr. James Thomson.

We were fortunate that CDI shared an interest in our work. Combining our labs expertise with that of CDI was critical to the success of this study, added Dr. Gamm.

Other members of the research team include:

Excerpt from:
Scientists produce eye structures from human blood-derived stem cells

Starting with the first-ever production of induced pluripotent stem cells (iPS cells) in 2006, cell reprogramming - the genetic conversion of cells from one type to another - has revolutionized stem cell research and opened the door to countless new medical applications. Inducing such reprogramming, however, is difficult, inefficient and time-consuming, involving a largely hit-or-miss process of selecting candidate genes.

In the current study, the OSC research team explored an alternative to iPS cells based on the use of transcriptional regulatory networks (TRNs), networks of transcription factors and the genes they regulate. Previous research by the team characterized the dynamic regulatory activities of such transcription factors during cellular differentiation from immature cell (monoblast) to developed (monocyte-like) cell using human acute monocytic leukemia cell lines (THP-1). Their findings led them to hypothesize that functional characteristics of the cell-type are maintained by its specific TRN.

Their new paper builds on this hypothesis, establishing a series of new methods for identifying transcription factors (TFs) for the monocyte network, which play a key role in inducing cell-specific functions. Four core TF genes of the monocyte TRN, identified using this approach, were introduced into human fibroblast cells, expression of which activated monocytic functions including phagocytosis, inflammatory response and chemotaxis. Genome-wide gene expression analysis of this reprogrammed cell showed monocyte-like gene expression profile, demonstrating that reconstruction of a functional TRN can be achieved by introducing core TRN elements into unrelated cell types.

Published in the journal PLoS ONE, the newly-developed methods open the door to a new form of direct cell reprogramming for clinical use which avoids the pitfalls of embryonic stem (ES) and induced pluripotent stem (iPS) cells, charting a course toward novel applications in regenerative medicine and drug discovery.

Provided by RIKEN (news : web)

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Study demonstrates cells can acquire new functions through transcriptional regulatory network

Doctor Wise Young in Hong Kong on February 22, 2012. Young, a leading researcher in spinal cord injuries, says China could hold the key to a cure that he has been searching for since he met late actor Christopher Reeve in the 1990s. AFP pic

US-based Doctor Wise Young first used the word cure in relation to his work after a conversation with Reeve, the Superman hero who became quadriplegic in an equestrian accident in 1995.

Reeve contacted him looking for help and the two became close friends. The actor died of heart failure in 2004 at the age of 52, having devoted his life to raising awareness about spinal cord injuries and stem-cell research.

But it was a star of a different sort, Chinese gymnast Sang Lan, who set Young on the path he believes has brought a cure closer than ever, thanks to ground-breaking clinical trials of stem-cell therapy he is conducting in China.

Everybody assumed that Im doing this in China because I wanted to escape George W. Bush, but thats not the case at all, Young said in an interview, recalling the former US presidents 2001 decision to effectively stop Federal funding of embryonic stem cell research.

I started the clinical trials in 2005 here in Hong Kong ... mainly because of a promise that I made to a young woman. Her name is Sang Lan.

Sang crushed her spine during a routine warm-up exercise at the Goodwill Games in New York in 1998. She met Young as she underwent treatment and rehabilitation in the United States over the next 12 months.

Her parents came to me and asked whether or not there would ever be a cure for her, and I said were working very hard on it, recalled Young, who was by then one of the leading US experts on spinal cord injuries.

When she went back to China after doing her rehabilitation in New York she cried and asked how would therapies go from the United States to China.

In those days China was still relatively poor and backward so she didnt think that any therapy would be coming from China. So I started in 1999 to talk to all the spinal cord doctors in China.

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Doctor looks to China for spinal injury ‘cure’

Cancer sufferer Pamela Bou Sejean wants your help to save her life

Pamela Bou Sejean has Hodgkin's Lymphoma and needs a stem cell transplant. Picture: Alison Wynd Source: News Limited

PAMELA Bou Sejean is fighting for her life.

After 16 months battling an aggressive form of Hodgkin's Lymphoma, the 26-year-old has turned to Facebook in a last ditch bid to find the stem cell donor to keep her alive.

TheVictorian woman in Belmont does not match with any registered bone marrow donor in the world so is now pleading for the public to come forward to be blood tested for a possible match.

"I don't know how much time I have, I get too afraid to ask," Ms Bou Sejean told the Geelong Advertiser.

"I want to focus on what we're doing now.

"The waiting process is hard."

With her life in the balance, Ms Bou Sejean's brother Matt a week ago set up the Facebook page How You Can Help Cure Pamela.

There, Facebook users are told about her fight and how to be blood tested for a possible stem cell match.

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Stem cells are my last hope. Can you help?