Stem Cell Clinic

Spring cleaning in your brain's stem cells?

Apr. 10, 2013 Deep inside your brain, a legion of stem cells lies ready to turn into new brain and nerve cells whenever and wherever you need them most. While they wait, they keep themselves in a state of perpetual readiness -- poised to become any type of nerve cell you might need as your cells age or get damaged.

Now, new research from scientists at the University of Michigan Medical School reveals a key way they do this: through a type of internal "spring cleaning" that both clears out garbage within the cells, and keeps them in their stem-cell state.

In a paper published online in Nature Neuroscience, the U-M team shows that a particular protein, called FIP200, governs this cleaning process in neural stem cells in mice. Without FIP200, these crucial stem cells suffer damage from their own waste products -- and their ability to turn into other types of cells diminishes.

It is the first time that this cellular self-cleaning process, called autophagy, has been shown to be important to neural stem cells.

The findings may help explain why aging brains and nervous systems are more prone to disease or permanent damage, as a slowing rate of self-cleaning autophagy hampers the body's ability to deploy stem cells to replace damaged or diseased cells. If the findings translate from mice to humans, the research could open up new avenues to prevention or treatment of neurological conditions.

In a related review article just published online in the journal Autophagy, the lead U-M scientist and colleagues from around the world discuss the growing evidence that autophagy is crucial to many types of tissue stem cells and embryonic stem cells as well as cancer stem cells.

As stem cell-based treatments continue to develop, the authors say, it will be increasingly important to understand the role of autophagy in preserving stem cells' health and ability to become different types of cells.

"The process of generating new neurons from neural stem cells, and the importance of that process, is pretty well understood, but the mechanism at the molecular level has not been clear," says Jun-Lin Guan, Ph.D., the senior author of the FIP200 paper and the organizing author of the autophagy and stem cells review article. "Here, we show that autophagy is crucial for maintenance of neural stem cells and differentiation, and show the mechanism by which it happens."

Through autophagy, he says, neural stem cells can regulate levels of reactive oxygen species -- sometimes known as free radicals -- that can build up in the low-oxygen environment of the brain regions where neural stem cells reside. Abnormally higher levels of ROS can cause neural stem cells to start differentiating.

Guan is a professor in the Molecular Medicine & Genetics division of the U-M Department of Internal Medicine, and in the Department of Cell & Developmental Biology.

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Spring cleaning in your brain's stem cells?

OncoMed Presents New Data in Six Anti-Cancer Stem Cell Programs at AACR

REDWOOD CITY, Calif.--(BUSINESS WIRE)--

OncoMed Pharmaceuticals, Inc., a clinical-stage company developing novel therapeutics that target cancer stem cells (CSCs), or tumor-initiating cells, today summarized new data highlighting the progress of OncoMeds pipeline of anti-cancer biologics presented this week in an oral presentation and five posters at the Annual Meeting of the American Association of Cancer Research in Washington, DC.

As part of the New Drugs on the Horizon Special Session, Timothy Hoey, PhD, OncoMeds Senior Vice President of Cancer Biology, gave an oral presentation titled, Development of FZD8-Fc (OMP-54F28), a Wnt signaling antagonist that inhibits tumor growth and reduces tumor initiating cell frequency. Dr. Hoey said that FZD8-Fc was shown to be a potent blocker of the Wnt pathway and have anti-tumor activity in multiple tumor types, particularly in pancreatic cancer. FZD8-Fc induced differentiation of tumor cells, reduced tumorigenicity, and promoted sensitivity to multiple chemotherapeutic agents. FZD8-Fc is currently in Phase 1 clinical testing in patients with advanced solid tumors and is part of OncoMeds collaboration with Bayer HealthCare.

Austin Gurney, PhD, Senior Vice President of Molecular and Cellular Biology at OncoMed, presented poster #218, R-Spondin (RSPO) signaling drives the growth of multiple human tumor types, in the Tumor Biology 2 Poster Session. This work indicated that specific blockade of RSPO-LGR signaling with novel anti-RSPO antibodies inhibited tumor growth in various patient derived tumors, including ovarian, lung and pancreatic cancers. RSPO blockade promoted tumor cell differentiation and reduced the frequency of tumor initiating cells. These data highlight the potential for therapeutic intervention targeting this recently characterized stem cell signaling pathway. The RSPO program is one of OncoMeds advanced research programs.

Poster #3725, Anti-DLL4 (demcizumab) Inhibits Tumor Growth and Reduces Cancer Stem Cell Frequency in Patient-Derived Ovarian Cancer Xenografts, was presented by Wan-Ching Yen, PhD, Senior Scientist at OncoMed, in the Tumor Biology 35 Poster Session. Anti-DLL4 was found to have broad activity in ovarian cancer xenografts to profoundly reduce CSC frequency in ovarian tumors. Demcizumab is currently in Phase 1b clinical testing in non-small cell lung and pancreatic cancers. OncoMed is also initiating a Phase 1b/2 clinical trial of demcizumab in combination with paclitaxel in recurrent ovarian cancer patients in collaboration with investigators at the MD Anderson Cancer Center of Houston, TX.

Poster #213, Novel NOTCH3 activating mutations identified in tumors sensitive to OMP-59R5, a monoclonal antibody targeting the Notch2 and Notch3 receptors, was presented by Breanna Wallace, PhD, Post-doctoral Research Fellow at OncoMed, in the Cancer Stem Targeting Therapies Poster Session. This research described the discovery of oncogenic Notch3 mutations in breast and colon cancer. Tumors harboring these mutations were found to be highly sensitive to OMP-59R5 (anti-Notch2/3) treatment. OMP-59R5 is a fully human IgG2 monoclonal antibody originally identified by binding to Notch2. It inhibits the signaling of both Notch2 and Notch3 receptors. OncoMed has completed a Phase 1a single agent clinical trial of this agent in solid tumor patients and has now advanced this clinical program to later stage development by initiating a Phase 1b/2 clinical trial called ALPINE of anti-Notch2/3 in combination with gemcitabine and abraxane in first-line pancreatic cancer. Anti-Notch2/3 is part of OncoMeds collaboration with GlaxoSmithKline (GSK).

Poster #3728, Anti-Notch1 antibody (OMP-52M51) impedes tumor growth and cancer stem cell frequency (CSC) in a chemo-refractory breast cancer xenograft model with an activating Notch1 mutation and screening for activated Notch1 across multiple solid tumor types, was presented by Belinda Cancilla, PhD, Associate Director of Translational Medicine at OncoMed, in the Tumor Biology 35 Poster Session. This work reported the discovery of an oncogenic Notch1 mutation in a chemorefractory breast cancer patient. Notch1 activation was detected in a range of epithelial tumor types and was particularly high in chemorefractory breast cancer patients. Anti-Notch1 is currently in two Phase 1a clinical trials in hematologic (lymphoid) malignancies and in solid tumors and is part of OncoMeds collaboration with GlaxoSmithKline (GSK).

Poster #4330, In vivo evaluation of anti-tumor activity by an anti-VEGF and anti-DLL4 bispecific antibody in a humanized skin graft model, was presented by Ann Kapoun, PhD, OncoMeds Vice President of Translational Medicine, in the Experimental and Molecular Therapeutics 28 Poster Session. This poster described the activity of OncoMeds novel bispecific antibody targeting DLL4 and VEGF. This antibody was created using OncoMeds proprietary bispecific antibody technology. This antibody has improved anti-angiogenic activity through simultaneous inhibition of VEGF and DLL4 and retains anti-CSC activity through Notch pathway inhibition mediated by the anti-DLL4 arm. The bispecific antibody is currently in late stage preclinical development and is wholly owned by OncoMed.

Paul Hastings, CEO of OncoMed commented: This is an exciting AACR meeting for OncoMed. Cutting-edge research was presented from four of our five clinical programs, as well as from two of our exciting new later-stage research programs. The data presented illustrates the comprehensive directions that OncoMed is taking to target cancer stem cells for therapeutic purpose as we strive to be on the leading edge of this new therapeutic approach in the treatment of cancer.

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OncoMed Presents New Data in Six Anti-Cancer Stem Cell Programs at AACR

New separation process advances stem cell therapies

Apr. 7, 2013 A new separation process that depends on an easily-distinguished physical difference in adhesive forces among cells could help expand production of stem cells generated through cell reprogramming. By facilitating new research, the separation process could also lead to improvements in the reprogramming technique itself and help scientists model certain disease processes.

The reprogramming technique allows a small percentage of cells -- often taken from the skin or blood -- to become human induced pluripotent stem cells (hiPSCs) capable of producing a wide range of other cell types. Using cells taken from a patient's own body, the reprogramming technique might one day enable regenerative therapies that could, for example, provide new heart cells for treating cardiovascular disorders or new neurons for treating Alzheimer's disease or Parkinson's disease.

But the cell reprogramming technique is inefficient, generating mixtures in which the cells of interest make up just a small percentage of the total volume. Separating out the pluripotent stem cells is now time-consuming and requires a level of skill that could limit use of the technique -- and hold back the potential therapies.

To address the problem, researchers at the Georgia Institute of Technology have demonstrated a tunable process that separates cells according to the degree to which they adhere to a substrate inside a tiny microfluidic device. The adhesion properties of the hiPSCs differ significantly from those of the cells with which they are mixed, allowing the potentially-therapeutic cells to be separated to as much as 99 percent purity.

The high-throughput separation process, which takes less than 10 minutes to perform, does not rely on labeling technologies such as antibodies. Because it allows separation of intact cell colonies, it avoids damaging the cells, allowing a cell survival rate greater than 80 percent. The resulting cells retain normal transcriptional profiles, differentiation potential and karyotype.

"The principle of the separation is based on the physical phenomenon of adhesion strength, which is controlled by the underlying biology," said Andrs Garca, the study's principal investigator and a professor in Georgia Tech's Woodruff School of Mechanical Engineering and the Petit Institute for Bioengineering and Bioscience. "This is a very powerful platform technology because it is easy to implement and easy to scale up."

The separation process was described April 7 in the advance online publication of the journal Nature Methods. The research was supported by the National Institutes of Health (NIH) and the National Science Foundation (NSF), supplemented by funds from the American Recovery and Reinvestment Act (ARRA).

"The scientists applied their new understanding of the adhesive properties of human pluripotent stem cells to develop a quick, efficient method for isolating these medically important cells," said Paula Flicker, of the National Institutes of Health's National Institute of General Medical Sciences, which partly funded the research. "Their work represents an innovative conversion of basic biological findings into a strategy with therapeutic potential."

An improved separation technique is essential for converting the human induced pluripotent stem cells produced by reprogramming into viable therapies, said Todd McDevitt, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and director of Georgia Tech's Stem Cell Engineering Center.

"For research purposes, depending on labeling reagents for separation is not a major problem," said McDevitt, one of the paper's co-authors. "But when we move into commercialization and manufacturing of cell therapies for humans, we need a technology approach that is unbiased and able to be scaled up."

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New separation process advances stem cell therapies

BrainStorm Partners With Dana-Farber for NurOwn(TM) Production in Phase II ALS Clinical Trial

NEW YORK, NY and PETACH TIKVAH, ISRAEL--(Marketwired - Apr 8, 2013) - BrainStorm Cell Therapeutics (OTCQB: BCLI), a leading developer of adult stem cell technologies for neurodegenerative diseases, announced today that Dana-Farber Cancer Institute ("Dana-Farber") has entered into an agreement to provide cGMP-compliant clean room facilities for production of BrainStorm's NurOwn stem cell candidate during its upcoming Phase II ALS trial in the USA. The Company's Phase II trial, to be launched in the second half of 2013 pending FDA approval, will be conducted at Massachusetts General Hospital ("MGH"), the University of Massachusetts ("UMass") Hospital and the Mayo Clinic. The Connell and O'Reilly Cell Manipulation Core Facility at Dana-Farber will produce NurOwn for the MGH and UMass Hospital clinical sites.

"We are pleased to begin this work that could be of great value to ALS patients," said Dr. Jerome Ritz, Director of the Connell and O'Reilly Cell Manipulation Core Facility at Dana-Farber and Professor of Medicine at Harvard Medical School. "This is exactly the kind of service that the facility was set up to provide. We appreciate the opportunity to work closely with BrainStorm and colleagues at MGH and UMass to advance cell therapy solutions for difficult diseases."

"Today's announcement brings us another step closer to developing a potentially effective treatment option for patients with ALS," said Alon Natanson, Chief Executive Officer of BrainStorm. "With plans in place at leading institutions like MGH, UMass, Mayo Clinic and Dana-Farber, we believe the company is well positioned to conduct our next Phase II trial at the highest clinical standards and with maximum efficiency."

Results of a Phase I/II clinical study of BrainStorm's NurOwn technology in patients with ALS were recently presented at the 65th Annual Meeting of the American Academy of Neurology. The data demonstrated a significantly slower decline in overall clinical and respiratory function, as measured by the ALS Functional Rating Score (ALSFRS-R) and Forced Vital Capacity (FVC) score respectively, in the six patients that received an intrathecal injection of the cells in the six months following treatment, as compared to the three months preceding treatment.

About NurOwnNurOwn is an autologous, adult stem cell therapy technology that differentiates bone marrow-derived mesenchymal stem cells into specialized, neuron-supporting cells. These neuron-supporting cells (known as "MSC-NTF" cells) secrete neurotrophic, or nerve-growth, factors for PROTECTION of existing motor neurons, PROMOTION of motor neuron growth, and RE-ESTABLISHMENT of nerve-muscle interaction. The ability to differentiate mesenchymal stem cells into MSC-NTF cells, and confirmation of their activity and potency before transplantation, makes NurOwn a first-of-its-kind approach for treating neurodegenerative diseases. More information about NurOwn can be found at http://brainstorm-cell.com/index.php/science-a-technology/-nurown.

About BrainStorm Cell Therapeutics, Inc.

BrainStorm Cell Therapeutics Inc. is a biotechnology company engaged in the development of first-of-its-kind adult stem cell therapies derived from autologous bone marrow cells for the treatment of neurodegenerative diseases. The Company holds the rights to develop and commercialize its NurOwn technology through an exclusive, worldwide licensing agreement with Ramot, the technology transfer company of Tel Aviv University. For more information, visit the company's website at http://www.brainstorm-cell.com.

Safe Harbor Statement - Statements in this announcement other than historical data and information constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, risks associated with BrainStorm's limited operating history, history of losses; minimal working capital, dependence on its license to Ramot's technology; ability to adequately protect the technology; dependence on key executives and on its scientific consultants; ability to obtain required regulatory approvals; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available at http://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

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BrainStorm Partners With Dana-Farber for NurOwn(TM) Production in Phase II ALS Clinical Trial

Stem Cell Treatment Heals Ailing Dogs

A couple of years ago, Brad Perry's dogs started having joint problems. Cowboy, the golden retriever, developed a severe case of arthritis, while Mr. Jones, the mutt, tore the ligaments in both of his knees during some overenthusiastic play.

"It was so sad. They wouldn't even come to the door to greet me they were in so much pain. It just broke my heart," recalled Perry, a tractor-trailer driver from Alexandria, Ky.

Perry gave the dogs all sorts of medications, but nothing worked, and he knew such medications could result in kidney and liver damage. The dogs' suffering became so great, Perry considered putting the pets down. But late last year he heard about a veterinarian in his area who performed stem cell therapy on dogs to regenerate and repair their joints and figured it was worth a try.

Cowboy underwent the procedure first. Mr. Jones followed a few months later. Perry said that within 10 days of receiving treatment the dogs were like puppies again, chasing his kids, running around in the park and swimming in the lake.

The treatment Perry's dogs received was developed by MediVet America of Lexington, Ky., one of several companies that sell equipment and training to veterinary clinics around the world. MediVet has more than a thousand clinics. Participating vets have performed more than 10,000 stem cell procedures about 7,000 of them in the past 12 months.

An operation like the one Cowboy and Mr. Jones underwent takes several hours. To start, the vet harvests a few tablespoons of fat cells from the pet's abdomen or shoulder, then spins the cells in a centrifuge to separate out the stem cells that are naturally present in fat. Next, the cells are mixed with special enzymes to "digest" any residual fat and connective tissue, and are then "activated" by mixing them with "plasma rich platelets" extracted from the animal's blood cells. The mixture is stimulated under a LED light for 20 minutes or so to further concentrate the stem cells. Finally, the newly awakened cells are injected back into the damaged joint.

Jeremy Delk, MediVet's chief executive officer, said that the therapy works because stem cells are the only cells in the body that have the ability to transform themselves into other types of specialized cells -- such as cartilage -- making them a potent tool for repairing damaged and deteriorating joints. There are 50 to 1,000 times more stem cells in the fat than bone marrow, a source that was more consistently used in animal and human -- stem cell therapy until the fat method started becoming more popular.

"As we age, humans and animals alike, our stem cells are starting to die off so we have fewer. What we are able to do with these techniques is isolate the cells in very large numbers, wake them up and put them back into the area that needs help," he explained.

While still largely unavailable to their owners, stem cell therapy from fat cells has been offered to our furry friends for several years. With fewer regulatory hoops to jump through in veterinary medicine and no contentious religious debates, experimental procedures are often tested and perfected on animals decades before they're green-lighted for use on humans.

One of the things veterinarians and owners alike praise about the procedure is it can be completed in one day, and all at the vet's office. Stem cells can also be banked for future injection so the animal does not have to endure extraction again.

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Stem Cell Treatment Heals Ailing Dogs

Arthritis Stem Cell Treatment for Dogs Leads Pack

A couple of years ago, Brad Perry's dogs started having joint problems. Cowboy, the golden retriever, developed a severe case of arthritis, while Mr. Jones, the mutt, tore the ligaments in both of his knees during some overenthusiastic play.

"It was so sad. They wouldn't even come to the door to greet me they were in so much pain. It just broke my heart," recalled Perry, a tractor-trailer driver from Alexandria, Ky.

Perry gave the dogs all sorts of medications, but nothing worked, and he knew such medications could result in kidney and liver damage. The dogs' suffering became so great, Perry considered putting the pets down. But late last year he heard about a veterinarian in his area who performed stem cell therapy on dogs to regenerate and repair their joints and figured it was worth a try.

Cowboy underwent the procedure first. Mr. Jones followed a few months later. Perry said that within 10 days of receiving treatment the dogs were like puppies again, chasing his kids, running around in the park and swimming in the lake.

The treatment Perry's dogs received was developed by MediVet America of Lexington, Ky., one of several companies that sell equipment and training to veterinary clinics around the world. MediVet has more than a thousand clinics. Participating vets have performed more than 10,000 stem cell procedures about 7,000 of them in the past 12 months.

An operation like the one Cowboy and Mr. Jones underwent takes several hours. To start, the vet harvests a few tablespoons of fat cells from the pet's abdomen or shoulder, then spins the cells in a centrifuge to separate out the stem cells that are naturally present in fat. Next, the cells are mixed with special enzymes to "digest" any residual fat and connective tissue, and are then "activated" by mixing them with "plasma rich platelets" extracted from the animal's blood cells. The mixture is stimulated under a LED light for 20 minutes or so to further concentrate the stem cells. Finally, the newly awakened cells are injected back into the damaged joint.

Jeremy Delk, MediVet's chief executive officer, said that the therapy works because stem cells are the only cells in the body that have the ability to transform themselves into other types of specialized cells -- such as cartilage -- making them a potent tool for repairing damaged and deteriorating joints. There are 50 to 1,000 times more stem cells in the fat than bone marrow, a source that was more consistently used in animal and human -- stem cell therapy until the fat method started becoming more popular.

"As we age, humans and animals alike, our stem cells are starting to die off so we have fewer. What we are able to do with these techniques is isolate the cells in very large numbers, wake them up and put them back into the area that needs help," he explained.

While still largely unavailable to their owners, stem cell therapy from fat cells has been offered to our furry friends for several years. With fewer regulatory hoops to jump through in veterinary medicine and no contentious religious debates, experimental procedures are often tested and perfected on animals decades before they're green-lighted for use on humans.

One of the things veterinarians and owners alike praise about the procedure is it can be completed in one day, and all at the vet's office. Stem cells can also be banked for future injection so the animal does not have to endure extraction again.

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Arthritis Stem Cell Treatment for Dogs Leads Pack