Drug Converts White Fat into Brown Fat and Induces Weight Loss


Exciting new research has determined that a variant of a drug used to treat pulmonary arterial hypertension induces weight-loss in obese mice. Among mice fed a high-fat diet, those who did not get the medication became obese while medicated mice did not.

The experimental drug used stimulates soluble guanylyl cyclase (sGC), and this drug is a member of the same class of novel drugs as the drug riociguat. The Food and Drug Administration approved riociguat in 2013 to treat high blood pressure in the lungs. Riocoguat is produced by Bayer HealthCare Pharmaceuticals, is marketed under the trade name Adempas.

In mice, the sCG stimulator stimulated a shift in fat tissue and turned stored white fat in the mice into brown fat, which burns up more energy and improves metabolic function. Beige or brown fat is a beneficial type of fat that is richly populated with mitochondria, which makes the tissue look brown under a microscope. White fat releases hormonal signals that prompt the storage of still more white fat, but brown fat burns up fat and protects against weight gain, even when caloric intake is high.

In this research, which was published in the journal Nature Communications, mice made obese by a high-fat, high-calorie diet were given the sCG stimulator. These mice not only experienced weight loss, but also showed improved glucose tolerance, reduced insulin levels and decreased the signs of fatty liver, which is a damaging consequence of established obesity. It also even shrunk white fat cells.

In plump mice on the sCG stimulator, circulating dietary fatty acids were increasingly drawn into the brown fat and burned up at high rates. Even muscle and white fat in those mice increased their use of the circulating fatty acids. These metabolic changes caused mice to burn more calories, and their abnormal metabolic function improved.

This new research was led by researchers at the University Hospital in Bonn, Germany, and it elucidated the biochemical pathway that generates brown fat. This brings potential targets into view that could shift white fat into brown fat.

The sCG stimulator used in this study, the authors concluded, “might be used to enhance weight loss induced by physical activity.”

If a drug related to riociguat is to enter broad use for obesity, however, it will need to be cheaper than its close chemical relative. At doses taken by those with pulmonary arterial hypertension, a typical month’s prescription of Adempas costs close to $2,800, or about $90,000 a year.

As a treatment for the nation’s more than 72 million obese adults, that cost could prove prohibitive, especially as obesity and its consequences are increasingly understood to be chronic conditions that will need long-term management.

McMaster Scientists Convert Blood into Neural Cells With One Gene


McMaster University stem cell scientists have discovered a way to adult sensory neurons from human patients simply by having them roll up their sleeve and provide a blood sample. The McMaster scientists directly converted adult human blood cells to both central nervous system (brain and spinal cord) neurons and peripheral nervous system (rest of the body) neurons responsible for pain, temperature and itch perception. This means that how a person’s nervous system cells react and respond to stimuli can be determined from their blood.

This breakthrough was published online recently and was also featured on the cover of the journal Cell Reports. The leader of this research, Mick Bhatia, serves as the director of the McMaster and Cancer Research Institute and holds the Canada Research Chair in Human stem Cell Biology and is a professor in the Department of Biochemistry and Biomedical Sciences in the Michael G. DeGroote School of Medicine.

Scientists do not have a robust understanding of pain and how to treat it. Neurons in the peripheral nervous system is composed of different types of nerves that detect mechanical forces like pressure or touch, and others and detect temperature, such as heat. Pain is perceived by the brain when signals are sent by peripheral pain receptors.

“The problem is that unlike blood, a skin sample or even a tissue biopsy, you can’t take a piece of a patient’s neural system. It runs like complex wiring throughout the body and portions cannot be sampled for study,” said Bhatia.

“Now we can take easy to obtain blood samples, and make the main cell types of neurological systems — the central nervous system and the peripheral nervous system — in a dish that is specialized for each patient,” said Bhatia. “Nobody has ever done this with adult blood. Ever.

“We can actually take a patient’s blood sample, as routinely performed in a doctor’s office, and with it we can produce one million sensory neurons, that make up the peripheral nerves in short order with this new approach. We can also make central nervous system cells, as the blood to neural conversion technology we developed creates neural stem cells during the process of conversion.”

This new protocol uses a gene called “Oct4” to directly reprogram blood cells. Additionally, if two proteins (SMAD and GSK-3) are inhibited with small molecules while the cells are transfected with the Oct4 gene, then the resultant cells transdifferentiate into blood-derived induced neural progenitor cells (BD-iNPCs). Now the direct conversion of skin cells called fibroblasts into neural progenitor cells that look a great like neural crest cells. However, these BD-iNPCs have the ability to differentiate into glial cells (support cells in the nervous system, multiple central nervous system neurons, and pain receptors, which are normally found in the peripheral nervous system.

image description

Using OCT-4-induced direct reprogramming, Lee et al. convert human blood to neural progenitors with both CNS and PNS developmental capacity. This fate alternation is distinct from fibroblasts that are primed for neural potential. Furthermore, human sensory neurons derived from blood phenocopy chemo-induced neuropathy in formats suitable for drug screening.

This new, revolutionary protocol that directly converts white blood cells into neurons with one gene has not only been patented, but has “broad and immediate applications,” according to Bhatia. He also added that it allows researchers to start asking questions about understanding disease and improving treatments. These cells could be used to determine why certain people feel pain instead of numbness, or whether or not the degree to which people perceive pain is genetically determines, or whether or not diabetic neuropathy ca be mimicked in a culture dish? Bhatia’s new protocol also provides a slick, new model system to find new pain drugs that don’t just numb the perception of pain, but completely block it.

“If I was a patient and I was feeling pain or experiencing neuropathy, the prized pain drug for me would target the peripheral nervous system neurons, but do nothing to the central nervous system, thus avoiding non-addictive drug side effects,” said Bhatia. “You don’t want to feel sleepy or unaware, you just want your pain to go away. But, up until now, no one’s had the ability and required technology to actually test different drugs to find something that targets the peripheral nervous system and not the central nervous system in a patient specific, or personalized manner.”

Bhatia’s team successfully tested their protocol by using fresh blood and frozen blood. This is an important piece of research since blood samples are usually taken and frozen. Freezing blood samples allows scientists or even physicians to create a kind of “time machine” that can show the evolution of a patient’s response to pain over a period of time.

For future studies, Bhatia and his colleagues would like to examine patients with Type 2 Diabetes to determine if his technique can help predict whether they will experience neuropathy by running tests in the lab using their own neural cells derived from their blood sample.

“This bench to bedside research is very exciting and will have a major impact on the management of neurological diseases, particularly neuropathic pain,” said Akbar Panju, medical director of the Michael G. DeGroote Institute for Pain Research and Care, a clinician and professor of medicine.

“This research will help us understand the response of cells to different drugs and different stimulation responses, and allow us to provide individualized or personalized medical therapy for patients suffering with neuropathic pain.”

Stem Cell-Extracted Proteins Promote Bone Regrowth


Scientists from the Gladstone Institutes have found a new technique to regrow bone by using the protein signals produced by stem cells. This new technology could potentially help treat victims who have experienced major trauma to a limb, such as soldiers wounded in combat or casualties of a natural disaster. This new protocol improves older therapies by providing a sustainable source for fresh tissue that also reduces the risk of tumor formation that can arise with stem cell transplants.

This study was published in a journal called Scientific Reports, and it is the first study that successfully extracted bone-producing growth factors from stem cells and showed that these proteins are sufficient to create new bone. This stem cell-based approach was as effective as the current standard treatment in terms of the amount of bone created.

“This proof-of-principle work establishes a novel bone formation therapy that exploits the regenerative potential of stem cells,” says senior author Todd McDevitt, PhD, a senior investigator at the Gladstone Institutes. “With this technique, we can produce new tissue that is completely stem cell-derived and that performs similarly with the gold standard in the field.”

Rather than using stem cells, the Gladstone scientists extracted the proteins that the stem cells secrete, such as a protein called bone morphogenetic protein (BMP). By extracting these proteins, they hoped to harness their regenerative power. McDevitt and his colleagues treated stem cells with a chemical that helped drove them to begin to differentiate into early bone cells. Then they analyzed the secreted factors produced by these cells that signal to other cells to regenerate new tissue. Afterwards, they took these isolated proteins and injected then into mouse muscle tissue to facilitate new bone growth.

Currently, laboratory technicians grind up old bones and extract the available proteins and growth factors that can induce the growth of new bone. Unfortunately, this approach relies on bones taken from cadavers, which are highly variable when it comes to the quality of the available tissue and how much of the necessary signals they still produce. Also, cadaver tissue is not always available.

“These limitations motivate the need for more consistent and reproducible source material for tissue regeneration,” says Dr. McDevitt, who conducted the research while he was a professor at the Georgia Institute of Technology. “As a renewable resource that is both scalable and consistent in manufacturing, pluripotent stem cells are an ideal solution.”

Marrow-Infiltrating Lymphocytes Safely Shrink Multiple Myelomas


Medical researchers at the Johns Hopkins Kimmel Cancer Center have published a report that appeared in the journal Science Translational Medicine in which they describe, for the first time, the safe use of a patient’s own immune cells to treat the white blood cell cancer multiple myeloma. There are more than 20,000 new cases of multiple myeloma and more than 10,000 deaths each year in United States. It is the second most common cancer originating in the blood.

The procedure under investigation in this study is called utilizes a specific type of tumor-targeting T cells, known as marrow-infiltrating lymphocytes (MILs). “What we learned in this small trial is that large numbers of activated MILs can selectively target and kill myeloma cells,” says Johns Hopkins immunologist Ivan Borrello, M.D., who led the clinical trial.

According to Borrello, MILs are the foot soldiers of the immune system that attack invading bacteria or viruses. Unfortunately, they are typically inactive and too few in number to have a measurable effect on cancers.

Experiments conducted is Borrello’s laboratory and in the laboratory of competing and collaborating scientists have shown that when myeloma cells are exposed to activated MILs in culture, these cells could not only selectively target the tumor cells, but they could also effectively destroy them.

To move this procedure from the laboratory into the clinic, Borrello and his collaborators enrolled 25 patients with newly diagnosed or relapsed multiple myeloma. Only 22 were able to receive this new treatment, however.

The Hopkins team extracted and purified MILs from the bone marrow of each patient and grew them in the laboratory to increase their numbers. Then they activated the MILs by exposing them to microscopic beads coated with immune activating antibodies. These antibodies bind to specific cell surface proteins on the MILs that induce profound changes in the cells. This induction step wakes the MILs up and readies them to sniff out tumor cells. These laboratory-manipulated MILs were then intravenously injected back into each patient (each of the 22 patients with their own cells). Three days before these injections of expanded MILs, all patients received high doses of chemotherapy and a stem cell transplant, which are standard treatments for multiple myeloma.

One year after receiving the MILs therapy, 13 of the 22 patients had at least a partial response to the therapy (their cancers had shrunk by at least 50 percent) Seven patients experienced at least a 90 percent reduction in tumor cell volume and lived and average of 25.1 months without cancer progression. The remaining 15 patients had an average of 11.8 progression-free months following their MIL therapy. None of the participants experienced serious side effects from the MIL therapy.

According to Borrello, several U.S. cancer centers have conducted similar experimental treatments (adoptive T cell therapy). However, only this Johns Hopkins team has used MILs. Other types of tumor-infiltrating cells can be used for such treatments, but Borrello noted that these cells are usually less plentiful in patients’ tumors and may not grow as well outside the body.

In nonblood-based tumors, such as melanoma, only about half of those patients have T cells in their tumors that can be harvested, and only about one-half of those harvested cells can be grown. “Typically, immune cells from solid tumors, called tumor-infiltrating lymphocytes, can be harvested and grown in only about 25 percent of patients who could potentially be eligible for the therapy. But in our clinical trial, we were able to harvest and grow MILs from all 22 patients,” says Kimberly Noonan, Ph.D., a research associate at the Johns Hopkins Universithttp://www.fiercevaccines.com/special-reports/gvax-pancreasy School of Medicine.

This small trial helped Noonan and her colleagues learn more about which patients may benefit from MILs therapy. As an example, they were able to determine how many of the MILs grown in the lab were specifically targeted to the patient’s tumor and whether they continued to target the tumor after being infused. They also found that patients whose bone marrow before treatment contained a high number of certain immune cells, known as central memory cells, also had better response to MILs therapy. Patients who began treatment with signs of an overactive immune response did not respond as well.

Noonan says the research team has used these data to guide two other ongoing MILs clinical trials. Those studies, she says, are trying to extend anti-tumor response and tumor specificity by combining the MILs transplant with a Johns Hopkins-developed cancer vaccine called GVAX and the myeloma drug lenalidomide, which stimulates T cell responses.

These trials also have elucidated new ways to grow the MILs. “In most of these trials, you see that the more cells you get, the better response you get in patients. Learning how to improve cell growth may therefore improve the therapy,” says Noonan.

Kimmel Cancer Center scientists are also developing MILs treatments to address solid tumors such as lung, esophageal and gastric cancers, as well as the pediatric cancers neuroblastoma and Ewing’s sarcoma.

Mesoblast Phase Degenerative Disc Disease Treatment Receives Positive Feedback from European Regulatory Agencies


Mesoblast Limited announced that European Medicines Agency has approved expansion of their Phase 3 clinical program of its product candidate MPC-06-1D for degenerative disc disease.

Mesoblast’s Phase 3 program for this product candidate is currently in the process of enrolling patients in the United States under an Investigational New Drug (IND) application filed with the US Food and Drug Administration (FDA).  Having received general agreement from EMA on the target patient population, trial size, primary composite endpoint, and comparators in the control population, Mesoblast now intends to additionally enroll patients across multiple European sites.

The discussions with EMA occurred as part of combined scientific and reimbursement advice under an EU pilot program known as Shaping European Early Dialogues (SEED). The SEED pilot program was established to facilitate early dialogue between EMA, European Health Technology Assessment reimbursement bodies, and selected companies with late-stage clinical development programs. Mesoblast’s product candidate MPC-06-ID is one of only seven medicines accepted for the SEED program.

Mesoblast and SEED representatives discussed key clinical trial aspects of the development of MPC-06-ID including the safety database, mechanisms of action, patient population and trial size, composite endpoints, and comparators. The discussions also focused on access to EU markets and pharmacoeconomic endpoints that may lead to reimbursement.

The guidance from the meeting with SEED representatives may result in a final comprehensive EU development and commercialization program that has an increased likelihood of producing data that will be acceptable for both registration and reimbursement review in multiple European countries.

Two Genes Control Breast Cancer Stem Cell Proliferation and Tumor Properties


When mothers breastfeed their babies, they depend upon a unique interaction of genes and hormones to produce milk and deliver it to their hungry little tyke. Unfortunately, this same cocktail of genes and hormones can also lead to breast cancer, especially if the mother has her first pregnancy after age 30.

A medical research group at the Medical College of Georgia at Georgia Regents University has established that a gene called DNMT1 plays a central role in the maintenance of the breast (mammary gland) stem cells that enable normal rapid growth of the breasts during pregnancy. This same gene, however, can also maintain those cancer stem cells that enable breast cancer. According to their work, the DNMT1 gene is highly expressed in the most common types of breast cancer.

Also, another gene called ISL1, which encodes a protein that puts the brakes on the growth of breast stem cells, is nearly silent in the breasts during pregnancy and in breast cancer stem cells.

Dr. Muthusamy Thangaraju, a biochemist at the Medical College of Georgia, who is the corresponding author of this study, which was published in the journal Nature Communications, said, “DNMT1 directly regulates ISL1. If the DNMT1 expression is high, this ISL1 gene is low.” Thangaraju and his team first observed the connection between DNMT1 and ISL1 when they knocked out the DNMT1 gene mice and noted an increase in the expression of ISL1. These results inspired them to examine the relationship of these two genes in human breast cancer cells.

Thangaraju and his co-workers discovered that ISL1 is silent in most human breast cancers. Furthermore, they demonstrated that restoring higher levels of ISL1 to human breast cancer cells dramatically reduced cancer stem cell populations, the growth of these cells, and their ability to spread throughout the tissue; all of which are hallmarks of cancer.

Conversely, Thangaraju and his team knocked out the DNMT1 gene in a breast-cancer mouse model, the breast will not develop as well. However, according to Thangaraju, this same deletion will also prevent the formation of about 80 percent of breast tumors. In fact, DNMT1 also down-graded super-aggressive, triple-negative breast cancers, which are negative for the estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (HER2-).

The findings from this work also point toward new therapeutic targets for breast cancer and new strategies to diagnose early breast cancer. For example, a blood test for ISL1 might provide a marker for the presence of early breast cancer. Additionally, the anti-seizure medication valproic acid is presently being used in combination with chemotherapy to treat breast cancer, and this drug increases the expression of ISL1. This might explain why valproic acid works for these patients, according to Thangaraju. Workers in Thangaraju’s laboratory are already screening other small molecules that might work as well or better than valproic acid.

Mammary stem cells maintain the breasts during puberty as well as pregnancy, which are both periods of dynamic breast cell growth. During pregnancy, breasts may generate 300 times more cells as they prepare for milk production. Unfortunately, these increased levels of cell growth might also include the production of tumor cells, and the mutations that lead to breast cancer increase in frequency with age. If the developing fetus dies before she comes to term, immature breast cells that were destined to become mature mammary gland cells can more easily become cancer, according to Rajneesh Pathania, a GRU graduate student who is the first author of this study.

DNMT1 is essential for maintaining a variety of stem cell types, such as hematopoietic stem cells, which produce all types of blood cells. However, the role of DNMT1 in the regulation of breast-specific stem cells that make mammary gland tissue and may enable breast cancer has not been studied to this point.

For reasons that unclear, there is an increased risk of breast cancer if the first pregnancy occurs after age 30 or if mothers lose their baby during pregnancy or have an abortion. Women who never have children also are at increased risk, but multiple term pregnancies further decrease the risk, according to data compiled and analyzed by the American Cancer Society.

Theories to explain these phenomena include the coupling of the hormone-induced maturation of breast cells that occurs during pregnancy with an increase in the potential to produce breast cancer stem cells. Most breast cancers thrive on estrogen and progesterone, which are both highly expressed during pregnancy and help fuel stem cell growth. During pregnancy, stem cells also divide extensively and as their population increases, DNMT1 levels also increase.

In five different types of human breast cancer, researchers found high levels of DNMT1 and ISL1 turned off. Even in a laboratory dish, when they reestablished normal expression levels of ISL1, human breast cancer cells and stem cell activity were much reduced, Thangaraju said.

Skull Suture Stem Cells Can Heal Birth Defect and Facial Injuries


A research group from the University of Southern California (USC) School of Dentistry have identified a new stem cell population that is responsible for a particular birth defect and might someday help treat wounded soldiers, accident victims and other patients recover from disfiguring facial injuries.

“This has a lot more implication than what we initially thought,” said Yang Chai, a lead researcher on the study at the Herman Ostrow School of Dentistry of USC. “We can take advantage of these stem cells not only to repair a birth defect, but to provide facial regeneration for veterans or other people who have suffered traumatic injury.”

According to Chai, treatments of human patients that utilize the new stem cell population he and his colleagues identified could become available within the next five to 10 years, but it must pass through the intense hurdles of clinical trials with human patients.

In their mouse studies, Chai and his team noticed a stem cell population that expresses the transcription factor Gli1+. These Gli1+ stem cells appear within the tissues that eventually fuse the craniofacial bones together. However, in mice that have a shortage or even absence of the Gli1+ stem cells, the skull bones prematurely fused together to cause “craniosynostosis,” a birth defect that locks the skull into a small structure can cannot accommodate the growing brain and can hinder brain development. Chai and his colleagues also found that these Gli+ stem cells are activated when the skull is injured. Therefore, they transplanted Gli1+ stem cells into injured mice, and within weeks, it was clear that the Gli1+ stem cells had migrated to the injured parts of the skull and were repairing those damaged areas.

“It is a very minimal procedure to just cut off a strip of bone instead of cutting the entire calvaria [skull-cap],” Chai said. A stem cell treatment “will truly restore the normal anatomy, which will then be able to respond to the continuous brain growth and the patient can live a normal life.”

These findings also have upset the bone development apple cart, according to Hu Zhao, the first author of this publication. “Before our findings, people just assumed the bones all around the body are the same,” Zhao said. “We are now showing that they are all totally different, that they have a different source of stem cells and a different healing mechanism.”

The discovery of these Gli1+ stem cells and their ability to regenerate craniofacial injuries might mean that physicians will be able to use them to treat people who have suffered disfiguring facial injuries and infants diagnosed with craniosynostosis through biological means instead of multiple, high-risk surgeries.

Presently, the surgeons, unknowingly, were destroying the regenerative stem cells that could potentially help the patient when they operated on craniosynostosis patients. During a typical craniosynostosis surgery, doctors break the skull into multiple pieces, staple them together and then discard the suture tissues as waste. Zhao said the procedure, intended to aid brain growth, actually interferes with healing because the Gli1+ stem cells are lost.

According to Chai, a biological approach that transplants Gli1+ stem cells into targeted areas could give infants with craniosynostosis the flexibility that they need for their brains to grow normally. For those patients who have suffered head trauma or facial disfigurement, the Gli1+ stem cells could repair fractured or injured areas.

Chai acknowledges the need to conduct additional experiments before such a treatment is tested in clinical trials with patients.

“One of our ideas is that we could probably use those healthy sutures and the healthy pieces from them and transplant them on the injured sides,” Zhao said.