Embryonic Stem Cells Offer Treatment Promise for Multiple Sclerosis

Scientists in the University of Connecticut’s Technology Incubation Program have identified a novel approach to treating multiple sclerosis (MS) using human embryonic stem cells, offering a promising new therapy for more than 2.3 million people suffering from the debilitating disease.

The researchers demonstrated that the embryonic stem cell therapy significantly reduced MS disease severity in animal models, and offered better treatment results than stem cells derived from human adult bone marrow.

The study was led by ImStem Biotechnology Inc. of Farmington, Conn., in conjunction with UConn Health Professor Joel Pachter, Assistant Professor Stephen Crocker, and Advanced Cell Technology (ACT) Inc. of Massachusetts. ImStem was founded in 2012 by UConn doctors Xiaofang Wang and Ren-He Xu, along with Yale University doctor Xinghua Pan and investor Michael Men.

“The cutting-edge work by ImStem, our first spinoff company, demonstrates the success of Connecticut’s Stem Cell and Regenerative Medicine funding program in moving stem cells from bench to bedside,” says Professor Marc Lalande, director of the UConn’s Stem Cell Institute.

The research was supported by a $1.13 million group grant from the state of Connecticut’s Stem Cell Research Program that was awarded to ImStem and Professor Pachter’s lab.

“Connecticut’s investment in stem cells, especially human embryonic stem cells, continues to position our state as a leader in biomedical research,” says Gov. Dannel P. Malloy. “This new study moves us one step closer to a stem cell-based clinical product that could improve people’s lives.”

The researchers compared eight lines of adult bone marrow stem cells to four lines of human embryonic stem cells. All of the bone marrow-related stem cells expressed high levels of a protein molecule called a cytokine that stimulates autoimmunity and can worsen the disease. All of the human embryonic stem cell-related lines expressed little of the inflammatory cytokine.

Another advantage of human embryonic stem cells is that they can be propagated indefinitely in lab cultures and provide an unlimited source of high quality mesenchymal stem cells – the kind of stem cell needed for treatment of MS, the researchers say. This ability to reliably grow high quality mesenchymal stem cells from embryonic stem cells represents an advantage over adult bone marrow stem cells, which must be obtained from a limited supply of healthy donors and are of more variable quality.

“Groundbreaking research like this furthering opportunities for technology ventures demonstrates how the University acts as an economic engine for the state and regional economy,” says Jeff Seemann, UConn’s vice president for research.

The findings also offer potential therapy for other autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and type-1 diabetes, according to Xu, a corresponding author on the study and one of the few scientists in the world to have generated new human embryonic stem cell lines.

There is no cure for MS, a chronic neuroinflammatory disease in which the body’s immune system eats away at the protective sheath called myelin that covers the nerves. Damage to myelin interferes with communication between the brain, spinal cord, and other areas of the body. Current MS treatments only offer pain relief, and slow the progression of the disease by suppressing inflammation.

“The beauty of this new type of mesenchymal stem cells is their remarkable higher efficacy in the MS model,” says Wang, chief technology officer of ImStem.

The group’s findings appear in the current online edition of Stem Cell Reports, the official journal of the International Society for Stem Cell Research. ImStem is currently seeking FDA approval necessary to make this treatment available to patients.

Newborns a hope for spinal injuries

It all started at a symposium five years ago. Catherine Gorrie, an expert in spinal cord injury, was listening to a presentation about the differences between the developing brains of children and the mature ones of adults when she had an “aah-haa” moment.

“I began to wonder if there is something in the spines of children that could be manipulated for repair,” says Dr Gorrie, a neuroscientist at the University of Technology, Sydney (UTS). It made sense. Dr Gorrie already knew that the more adaptable, or “plastic”, spinal cords of infants responded more efficiently to injury than did those of adults.

If she could tease out the factors that encouraged generic cells, so-called stem cells, in the spines of newborns to become new nerve cells, neurones, Dr Gorrie reasoned that it should be possible to mimic the process and help repair spinal cord injuries in people of all ages. That would be incredibly important because, to date, there is no cure for spinal cord injury and no proven drug treatment.

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Herpes-loaded stem cells used to kill brain tumors

Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital have a potential solution for how to more effectively kill tumor cells using cancer-killing viruses. The investigators report that trapping virus-loaded stem cells in a gel and applying them to tumors significantly improved survival in mice with glioblastoma multiforme, the most common brain tumor in human adults and also the most difficult to treat.

The work, led by Khalid Shah, MS, PhD, an HSCI Principal Faculty member, is published in the Journal of the National Cancer Institute. Shah heads the Molecular Neurotherapy and Imaging Laboratory at Massachusetts General Hospital.

Cancer-killing or oncolytic viruses have been used in numerous phase 1 and 2 clinical trials for brain tumors but with limited success. In preclinical studies, oncolytic herpes simplex viruses seemed especially promising, as they naturally infect dividing brain cells. However, the therapy hasn’t translated as well for human patients. The problem previous researchers couldn’t overcome was how to keep the herpes viruses at the tumor site long enough to work.

Shah and his team turned to mesenchymal stem cells (MSCs)—a type of stem cell that gives rise to bone marrow tissue—which have been very attractive drug delivery vehicles because they trigger a minimal immune response and can be utilized to carry oncolytic viruses. Shah and his team loaded the herpes virus into human MSCs and injected the cells into glioblastoma tumors developed in mice. Using multiple imaging markers, it was possible to watch the virus as it passed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.

“So, how do you translate this into the clinic?” asked Shah, who also is an Associate Professor at Harvard Medical School.

“We know that 70-75 percent of glioblastoma patients undergo surgery for tumor debulking, and we have previously shown that MSCs encapsulated in biocompatible gels can be used as therapeutic agents in a mouse model that mimics this debulking,” he continued. “So, we loaded MSCs with oncolytic herpes virus and encapsulated these cells in biocompatible gels and applied the gels directly onto the adjacent tissue after debulking. We then compared the efficacy of virus-loaded, encapsulated MSCs versus direct injection of the virus into the cavity of the debulked tumors.”

Using imaging proteins to watch in real time how the virus combated the cancer, Shah’s team noticed that the gel kept the stem cells alive longer, which allowed the virus to replicate and kill any residual cancer cells that were not cut out during the debulking surgery. This translated into a higher survival rate for mice that received the gel-encapsulated stem cells.

“They survived because the virus doesn’t get washed out by the cerebrospinal fluid that fills the cavity,” Shah said. “Previous studies that have injected the virus directly into the resection cavity did not follow the fate of the virus in the cavity. However, our imaging and side-by-side comparison studies showed that the naked virus rarely infects the residual tumor cells. This could give us insight into why the results from clinical trials with oncolytic viruses alone were modest.”

The study also addressed another weakness of cancer-killing viruses, which is that not all brain tumors are susceptible to the therapy. The researchers’ solution was to engineer oncolytic herpes viruses to express an additional tumor-killing agent, called TRAIL. Again, using mouse models of glioblastoma—this time created from brain tumor cells that were resistant to the herpes virus—the therapy led to increased animal survival.

“Our approach can overcome problems associated with current clinical procedures,” Shah said. “The work will have direct implications for designing clinical trials using oncolytic viruses, not only for brain tumors, but for other solid tumors.”

Further preclinical work will be needed to use the herpes-loaded stem cells for breast, lung and skin cancer tumors that metastasize to the brain. Shah predicts the approach will enter clinical trials within the next two to three years.

Stem Cells Engineered to Become Targeted Drug Factories

A group of Brigham and Women’s Hospital, and Harvard Stem Cell Institute researchers, and collaborators at MIT and Massachusetts General Hospital have found a way to use stem cells as drug delivery vehicles.

The researchers inserted modified strands of messenger RNA into connective tissue stem cells—called mesenchymal stem cells—which stimulated the cells to produce adhesive surface proteins and secrete interleukin-10, an anti-inflammatory molecule. When injected into the bloodstream of a mouse, these modified human stem cells were able to target and stick to sites of inflammation and release biological agents that successfully reduced the swelling.

“If you think of a cell as a drug factory, what we’re doing is targeting cell-based, drug factories to damaged or diseased tissues, where the cells can produce drugs at high enough levels to have a therapeutic effect,” said research leader Jeffrey Karp, PhD, a Harvard Stem Cell Institute principal faculty member and Associate Professor at the Brigham and Women’s Hospital, Harvard Medical School, and Affiliate faculty at MIT.

Karp’s proof of concept study, published in the journal Blood, is drawing early interest from biopharmaceutical companies for its potential to target biological drugs to disease sites. While ranked as the top sellers in the drug industry, biological drugs are still challenging to use, and Karp’s approach may improve their clinical application as well as improve the historically mixed, clinical trial results of mesenchymal stem cell-based treatments.

Mesenchymal stem cells have become cell therapy researchers’ tool of choice because they can evade the immune system, and thus are safe to use even if they are derived from another person. To modify the cells with messenger RNA, the researchers used the RNA delivery and cell programming technique that was previously developed in the MIT laboratory of Mehmet Fatih Yanik, PhD. This RNA technique to program cells is harmless, as it does not modify the cells’ genome, which can be a problem when DNA is used (via viruses) to manipulate gene expression.

“This opens the door to thinking of messenger RNA transfection of cell populations as next generation therapeutics in the clinic, as they get around some of the delivery challenges that have been encountered with biological agents,” said Oren Levy, PhD, co-lead author of the study and Instructor of Medicine in Karp’s lab. The study was also co-led by Weian Zhao, PhD, at University of California, Irvine who was previously a postdoctoral fellow in Karp’s lab.

One such challenge with using mesenchymal stem cells is they have a “hit-and-run” effect, since they are rapidly cleared after entering the bloodstream, typically within a few hours or days. The Harvard/MIT team demonstrated that rapid targeting of the cells to the inflamed tissue produced a therapeutic effect despite the cells being rapidly cleared. The scientists want to extend cell lifespan even further and are experimenting with how to use messenger RNA to make the stem cells produce pro-survival factors.

“We’re interested to explore the platform nature of this approach and see what potential limitations it may have or how far we can actually push it,” Zhao said. “Potentially, we can simultaneously deliver proteins that have synergistic therapeutic impacts.”

Using Fat to Fight Brain Cancer

In laboratory studies, Johns Hopkins researchers say they have found that stem cells from a patient’s own fat may have the potential to deliver new treatments directly into the brain after the surgical removal of a glioblastoma, the most common and aggressive form of brain tumor.

The investigators say so-called mesenchymal stem cells (MSCs) have an unexplained ability to seek out damaged cells, such as those involved in cancer, and may provide clinicians a new tool for accessing difficult-to-reach parts of the brain where cancer cells can hide and proliferate anew. The researchers say harvesting MSCs from fat is less invasive and less expensive than getting them from bone marrow, a more commonly studied method.

Results of the Johns Hopkins proof-of-principle study are described online in the journal PLOS ONE.

“The biggest challenge in brain cancer is the migration of cancer cells. Even when we remove the tumor, some of the cells have already slipped away and are causing damage somewhere else,” says study leader Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery, oncology and neuroscience at the Johns Hopkins University School of Medicine. “Building off our findings, we may be able to find a way to arm a patient’s own healthy cells with the treatment needed to chase down those cancer cells and destroy them. It’s truly personalized medicine.”

For their test-tube experiments, Quinones-Hinojosa and his colleagues bought human MSCs derived from both fat and bone marrow, and also isolated and grew their own stem cell lines from fat removed from two patients. Comparing the three cell lines, they discovered that all proliferated, migrated, stayed alive and kept their potential as stem cells equally well.

This was an important finding, Quinones-Hinojosa says, because it suggests that a patient’s own fat cells might work as well as any to create cancer-fighting cells. The MSCs, with their ability to home in on cancer cells, might be able to act as a delivery mechanism, bringing drugs, nanoparticles or some other treatment directly to the cells. Quinones-Hinojosa cautions that while further studies are under way, it will be years before human trials of MSC delivery systems can begin.

Ideally, he says, if MSCs work, a patient with a glioblastoma would have some adipose tissue (fat) removed — from any number of locations in the body — a short time before surgery. The MSCs in the fat would be drawn out and manipulated in the lab to carry drugs or other treatments. Then, after surgeons removed the brain tumor, they could deposit these treatment-armed cells into the brain in the hopes that they would seek out and destroy the cancer cells.

Currently, standard treatments for glioblastoma are chemotherapy, radiation and surgery, but even a combination of all three rarely leads to more than 18 months of survival after diagnosis. Glioblastoma tumor cells are particularly nimble, migrating across the entire brain and establishing new tumors. This migratory capability is thought to be a key reason for the low cure rate of this tumor type.

“Essentially these MSCs are like a ‘smart’ device that can track cancer cells,” Quinones-Hinojosa says.

Quinones-Hinojosa says it’s unclear why MSCs are attracted to glioblastoma cells, but they appear to have a natural affinity for sites of damage in the body, such as a wound. MSCs, whether derived from bone marrow or fat, have been studied in animal models to treat trauma, Parkinson’s disease, ALS and other diseases.