Athersys’ MultiStem® Cell Therapy Provides Benefit in Neonatal Stroke Patients


In an article published in the Journal of Neuroinflammation (2015 12(1):241), Dr. Reint Jellema, in collaboration with scientists from Maastricht University, Maastricht University Medical Center and Máxima Medical Center Veldhoven in the Netherlands, and Athersys scientists described the results of experiments designed to evaluate the potential for Multipotent Adult Progenitor Cells (MAPCs) to stroke patients.

In the series of experiments described in this publication, Jellema and others examined pre-term sheep that suffered strokes while still in the womb. Such injuries in human babies are one of the main causes of cerebral palsy. In the case of these pre-term sheep, the intravenous administration of MAPCs reduced both the number and duration of seizures compared to placebo-treated animals.

Seizures commonly follow strokes in new born babies and these strokes usually cause several detrimental neurodevelopmental outcomes. MAPC treatment significantly reduced inflammation in the injured brain. The implanted cells reduced activation and proliferation of immune cells in the brain. In general the immune response after the onset of the stroke was tamped down.

This paper provides further evidence that multipotent adult progenitor cells (MAPCs) have can provide benefit following strokes. Such injuries are caused by oxygen deprivation to the brain before or during birth and are a leading cause of cerebral palsy.

“This study in a large animal model of pre-term hypoxic-ischemic injury further demonstrates the potential for MultiStem therapy to provide benefit to patients suffering from an acute neurological injury,” said Dr. Robert Mays, Vice President and Head of Neuroscience Research at Athersys. “These results are consistent with those from previous studies testing our cells in rodent models of hypoxic ischemia and ischemic stroke, and confirm our previous findings supporting the biological mechanisms through which MAPC treatment provides benefit following acute neurological injury. The results strengthen the biologic rationale for our ongoing clinical and preclinical research in ischemic stroke and hypoxic-ischemic injury, as well as traumatic brain and spinal cord injury.”

Encapsulated Human Islet Cells Halt Diabetes for 6 Months in Mice


Researchers from the Massachusetts Institute of Technology (MIT), Boston’s Children Hospital, and several other institutions have successfully used human pancreatic islet cells encased in a porous capsule to halt Type 1 diabetes in mice without causing an adverse immune response for six months. These experiments been reported in two separate scientific journals.

The first study utilized a modified alginate material to encapsulate the pancreatic islet cells. Alginate is a material that originally was derived from brown algae, and has been used to encapsulate cells without harming them or preventing them from sensing and responding to biochemical signals.

Despite all these advantages to alginate, nonspecific kept theior immune responses against it eventually result in the build up of scar tissue around alginate capsules that renders any implanted cells placed inside them ineffective.

The MIT group tested modified alginate derivatives that would not elicit this nonspecific immune response. From a library of over 800 alginate derivatives, the group came upon one particular alginate derivative called triazolethiomorpholine dioxide (TMTD).

To test TMTD capsules in diabetic mice, The MIT group teamed up with Harvard researcher Doug Melton, who supplied human pancreatic beta cells derived from human embryonic stem cells. Once the TMTD-encased beta cells were implanted into mice suffering from type 1 diabetes, the cells immediately began producing insulin in response to increases in blood glucose levels. Diabetic, laboratory mice with these islet cell TMTD-encased implants kept their blood glucose levels within a healthy range for 174 days, which was the whole length of the study.

“Encapsulation therapies have the potential to be groundbreaking for people with Type 1 Diabetes. These treatments aim to effectively establish long-term insulin independence and eliminate the daily burden of managing the disease for months, possibly years, at a time without the need for immune suppression,” said Julia Greenstein, an executive with the Juvenile Diabetes Research Foundation, who funded these two studies.

See here and here.

Cartilage Cells from Cow Knee Joints Grow New Cartilage Tissue in Laboratory


A research team from Umeå University in Sweden has used cartilage cells isolated from the knee joints of cows engineer joint-specific cartilage. Such a technique might lead to a novel stem cell-based tissue engineering treatment for osteoarthritis.

Hyaline cartilage is a specific type of cartilage found at joints where bones come together. Hyaline cartilage is a tough, pliable shock absorber, but because it is poorly supplied by blood vessels its capacity to regenerate is also poor. Knee injuries and the everyday wear-and-tear wear down cartilage tissue and might lead to a condition called osteoarthritis. In Sweden along, 26.6 percent of all people age 45 years or older were diagnosed with osteoarthritis. According to the Centers for Disease Control, in the United States, osteoarthritis affects 13.9% of adults aged 25 years and older and 33.6% (12.4 million) of those older than 65 in 2005; an estimated 26.9 million US adults in 2005 up from 21 million in 1990 (believed to be conservative estimate). Serious osteoarthritis cases can involve the loss of practically the entire cartilage tissue in the joint. Osteoarthritis causes pain and immobility in patients, but it also burdens society with accumulated medical costs.

“There is currently no good cure for osteoarthritis,” says Janne Ylärinne, doctoral student at the Department of Integrative Medical Biology. “Surgical treatments may help when the damage to the cartilage is relatively minor, whereas joint replacement surgery is the only available solution for people with larger cartilage damage. However, artificial joints only last for a couple of decades, making the surgery unsuitable for young persons. So we need a more permanent solution.”

Fortunately, tissue engineering might provide way to successfully treat osteoarthritis. Ylärinne and his colleagues developed new methods to produce cartilage-like “neotissues” in the laboratory.

Normally, tissue engineering methods that grow cartilage use cartilage-making cells, signaling molecules such a growth factors, and some sort of three-dimensional scaffold that acts as an artificial support system that makes the culture system more realistic for the cells. Unfortunately, such protocols are difficult, inexact, and generate respectable variation in what they produce. Consequently, it is also unclear whether stem cells or primary cells are best suited for cartilage tissue engineering experiments.

In these experiments, Ylärinne and others used primary cow chondrocytes (cartilage-making cells from cows) to which they successfully devised improved methods for growing cartilage tissue in a laboratory environment. The cartilage made by Ylärinne and others is similar to that normally present in the human joints.

Bovine cartilage made in laboratory

In the future, protocols like this one might help the development of neocartilage production for actual cartilage repair. If this protocol or others like it can be adapted to stem cells rather than primary cartilage cells, then perhaps these cells can be grown to provide unlimited amount of material for tissue engineering. However, despite the hopefulness of this research, more research is needed to improve the tissue quality and make it more structurally similar to the hyaline cartilage found at human joints.

VM202 is a Safe, Beneficial Treatment for Limb Ischemia


The Korean biotechnology company ViroMed Co., Ltd. has announced the publication of a Phase 2 study that evaluated their VM202 product in patients with critical limb ischemia. This study involved 52 patients in the United States and showed that VM202 is not only safe, but also produced significant clinical benefits.

VM202 is a plasmid (small circle of DNA) that encodes the human hepatic growth factor (HGF) gene. When injected into muscles, VM202 is readily taken up by nearby cells that then quickly synthesize the two isoforms of HGF. Heightened HGF concentrations can treat ischemic cardiovascular diseases by inducing the formation of new blood vessels (angiogenesis). These new collateral vessels increase blood flow and tissue perfusion in the sick tissue, which effectively treats any tissue ischemia.

VM202

Severe obstruction of the arteries that feed the extremities (hands, feet and legs) is the cause of critical limb ischemia (CLI). The term “ischemia” refers to the starvation of a tissue for oxygen. The lack of sufficient blood flow to an organ or tissue can cause severe pain and even skin ulcers, sores, or gangrene. CLI-induced pain can awaken the patient during the night, and, therefore, is called “rest pain.” Rest pains often occur in the leg and is usually temporarily relieved by dangling the leg over the bed or getting up and walking.

CLI does not improve on its own. It is a severe condition that requires immediate by a vascular surgeon or vascular specialist.

Look at the right side of these angiograms and you will see that a vessel is obstructed and blood is not flowing through it. This is an example of Critical Limb Ischemia.
Look at the right side of these angiograms and you will see that a vessel is obstructed and blood is not flowing through it. This is an example of Critical Limb Ischemia.

In this Phase 2 study, patients were divided into three groups, one of which received a placebo treatment, the second of which received a low-dose treatment VM202, and a third group that received a high-dose of VM202.

Both patient groups that received VM202 showed improvement compared to the placebo group, but patients in the higher-dose group showed significantly better ulcer healing and higher tissue oxygen levels than the placebo group. For example, 62 percent of the ulcers healed in patients treated with high-dose VM202 compared to only 11 percent of ulcers in patients who were treated with the placebo. Also, 71 percent of patients who received the high-dose VM202 showed improved oxygen concentrations in their tissues, compared to only 33 percent of patients who were treated with the placebo.

Emerson C. Perin, Director of the Stem Cell Center at the Texas Heart Institute and the principal investigator of this Phase 2 study, said: “These positive results are exciting, and VM202 shows great promise for treating patients with this debilitating disease who often have limited therapeutic options. We are looking forward to conducting a phase III trial to better understand the potential of this novel approach, especially in treating non-healing ulcers, which is a serious symptom that often leads to amputation because of the lack of medical therapies available.”

ViroMed has already been granted an IND or Investigational New Drug approval by the USFDA to initiate a Phase 3 study in diabetic patients who suffer from non-chronic ischemic foot ulcers. This study will enroll 300 subjects who will be divided into a VM202 group and a placebo group. The treatment regiment will mimic that of this smaller Phase 2 study and will only follow patients for seven months. This time, ViroMed is interested in determining if VM202 helps wound closure, which will constitute the primary efficacy endpoint on this new study.

Godspeed ViroMed!!

Killing off Senescent Cells Extends the Life and Improves the Health of Laboratory Mice


Our bodies contain a mixture of cells that grow and others whose growing days are long since over. Such cells are called “senescent cells” and there is some indication that accumulations of worn out cells that have given up the ghost can contribute to the onset of age-related diseases.

A new study from the Mayo Clinic in Rochester, Minnesota has shown that eliminating senescent cells can extend the healthy lives of lab mice. These results constitute one of the first direct demonstrations that treatments that specifically target these deadbeat cells, either by killing them off of blocking their deleterious effects, might provide a new strategy to combat age-related diseases in human patients.

Aging is a fact of life for animals. Aging bodies contain cells that have lost the ability to divide. These senescent cells build up throughout our bodies and release molecules that can potentially harm nearby tissues. Diseases of advanced age, like type 2 diabetes, kidney failure, and heart disease, have been linked to the presence of large numbers of senescent cells.

Two Mayo Clinic molecular biologists, Darren Baker and Jan van Deursen, devised an ingenious way to test the relationship of accumulations of quiescent cells with age-related diseases. They engineered laboratory mice with a construct they called “ATTAC.” This construct expresses the FK506-binding-protein–caspase 8 (FKBP–Casp8) fusion protein and green fluorescent protein (GFP) under the control of a promoter that is only active when cells are senescent. The ATTAC construct is not harmful to cells, but if ATTAC-containing cells that have become senescent are hit with a drug called AP20187, they die. Baker and van Deursen injected one-year-old mice with AP20187 twice a week starting at one year of age. They injected a control group of mice with buffer only.

The AP20187 treatments extended the median lifespan in both male and female mice. To make sure that nothing strange was going on with the genetic backgrounds of these mice, they conducted these experiments in mice strains with two distinct genetic backgrounds, but the results were the same. The engineered mice that were injected with AP20187 showed consistent clearance of quiescent cells and extended, healthier life spans.

The AP20187-injected mice showed clearance of fat cells, their kidneys functioned at a higher level, and their hearts were more resilient to stress. These same mice also showed more energetic behaviors, since they explores their cages more and they developed cancers at later ages. There was also evidence of less inflammation in the AP20187-injected mice.  These mice had their lifespans extended by 20–30%. These results were published in the journal Nature on February 3rd of 2016.

Despite the rather fancy genetics involved with this experiment, the design is somewhat easy to follow and the results have a ring of credibility to them. “We think these [quiescent] cells are bad when they accumulate. We remove them and see the consequences,” says Baker. “That’s how I try to explain it to my kids.”

In 2011, Baker and van Deusen and others investigated mice that harbor a mutation that greatly accelerates aging. This mutation mimics the human genetic disease “progeria,” which is a rare, fatal genetic condition characterized by accelerated aging in children. The name of the condition, progeria, comes from Greek and means “prematurely old.” Classic progeria is also called “Hutchinson-Gilford Progeria Syndrome,” which was named after Dr. Jonathan Hutchinson and Dr. Hastings Gilford, who first described it.

In their 2011 Nature paper, Baker and others showed that removing senescent cells in mice with an engineered type of progeria benefited those mice. Therefore, this 2016 paper is a follow-up to that 2011 study.

On the coattails of these experiments, Baker, van Deusen and others in their laboratories are beating the bushes for drugs that can directly eliminate senescent cells, or, at least, stop them from secreting the damaging factors that do so much damage to nearby tissues. In fact, van Deursen has co-founded a company that has licensed patents to develop such drugs.

According to Dominic Withers, a clinician-scientist who studies ageing at Imperial College London, the experiments and Baker, van Deusen and their colleagues, “gives you confidence that senescent cells are an important target.” Withers also said: “I think that there is every chance this will be a viable therapeutic option.”