ISCO Reports that Their Parthenogenetic Neural Stem Cells Improve Brain Function In Rodents with Traumatic Brain Injuries


International Stem Cell Corporation (OTCQB:ISCO) announced that the company’s proprietary ISC-hpNSC readily expandable neural stem cells improved cognitive performance and motor coordination in laboratory afflicted with traumatic brain injuries. ISC-hpNSCs consists of a highly pure population of neural stem cells derived from human parthenogenetic stem cells.

This preclinical study was conducted by scientists at the University of South Florida Morsani College of Medicine. The study examined rodents that had suffered from controlled cortical impact injury (rather well-known to be an established model of traumatic brain injury model).

The University of South Florida researchers divided their laboratory animals into four different cohorts. One group was treated with vehicle (the buffer in which the stem cells were delivered). This group of animals were the control group for this experiment. The next three groups were treated with ISC-hpNSCs, but the animals were given these cells in three different ways. Interestingly, laboratory animals that had received injections of ISC-hpNSCs showed the highest levels of improvements in cognitive performance and motor coordination when compared to those animals injected with only vehicle. Improvements in cognitive tests in animals transplanted with ISC-hpNSCs appeared only a few days after implantation.

ISCO’s new traumatic brain injury program will use the same cellular product (ISC-hpNSC) as their ongoing Parkinson’s disease program, which is presently in clinical trials. The safety data from the Parkinson’s disease trial can be used for future trials in patients with traumatic brain injuries.

Cell banks of ISC-hpNSCs were made under so-called “Good Manufacturing Practices,” which means that they are clean enough to be used in human patients. All of these stem cells have been extensively tested for sterility, purity, identity and safety. These extensive preclinical studies conducted during the development of the Parkinson’s disease program nicely demonstrate the safety of ISC-hpNSCs, even at high doses.

There is no approved treatment for traumatic brain injuries, and these injuries can cause long-term neurological disability. However, transplantation of neural stem cells may improve some of the symptoms of traumatic brain injury. Over 1.7 million people in North America suffer annually from traumatic brain injury, with associated medical costs exceeding $70 billion. According to the World Health Organization, the global incidence for traumatic brain injury is approximately 10 million people annually.

Preclinical studies in rodents and non-human primates have shown improvement in Parkinson’s disease symptoms and increase in brain dopamine levels following the intracranial administration of ISC-hpNSCs.

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Cynata’s MSC Technology Produces Significant Relief of Asthma in Preclinical Study


An Australian stem cell company called Cynata Therapeutics Limited is in the process of developing a therapeutic stem cell platform technology that they called “Cymerus.” The idea for Cymerus originated at the University of Wisconsin-Madison, but Cymerus would generate a protocol by which clinical laboratories could produce very immature mesenchymal stem cells from induced pluripotent stem cells. Such cells would be personalized for patients and their needs, and Cynata’s goal is to produce a platform that is economically feasible and relatively fast so that patients can receive infusions of the cells they so badly need in a timely fashion. These are very ambitious goals to say the least, but Cynata has been hacking away at this problem for some time, and we certainly wish them the best.

Cynata has recently released some very encouraging data in which their personalized mesenchymal stem cells were used to treat laboratory animals with a laboratory-induces form of asthma. Briefly, female mice (BALB/c mice for those who are interested) were injected with a yolk-protein called “ovalbumin.” Ovalbumin is a protein found in egg whites, and because it is an egg-specific protein, mice do not have it and their immune systems have never seen it before. Such an injection causes the mice to mount an immune response to the ovalbumin, and these mice are then administered aerosolized ovalbumin by means of a nebulizer. This causes the animals to develop a rather severe asthmatic attack against ovalbumin.

In this study, Cynata scientists and their collaborators used 48 mice that were divided into six different groups. The first group was untreated animals that did not suffer from ovalbumin asthma. The second group contained eight animals that had no asthma but were treated intravenously with one million mesenchymal stem cells. The third group also had no asthma, but were treated with an intranasal infusions of one million mesenchymal stem cells. The fourth group contain eight asthmatic animals that were untreated during the course of the experiment. The fifth group contain eight asthmatic animals that were treated intravenously with one million mesenchymal stem cells. The final group contained eight asthmatic animals that were treated with intranasal infusions of one million mesenchymal stem cells. As a note, all animals that were treated mesenchymal stem cells were treated three times. So-called airway hyperresponsiveness (AHR) is a measure of the sensitivity and irritability of the bronchial tissues. AHR is an important measure of the tendency of the lungs to undergo constriction during an asthma attack and AHR is usually measured by administering a drug that can cause bronchoconstriction. The greater the degree of bronchoconstriction in such an experiment is indicative of great AHR. The successful treatment of asthma results in reduction in AHR.

The results of this experiment were wonderfully successful. Exposing mice to the ovalbumin caused them to exhibit significantly increased AHR. However, intravenous administration of Cynata’s MSCs in asthmatic animals caused a statistically significant (60-70%) decrease in AHR compared to untreated, sensitized animals. Additionally, intranasal administration of Cynata’s MSCs completely normalized AHR. The AHR in these asthmatic mice was brought down to a level that was largely the same as the non-asthmatic mice. Also, importantly, no adverse side effects were observed during the study.

This study was conducted under the supervision of Associate Professor Chrishan Samuel and Dr. Simon Royce from the Department of Pharmacology at Monash University, Melbourne, Australia. Because the features of this model asthma system closely resemble the clinical manifestations of asthma in humans, these results provide excellent evidence that such a treatment stands a chance of working in human patients.

“We are very excited by these results, which indicate that Cymerus™ MSCs could have a profound effect in the treatment of asthma. This is a debilitating condition, which affects about 10% of the population, resulting in close to 40,000 hospitalizations and several hundred deaths each year, in Australia alone,” said Cynata Vice President of Product Development, Dr. Kilian Kelly. “Although a number of drugs are approved for the treatment of asthma, studies have shown that conventional treatments result in as few as 5% of asthma patients achieving full control of their condition. Consequently, there is a widely recognized need for novel treatments that address – and potentially eliminate – the underlying disease”, added Dr. Kelly.

“This study has clearly demonstrated that Cynata’s MSCs have a dramatic effect on AHR in our model, particularly when directly administered into the allergic lung. We look forward to continuing our analysis of the effects of these unique cells on markers of inflammation and airway remodeling, and we are optimistic of building on the very positive data we have generated so far,” said Associate Professor Samuel.

Asthma is a condition characterized by the inflammation, narrowing, and swelling of the airways, accompanied by excessive mucous production that makes it difficult to breathe. According to the Global Asthma Network, asthma affects over 330 million people globally. Cynata had partnered with Monash University to examine the potential of its Cymerus technology as an alternate treatment for asthma sufferers.

Cymerus™ makes us of induced pluripotent stem cells (iPSCs) that are then differentiated into a specific type of mesenchymal stem cell precursor known as a “mesenchymoangioblast” or MCA. Cymerus potentially provides a source of MSCs that can be made for so-called “off-the-shelf” therapeutic uses.

Lead Induces Oxidative Stress in Neural Stem Cells


Researchers from the Harvard T.H. Chan School of Public Health have elucidated the potential molecular mechanism by which lead, a pervasive environmental toxin, harms neural stem cells and neurodevelopment in children.

The results of this study by Quan Lu and his colleagues suggest that exposure to lead leads to oxidative stress, which perturbs cell behavior. However, Lu and his coworkers found that lead also seems to disrupt the function of certain proteins within neural stem cells.

This study resulted from a collaboration between the Departments of Environmental Health, Biostatistics, and Genetics and Complex Diseases and the T.H. Chan School of Public Health, and the Department of Environmental Health Sciences at Columbia University Mailman School of Public Health, and Department of Preventative Medicine, Mount Sinai School of Medicine.

Epidemiological studies that conclusively linked lead exposure to specific health problems. Lu used these valuable studies are married the epidemiological data with the molecular data from his own work. In fact, this paper by Lu and others, is one of the first to integrate genetic analysis in the lab with genomic data from participants in an epidemiological study.

Lead exposure affects the early stages of neurodevelopment, but the underlying molecular mechanisms by which lead affects early childhood development remain poorly understood.

Lu and others in his laboratory identified one key mechanism that might lead to new therapeutic approaches to treat the neurotoxicity associated with lead exposure.

Numerous studies have suggested that lead exposure can harm the cognitive, language, and psychomotor development of children. Lead exposure also increases the risk that children will later engage in antisocial and delinquent behavior.

Although regulatory limits on the use of lead have definitely reduced blood lead levels in U.S., half a million children aged 1-5 in the U.S. have lead blood levels that are twice those deemed safe by the U.S. Centers for Disease Control. Recent incidents of lead contamination in drinking water in Flint, Mich., and several U.S. cities highlight the continued threat.

Outside the U.S., environmental levels of lead remain high in many countries where lead has not, or has only recently, been phased out from gasoline, paint, and other materials.

Lu and his coworkers explored the molecular mechanisms through which exposure to lead may impact neural stem cells. Neural stem cells can differentiate into other kinds of cells in the central nervous system and play a key role in shaping the developing brain.

In this paper, scientists in Lu’s laboratory and his collaborators conducted a genome-wide screen in neural stem cells for genes whose expression is changed during lead exposure. 19 different genes were identified, and many of these 19 genes are known to be regulated by a protein called NRF2. This is a significant finding, since the NRF2 proteins is known to control the oxidative stress response in cells. This led Lu and others to hypothesize that lead exposure induces an oxidative stress response in cells. However, the Lu group and their collaborators identified a new target of NRF2; a gene designated as SPP1 (also known as osteopontin).

Others involved in this work also conducted genetic analyses on blood samples from a group of infants who were part of the Early Life Exposures in Mexico and NeuroToxicology (ELEMENT) prospective birth cohort. The ELEMENT study was designed to assess the roles of environmental and social factors in birth outcomes and in infant and child development.

Data from the ELEMENT study showed that genetic variants in SPP1 in some blood samples that were statistically linked to abnormal cognition development in those children, whose neurodevelopmental progress was followed through age two. This suggests that lead exerts its deleterious effects, in part, through SPP1. Therefore, drugs that target SPP1 might provide protection against lead exposure in at-risk children.

This paper appeared here: Peter Wagner et al., “In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Upregulated Genes and Cognitive Scores in Children,” Environmental Health Perspectives, 2016; DOI: 10.1289/EHP265.

RepliCel Injects Their Final Subject in Their Tendon Repair Clinical Trial


RepliCel Life Sciences Inc., a biotechnology company based in Irvine, California, has reported the administration of the final injection in its phase 1 safety trial of their proprietary product RCT-01 in the treatment of patients with chronic Achilles tendinopathy.

RepliCel’s RCT-01 consists of cells taken from a patient’s own hair follicles. These “non-bulbar dermal sheath” or NBDS cell are isolated from the hair follicle sheath and expanded in culture.

nbds-cells-follicle

In this clinical trial, the NBDS cells are used to treat patients with chronic tendinosis, a condition caused by acute and chronic tendon overuse. RepliCel has received Health Canada Clearance and UBC Ethics approval to conduct its Phase 1/2 clinical trial for the treatment of chronic Achilles tendinosis. The RCT-01 chronic Achilles tendinosis clinical research study will take place at the University of British Columbia in Vancouver, BC.

RepliCel’s Phase 1/2 trial will enroll 28 subjects, all of whom suffer from chronic tendinosis and have failed traditional tendon treatments, but are, otherwise, in good health.

NBDS cells will be isolated from a small punch biopsy taken from the back of the scalp, expanded in culture and then reintroduced into the wounded tendons under the guidance of ultrasound. After these injections, all subjects will return to the clinic for assessments of safety, function and pain, as well as changes in tendon thickness, echotexture, interstitial tears and neovascularity.

Since the last patient has been injected with their own NBDS cells, the last scheduled patient visit to collect treatment follow-up data will be in late November. All data from this trial will be assessed for clinical safety of NBDS cells and six-month efficacy. These data should be un-blinded and made available for analysis and dissemination near the end of this year. year-end.

This trial is designed to ascertain the signs of efficacy but it is simply not statistically powerful enough to draw any strong conclusions about efficacy.

“What we are looking for is a convincing signal, in at least some of the treated patients, that the product has clinically relevant outcomes in terms of restoration of function, reduction of pain, and/or regeneration of the tendon structure as measured by ultrasound imaging,” said RepliCel’s Rolf Hoffmann.

Data from this trial, will, however, inform and guide RepliCel’s product development and clinical trial strategy not only for Achilles tendinopathy but also for several other tendon repair applications including the treatment of jumper’s knee, golfer’s elbow, tennis elbow, and rotator cuff.

RCT-01 contains, largely, type 1 collagen-expressing fibroblasts derived from the hair follicle. These NBDS fibroblasts have the potential to address many clinical conditions that result from a deficiency of active fibroblast cells, which are required for tissue remodeling and repair.

NBDS fibroblast cells, isolated from healthy hair follicles, are a rich source of fibroblasts unique in their high-level expression of the necessary proteins, such as Type I collagen, which can jump-start the stalled healing cycle.

RepliCel is in the process of developing a series of products from this platform that have the potential to address large commercial markets in the areas of musculoskeletal and skin-related conditions.

Capricor Therapeutics Enrolls Patients in HOPE Clinical Trial


The Beverly Hills-based biotechnology company Capricor Therapeutics, Inc. (CAPR) has announced the enrollment of 25 patients for their randomized Phase 1/2 HOPE-Duchenne clinical trial.

“HOPE” stands for “Halt cardiomyOPathy progrEssion in Duchenne” Muscular Dystrophy. The HOPE trial will evaluate the company’s CAP-1002 investigational cardiac cell therapy in patients suffering from Duchenne muscular dystrophy (DMD)-associated cardiomyopathy. If all goes as planned, CAPR expects to the first data points from this trial in six months (first quarter of 2017).

DMD most seriously affects skeletal muscle, but the disease can also devastate heart muscle. In fact, the most common cause of death from DMD results from the consequences of the disease on heart muscle.

The HOPE trial will assess the safety and efficacy of CAP-1002 in these 25 patients.

In DMD patients, scar tissue gradually accumulates in the heart, which leads to a deterioration of cardiac function.

CAP-1002 consists of cells donated from the hearts of healthy volunteers. These “cardiosphere-derived cells” or CDCs, have been shown by work in the laboratory of Dr. Eduardo Marbán, Director of the Heart Institute at Cedars-Sinai Medical Center, to reduce scar tissue in damaged hearts and improve heart function in studies with laboratory animals. Furthermore, a clinical study with CDCs, the CADUCEUS study, showed that the reduction of heart scar tissue in patients given infusions of CDCs. Therefore CAD-1002 might be the only therapeutic agent that can potentially reduce scar tissue in the damaged heart.

The HOPE trial enrolled 25 boys with DMD who were at least 12 years of age at the time of screening and who show signs of DMD-associated cardiomyopathy. These boys all have significant scar tissue in at least four left ventricular segments, according to magnetic resonance imaging (MRI) scans.

Of these 25 subjects, 13 subjects were randomly assigned to receive CAP-1002 by means of intracoronary infusion into each of the three main coronary arteries in a single procedure.

The 12 subjects randomized to the control arm received usual care and received no such infusion.

Efficacy of CAD-1002 will be assessed by means of specified secondary outcome measures that include absolute and relative changes in cardiac scar tissue and cardiac function as measured by MRI, performance on the Six-Minute Walk Test (6MWT) and the Performance of the Upper Limb (PUL), and scoring on the Pediatric Quality of Life Inventory (PedsQL).

The HOPE trial is a multicenter study; it is being conducted at Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio, Cedars-Sinai Heart Institute in Los Angeles, Calif., and the University of Florida in Gainesville, Fla.

DMD is a genetically inherited condition. The dystrophin gene that is abnormal in DMD patients is on the X chromosome, and therefore, the vast majority of DMD patients are male. DMD afflicts approximately 20,000 boys and young men in the U.S. The dystrophin complex is a structural component of muscles, integral to the integrity of muscle fibers. Abnormalities in dystrophin leads to chronic skeletal and cardiac muscle damage.