Potential Clinical Utility of MSCs

There has been extensive interest in the development of MSCs as therapeutic agents: as of January 2017, there were over 600 trials of MSCs listed on the US National Institutes of Health clinical trial registry,clinicaltrials.gov, involving at least 70 different medical conditions.

Unmodified MSCs:

MSCs display a number of important innate functions, including: (i) homing to sites of inflammation or injury; (ii) releasing bioactive molecules that stimulate recovery of injured cells and inhibit inflammation; and (iii) modulating the immune system.

As a result of this multifactorial mechanism of action, MSCs in their natural or unmodified state are believed to have the potential to treat a diverse range of debilitating medical conditions. In broad terms, these conditions can be categorised as (i) those in which an ability to temper an inappropriate immune response might be helpful (such as graft versus host disease (GvHD), rheumatoid arthritis and Crohn’s disease), and/or (ii) those that might benefit from MSCs’ “trophic” or regenerative function (such as cardiovascular disorders, stroke, diabetes and arthritis).

Graft versus Host Disease

This is a condition of variable clinical severity that may follow a bone marrow transplant procedure. GvHD occurs when the immune cells (white blood cells) in the donor material (the graft) attack the recipient’s tissues (the host) as “foreign”. GvHD is usually treated with steroids; however, when steroid medication fails – which happens in up to 50% of patients – the outcome is usually fatal.

Administration of allogeneic MSCs may blunt the aggressive immune response mounted by the donor cells, an observation that has led to a number of clinical trials being conducted, some with positive results.

Cynata has obtained very favourable efficacy and safety data in a preclinical study in a model of GvHD. In this study, conducted at the University of Massachusetts Amherst (UMass), USA, severe acute GvHD was induced by infusing human peripheral blood mononuclear cells (PBMCs) into mice. Animals were randomly assigned to control or treatment groups. Treated animals received either one or two doses of Cymerus™ MSCs, while control animals received only saline.

Interim data demonstrated that Cymerus™ MSC treatment substantially prolongs survival in this model. Animals in the control group had a median survival time of just 25.5 days, compared to 54-58 days in the Cymerus™ MSC-treated groups (p=0.0011). All control animals succumbed to the disease between 24 and 31 days after induction. In contrast, survival among the Cymerus™ MSC-treated animals was 31-68 days, while three animals were still alive at 58 days post induction.

The interim data were sufficiently compelling to support regulatory approval of the first Phase 1 clinical study of Cymerus™ MSCs in patients with steroid-refractory GvHD. The final report is anticipated early in 2017.

Critical limb ischemia (CLI):

Peripheral arterial disease is a condition causes impaired blood flow to the limbs, which is caused by the formation of atherosclerotic plaques in the principal arteries. This results in a chronic lack of tissue oxygenation and then ischaemia.  Critical limb ischemia (CLI) is where the arterial occlusion and resulting anoxia is severe, resulting in resting pain, non-healing ulcers and gangrene. CLI is also a major risk factor for cardiovascular events, and 25% of patients die within a year of diagnosis.

Cymerus™ MSCs have been successfully tested in a mouse model of CLI, in a study conducted by a group of independent scientists at the University of Wisconsin-Madison. A paper summarising their findings was published in the prominent peer reviewed journal Cytotherapy, The Journal of Cell Therapy – the official journal of the International Society for Cellular Therapy (ISCT).

In this study, hindlimb ischemia was created in mice by ligating the left common iliac artery and vein, and ligating and severing the femoral artery. Adductor muscles on the ischaemic leg were then injected with either Cymerus™ MSCs (n=10) or control (n=9) immediately after surgery. Cymerus™ MSCs Over a four week follow-up period, the return of blood flow to the lower limb was measured, using a laser Doppler flow technique.  As the chart below (Figure 1) shows, in animals treated with Cymerus™ MSCs, blood flow in the injured limb was significantly higher at every time point than in animals treated with saline (P<0.006). Moreover, blood flow recovery was faster in the treated animals (P<0.001).



Figure 1: Comparison of Cymerus™-MSCs and saline in blood flow recovery

This can be seen more graphically in Figure 2, in the series of images of two individual mice.  Mouse 1 on the left was treated with Cymerus™ MSCs, and as can be seen, blood flow (as depicted by a red colour) gradually returns to the injured right hind limb.  In contrast, Mouse 2 on the right was treated with saline. The affected limb remains blue (indicating low blood flow), and by day 7 the mouse eventually loses the foot. This can be better seen by the black and white photographs on the far right.


Figure 2: Laser Doppler flow comparison in Cymerus™-MSCs and saline treated mice

Histopathology assessments also found significantly less tissue damage in the treated animals, as assessed by myofiber heterogeneity, nuclear centralization, fatty degeneration and fibrosis. The authors of the paper commented “These observations indicate that the extent of improved blood flow observed is likely to be associated with a clinically meaningful benefit”.


Asthma is a chronic, long term lung condition that impacts over 330 million people globally.  It is a debilitating condition, resulting in close to 40,000 hospitalisations and several hundred deaths each year, in Australia alone. Cynata, through its partnership with Monash University, has demonstrated that Cymerus™ MSCs have significant efficacy in well-established chronic allergic airways disease model in mice. The features of this model closely resemble the clinical manifestations of asthma in humans, so these results suggest that Cymerus™ MSCs may be a potential alternate treatment for asthma sufferers.

In this study, the chronic allergic airways disease model was induced by sensitising and challenging mice with a protein called ovalbumin. The study involved a total of 48 mice, which were randomly assigned to one of the following six groups (eight animals per group):

  1. Untreated controls (no asthma)
  2. Controls (no asthma), treated with intravenous (IV) MSC injections
  3. Controls (no asthma), treated with intranasal (IN) infusion of MSCs
  4. Untreated sensitised animals (asthma)
  5. Sensitised animals (asthma), treated with IV MSC injections
  6. Sensitised animals (asthma), treated with IN infusion of MSCs

All MSC-treated animals received a dose of 1 million cells by the specified route of administration on three occasions. Airway hyper-responsiveness (AHR) in response to the bronchoconstrictor methacholine was measured by invasive plethysmography.

As expected, subjecting mice to the ovalbumin sensitisation regime caused them to exhibit significantly increased airway AHR (p<0.001 vs saline-treated control group), which is the key characteristic of asthma. Intravenous administration of Cynata’s MSCs in these animals caused a statistically significant (p<0.01) decrease in AHR (60-70%) relative to untreated sensitised animals.  Moreover, intranasal administration of Cynata’s MSCs completely normalised AHR, to a level that was no longer different to healthy animals, in which the asthma model had not been induced. No adverse safety findings were observed during the study.

Myocardial Infarction (Heart Attack):

Cardiovascular diseases are the greatest non-communicable cause of mortality worldwide. MSCs from various sources have been shown to improve cardiac function after injury and are already being tested in clinical trials. The mechanism of MSC action in this setting is believed to include reduction of fibrosis, stimulation of angiogenesis and restoration of contractile function. Delivery of MSCs in both animal models and human clinical trials has also been shown to decrease the risk of dangerous heart rhythm disorders.

Cynata is collaborating with the University of Sydney to test the potential therapeutic efficacy of Cymerus™ MSCs in animal models of myocardial infarction (heart attack) and associated heart rhythm abnormalities. These studies are being performed under the leadership of Dr James Chong, a cardiologist at Westmead Hospital and Senior Lecturer in Medicine at the University of Sydney, who is also Research Group Leader at the Westmead Millennium Institute for Medical Research. Dr Chong has extensive experience in stem cell therapy for heart disease and has had several high impact publications, including a breakthrough study that demonstrated regeneration of non-human primate hearts, which received worldwide attention after its publication in the highly prestigious journal Nature in 2014.

Idiopathic Pulmonary Fibrosis:

Lung fibrosis occurs in a range of disorders characterised by excessive deposition of extracellular matrix proteins within the lung, leading to impaired gas transfer and a loss of lung function. In the lung, fibrosis may be caused by known insults such as asbestos or radiation exposure, but it can also develop in the absence of a known stimulus, such as in idiopathic pulmonary fibrosis (IPF). To date, no treatment has been shown to be effective for IPF, and on average, patients survive for only 3-5 years after diagnosis with this extremely debilitating condition. The development of more efficient therapeutic approaches is urgently required to suppress and reverse the fibrotic response.

There is considerable interest in the therapeutic potential of MSCs for lung diseases. Many studies have provided direct evidence that MSCs can potentially be used for the treatment of lung diseases including IPF.

Cynata is collaborating with The University of Western Australia’s Centre for Cell Therapy and Regenerative Medicine (CCTRM) to conduct a study of Cymerus™ MSCs in an animal model of IPF. The study is being conducted by researchers who have a wealth of expertise in lung fibrosis and regenerative medicine, led by Professor Geoff Laurent, who is a world authority in extracellular matrix regulation and lung fibrosis. This study is intended to provide further proof-of-concept data on Cynata’s Cymerus™ MSCs.

Other Uses of Unmodified MSCs:

Unmodified MSCs also have potential uses in a wide range of other therapeutic indications. Conditions in which MSCs are currently being studied in clinical trials include:

  • Stroke
  • Osteoarthritis
  • Rheumatoid arthritis
  • Non-healing fractures
  • Degenerative disc disease
  • Diabetes
  • Age-related macular degeneration

Modified MSCs:

MSCs have a natural tendency to home to sites of inflammation and injury, including solid tumours. They can also be modified so they secrete molecules to target specific diseases. This raises the possibility that MSCs could be modified to act as vehicles that deliver drugs to where they are needed, such as the delivery of anticancer agents directly to the site of tumours.

Brain Tumours:

Cynata has entered into a collaborative agreement with Massachusetts General Hospital (MGH) in Boston, Massachusetts, USA, which is the original and largest teaching hospital of Harvard Medical School to access leading-edge cell-modification technology developed under the direction of Dr Khalid Shah. Dr Shah leads the Molecular Neurotherapy and Imaging Laboratory and is Director of the Stem Cell Therapeutics and Imaging program at MGH. He is also an Associate Professor in Radiology and Neurology at Harvard Medical School, and a principal faculty member at the Harvard Stem Cell Institute.

Dr Shah’s team have established a process to modify stem cells in the laboratory so that they secrete cancer-killing toxins. Importantly, they have also devised a process to engineer the stem cells so that they themselves resist being killed by the toxins. This could facilitate selective killing of cancer cells, without affecting normal cells, which could improve efficacy with reduced side effects, an approach that might be especially useful for inaccessible cancers, such as brain tumours.

Dr Shah has previously led studies in which stem cells modified in this way were tested in a clinically relevant animal model of glioblastoma – the most common and aggressive type of brain tumour in adult humans – which found that the treatment killed cancer cells and prolonged survival in preclinical studies. Dr Shah’s group is now investigating similar modification of Cymerus™ MSCs.

Other Uses of Modified MSCs:

Alternative approaches could also be used to modify MSCs, for example to cause the cells to secrete other drugs/bioactive molecules to target other types of cancers, or indeed other diseases. The cells could also be modified to amplify or reduce the magnitude of one or more of their innate effects. Cynata is actively pursuing additional collaborations, with a view to developing further modified Cymerus™ MSC products for a number of additional conditions.