PharmaTelevision: Midkine Symposium 2016


Professor Takashi Muramatsu and Professor Kenji Kadomatsu  (Nagoya University Graduate School of Medicine, Nagoya, Japan) 

The history behind the discovery of Midkine   

 The discoverers of Midkine discuss the research that led to the discovery of the molecule and its particular role in neurons and cancers.   Professor Muramatsu reflects on the discovery of midkine in his laboratory 30 years ago, and its context in the setting of cell differentiation in the early days of stem cell research.  He discusses the identification of the protein as an important factor in differentiating cells, and subsequent isolation and purification the molecule followed by their discovery of its ability to promote neurite outgrowth and survival.   Professor Muramatsu highlights their creation of midkine knock-out mice as an important factor accelerating research into midkine’s roles in many biological processes and disease indications and how this has led to a high number of discoveries.  Professor Muramatsu also discusses research into structure and function of the midkine molecule and its potential impact on the future of midkine research and disease therapies.  

Professor Kadomatsu also describes the early research into midkine’s role in neuronal regeneration and growth, and the discovery of increased midkine levels in many cancer types. Professor Kadomatsu highlights his current research into axon regeneration, which does not occur readily in humans, showing that applying midkine can stimulate and enhance the process of neural regrowth.

Dr Victoria Campbell -  Intensive Care Specialist and Nephrologist (Nambour General Hospital, Queensland)

The role of midkine in kidney disease.   

Dr Campbell discusses the potential role of Midkine in the detection and treatment of acute and chronic kidney disease.   Chronic kidney disease (CKD) and acute kidney injury (AKI) can progressively develop into kidney failure requiring dialysis, transplant or resulting in death via a number of systemic complications. Closely associated with the development of CKD are lifestyle related conditions such as diabetes which are becoming an increasing health burden in the Western world.  Despite the growing problem posed by CKD there is a high unmet need as current treatments, such as controlling blood pressure and other risk factors, do not stop progressive disease.  

Dr Campbell describes midkine’s role as a biomarker for progressive disease, highlighting her recent clinical study which associates increasing midkine concentration with later stages of the disease.  Additionally, Dr Campbell discusses the exciting pre-clinical research on midkine in kidney disease and injury, highlighting the potential to translate this into the clinic aided by the use of midkine as a companion biomarker.

Professor Peter Ferdinandy – CEO, PharmaHungary and Semmelweis University, (Budapest, Hungary)

Midkine in ischaemic heart injury and cardiovascular disease. 

Professor Ferdinandy has been involved in studies showing the value of midkine protein administration in preventing ischaemic cardiac muscle injury following acute myocardial infarct. These exciting findings from Professor Ferdinandy and other groups demonstrate that delivering midkine protein into the damaged heart muscle following blockage to the coronary blood supply is very efficient in protecting cells and reducing the size of the infarct area. The mechanism of midkine’s protective properties in heart muscle include stopping cell death by necrosis and apoptosis and also by stimulating growth of new blood vessels that promote repair in damaged cardiac muscle.  Professor Ferdinandy highlights how these results can be translated into treatments for myocardial infarct in acute and sub-acute cardiovascular settings, including after restoration of blood flow by balloon angioplasty that can itself cause more prolonged injury by creating subsequent coronary blockages leading to chronic heart failure. These results with midkine protein have great potential as a new therapy for the ongoing unmet need for treating post-ischaemic heart failure.

 Professor Guillermo Velasco (Complutense University, Madrid, Spain)

The role of midkine in brain tumours  

Professor Velasco outlines his groups research into how midkine may be involved in the poor survival linked to the very aggressive brain tumour gliobastoma multiforme. He has shown that midkine promotes the survival of cancer stem cells that often remain after surgery and lead to recurrence of the tumour. One of Professor Velasco’s key goals is to test the ability of midkine therapeutic antibodies developed by Cellmid to block signalling pathways in tumour cells and disrupt their stem cell properties leading to malignant cell death. He has shown that midkine activates a number of key receptors that are critical for tumour growth and therefore inhibiting midkine and the signalling pathways downstream of these receptors may lead to new therapies for brain tumours.  In addition, he is exploring how inhibiting midkine may overcome the resistance of tumour cells to cannabinoid treatment.

 Professor Gonzalo Herradon (Universidad CEU San Pablo, Madrid, Spain)

The role of pleiotrophin in addiction.  

Drug addiction is an important health and socioeconomic issue in the western world. For example alcoholism has an economic impact on the EU of ~155 billion EURO p.a..   Professor Herradon discusses how midkine and pleiotrophin are increased in abundance in the brains of alcoholics, potentially having a role in protection from injury and neurotoxicty.    Gonzalo also focuses on the role of midkine and pleitrophin in addiction, particularly how mice with no midkine (knock out) are more prone to substance addiction, and how over-expression of midkine blocks the reward pathway of addiction.  The reward pathway is conserved in addiction to all substances making it an ideal target for treatment. Professor Herradon also discusses the value of midkine and pleiotrophin as biomarkers of addiction or addictive biological phenotypes.  Gonzalo and Dr Walton close with a discussion around PTPR zeta, one of the identified receptors for midkine and pleitrophin, and how designing small molecules to target PTPR zeta could be useful for treatment of addiction.

Professor Evangelia Papadimitriou (University of Patras, Patras, Greece)

Pleiotrophin and angiogenesis 

Professor Papadimitriou studies pleiotrophin, the other member of the midkine family, and has had a long-standing interest in its role in the process of creating new blood vessels called angiogenesis. She has made important contributions to the field with many novel findings about how pleiotrophin can control angiogenesis. These discoveries are particularly important to cancer biology as angiogenesis permits tumours to keep malignant cells supplied with blood. She describes how pleiotrophin modulates the behaviour of one of the key angiogenic pathways called VEGF that is the target of new targeted drug therapies for many tumour types. She found that pleiotrophin may be involved in the lack of response or resistance to VEGF-based drugs, highlighting the potential for blocking pleiotrophin as a new anti-cancer strategy. 

Assistant Professor Esther Gramage (University CEU San Pablo, Madrid, Spain)

Midkine in neural regeneration 

Zebra fish are a very useful biological model to study regeneration, and Dr Gramage is making use of this model to study neural regeneration after retinal injury.  In particular, Dr Gramage discusses the up-regulation of midkine expression following neural damage.  Midkine plays a key role in early neural regeneration from glial cells and differentiation into neurons, highlighted by the findings that MK gene silencing prevents neural regeneration. Esther and Dr Walton also discuss the search for the receptors involved in the regenerative process and the potential to move away from zebrafish and into mammalian models

Professor Richard Barker, Founding Director of the Centre for the Advancement of Sustainable Medical Innovation (Oxford, UK); Chairman of the UK Precision Medicine Catapult; Board member of several Biotechs (eg Celgene)

Bioscience – lost in translation? How precision medicine is closing the innovation gap. 

In this interview Professor Barker provides his insights and recommendation for how to promote the translation of medical research and innovation for advancing more drugs into the clinic and especially for patient benefit. He describes how there has been an exponential explosion in life sciences discoveries that appears to represent rapid progress, but that have actually resulted in only limited numbers of drugs reaching the clinic. He points out that out of the 2 million biomedical research papers published per year, only 40-50 new drugs are approved. To overcome this disappointing fall off rate he suggests that precision medicine is the solution for improving the translation of research discoveries to successful drugs entering widespread clinical use. In his recently published book Professor Barker identifies 7 current gaps in the process of translational medicine and advocates a number of developmental and regulatory processes to bridge this innovation gap. He sees a lot of encouragement in exciting new therapies that incorporate precision medicine with a better understanding of pathogenic mechanisms to account for the specific needs of patients at different stages of their disease journey.