PharmaTelevision: Midkine Symposium 2016
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.
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.
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.
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.
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
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.
Herradon (Universidad CEU San Pablo, Madrid, Spain)
The role of pleiotrophin in addiction.
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.
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,
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
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
– lost in translation? How precision medicine is closing the innovation gap.
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.