Cynata & The Rubik of Cell Science

As with the sun rising in the East so have the first two pioneering programs using Induced Pluripotent Stem Cell (iPSC) technology for human clinical study. Independently initiated, but now strategic brethren, the Japanese and Australian efforts to provide a next gen proof-of-concept foundation have all the makings of a new dawn in Stem Cell Science, one that many hope will deliver on unfulfilled expectations for the field.

Methods and mechanics, protocols and parameters - these are but a few of the myriad of defining characteristics that a commercial cell product needs to elucidate in the highly complex rubik of molecular innovation and translational steps. Barcodes if you will of cell product definitions underlying the very nature of scientific clarity and positioning that will pave the road moving forward and deliver safely on The N Factor of human trials with data.

To highlight movement in this direction I’ve addressed a few questions to Dr. Ross MacDonald, CEO of the Australian stem cell company Cynata Therapeutics, on recent progress with their iPSC programs and business plan for this update review piece on the previous conversation I posted last year.

Q&A:

M - Cynata is poised to begin an important sector accomplishment with a first-in-man clinical trial involving a therapeutic product derived from Allogeneic Induced Pluripotent Stem Cells (iPSCs). Can you kindly provide a brief refresh for us on the cell type/technology being used, the target indication and the clinical trial sites prep/patient application/data timelines?

R - We are using a clinical grade, human iPSC as the starting material.  The iPSC cells were obtained from Cellular Dynamics International (CDI).  From these cells we manufacture our finished product, a therapeutic mesenchymal stem cell (MSC) preparation, using our proprietary Cymerus™ manufacturing process.  The target indication is steroid-resistant acute Graft versus Host Disease (GvHD) and the Phase 1 clinical trial is entitled: “An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease”.  The trial will aim to recruit approximately 16 participants who have undergone a bone marrow transplant or similar procedure, and were subsequently diagnosed with steroid-resistant Grade II-IV acute GvHD.  The study centers are located in the United Kingdom and in Australia and we expect the study should conclude by the end of 2017. GvHD is a potentially fatal disease that often follows a bone marrow transplant procedure and occurs when the immune cells in the donor material (the graft) attack the recipient’s tissues (the host) as “foreign”. 

M - Your recent validating announcement that Cynata has signed a definitive License Option and Equity Investment Agreement with FujiFilm reiterates your strategy to develop and partner development programs with leading sector players. Could you review for us this strategy, the determining factors involved in the decision to sign a partner to your lead program at this stage and the synergy with FujiFilm’s Regenerative Medicine divisions moving forward.

R - Cynata’s Cymerus technology enables the economic manufacture of a consistent and robust therapeutic MSC product.  Given the very many potential therapeutic applications for MSCs (noting the >600 clinical trials underway using MSCs) it would not be possible for Cynata on its own to adequately exploit even a small fraction of the potential commercial opportunities.  Moreover, the Australian environment for biotech companies is challenging for those seeking to become a fully integrated, sales and marketing enterprise.  Accordingly, we believe the best path to ensure shareholders derive stellar returns is to partner our technology with those companies that have the resources, expertise, enthusiasm and global exposure to drive commercialisation of our products.  Clearly Fujifilm is a very active participant in the regenerative medicine sector and has shown a willingness to invest very heavily to maximise the chances of success.  They are an ideal partner for Cynata.  We have however left open the opportunity to work with other companies as well.

M - In your press release on the deal with FujiFilm you mentioned that the arrangement included “certain rights to other Cynata technology.” Are you at liberty to detail somewhat the nature of the technology and the rights granted.

R -  No.

M - Currently Cynata has targeted UK/Europe and Australia as its initial trial territories and has received favorable green light feedback from the respective regulators. Could you comment on the developing regulatory framework to commence these types of pioneering iPSC studies in the US and Cynata’s plans for clinical work in the US market.

R - We have already had very positive initial dialogue with the US FDA. We plan to progress these interactions this year, and we will certainly seek to include US centres in our clinical trials as we move forward. The Regenerative Advanced Therapy Designation process, which the FDA has recently introduced, is of great interest to us and potentially has numerous advantages, including accelerated approval, greater interaction with the FDA, assistance with study design, smaller trials, and ability to rely on real world evidence rather than solely data from formal clinical trials.

M - As Cynata is a leader in the development of Pluripotent derived Allogeneic iPSC treatment technology is there a perspective you could share that puts into context the application specific potential for programs that seek personalized treatment options with Autologous iPSC technologies versus Allogeneic iPSC approaches. Is there a case for both, putting aside the cost issues for a moment, with regard to targeted therapeutic potential, safety and immunogenicity?   

R - I do think there is a case for both, but as always it will come down to (i) the weight of clinical evidence and (ii) cost. Autologous iPSCs may have a greater role to play in tissue engineering applications, where the aim is directly replace or repair damaged tissue at a site of injury or disease.  With our Cymerus technology we have sought to provide a solution to the practical shortcomings associated with manufacturing an “off-the-shelf” allogeneic MSC product.  We firmly believe that our approach, ie using iPSCs, will yield a huge cost and regulatory advantage, at least insofar as MSC therapeutics are concerned.  The broader applications of iPSC-derived cell therapy products is being hotly debated and much research capital is being expended on developing the “super haplobanks” to make allogeneic products more practical. 

M - As previously reviewed, the IP surrounding your technology was invented by scientists at the University of Wisconsin and exclusively licensed to Cynata by the University’s IP management arm, WARF. You note that that these foundational patents are being expanded upon by the filing of additional Cynata patent applications related to progressive discoveries to the underlying technology. Could you provide some specifics at this stage as to the substance of the novel and unique aspects of the invention mentioned, given, I believe, these innovations are as yet unpublished.

R - Indeed we are seeking to build the IP platform with additional patents around new inventions in our Cymerus technology.  As these applications are in the early stages of prosecution we are unable to provide details at this stage.

M - In respect to your other program assets, could you highlight recent developments that pertain to Cynata’s pipeline and any news on initiated research into new indications, such as the positive impact Cymerus™ mesenchymal stem cells (MSCs) could have for Asthma suffers.

R - The data we reported late last year in the well-established chronic allergic airways disease model was certainly very exciting and accordingly we have been encouraged to further study the effects of our Cymerus MSCs in related models and potentially into the clinical setting.  We also have active programs underway in cancer (through Harvard/MGH) and in cardiovascular disease (with Westmead Hospital/University of Sydney).  With the success of our recent capital raising the company is now very well positioned to accelerate these ongoing programs as well as to consider other areas where we might be able to quickly build value.

M - Finally, at present Cynata is a publicly traded entity on the Australian securities exchange (ASX). Do you have any plans in the near term to reach out to more investors through a UK or US listing?

R - This is a question that stimulates much discussion around the boardroom tables of Australian biotech companies.  Certainly US and European investors have a very high level of understanding of the potential risks and rewards of biotech and the availability and quantum of capital is typically higher than in Australia.  However, an offshore listing is not for the faint hearted and some recent spectacular fails have made Aussie’s very circumspect. We have an open mind, but would prefer to really build a solid and supportive shareholder base in Australia first and thus have a solid foundation beneath us before we would contemplate a foreign exchange.

M - Thank you Ross for your time and all the best for the upcoming trial. Cheers

UPDATE: See latest Cynata program news at "Cynata's iMSCs" blog tab.

Creation, Ensoulment, Birth & The Ethical Use of a Donated Cell

“School of Athens” by Rafael w/ Plato and Aristotle - referred to by
Pope Francis during EU Parliamentary address Nov 25, 2014

There is a bridge between the opinions that divide us on this subject. I have written a number of times on the Middle Way, a Compromise if you will, that will heal the scar and abate the fear.

There is an ethically sound scientific process to allow for a donated Pluripotent stem cell from Human pre-embryos to be used for medicine.

The cellular process of embryogenesis has been studied at great length. The fundamental origin of Human Life is indeed the Creation of a pre-embryo – that Sperm and Egg moment and the days thereafter of cell preparation for a Mother’s acceptance. This fertilization moment and the immediate cell divisions after are central to the beginnings of Healthy Physical Life. This understanding is universally acknowledged.

The success of that biological union in the combination of DNA from both parental sexes (male & female) provides the early catalytic events that set in motion the journey to deliver a full term baby. The process is clearly not perfect by anyone’s measure and doesn’t at all guarantee stepwise progress nor a healthy outcome. There are a number of important & vital moments along the way – most importantly to all is the Mother’s acceptance of the pre-embryo into her uterus via the Implantation process around Day 8 or 9 post fertilization.

The period before Implantation is referred to as the “pre-embryo” phase, as it is clear from the scientific evidence and analysis that the cellular process of developmental Life isn't sufficiently complete to begin the formation phase of Human Life unless these early individual cells develop to the Blastocyst stage, are accepted and successfully embedded in the uterus wall of the Mother. Unless that happens a woman will pass the pre-embryo cells out of her system, as she does with the uterus walls during her monthly period cycle. Some women never accept a pre-embryo into their uterus as a result of many possible problems, including the genetic instability or malformation of the combined DNA nucleuses. Some women can only conceive with IVF assistance and pre-embryo screening help.

IVF is not the topic here so I will leave that for others to continue to debate its validity as this blog article is in reference to the pre-embryo period and the possible non-destructive removal of a single cell during this post-fertilization phase prior to Implantation.

Fertilization and the pre-embryo period is a starting cycle without which Human Life couldn't develop, yet it is still merely a starting signal for the remaining many phases that will confirm and define what it is to Be Human.

The scientific distinction is as clear as an Egg and Sperm. A pre-embryo is the union of DNA strands ready to embark on the journey to create a Human. A ball of intelligent cells pre-programmed to develop if the formation is correct, the proper signals received and the internal script processed successfully. An embryo is the resultant accepted & developing Lifeform once embedded in the Mother’s uterus. A Fetus is an established growing person with a beating heart and developing brain within the Mother’s womb. These stages of Life are clearly delineated by the process itself. Science merely exposed what Nature has already defined. The success ratio of Nature is nowhere near perfect in this process, as naturally fertilized ovums are discarded regularly and assisted conception ratios low.

What is important to note here is the difference between a pre-embryo, an embryo and an Human Fetus.

Needless to say all stages are Life and should be duly respected.

Healthy Human Life can and does develop from a pre-embryo after one cell is extracted for analysis and medically screened while the remaining pre-embryo cells continue to divide and develop. The same biological process is required for all pre-embryos to be accepted into and nurtured by the Mother’s uterus – including the one that had a cell extracted for genetic screening. Healthy babies are born every day using various cell extraction screening techniques, free of genetic issues as a result.

The confusion here is that during these past years of discovery cells were used from leftover & donated pre-embryos that were not needed any longer by couples that had fertility treatment to conceive. These pre-embryos were donated and had their cells removed in a process which terminated the pre-embryo’s development. This method of obtaining cells via donated pre-embryos for science continues. This method of cell extraction isn't necessary as a cell can be extracted from an earlier stage pre-embryo using a technique called Preimplantation Genetic Diagnosis (PGD), which is used daily by fertility clinics world-wide. It can and should be used as the method of choice to extract a Pluripotent cell from a pre-embryo in order to screen for genetic issues while also enabling the process of scientific discovery & cellular science. A Pluripotent cell is not a pre-embryo nor is it capable of developing to become a pre-embryo or embryo. The use of this PGD process can & does maintain the integrity of the pre-embryo state and it’s potential, while allowing for genetic screening & vital treatments for those that suffer from disease. One does not negate the other.

While I can appreciate the moral dilemma with respect to those that feel a pre-embryo is a Human Life, I must differ in that the science has proven that Human Life isn’t yet defined in these cells. There is Biological Life of course present and the potential to develop further into a Human but it isn’t sure whether it may or may not have the integrity to be viable nor capacity to develop further. It isn't sure either that the Mother’s system will accept the pre-embryo into her uterus and begin the developmental process of formation to become what is defined by all as being Human. This process is dependent on a number of natural system checks and balances. It has been revealed that a successful pre-embryo must first properly create a DNA construct and divide correctly to the point of being presentable to the Mother’s uterus. Incorrectly formed pre-embryos don’t, in almost all cases, pass this initial test. To say that an incorrectly formed pre-embryo that is rejected by the Mother’s system is a Human is wrong. This would by extension apply also to a pre-embryo that seems to have the right cellular makeup but still doesn't get accepted by the Mother’s uterus for other natural selection reasons. There are chemical signals within the Mother’s body that function as a viability filter and She initiates acceptance & provides the signal environment for Human organ development post Implantation. So unless a pre-embryo embeds in the uterus we cannot begin to be classified as Human as we haven’t started to emerge from that pre-embryo ball of cells and take shape. Even then the issue of the many and correctly passaged development stages of the embryo into a Fetus lies ahead.

Our Churches, Temples & Shrines aren't the sole purveyors of ethics and moral standing in our community. They certainly can help us along the path but we must all accept our own responsibility to understand and draw conclusions on the reality of our progress as a society. If Religion is anything it is a bellwether for the community and when some within the community need its guidance it has a duty to inform and guide based on the best interests of the people themselves, by disseminating knowledge and wisdom in a practical and spiritual context.

I say this as it has long been debated whether pre-embryo cells from donated IVF fertility treatments are sound ethical starting blocks for medical science. Will this still be the case when the truth is known that pre-embryos need not be destroyed and their potential maintained?

It is my opinion that to negate the progress of medical science in assisting the creation of Life is tantamount to ignoring Man in their quest for Love & Happiness. Especially if it doesn't harm the potential of further Life becoming a reality. It is also important to acknowledge that while assisting Life science has opened a door for simultaneous treatment of the sick. Life and Treatments together in one, as God intended.

Will there be criticism when medical science proves that Mother Natures’ most important cells – the potential Life forming pre-embryo cells – are used for the living that suffer and provide needed relief? Or will the misunderstood concept of the need to destroy prevail while the true facts of early Life processes, the nature of an independent cell state & its developmental knowledge be withheld from God’s people?

Pre-embryo cells can be taken without harm to the potential of Life and donated to help the living. Tissue willingly provided, as is done regularly today with blood and organs. A child can be born only when a pre-embryo is accepted by a Mother’s uterus, develops and successfully grows to term.

A day 3-4 Morula stage cell extraction does not destroy the potential to create Life. 

Later stage cell extractions at the Blastocyst Stage terminates the pre-embryo.

 

Ensoulment is by a far the greatest gift to Human Life – for without it we would be unconscious. Consciousness defines our Personhood, our Self. It is the defining characteristic that allows the physical to exist and the non-physical to be reasoned. One could say that this component of Humanity is Divine. It certainly is one of the central tenets of Religion and for which a valued guide in our community is sought.

Throughout the History of Christianity there has been an overriding concept debated within the inner halls of the Institution itself – Ensoulment and when it occurs.

More clearly than ever today is the molecular insight into the developmental phases of the origins of Human Life. This in itself requires the ethical and moral concepts of the day to be reflected upon.

Terminating a pregnancy – once it is established in the Mother’s womb – has always been an immoral act in the eyes of the Christian Church. In certain circumstances the willful termination of a developing Life was considered unavoidable if the Life of the Mother was at risk. The implications of this Human Act in the eyes of the Catholic Church was Excommunication as the punishment, in most cases. However, this was not universally true throughout history as there was a clear separation between the ethics of the immoral act of terminating a Life willfully and the punishment itself, if it was performed early in the developmental cycle post fertilization.

It seems the “Ensoulment” moment was the dividing line. A uniformly accepted believe for most of recorded history as occurring after a period of weeks post fertilization. Therefore the doctrine of a Human Life’s relationship to God, beyond the potential of a developing Lifeform, was enshrined in the Church’s teachings in this fundamental Ensoulment moment. These philosophical discussions within the Catholic Church are a documented series of changing positions dating back to the beginnings of the Christian Church.

When the issue was debated it was framed by the obvious question of at what point in the development of a Life in the Mother´s womb is that Life considered Human with a Soul and therefore one with God.

That Ensoulment moment was long considered 40 days after fertilization at a minimum for a male Fetus and 90 days at the outside for a female Fetus. The documentation dates back thousands of years to the Ancient Greek scholars & Aristotle in 350 BC. However, even at that time there were contradictory opinions that held the Soul entered at the moment of conception. The teachings of Aristotle of a later Ensoulment moment became widespread by the time of Augustine in the fifth century as the concept of stage development of a Lifeform from vegetative to animal to Human became accepted. Prevailing Christian thought became documented in the 12^th century by the preachings of Thomas Aquinas and the Council of Vienne to that of Aristotle. Yet subsequent Popes differed on the doctrine of excommunication on the basis of formed versus unformed Fetuses and the topic of Ensoulment as a consequence. Early Church theologians attempted to bridge this divide with a Casuistry compromise that allowed for non-ensouled Life to be regarded as different than that of an ensouled Human Life. Since the eighteenth century the Church has considered Human Life beginning at conception along with Ensoulment. Needless to say this debate has raged in the Church since it’s inception as an Institution.

What is apparent from a lay perspective is that the Church has adapted its own views to the popular reality of the day and considered scientific facts, as presented. The difference between then and now is fundamental in that today there is molecular science and it has revealed to all the embryonic process and the value of the cell in curing the living.

As the reality of the day becomes the norm, there is and will be assisted births, genetic treatments and cellular science derived from the earliest stage of Life (naturally conceived, programmed or reprogrammed). An altered series of biological interventions by science in the process of serving his fellow man.

This process can be done without destroying a naturally fertilized union between an Egg and Sperm. There are many ways to create that don’t destroy. There is a need to accept and understand what the difference is between the viability to create Life, the potential of cells and Human Life itself. Without bridging the divide on the issues a meaningful opportunity to engage and grow stronger together will be lost.

There is no question in my mind that there is a Duty in respecting existing and developing Human Life Implanted, Developing & Ensouled in the womb through all possible means.

Medical assistance by way of Non-Destructive cell science for the benefit of those in need is similarly a Duty and Humane.

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See: The Blastomere Foundation - related blog article 

References:

Pope Francis EU Parliamentary Address Nov 25, 2014 

Vatican hESC Declaration 2000 

Charter of the Rights of the Family

'Black Box' of Embryo Development 

Nonviable Human Embryos

Totipotency 

In the beginning: The story of the embryo 

The Morality of Embryo Use

German Supreme Court on Brüstle 

EU Court of Justice Advocate General on Parthenotes 

Timepoints in Human Development 

Human Embryonic Stem Cell Lines Generated without Embryo Destruction 

Single Blastomere Non-Destructive 3rd Party Validation(Spain)

An ethical analysis of alternative methods to obtain pluripotent stem cells without destroying embryos 

Stem Cells in Reproductive Medicine 

Biopsy of Human Morula-Stage Embryos