The Coming of Age of Pluripotent Science & Musings on a Sonogram

One of the most memorable images I can recall on the effect of catalytic dynamics for me during these years of scientific curiosity was the explosive result of sperm enzyme successfully impacting a human egg - almost Big Bang like in all its microscopic potential.

One can now extend that impact phenomena analogy to the very pertinent research and translational effect Induced Pluripotent Stem Cell (iPSC) technology has had on the field of molecular biology and regenerative medicine.

Nature - Andy Potts
It’s been ten years since Shinya Yamanaka and Kazutoshi Takahashi opened the portal to a whole new way of thinking and practicing the Art of Stem Cell Science by announcing that embryonic like properties could be regained in adult cells through molecular reprogramming.

Royal Society
Much has been written about this apex moment of foundational innovation which ushered in the era of mainstream adoption of reverse engineering techniques on human cells but as we celebrate the ten year anniversary of iPSCs the opportunity presents itself to reflect and celebrate the coming age of Pluripotent science, specifically iPSCs.

Signals of Canada, a leading destination for "insiders’ perspectives on the world of regenerative medicine and stem cell research, written by scientists and professionals in the field" is hosting a "Blog Carnival" of which this article is one of a number being written covering the iPSC anniversary topic. Please click here to read what other bloggers think.

Inherently complex the various Pluripotent states and the multitude of their progressively differentiated descendants, as they relate to human biological microsystems, have only begun to be explored and understood. The inherent processes by which these interconnected derivative cells work and communicate are by and large just now being decoded and mapped. Although it’s been only ten years since the discovery of iPSCs and nearly 20 years since the human embryonic stem cells were first isolated the progress made to-date in translating Pluripotent science into real world clinical programs is very much the focus now of countless labs in the field, thanks in large part to the advent of “open source” iPSC technology. 

Prior to iPSCs the use of hESCs and the technology associated with its clinical translation was largely a specialty area limited in scope by funding, rules, regulations and IP. The advent of iPSCs changed that and with it the stem cell industry added a universal layer of potential. Whether it be using Pluripotent derived cells as tools or more notably to develop therapeutic cell candidates for clinical use those researching and developing applications using these cells are pioneering the way forward for the emerging era of next generation stem cell products.

To put not too fine a point on it, we have only scratched the surface and in the next ten years I expect there will be a number of Pluripotent treatments on the market in various countries and many many more still in the clinic moving towards approval with positive results over standard of care or filling-in where there is currently nothing to offer patients in need.

The topic of what can we expect to see on the frontline of the developing therapeutic market using Pluripotent derived cell products is often highlighted as a discussion point and rightly so given the limited public depth of awareness on the subject and the long standing promise by the sector as a potential basis for effective treatments.

Below are some of the targets and iPSC programs representative of the state of play in the field to look out for:

Riken/HealiosMasayo TakahashiiRPE++Wet/Dry AMD++Auto>Allo
     Notes: Program will address many disease states of Retina/Eye
Astellas RegMedLanza/MacLareniRNP++Dry AMD/RP++Allo
     Notes: Program will address many disease states of Retina/Eye
UWisconsin WaismanGamm/MeyeriRNP/RPEStargardt+Allo
     Notes: Representative of next gen concept using eye "organoids" 
NEI/CDI-FujiBharti/MilleriRPEDry AMDAuto
     Notes: US Govt backed program 
Cedars Sinai/CIRMShaomei WangiRNPRPAllo
     Notes: Advanced status w/ IND enabling studies 
Kyoto UnivJun TakahashiiNCPakinsonsAllo
     Notes: Leading iPSC Parkinson program due to start in 2017
Sloan KetteringLorenz StudereNC/iNCPakinsonsAllo
     Notes: Top tier US hESC/iPSC lab moving to clinic
Scripps/CIRMJeanne LoringiNCPakinsonsAuto
     Notes: Bringing it home full circle w/ CIRM onboard 
CynataSlukvin/U WisconsiniMSCGvHD++Allo
     Notes: Entering clinic later in 2016 w/ solid pre-clinical data
Astellas RegMedRobert LanzaiMSCSepsis, Lupus++Allo
     Notes: Multiple targets across board w/ pre-clinical hPSC data
     Notes: Leading Japanese program poised to enter clinic in 2017
Novosang-Roslin/SNBTS++Marc TurneriRBCThalassaemia++Allo
     Notes: Leading UK Consortia looking to clinic in 2017
Inserm/PlatODDominique BaruchiPlateletsCancer/Surgery++Allo
     Notes: Leading French program nearing clinic in 2017 
Astellas RegMedRobert LanzaiPlateletsCancer/Surgery++Allo
     Notes: Had a leading program using research grade iPSC line in 2013
Players in CAR/Immuno SpaceiBloodCellsCancer/ImmuneAuto>Allo
     Notes: Auto/Allo B, T, NK, DC+ benefits 4 immuno product requirements

*The above listing is representative of the sector and is not at all comprehensive. Apologies to the many great programs that should be there also.

hiPSC science has industry wide support globally and is a mainstream technology acceptable in jurisdictions in which other ES methods face challenges. Translational hurdles for hiPSC are specific to their reprogramming and to the adult to youthful conversion which forms the basis of the applied technology. This presents an additional safety component to the already strict regulatory oversight applied to the clinical translation of Pluripotent programs now and in the future. 

Will they be highly successful and achieve revolutionary paradigm shifting status and establish new standards of care in their go-to-market quests? 

That is a subjective question for each and every program and one which you could speculate on, yet it would be Hype to suggest definitively without established patient data. However, the indicative MOA and technology basis of those programs on the list point to a sound foundation to work from. 

In my opinion, Pluripotent science, specifically hiPSCs as a universal technology, has the very best chance to score across the board wins for the patient in areas of unmet medical needs. 


Some of the reasons I have doggedly believed that lie in the very nature of the plasticity of the sources, youthful phenotypes, cell expression and innate modulatory properties. Other reasons specifically relate to the field’s capacity to precisely derive and modify them in-vitro while perfecting their required derivative purities and expandability to consistently replicate them indefinitely in volume under strict quality control for regulated mass market applications. 

This potential, if successfully delivered together, will usher in a new Pluripotent Era in the Stem Cell Story. 


Are we at an inflection point?

Certainly the perceived slow pace of translational activities has been a media drag on the sector, irrespective of the actual comparative timelines to move from bench to bedside. In retrospect there are still only a surprisingly small number of clinical programs in trials worldwide using Pluripotent derived cells, due in large part to stricter preclinical and regulatory standards applied to safety issues associated with these cell sources. So one would say we’re definitely due some momentum building inflection points….  

Human embryonic stem cell trials were initiated in the US some 6 years ago on the basis of only research cell lines after lengthy preclinical research and safety checks. Subsequent small studies in Europe and Korea using hESCs added additional safety data. These trials paved the way for iPSCs yet still today the only enrolled clinical trial for iPSC derived therapeutics is in Japan. This pioneering trial had been on hold for over a year as the cell source analysis flagged possible genetic instability issues and was switched out from an autologous approach to a recently approved allogeneic cell line and is due to resume in 2017. The one patient to-date receiving the iPSC based iRPE cell sheet for Wet AMD has been reported to be in good condition with no apparent safety issues associated with her procedure.

The rigorous standards of the need to use an NIH approved clinical grade cell line in the US has delayed the start of US trials on iPSCs and only just recently has one been announced as available. Pre-clinical lab work one would assume would now need to be done using that line for the clinical trial programs wishing to enter the clinic sometime in the future (yrs) or approval sought and granted for proprietary lines already used for clinical prep on existing developmental programs. This safety issue, albeit necessary and prudent, has forestalled the advancement of Western work and raised the bar from where hESCs entered the clinic.

When discussing timelines and where this segment of the sector is headed it’s important to factor in these types of regulatory hurdles one must overcome on the road to a Pluripotent IND, clinical trial approval and human phased testing. Trial design considerations require stringent oversight monitoring of Pluripotent trials and have and will slow down the translational best efforts of those academic and commercial players entering the space.

Generally if it takes longer that the average drug development process to see stem cell based products enter trials and progress through the Phases and a therapeutic emerge from any stem cell specific regulatory approval pathway people will continue to be disappointed. A scaled approach to the sector’s product entry and exit criteria seems reasonable given the variance of risks associated with different stem cell products under some form of adaptive umbrella.

Safety is of the essence and the nascent SC sector requires everyone err on the side of caution. This is the mantra I hear regularly and I can’t really say it’s not appropriate to a great extent. However, it is this writer’s opinion that the priority should not be overly weighted towards the slowest approach to protect the sector at the expense of patients willing to engage in regulated, open and comprehensive phase development programs designed to enroll and prove the science. Sufficient data can only be generated from a participatory system that is adaptive and accommodating not restrictive and burdensome by design or intent.

A Quad Pregnancy demands care & attention.

Ashley Gardner Quad IVF Reaction cnn
When I recently scanned the Pluripotent sonogram I saw some Art where 4 heads appeared! Unlike our shock horror double take when 2 appeared in my wife’s scan, I was glad to see the 4 represented there, happily squished together and well. One seems to be growing bigger at the expense of a couple of the others but by and large it’s a Bridge Gang willing and able to take on the challenges when alive and kickin. I personally look forward to seeing them all born healthy and grow, in addition to their Olympic caliber Adult cousins. That would give us semi-oldies the best chance when it´s our turn to ask for help from those wise and experienced in the Jedi ways of healing. This is where Advocacy for Cures comes in. 

Hope is a powerful force and will always be there for patients in need. Unfortunately the reality is that most next generation Pluripotent cell solutions are still a few steps away, if not more, for those that suffer. High science, low science, no science - too many people continue to be excluded, lack alternatives, suffer & die from disease. Stem Cell Science offers potential solutions and requires stakeholders to rally around programs and data that deliver real world results, even marginal benefits over existing options while awaiting more advanced solutions.

To conclude I have reported on the stem cell industry, specifically the Pluripotent segment for many years, and it has been easily influenced by sentiment and competitive currents rather than sharpening its aim on achieving sector growth. What we all care about most are real solutions for the long list of conditions that continue to ail us and for those that we love. Rather than future technology leading, current programs built on the foundation of pioneering efforts in both the Adult and Pluripotent fields need to be clinically accessible and then successfully delivered widely. Supporting and driving all safe and effective stem cell solutions will propel the entire sector forward.

Safety with pace, open and inclusive. Driving patient centric solutions forward as a community, in a modernized regulatory environment, by design and for the people.

Advocacy for Cures. 



Cell Press Nucleus - "iPSCs: A Decade of Discovery" (comprehensive review issue)

Cell Stem Cell Editorial: "10 Questions: Clinical Outlook for iPSCs" Cell Stem Cell, Vol 18, Issue 2, 170-173, DOI: 10.1016/j.stem.2016.01.023 (included in review issue ref above)

Ilic, D. and Ogilvie, C. (2016), "Human Embryonic Stem Cells — What Have We Done? What Are We Doing? Where Are We Going?". Stem Cells. doi:10.1002/stem.2450

The Niche, P.Knoepfler: "Yamanaka's baby turns 10 so here's a top 10 list of IPS cell hot button bullet points"  

The Wild Card of Pluripotency - The Egg

The causality dilemma of what comes first has perplexed our conscious brains and imbued scope to our circular conversations of how. This notion of preconceived programming, intelligent yet evolving, within a time continuum of universal dimensions always brings us back to the intersection of life's origins and its elements. What is consistent in this saga of reality and human perception is that there are new beginnings where The Egg plays a central role - a protagonist of life, without which, for the moment, we wouldn't be.

This thought provoking origin story, fascinating as it is, distracts from the practical issues of the here and now where scientific investigators are just beginning to fathom the power of a woman's fertility process - be it amniotic fluid, menstrual blood, neonatal membrane, umbilical cords or The Egg itself and all the wondrous micro molecules it holds.

Regenerative medicine and those that search for the answers to our ills have long sought the primordial knowledge within the woman's body to the process of reproduction. That sacred temple from which life emerges in all its form and function. The "V" mainframe of life's blueprint in regenerative science. Call it the black box if you like but it holds the holy grail of developmental knowledge for man - the how in practical terms.

While controversial to some the use of Eggs to research and develop cellular solutions is necessary as a player in the age old two step union and potentially as an invaluable starting source for embryonic cells via a non-fertilization development pathway. This process is called Parthenogenesis and is the unique domain of International Stem Cell Corporation ("ISCO").

ISCO was formed as a continuation of scientific endeavors establishing primary cell technology and regenerative therapies for the skincare market. As early leaders in the research business they established the foundation and management reached out to pioneering Russian scientists to employ proprietary techniques in the use of Eggs for parthenogenetically derived pluripotent stem cell lines for therapeutics. The company's focus on chemically activating Eggs to stimulate cell division without fertilizing side-stepped the then burning issue of the use of embryos in science. Independence and solid support from the scientific management team has brought the technology front and center with the start of the first parthenogenetic derived stem cell trial for Parkinson's disease.

Having followed ISCO for some time I reached out the Dr. Russell Kern, ISCO's CSO, for a Q&A on their technology, the data and progress the company has made getting it's lead program into the clinic and to review where things stand overall as they move ahead with proof of concept.



1. The science of parthenogenetic pluripotency, your company’s core focus, is closely linked with SCNT and the early work on developing reprogramming technology using activated human eggs without fertilizing them. To differentiate the two technologies, parthenogenetics versus SCNT, would you briefly review for us the unique science techniques involved here?

In somatic cell nuclear transfer (SCNT), the nucleus of an oocyte is replaced by the nucleus of a somatic cell¹. Once the somatic nucleus is inserted into the oocyte, the nucleus is reprogrammed by the host egg cell and is stimulated to divide to reach a blastocyst stage. This activated egg is viable and capable of producing an adult organism with all the necessary genetic information. Human embryonic stem cells are isolated from the inner cell mass of the blastocyst for use in cell therapy or disease modeling.

Parthenogenesis consists of the chemical activation of an unfertilized oocyte. The activated oocyte starts to divide to reach a blastocyst like state and eventually becomes diploid but it is not capable of producing an adult organism. Human parthenogenetic stem cells are isolated from the inner cell mass of this blastocystlike state, they are also pluripotent and can be usedfor cell therapy and drug screening.

2. With regard to your therapeutic programs, could you outline the clinical and preclinical work you are engaged in and the rough pipeline schedule you envision moving forward?

ISCO’s Phase I study evaluating the safety and tolerability of ISChpNSCs for Parkinson’s disease is currently being conducted in Australia and we plan to move forward with a Phase II study in Australia and USA.

The company also has a traumatic brain injury (TBI) program in development which uses the same ISChpNSC cells. The program is under preclinical development and we hope to complete it and file for regulatory approval in the near future.

ISCO is also working in osteoarthritis. The osteoarthritis program is an autologous cell therapy. We will use the patient’s own adipose tissue to derive chondrocyte for cartilage repair. We will use our 3D bioprinting technology to print cartilage tissue tailored to patient’s specific needs.

3. The Parkinson’s Disease program is now enrolling patients in Australia for a first in man trial using pluripotent stem cell. This achievement has excited the patient community and raised questions from your neuroscientist colleagues in the field. Would you kindly address the pertinent issues related to those published comments² and speak to the patient community with regard to the proposed trials in development.

a. What is being transplanted, and what is the proposed mechanism of action?

The clinical trial will be transplanting human parthenogenetic stem cells (ISChpNSCs). Human parthenogenetic stem cells are pluripotent stem cells that express all the pluripotent stem cell markers and, more importantly, have the ability to differentiate into all three germ layers, including dopaminergic neurons. The therapeutic potential of parthenogenetic stem cells derived cells have been tested by ISCO and other laboratories in various animal disease models, including Parkinson’s disease (PD).

ISCO’s preclinical work indicates that the proposed mechanism of action of ISChpNSCs is neurotrophic support and cell replacement to the dying dopaminergic neurons of the recipient PD brain. The ISChpNSCs secrete neurotrophic cytokines in vitro and have been shown to significantly increase the levels of these cytokines in vivo³.

ISCO has shown that ISChpNSCs differentiate into dopaminergic (DA) neurons (TH+, FOXA2+, GIRK2+, and DAT+) that secrete dopamine and fire spontaneous action potentials³.

Additionally, in a recent publication from Roger Barker’s lab titled “PAX6 expression may be protective against dopaminergic cell loss in Parkinson’s disease” they found that the transcription factor, PAX6 is expressed in midbrain dopaminergic neurons and concluded that it may be protective against dopaminergic cell loss in Parkinson’s disease.

We have shown that ISChpNSCs also differentiate in situ into DA neurons in two different PD animal models, 6O HDA lesioned rats and MPTP lesioned African green monkeys.  The percentage of ISChpNSCs differentiating into DA neurons in vivo is around 1 to 2% of the engrafted cells, which is enough to have a significant increase in the total number of DA neurons in the substantia nigra and fiber innervation in the striatum.

b. What are the preclinical safety and efficacy data supporting the use of the proposed stem cell product?

ISCO has published and presented its preclinical data at multiple international scientific conferences including International Society for Stem Cell Research, American Academy of Neurology, American Neurological Association, Society for Neuroscience, International Society for Cell Therapy, International Society for Neural Therapy and Repair, and the American Society of Gene and Cell Therapy.

In addition to the 10 rats and the 2 monkey study mentioned in the commentary, we have completed a long term 12 month transplantation study of hpNSCs in 20 MPTP lesioned African green monkeys with moderate to severe clinical Parkinsonian symptoms. The ISChpNSCs were manufactured under current good manufacturing practice (cGMP) conditions and were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of ISChpNSC was found to be safe and well tolerated by the animals. We observed higher behavioral recovery, dopamine levels, innervation and number of dopaminergic neurons than in vehicle control animals.

c. Can arguments concerning ethics, risk mitigation, or trial logistics outweigh concerns regarding the expected efficacy of the cell and constitute a primary justification for choosing one cell type over another in a clinical trial?

The assumption that the study received approval based on ethical considerations is incorrect.

The ISChpNSC line has undergone stringent quality control measures and has received FDA approval to be used for IND submission in clinical trials. 

The Australian Therapeutics Goods Administration (TGA), which is FDA’s Australian counterpart and the Human Research Ethics Committee (HREC) have reviewed ISCO’s extensive preclinical data and decided to grant approval for its treatment of Parkinson’s disease. The ISChpNSCs are a more practical source of cells than obtaining fetal cells from aborted human fetal brains. ISCO can manufacture an unlimited supply of homogenous populations of ISChpNSCs under cGMP conditions and preclinical studies indicate that they are safe and promote behavioral and biochemical functional improvements in a nonhuman primate Parkinson’s disease model.

d. What is being claimed regarding the potential therapeutic value of the stem cellbased therapy – better control of symptoms or a cure?

ISCO claims that preclinical studies have shown improvement in PD symptoms and increase in brain dopamine levels following the intracranial administration of ISChpNSC.

e. What is the regulatory oversight of the trial and is it guided by input from experts in the field?

The Australian regulatory agency, TGA, is in possession of the criteria and expertise for evaluating preclinical studies and clinical investigators and members of ethics committees are properly disposed to evaluate complex scientific data and thereby weigh risk against potential benefit on behalf of PD patients.

It is worth noting that ISCO’s trial is fully funded by the company with no economic involvement from patients. ISCO’s trial has a five year follow up with a number of safety and efficacy measures, including Fdopa positron emission tomography (PET) scans.

4. In regard to the cell type being used in your PD trial are there any specific inherent advantages or disadvantages in using parthenogenetic derived cells as opposed to other cell types for Parkinson’s Disease?

The derivation of human parthenogenetic stem cells (hpSCs) does not involve the destruction of a human embryo, so they are free of the ethical concerns associated with hESCs. They can be produced in abundant quantities which will be important in treating patients. The hpSCs can be derived homozygous at the HLA loci from both heterozygous and homozygous donors. HLA homozygous lines have the potential to immune match millions of patients in cell based therapy applications if the HLA type is common. For that reason, they are a promising choice for regenerative medicine applications.

Additionally, a recent study comparing the frequencies of coding mutations in human pluripotent stem cells has also found that hpSCs have lower number of de novo coding mutations than iPSCs and NTESCs.

5. In a recent news release there was mention of additional cell types in development, one of which was neurons specifically for the Parkinson’s program, can you elaborate on that?

ISCO is using human parthenogenetic derived neural stem cells (ISChpNSC) for its Parkinson’s and Stroke programs but not neurons.

6. Why is ISCO not part of the consortium called GForce PD, joining the collaborative effort to share development data on Parkinson’s therapeutic research?

GForce PD is formed by nonprofit academic institutions. ISCO, being a for profit biotechnology company, cannot be as open to share research and development data for intellectual property reasons. We try to the best of our ability to share our data with the appropriate forums to the extent that we can without compromising our work. For example, we frequently present preclinical data at multiple international scientific conferences including International Society for Stem Cell Research, American Academy of Neurology, American Neurological Association, Society for Neuroscience, International Society for Cell Therapy, International Society for Neural Therapy and Repair, and the American Society of Gene and Cell Therapy among others.

7. Being a California company have you applied for CIRM support funding for your programs? If so was there a reason CIRM did not approve support funding given the potential? 

We were not able to apply for CIRM funding for our clinical trial in the Australia because CIRM funding can only be used to conduct clinical trials in California.

8. Is there an update you can share on the enrollment in Australia for the PD trial? Have you completed enrollment as anticipated? Has Foley started treatment procedures and when do they expect to complete the cohorts? 

Enrollment has started and dosing is anticipated to be completed in 2016.

9. You have indicated that the FDA has approved your parthenogenetic cell line for clinical use in the USA. Can you provide an overview of those discussions and the approval process in light of the questions regarding cell line safety data and US trial plans? 

The ISChpNSC line has undergone extensive testing and stringent quality control measures and has received permission from the FDA for use in clinical trials under the Investigative New Drug (IND) application procedure. Critical to the approval for clinical use was the data package provided to the FDA in which ISCO summarized the methods, standards and results of the testing performed on the cell line. The data package was developed as a result of the company’s discussions with the FDA to clarify the safety and acceptability of the proposed cell line for therapeutic use in clinical trials for Parkinson’s disease.

10. You’ve highlighted the creation of a parthenogenetic stem cell bank as one of the keys to unlocking the potential to better match patients to your derived treatments, as is the case also with other pluripotent stem cell sources. Can you review the topic and progress made to establish the UniStemCell bank?

UniStemCell bank is the life science industry’s first collection of histocompatible parthenogenetic stem cells available for research and commercial use. ISCO uses its proprietary technique of parthenogenesis to create histocompatible stem cells. These cells have a duplicate set of human leukocyte antigen (HLA) genes which significantly reduces the possibility that they will be rejected by an individual’s immune system, making a single cell line suitable for treating millions of individuals. An additional benefit is that a relatively small number of such cell lines could be sufficient to provide “immune matched” cells to a large percentage of the world’s population.

When used for cell based therapies, stem cells face the same HLA matching issues that limit solid organ allogeneic transplants and lead to immune rejection. The risk of rejection is proportional to the degree of disparity between donor and recipient cell surface antigen presenting proteins. ISCO is continuing the development of the UniStemCell bank.

11. Recently haploid stem cells were isolated using parthenogenetic techniques. Can you comment on this development and its impact on your science and intellectual property position?

In the recent paper published in Nature, Sagi and colleagues isolated and maintained for the first time human pluripotent stem cell lines with a normal haploid karyotype. They found that some human parthenogenetic stem cell lines have a small percentage of haploid cells in culture and they were able to isolate these cells and expand them in culture to obtain a population of haploid pluripotent stem cells. These haploid stem cells are useful for studying human functional genomics and development but they are unlikely to be used for cell therapy applications because they spontaneously become diploid, at a rate of 3–9% cells per day, and require constant sorting to maintain a population of haploid cells.

12. Human eggs are required for the creation of parthenogenetic stem cell lines which in some circles raised a red flag on the ethics of use and the safety of women undergoing the now standard IVF fertility treatment stimulation procedure. Can you address this issue, the scope of donations required to establish a working stem cell bank and the need for egg donors moving forward given possible reprogramming technology advances.

Donation of oocytes to ISCO occurs under informed consent (IC), and with the approval and oversight of an institutional review board (IRB), both of which provide assurance that the donor is fully aware of the IVF procedures, risks, purpose, potential benefits and voluntary nature of the donation. Since the donation involves eggs left over from IVF, the donor is at no higher risk for participating than she would otherwise experience from the procedure itself.

A single parthenogenetic stem cell line can be expanded to generate large numbers of cells in the form of Master and Working Cell Banks (MCB and WCB) which are cryopreserved to maintain a viable repository over an extended period of time. The ability to amplify and preserve large populations of clonally derived cells in this manner is advantageous for maintaining consistency of the clinical product, as well as for minimizing the need for a continuous source of donated oocytes. Oocytes do not fall into the controversial category of embryos and hence the ethical concerns associated with the use of embryonic stem cells do not apply to parthenogenetic stem cells.

13. Lastly I’d like to address the issue of the uplist from the OTC and finances. In your recent prospectus it was stated that you will look to uplist to Nasdaq – is that still the case and if so when will that occur? Also, of late you have been largely self funded through Dr. Andrey Semechkin, CEO and Co-Chairman of the company. Could you speak to the issue of choosing to back the company with insider funding support, business development plans for program partnerships and the longer term strategy given the requirements of your core business to bring therapeutic stem cell treatments to market?

Our focus right now is to do great work with our clinical trial in Australia as well as advance our other development programs in the pipeline. We believe that the way the company is structured now makes a lot of good business sense and we don’t have any plans to change things any time soon. Our management is fully committed to see our different programs to fruition and is fully confident in our technology and therefore decided to further invest in the company.

We believe we are well funded to get a few of our programs to the next milestone. At different times of development, the company has had discussions with potential partners and we may very well decide to partner with another company as we prepare to bring products to market. However, currently we are focused on moving our development programs forward.


1. Tachibana, M. , et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 12281238 (2013).

2. Barker, R.A. , et al. Are Stem CellBased Therapies for Parkinson's Disease Ready for the Clinic in 2016? Journal of Parkinson's disease 6, 5763 (2016).

3. Gonzalez, R. , et al. Deriving dopaminergic neurons for clinical use. A practical approach. Scientific Reports 3, 15 (2013).

4. Thomas, M.G. , et al. PAX6 expression may be protective against dopaminergic cell loss in Parkinson's disease. CNS & neurological disorders drug targets 15, 7379 (2016).

5. Gonzalez, R. , et al. Proof of concept studies exploring the safety and functional activity of human parthenogeneticderived neural stem cells for the treatment of Parkinson's disease. Cell transplantation 24, 681690 (2015).

6. Johannesson, B. , et al. Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors. Cell stem cell 15, 634642 (2014).

7. Sagi, I. , et al. Derivation and differentiation of haploid human embryonic stem cells. Nature (2016).

Balancing Paradigms with Mesenchymal Stromal Cells

Steve Gschmeissner/Science Photo Library
Innovation isn't uniquely devoid of commonality of adoption by discipline. Rather the likelihood of acceptance generally tracks evenly to historical norms in parallel with society's openness to progress and the search for solutions. However, the impact of technological change is variable and dependent on societal factors related to income and health. One could argue the greatest benefit comes when change drives both economic prosperity and improved health standards.   

While the average pace of technological innovation slowed some decades ago the recent rapid rise of medical science has taken on the mantle of sustainability for growth. The dramatic impact potential of fundamentally transformative practices in healthcare is being fueled by access to new knowledge and a greater sharing of insight. 

Today, due to the convergence of various technology led disciplines, there are many important catalysts for paradigm shifting change. A key criteria common to all are the Drivers - fundamental products or processes that opens up the gates to new realms of understanding and acceptance. At each juncture a bridge must span the divide and a stake ground into new terrain. 

Are MSCs a Driver that can forge a paradigm shift in stem cell healthcare & how did we get here?
The investigation of bone marrow (“BM”) stem cells led to the establishment and widespread clinical practice using cells of the mesodermal blood lineage via bone marrow transplantation – known as hematopoietic cells (“HSCs”).
The first use of these BM  stem cells as therapy was pioneered over 50 years ago when transplants were first introduced experimentally to treat leukemia. However, as with most donor tissue the understanding of immune rejection of foreign non-self cells was and still is of major concern for the successful treatment of disease using allogeneic (donor) tissue. This is even the case when immuno-histocompatibility is done via matching of the cells to the host. This complication has stymied the field of cellular therapeutics due to the severe adverse events that can result from the administration of donor derived cellular treatments. In the case of BM transplantation they routinely cause Graft versus Host Disease (“GvHD”) as a result of the treatment, with approximately 50% of all such patients reporting complications. The percentage of mortality as a result of this last resort treatment intervention even today is staggering with up to 17% of all severe liver/gut GvHD cases resulting in death(1).
As a field the discovery and isolation of Mesenchymal Stromal Cells (“MSCs”), a small subset of BM niches representing less than 0.01% of all HSCs, was a watershed moment. It was a true breakthrough as these cells were found to be able to replicate as multipotent precursors and can be differentiated into fat, bone and cartilage. The isolation and clonal nature of these MSCs opened up a whole new avenue for cellular investigation. Further sources of MSCs were discovered in a range of bodily tissues, including fat, perinatal tissue and dental pulp. The technology for human application of these adult cells gave rise to the stem cell industry we know today. Upwards of 500+ clinical trials using MSCs are registered currently in the US central database for a variety of unmet disease indications (2).
In addition, there is a large growing trend of undocumented cases using MSC products in private medical offices as marketed treatments via autologous (self-to-self) therapies (3). These unlicensed medical practitioners using MSCs products are the subject of considerable debate as to where the line should be drawn between required regulatory oversight and freedom of medical use in private clinics for autologous treatments. The US FDA is currently reviewing draft guidelines (4,5,6,7) for treatment products using MSCs. They are preparing to define what constitutes more than minimal manipulation and cell use parameters. This is with a view to determining clinical trial requirements for MSC biologics, in keeping with current drug development procedures already in place.

Safe and Effective?   
The prospect of MSC utility for therapeutics has been due in large part to the evident immunological privileged nature of MSCs and their potential for universal application without immunosuppressive drugs – unlike HSCs themselves. Although MSCs have an antigen profile they lack major class antigens which makes them relatively immune-privileged to the host system thereby allowing for donor derived cell treatments without treatment rejection in low dose regimes.      
The Scientist - Keith Kasnot
The properties of MSC have been appropriately described as “ambulatory” and “paramedic” – i.e. they’re built to respond to injury in the body and assist in its repair. How they detect, migrate and signal, in addition to what biological manner they act, and what way in different circumstances, is a source of considerable study. It seems clear though now that their “method of action” (“MOA”) is modulatory in nature via complex regulatory mechanisms (8). One such mechanistic attribute is via the excretion of bioactive factors (vesicles, exosomes et al) and work to facilitate cell to cell communication networks (9).
Much has been written about the potential of tissue derived MSCs as a treatment option for a host of acute, immune and degenerative conditions. However, the field is still developing and protocols are being tested and adjusted to maximize possible outcomes. I’ve added an overview video below on the challenges and issues faced by MSCs product developers’ to-date by a leading expert in the field Dr. Jacques Galipeau of Emory University. The presentation highlights a number of findings on research and data in this sector and is well worth watching
Dr. Jacques Galipeau of Emory University

As mentioned, and referred to in the video, numerous clinical studies are underway on the use of MSCs and case reports have been published on both the potential benefits and in certain cases a lack of statistical benefit in patients receiving these cells from a variety of tissue sources.
With regard to the clinical trial results there is clear validation of MSCs safety profile, which is fundamental to their successful translation. Potential treatment efficacy of MSCs is suggestive to-date of positive activity on various outcome measures in a number of reported studies. These positive results are counter-balanced with questions on method of action (“MOA”) and some failed studies. This somewhat mixed picture generally points to issues relating to the development of medicinal products and cellular biologics should be viewed as no different.
A few of the better known company examples of MSC sector developments in the sector are briefly summarized below with links to the company for further details on the data.
  • TiGenix (adipose/fat) – has moved on from the 1st EU approved and marketed autologous (“auto”) MSC cell therapy called ChrondroCelect for cartilage repair to an allogeneic (“allo”) product strategy with solid Phase III results in hand for Cx601 in Crohn’s Disease. This will mark their first allo indication nearing approval with other adipose stem cell products in the pipeline. 

  • Mesoblast (BM) – bought the first approved western auto cell therapy Prochymal for GvHD from Osiris which had mixed results and was never released. They are developing a full in-house line-up of allo product candidates with good support data and are partnered with a Teva Pharma. Notable pipeline news include marketing approval of TemCell in Japan for GvHD with local partner JCR Pharma (repackaged Osiris product) and solid data in late stage trials (MSC-100-IV for GvHD also, MPC-150-IM for heart and MPC-06-ID for back pain, amongst others).

  • Athersys (BM) – lost Pfizer as a program partner for MultiStem after releasing mediocre data in ulcerative colitis. A second Phase II read-out, this time in stroke, also failed to meet endpoints. However, newly released interim data in its ongoing stroke study is now suggestive of positive results from the homing-in strategy on potential earlier treatment window benefit. Also of note are the additional clinical programs in development for cardiovascular and inflammatory/immune indications. In addition there’s a solid validation deal with Healios of Japan for MultiStem in that market and use of the product for Healios’ ongoing development programs.

  • Pluristem (placenta) – “PLX” product line for vascular, muscular and immune indications in early stage clinical trials (PI & PII) with solid data in muscle and critical limb ischemia. Promising preclinical results for bone marrow repair with government sponsorship for rapid route to market in acute radiation syndrome.

  • Vericel (BM for heart program) – previously known as Aastrom with a long history of development of auto MSCs for heart and CLI indications with poor accumulated data continues to develop the heart product in clinical studies with recent positive data after previous endpoint failure, indicative of statistical benefit. In 2014 they secured additional auto cell therapy products from Sanofi (Carticel & MACI – cartilage and Epicel – skin) which had previously received certain market authorizations and are generating revenue with patient benefit.

Indicative data sets for comparative analysis and ratio breakout are yet to be tabulated with regard to which conditions and methodologies the cells work well for and in which cases they don’t help all that much or at all. However, one must be cautious when assessing the efficacy value of cellular products as they are biologics and there are many issues relating to their degree of effectiveness, such as: their source; derivation method; inherent donor variability; passage potency; culture conditions & scale-up manufacturing; cold chain methodology; target indication; patient population; disease states and application methods, amongst others. As a result not all cellular products will perform well in human studies. These issues play a significant role in whether they achieve benefit in tests on patients, and to what extent in relation to standard of care. Although the jury is still out there is a general agreement based on empirical data that these cells are on the whole safe, when developed and used appropriately. Where they have been shown to have positive outcome and biological activity there is acknowledged room for improvement with regard to enhancing efficiency, potency and cell mechanistic action, which is encouraging.
One aspect of the development of industrial scale cellular therapies speaks to the need for increased replicative capacity, lower passaged products and standardization via use of optimization technologies and shifting to pluripotent cell sources instead of donor derived batch processing of multipotent cells.
Octane Bioreactors
As a result of this progressive development culture method adjustments gleaned from the early pioneering work of MSC development are giving rise to efficiencies of process and improved manufacturing protocols for next generation methods in both multipotent and pluripotent products. The above mentioned early leaders in MSC product offerings are beginning to line up their treatments for entry to the market, while the sector looks to prepare and trial the more advanced cell factories of the future.

UC Davis MSC Investigators
This momentum is also being driven by the rise of synthetic constructs using MSCs - the personalized tailoring of targeted medicines for improved performance. MSCs possess inherent homing and immunomodulatory properties and therefore are ideal for use in combination with gene and nano technologies. In addition, the extraction of the inherent cell properties of MSCs for standalone biologic products adds to the overall picture and excitement in the field.

MSC products are representative of the wider cell therapeutic field and are the standard bearers in the effort to bridge the shifting paradigms of new treatment modalities for patients in need.

Ref: Sector Update on Asian Market for MSCs > "Cell Therapy in Asia Erupts with Partnerships and Joint Ventures"