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.


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

The N Factor

The mere mention of a possible stop-gap option to the grave medical realities of those that suffer, let alone a lifeline to a solution, is enough to get most patients and their families/friends talking. Clinical trials however are relatively few and far between for specific diseases and those that are available are currently akin to drawing the lottery where circumstances such as referral, timing, scale, proximity and onerous inclusion criteria set a very high bar to entry.

The vast majority of patients don’t have any options.

I’ll relay a representative case in point - a friend of mine was diagnosed recently with Stage 4 Melanoma, an advanced skin Cancer which is all but fatal in relatively short order. His doctors gave him the ticking clock and little hope. However, given his wish to live and determination to see his young son grow up he studied, turned over every rock and reached out. He landed a very rare spot as a tag along to a new immunotherapy trial. He was lucky, most are not, given he didn’t meet the strict criteria for official entry. The trial treatment saved his life.

T-Cells in Action
Hope is a cruel bedfellow with its constant draw of energy and resources from the very reservoir it seeks to fill. Yet without that flicker of a flame gasping for oxygen the very medical system built upon empirical data derived from clinical trials designed to advance knowledge wouldn’t exist.

The system needs patients and patients need the system - both rely on the other and as such require inclusive practices to further the agenda of progress towards real solutions.

Emily Whitehead
N is a strong and decisive letter in our everyday language but in investigative medicine it’s a defining research statement which confers status and validity where quantitative analysis imbues significance and wields judgement on meaningfulness. For those not on the in, the N is translational science parlance for the number of patients treated and their data sets. The lower the N the more likely there will be variability in the eventual safety and benefit outcomes when applied to the patient population at large. While the larger the N the more significant the potential correlation in delivering a safe option and potentially treating the targeted disease indication. 

As fundamental as the N is to applying the scientific method to proving the safety and potential for wide scale application, it cannot be suggested to be devoid of meaning at any level, especially considering the human impact and nascent development of promising new therapeutic modalities for treating previously unmet medical needs.

The mere fact that we will all suffer in one form or another from the debilitating conditions of age is enough to warrant more attention to the secondary benefits in N data given the lack of achieved endpoints of trialed drug interventions to-date. Combine the natural degenerative conditions of the aged with a population rife with chronic and acute medical issues that continue to overburden the system, leaving a significant population of those in need without a solution, and you have the argument for considered change.

Breakthroughs in medical science indeed offer a real opportunity to effect change and the more that can be done to allow for inclusion and support for that transformative process to occur the more representative the N will be that correlates to real tangible wellbeing data logged for the betterment of the science as well as the patient. 


Ref: Related Cancer Blog on Emily Whitehead

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).