Parthenotes - Flying Under the Radar of Pluripotent Science

Positive interim results in the 1st in human study of parthenogenetically derived neural stem cells ("hpNSCs") for Parkinson's Disease were recently announced by International Stem Cell Corp. ("ISCO"). From the announcement the cells have to-date been well tolerated and no adverse side-effects from the treatment have been observed. Although the limited number of patients treated limits statistical conclusions, initial evidence suggests there may very well be an encouraging therapeutic effect to the experimental therapy and with additional positive data on the increased dosage cohorts there is reason to be optimistic for the continuation of the trial into a larger Phase 2 powered for a more representative efficacy read-out.

From the company's interim announcement:

"We are already seeing some positive efficacy results six months post-transplantation in this 12-month study. While the relatively small sample size makes it difficult to observe statistically significant differences, the interim efficacy results are very encouraging. The first dose tested was used to determine the safety and tolerability of ISC-hpNSC therapy and is below the optimal therapeutic dose established in our preclinical studies," commented Russell Kern, PhD, ISCO's Executive Vice President and Chief Scientific Officer. "We are anticipating strong results in the second cohort (receiving a higher dose of cells) in which two patients have been treated already. These clinical results build a strong foundation to start phase II clinical trials in PD and traumatic brain injury, which are some of the biggest current unmet medical needs," continued Dr. Kern.     

I had asked Russell Kern ("RK"), EVP / Chief Science Officer of ISCO, a few follow-up questions to my previous interview with him on this ongoing clinical trial in Australia using a pluripotent derived cellular therapy.

Q: The main theme of peer investigator comments in the sector working on pluripotent Parkinson therapeutics it seems, is the issue of using progenitor stem cells and their safety in patients versus the mainstream approach of using differentiated neurons. Do you have a comment on this safety issue and why ISCO's approach is not to use fully differentiated neurons? Also is there any limiting IP issue with using fully differentiated parthenogenically derived neurons, if you wanted to, as there was some thought by some that you may be restricted from doing so.

RK: Progenitor stem cells, in particular neural stem cells, have been extensively tested in patients and shown to be safe in a number of neurological indications, including spinal cord injury, stroke, Amyotrophic Lateral Sclerosis, age-related macular degeneration, myelination disorders and lysosomal storage disorders1-4. StemCells Inc. tested up to 1 billion neural stem cells in children with neuronal ceroid lipofuscinoses disease, a fatal lysosomal storage disease1. The neural stem cells were well tolerated without test article related adverse events1. We have ample preclinical evidence showing that our neural stem cells (ISC-hpNSC) are safe and well tolerated5. We have transplanted hundreds of animals with ISC-hpNSC and shown that the cells are safe and do not cause overgrowth or tumors5.

In regards to using fully differentiated DA neurons for therapy, it is an approach that investigators in the field are not using because it takes an average of 60-90 days to get mature DA neurons that are electrophysiological active6. Fully mature DA neurons are fragile, hard to work with, and do not survive well cryopreservation or transplantation. Most of the pluripotent based Parkinson’s disease (PD) therapies are transplanting DA neuron progenitors instead, which are differentiated 15-25 days from the pluripotent state. DA neuron progenitors are easier to work with and cryopreserve but if they are not sorted before transplantation, they have the risk of containing undifferentiated pluripotent stem cells. Some reports have shown the formation of overgrowth, deformations or tumors after transplantation of DA progenitors raising concerns about the feasibility of this approach7,8. Our ISC-hpNSC are cultured and expanded into master and working cell banks in medium that is not conducive for the maintenance or growth of pluripotent stem cells5. We have performed exhaustive in vitro testing to demonstrate the absence of pluripotent stem cells in our clinical grade ISC-hpNSC5.

Additionally, we have compared DA neuron progenitors and ISC-hpNSC in two animal models of PD and consistently seen better results with ISC-hpNSC, which is the main reason why we chose this approach. If DA neuron progenitors had been better, we would have chosen these cells for therapy because we do have the IP. We have a patented chemically defined differentiation protocol for deriving DA neurons from pluripotent stem cells9.  

Q: Another observation of your approach was the perceived over reliance on neurotrophic factors as the mechanistic action with limited progenitor cell differentiation into dopaminergic neurons and the lack of survival/engraftment potential to maintain therapeutic value. Do you have a comment on this and the differing strategy of looking to directly repopulate a larger percentage/number of dopaminergic neurons.

RK: Results from the fetal PD trials indicate that grafts containing only 50,000–100,000 TH+ DA neurons are sufficient to provide long-term symptomatic relief in patients10-14. We have shown that approximately 10% of the transplanted ISC-hpNSC cells survive and 2% of the engrafted cells differentiate into DA neurons15. We are transplanting 30-70 million ISC-hpNSC cells in patients, which means that approximately 3-7 million cells will survive transplantation and out of which, 60,000-140,000 will become DA neurons. Therefore, we believe our therapeutic approach will provide the necessary number of DA neurons for clinical efficacy.  Additionally, ISC-hpNSC provide neurotrophic support and immunomodulation that can be critical in rescuing the dying host DA neurons and treating non-motor related symptoms16,17, which cannot be achieved with a dopaminergic  replacement approach18.

Q: On the topic of parthenogenetic derived cells there was some concern with the possible effective loss of heterozygosity in the ISCO cells as a result of the derivation method which may add to the safety issue, due to the potential genetic limitation to identical alleles and the association of such with cancer. Do you have a comment on this?

RK: To clarify, ISC-hpNSC is derived from a heterozygous human parthenogenetic stem cell line and does not have the risk associated with loss of heterozygosity9,19. It is true that there is inherent risk with the use homozygous human parthenogenetic stem cells20, as there is with the derivation of iPSC from older donors, with higher risk of cancer causing mutations21.  That is why it is important to conduct preclinical safety studies before clinical translation.