Letter to CIRM Grant Pre-Application Review

San Diego Regenerative Medicine Institute Releases Dr. Parsons’ Letter to CIRM Grant Pre-Application Review.

Dear CIRM,

First, we’d like to let CIRM know that SDRMI announced the publication of ground-breaking technique on direct conversion of human embryonic stem cells into neuronal cells. Realizing the developmental and therapeutic potential of human embryonic stem cells has been hindered by the inefficiency and instability of generating desired cell types from pluripotent cells through multi-lineage differentiation. The original research, titled “Efficient Derivation of Human Neuronal Progenitors and Neurons from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction” is the first to show that pluripotent human embryonic stem cells can be uniformly converted into a neuronal lineage by simple provision of small molecules. This technology breakthrough not only provides a large supply of clinical-grade human neuronal therapeutic products for neuron regeneration and replacement therapy against a wide range of neurological disorders, but also offers means for small-molecule-mediated direct control and modulation of the pluripotent fate of human embryonic stem cells when deriving an unlimited supply of clinically-relevant lineages for regenerative medicine. The protocol of this novel technology was published in JoVE (http://www.jove.com ), and more information can be found on SDRMI & Xcelthera website.

Second, we are surprised how irresponsible, biased, and non-transparent (sorry have to say so) CIRM’s pre-grant selection process still is that left CA’s promising and critical human embryonic stem cell research unfunded by Prop71. CIRM is supposed to dole out CA stem cell research & cure bond act for using human stem/progenitor cells, prioritizing human pluripotent stem cells, for developing cell therapy and cure. So far, human embryonic stem cells remain the only pluripotent normal stem cells. Whether the proposal is eligible for CA stem cell bond act should be the first and only consideration for pre-selection of grants, considering the abstract style of pre-application, which limits words and space, not allow data, description, and anything more than general statement. In answering of your reviewer to our Pre-App CIRM RFA-11-02 TR3-05505, titled “Heart precursors directed from human embryonic stem cells for myocardium regeneration.”

“CIRM Reviewer: Target product indication is very vague; this especially needs clarification given that proposed mechanism of delivery is injection during open heart surgery.”

Answer: Our target product described in the App: Cardiac precursors induced direct from pluripotent hESCs with small molecule treatment will contain a homogeneous population of cells that express heart precursor markers and generate beating cardiomyocytes with a drastic increase in efficiency in vitro, compared to untreated control. Following transplantation, hESC-derived cardiac precursors will survive, integrate and differentiate into contracting myocardium to remuscularize the injured heart and rescue the contractile function, and the function improvement will depend on the contractile properties of human myocardial grafts. We are the first to develop the novel technology to convert human embryonic stem cells directly and exclusively into cardiac precursors that yield beating heart muscle cells efficiently, potentially useful for developing effective cell therapy for heart muscle repair, so far has no cure. However, there is 600 character limitation/space in the pre-app to allow us to be more clear and specific. By contrast, CIRM awarded endogenous heart cells of cedars-sinai did not have to show any stem/progenitor activity, only improving the pump factor from ~ 30 to ~ 40.

“CIRM Reviewer: Other approaches to accomplishing cardiac repair with hESC are available and well ahead of this one. The real issue is whether the culture system the applicant has developed with nicotinamide induction offers any benefits in efficiency, stability, safety or manufacturing to the other systems. This is not clear from the general statements made in the application.”

Answer: So far, other approaches have been using multi-lineage differentiation of hESCs, efficiencies are low, especially in generating the contracting heart muscle or myocardium. Reprograming/trans-differentiation of adult cells not only efficiency is low, and abnormal, and immnuo-rejection has been a big issue even for transplanting normal adult cells. Our small molecule NAM induction approach offers the benefits in efficiency, stability, safety, and scale-up production over existing conventional approaches. However, the character limitation in the pre-app made us unable to be clear besides general statements.

“CIRM Reviewer: The applicant does not address the issue of immunogenicity.”

Answer: hESCs and their derivatives are less immunogenic than any other cells and tissues, and also can find isotype matches through hES cell lines. It is adult cells, like mesenchymal stem cells, and adult cell derived or trans-differentiated cells that have a big issue of immune-rejection, aging, not graftable. The word and space limited pre-app did not specify us to address the issue of immunogenicity, which has not been one of the major obstacles of hESC therapy. None of CIRM awarded grants, like last round of 5 or 6 mesenchymal stem cell awards, addressed their major well-known issue of immunogenicity either. Turning down a promising hESC grant by CIRM for not addressing an issue not so critical in the hESC field than the adult cell field seems more of an issue of conflicts or opponents of hESC research or anti-the law of Prop71.

“CIRM Reviewer: She has no apparent experience in drug development.”

Answer: Prop71 is for human stem/progenitor cells and cell therapy, not for drug development company. I have extensive experiences in developing the hESC therapeutic product and technology we proposed here for heart repair that give me the skill and knowledge to lead the preclinical study of this early translation project to clinical development. If those experiences may not be enough, CIRM should provide resources and training to help investigators to reach the goals of prop71. Many PIs of CIRM awarded grants have no stem/progenitor experience or cell therapy development experience that the law requires, let the public wonder how they are going to make progress.

Third, Our grant application RFA 10-05 Application number DR2-05339, titled “ Developing human-pluripotent-stem-cell-derived neuron regeneration therapy for spinal cord repair.” was not on you scored or not scored list, what happened to it? Our grant addresses developing new pluriptotent stem cell therapy of Prop71, why it was not even brought up for consideration? Rather, last round of grants, there were cancer stem cells (still cancer cells not stem cells), no stem cell awards, not eligible for Prop71, and a cluster of 5/6 went to the same UC, a obvious sign of conflict or violation of transparence. Mesenchymal stem cells are known to have no stem/progenitor cell activity, extremely toxic, not graftable (> 1000 papers on it). Do you need state legislation to change CIRM’s grants criteria in the stem cell bond ballot? Not talking about these adult mesenchymal stem cell awards, I know my mentor Stuart Lipton’s mef cells are neither dopaminergic nor have any in vivo functional data. How come you did not require them to do all those things you required us to do?

Fourth, CIRM’s funding process, as State’ agency for its stem cell bond act, is supposed to be transparent, is it ok for us to discuss it on the internet?

Best regards,