San Diego Regenerative Medicine Institute (SDRMI) Open Appeal Letter to ICOC for CIRM Flawed Grant Review Showing That a Demonstrable Financial and Scientific Conflicts of Interest Had a Negative Impact on the Review Process

Dear ICOC,

We would like to appeal CIRM’s review & score for Application number TR4-06762, titled “Small Molecule-Directed Human Embryonic Stem Cells (hESCs) Cardiomyocyte (CM)-Specific Derivatives for Myocardium Regeneration in Preclinical Models” according to California Institute for Regenerative Medicine (CIRM) official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, which specifies appeals of scientific review showing that a demonstrable financial or scientific conflicts of interest had a negative impact on the review process and resulted in a flawed review, indifference of the type of applications.

According to CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, CIRM Application Review should be in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71. In accordance with Proposition 71 & pursuant to Proposition 71 (Health and Safety Code section 125290.60), the ICOC has established criteria for the evaluation of Applications by the GWG, including: A demonstrated record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine. CIRM review comments, including “hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells” (please see more such comments below provided by CIRM review summary), are against Prop 71 and scientific evidences, which have provided evidences for a demonstrable financial and scientific conflicts of interest that had a negative impact on the review process and resulted in a flawed review.

A demonstrable financial conflicts of interest that had a negative impact on the review process and resulted in a flawed review: Only UC & Sanford consortium groups with multiple ICOC members on CIRM board have financial interests in direct differentiation & reprogramming & deprogrammed somatic cells that have no stem cell or stem cell research involved as provided by CIRM review summary, which has financial conflict of interest with California stem cell research & cure bond initiative Prop 71 & hESC research of regenerative medicine startup with no member on CIRM board.

A demonstrable scientific conflicts of interest that had a negative impact on the review process and resulted in a flawed review: Only UC & Sanford consortium groups with multiple ICOC members on CIRM board have scientific interests in direct differentiation & reprogramming & deprogrammed somatic cells that have no stem cell or stem cell research involved, which has scientific conflict of interest with California stem cell research & cure bond initiative Prop 71 & hESC research of regenerative medicine startup with no member on CIRM board.

According to CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf, CIRM Application Review should be in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71. Consistent with Proposition 71, only the 15 scientist members of the GWG shall score Applications for scientific merit. However, not consistent with Proposition 71, CIRM officials not in the GWG with 3 biased unidentifiable reviewers selected by themselves scored the application according to their own opinions that show that a demonstrable financial and scientific conflicts of interest had a negative impact on the review process and resulted in a flawed review, as evidenced by CIRM review summary.

We will appreciate your consideration for our appeal for CIRM flawed grant review showing that a demonstrable financial and scientific conflicts of interest had a negative impact on the review process in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71 according to CIRM official grants policy via this link: http://www.cirm.ca.gov/sites/default/files/files/funding_page/NPGAP_11012012.pdf. Please see below SDRMI application in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, CIRM score & review NOT in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, & our responses.

SDRMI presents its application in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71.

Preliminary Application for RFA 12-07

Application number TR4-06762

Project Title (300): Small Molecule-Directed Human Embryonic Stem Cells (hESCs) Cardiomyocyte (CM)-Specific Derivatives for Myocardium Regeneration in Preclinical Models

Objective (1000): Due to the prevalence of heart disease worldwide and acute shortage of human myocardial grafts, there is intense interest in developing hESC-based therapy. However, realizing the potential of hESCs has been hindered by uncontrollable and inefficient multi-lineage differentiation. We found that pluripotent hESCs maintained under defined culture can be uniformly converted into a cardiac specific lineage by small molecule induction. To address unmet medical need in regenerating the damaged myocardium, this proposal uses small molecule directing hESC cardiac lineage-specific differentiation into human CM-specific derivatives at scale, purity, and myocardium regenerative potential adequate for clinical translation. The hESC CM cell therapy products will be characterized and their potential in myocardium regeneration and contractile function restoration will be assessed by transparentation into infracted models. Fulfilling the goal will lead to hESC-based therapy to restore heart function.

Rationale, Significance and Responsiveness (2000): To date, lack of a suitable human cardiomyocyte (CM) source with adequate myocardium regenerative potential has been the major setback in regenerating damaged human heart. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing hESC-based therapy for heart disease and failure. However, realizing the therapeutic potential of hESC derivatives has been hindered by generating CMs from pluripotent cells through uncontrollable and inefficient multi-lineage differentiation. Grafts generated by such hESC-derived CMs have been small, insufficient to restore heart function and functional enhancement not related to regeneration from the grafts. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a cardiac specific lineage by small molecule induction. This technology breakthrough enables well-controlled efficiently directing cardiac lineage-specific differentiation of pluripotent hESCs towards human CM derivatives at scale, purity, and myocardium regenerative potential adequate for restoring heart function. With reproducible and scalable production of clinically-suitable hESC CM precursors and CMs, the goal of this project is to provide all necessary evidences of safety and efficacy in preclinical infracted models for moving into IND-enabling preclinical development for tissue and function restoration in myocardium infraction. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Fulfilling the goal of this project will lead to extending healthy life span for millions of patients suffering from end-stage heart failure and reducing the burden of illness and disability of major health problems.

CIRM presents its score & review NOT in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, demonstrating that CIRM officials & reviewers financial and scientific conflicts of interest had a negative impact on the review process and resulted in a flawed review.

SUMMARY OF REVIEW

Overall Scientific Score: 44.00

Comments provided by reviewers:

The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed. 

hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation

Unmet need: Heart Failure

Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available

SDRMI presents its response to CIRM flawed review & score in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71.

Comments provided by CIRM: The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed. 

Our response: This reviewer’s comment is a factual error. Our approach to MI in this application has not been represented in CIRM portfolio. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. CIRM current portfolio does not have any approach that can efficiently regenerate heart muscle (myocardium). CIRM portfolio Cedars-Sinai’s Eduardo Marban & Capricor have no scientific evidences that their adult heart cells can regenerate heart muscle, may produce some smooth muscle or other supporting cells to slow down the dying patient heart muscle cells. CIRM portfolio Joe Wu/Robbin of Stanford U use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function. Gladstone/UCSF reprogrammed adult cells or trans-differentiated cells are abnormal, have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics. We have addressed previous reviewers’ biased comments and our effective directed CM differentiation approach by small molecule induction has been fully developed for preclinical studies in this application (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications).  

Comments provided by CIRM: hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

Our response: This reviewer’s comment is biased, anti-Prop 71, anti-hESC research, and a factual error. This project translates advances and medical innovations in hESC research, not pluripotent hESC cell type, which itself cannot be used for therapeutic application. It has been recognized that pluripotent hESCs must be transformed into fate-restricted derivatives before use for cell therapy. This project translates hESC cardiomyocyte (CM) derivatives, including CM precursors & CMs, by direct differentiation of hESCs using small molecule induction, which is more likely to be approach of the future. Human embryonic stem cell (hESC) research holds tremendous potential for tissue and organ regeneration and function restoration. Clinical applications of hESC therapy derivatives provide the right alternate for many incurable diseases & major health problems that the regular mode of treatment cannot. Each single one of those world-wide major health problems cost the health care system or taxpayers more than $10 billion annually. In particular, hESC cardiac derivatives are the only cell source so far that can regenerate the contractile heart muscle (known as cardiomyocytes), vital for cardiovascular repair. In fact, partially or fully deprogrammed or reprogrammed somatic cells are abnormal, & have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics, or partially or fully deprogrammed or reprogrammed somatic cells are clearly not translatable cell type. By the way, Prop 71 is passed by CA voters to fund hESC research, majority of CA voters have said that hESCs are clearly translatable cell type. Did this CIRM reviewer intentionally make comments in CIRM grant review against CA Prop 71 or hESC research, or have any COI with translating hESC research of this CIRM RFA, or telling the public that Prop 71 is not translatable? Such reviewers abuse CIRM pre-application procedure to cover up their false or biased reviews against scientific evidences, and should be disqualified from reviewing any CIRM grants by making anti-hESC research & anti-Prop71 biased political comments to CIRM applicants. We all know we are translated from embryos, not any somatic cells or skin cells. Is this review telling the public that he was translated from some somatic cells, against billions of living evidences? It is shocking to hear such anti-hESC research anti-Prop 71 false or biased comments from CIRM grant reviewers so often.

Comments provided by CIRM: DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation, Unmet need: Heart Failure. Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available.

Our response: This reviewer’s comment is biased. Our novel hESC direct differentiation protocols have been published, are now widely available in public domains, which should be strengthen of this project to CIRM. Only those without scientific integrity like this reviewer, who like to take others’ research for their own private use, would think widely available protocols as weakness to them. Our protocol of hESC CM lineage-specific differentiation by small molecule is novel and ground-breaking, has not been represented in CIRM portfolio (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications). This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Conventional protocols to generate CMs from ESC through traditional multi-lineage differentiation are widely available, but have extremely low efficiency (<4%). CIRM current portfolio does not have an approach that can efficiently regenerate heart muscle (myocardium). CIRM Joe Wu/Robbin of Stanford & Geron use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function.