Directors’ Conflict of Interest Alliance: CIRM Grant Reviews Reveal Some Shocking Anti-Prop 71 Anti-hESC Research Biased Comments Full of Factual Errors against Scientific Evidences

California Institute for Regenerative Medicine (CIRM) grant reviews reveal some shocking anti-Prop71, anti-hESC research, biased comments full of factual errors against scientific evidences, please see most recent example below. We understand there are some directors’ conflict of interest (COI) alliance who are not only not doing any Prop71 stem cell research, but block those who are doing stem cell research to get funding from government funding agencies (e.g., NIH, CIRM), such as Gladstone’s Deepak Srivastava who talks pediatric heart disease in public, then blocks hESC research for pediatric heart disease using his well-connected alliance. It is serious scientific misconducts for those reviewers without scientific integrity use false statements & biases to predispose grants & papers of their COI. We’d like to bring your attention to such procedural flaw in CIRM grant review. 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. Scientific grant review process is supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. CIRM reviewers’ comments are full of biased or false statements, not even near to any standards of scientific grant review involving the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications. Even we are just scientists or applicants, we strive to voice transparency & fair competition & accountability, not COI & corruption.

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 transplantation 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.

Dear CIRM President and Chair,

We would like to appeal CIRM’s pre-application review for above application for evidences that have indicated a flawed review for lack of appropriate expertise, factual errors, bias or predisposition, and conflict of interest (COI) that have compromised the integrity of scientific review for CIRM. Could you please let me know who to contact and how to appeal a flawed grant review of CIRM, and information about CIRM procedure for appealing a flawed grant review or procedural flaw in CIRM grant review. I just received CIRM announcement yesterday that it seems CIRM proposed dramatic changes in response to IOM report. CIRM must have implemented or will implement their recommendations to ensure CIRM grant review process involve the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications to CIRM. Is CIRM grant review process supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. The reviewers’ comments below are not even near to any standards of scientific grant review. We will appreciate your consideration for our appeal. Please see the procedural flaw in CIRM grant review indicated by the reviewers’ comments below and do not hesitate to contact us should you have any questions.

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.
 

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 reviewers: 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 reviewers: 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 a 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.

From: Gil Sambrano [mailto:GSambrano@cirm.ca.gov]
Sent: Friday, January 25, 2013 5:07 PM
To: parsons@sdrmi.org
Subject: CIRM ET4 PreApp Review

Dear Dr. Parsons:

Thank you for submitting your proposal under the CIRM RFA 12-07: Early Translational IV Awards. After careful consideration, your PreApp was not selected for further review under this RFA.

 The goal of the PreApp process is to identify proposals that are the most responsive to the RFA objectives and likely to be competitive. For this competition we received 151 PreApps and selected about 40 for a full application. The process was designed to handle a large volume of proposals and to ensure a rapid turn-around on the review. Reviewers may provide brief comments that highlight strengths and weaknesses where appropriate. Each application is assigned to 3 independent reviewers and each reviewer assesses approximately 20 PreApps within their area of expertise and scores the applications on a scale of 1 to 100, 100 being the most meritorious. CIRM scientific staff further assesses proposals to ensure that projects meet eligibility requirements and are responsive to the RFA. CIRM invites the most highly ranked and responsive PreApps as determined by the external scientific reviewers and CIRM science officers.

 The summary below shows the final score for your PreApp and comments provided by reviewers.

 We thank you for your interest, and we encourage you to respond to future CIRM initiatives. We look forward to your future applications to CIRM. If you have any questions about the review please feel free to contact me.

 Sincerely,

 Gil Sambrano

Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107
Phone: 415-396-9103
gsambrano@cirm.ca.gov

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