NIH Response to Letter to NIH Director Francis Collins

Dear Dr. Gadbois,

Thank you for your response on behalf of Dr. Francis Collins. Although we do not have NIH actual award# for human embryonic stem cell (hESC) research, according to NIH online statistics at http://stemcells.nih.gov/research/funding/pages/Funding.aspx, in 2012, only 10% of total NIH fund to stem cell research (~ $1.468 billion) was gone into hESC research, while 56% (~ $822 million) was gone into non-human stem cells. The significance and benefit of hESC research should be in reverse with the fund supported by NIH. In the 10%, hESC research is often only a tiny fraction or small project of adult induced pluripotent stem (iPS) cell U grants or large center grant awards, so the actual NIH fund to hESC research is even much less than the 10%.

My hESC grant applications have encountered such non-peer reviewed processes or events in NIH CSR (Center for Scientific Review) peer review as that study section overridden the reviewers’ scores to outside of funding range or biased reviewers scored to as low as exclusive 9s or 8s (in a scale of 1 to 10 with 1 the strongest and 10 the weakest) for the scientific merits and overall impact of hESC research with significance and impact to understanding human embryonic development and finding a cure for PD, neurological and heart diseases as currently the most promised therapeutic approach closet to provide a cure. I have gone through NIH appeal system for at least 3 times (please see the appealed project title and summary below), the appeals were either not brought up for consideration, or concurred by NIH appeal system to reviewers’ biased recommendation. Therefore, it seems NIH appeal system did not work, at least for my hESC applications. Please do not hesitate to contact me should you have any questions, thanks,

R01 HD073109-01A, Parsons, Xuejun H.

Title: Preclinical study of a novel neuronal progenitor induced from human embryonic stem cells in spinal muscular atrophy model, in response to NIH funding opportunity Program Announcement (PAR) Number: PAR-11-038 Title: Preclinical Research on Model Organisms to Predict Treatment Outcomes for Disorders Associated with Intellectual and Developmental Disabilities (R01).

Project summary: Spinal muscular atrophy (SMA) is a devastating, untreatable, and one of the most common genetic neurodevelopmental diseases leading to infant mortality. Human stem cell transplantation represents a promising therapeutic approach closest to provide a cure to restore the lost nerve tissue and function for SMA. However, to date, lacking of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing effective cell-based therapies. In spite of proffering cures, realizing the developmental and therapeutic potential of pluripotent human embryonic stem cells (hESCs) has been hindered by the inefficiency and instability of generating desired cell types from pluripotent cells through multi-lineage differentiation. To achieve uniformly conversion of pluripotent hESCs to a neuronal lineage, I have established a small molecule induction approach to generate a large supply of novel nurr1-positive human neuronal progenitors direct from the pluripotent state of hESCs (hESC-I hNuPs) in high efficiency, purity, and neuronal lineage specificity to support preclinical research. SMA, characterized by selective degeneration of spinal cord motor neurons, provides an ideal model for in vivo motor neuron dysfunction bioassay. In this project, hESC-I hNuPs will be transplanted into animal models of SMA to determine if the engrafted cells will extend life-span and improve the motor function by differentiation into motor neurons for nerve regeneration and reinnervation of host muscle to provide preclinical evidences of efficacy and safety against incurable motor neuron disease. Their therapeutic behavior, including engraftment/cell survival/integration, migration, differentiation into motor neurons, graft-dependent nerve regeneration and reinnervation of host muscle, and motor function recovery will be assessed for evidences of efficacy, and a lack of tumors and inappropriate cell type formation will be assessed for evidences of safety. Assessment of the potential of hESC-I hNuPs in disease models of SMA will offer critical insights into novel therapeutic strategies against incurable motor neuron disease as well as provide necessary and sufficient preclinical evidences of safety and efficacy to demonstrate their potential as stem cell therapy to be translated to SMA patients for motor neuron repair in clinical trials. The outcome of this proposal will have significant impact on the advance of medicine to provide treatment options for incurable motor neuron diseases in pediatric patient populations.

1 R43 TR000349-01      Parsons, Xuejun H

Title: Dopaminergic specification of human embryonic stem cells for cell-based therapy against Parkinson’s disease (Phase I), in response to NIH funding opportunity Program Announcement (PA) Number: PA-10-122 Title: SHIFT Award: Small Businesses Helping Investigators to Fuel the Translation of Scientific Discoveries [SBIR: R43/R44].

Project summary: To date, lacking of a large supply of clinical-grade human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing effective cell-based therapies for restoring the damaged CNS. Pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for repair. However, realizing the therapeutic potential of hESCs has been hindered by the current state of the art for generating neuronal cells from pluripotent cells through multi-lineage differentiation, which is uncontrollable, inefficient, instable, highly variable, difficult to reproduce and scale-up. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific lineage by small molecule induction. The goal of this project is to use a novel small molecule induction approach for well-controlled efficiently directing neuronal lineage-specific differentiation of hESCs from the pluripotent stage towards human neuronal progenitors and neurons at scale, purity, and DA regenerative potential suitable for preclinical development of cell-based therapy against Parkinson’s disease (PD), a prototypical age-related neurodegenerative disorder. Retinoic acid (RA) was found to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger progression to neuronal progenitors and neurons efficiently by promoting nuclear translocation of Nurr1. In the phase I of this project, the cascade of hESC neuronal lineage-specific differentiation by small molecule induction will be characterized. These characterizations will be used to optimize the hESC neuronal differentiation protocol and to define their homogeneity and dopaminergic (DA) potential. These studies in Phase I will be used to establish the feasibility of this approach prior to initiating Phase II for large-scale molecular profiling to define stage-specific human embryonic neurogenic factors and for preclinical studies of their therapeutic effect in vivo in the DA dysfunction models. These studies will lead to producing a large supply of well-characterized human neuronal progenitors and neurons in high purity and adequate DA regenerative potential for therapeutic applications. Further assessment of their potential in the PD models will offer critical insights into novel neuron replacement therapy as well as provide necessary and sufficient preclinical evidences of safety and efficacy for predicting stem cell therapy outcomes in clinical trials against PD. The outcome of this proposal will have significant impact on the advance of medicine to provide novel graft-dependent stem cell therapy for restoring the lost tissue and function in CNS disorders.

1 R43 HL114131-01A1      Parsons, Xuejun H

Title: Cardiomyocyte specification of human embryonic stem cells (hESCs) for cell-based therapy for myocardium regeneration (Phase I), in response to NIH funding opportunity Program Announcement (PA) Number: PA-09-249 Title: Directed Stem Cell Differentiation for Cell-Based Therapies for Heart, Lung, and Blood Diseases (SBIR),

Project summary: To date, lacking of a suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Pluripotent human embryonic stem cells (hESCs) proffer unique revenue to generate a large supply of cardiac lineage-committed cells as human myocardial grafts for cell-based therapy. 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 hESCs has been hindered by the current state of the art for generating cardiomyocytes from pluripotent cells through multi-lineage differentiation, which is uncontrollable, inefficient, instable, highly variable, difficult to reproduce and scale-up. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific lineage by small molecule induction. The goal of this project is to use a novel small molecule induction approach for well-controlled efficiently directing cardiac lineage-specific differentiation of pluripotent hESCs towards human cardiac precursors and cardiomyocytes at scale, purity, and myocardium regenerative potential adequate for preclinical development of cell-based therapy for heart disease. Nicotinamide was found to induce the specification of cardiomesoderm direct from the pluripotent state of hESCs and trigger progression to cardiac precursors and cardiomyocytes efficiently. The cascade of hESC cardiac lineage specific differentiation by small molecule induction will be characterized. These characterizations will be used to identify cardiac stage-specific markers and optimize hESC cardiac lineage-specific differentiation by small molecule induction to beating cardiomyocytes. These studies in Phase I will be used to establish the feasibility of this approach prior to initiating Phase II for large-scale molecular profiling and for preclinical studies of their therapeutic effect in myocardium regeneration in vivo. These studies will lead to producing a large supply of well-characterized human cardiac precursors and cardiomyocytes in high purity and adequate myocardium regenerative potential for commercial and therapeutic applications. This project is crucial to driving the advance of medicine to provide optimal treatment options for the damaged or diseased hearts that have been lacking. The outcome of this project will have a transformative impact on a broad area of biomedical sciences and public health.

From: Gadbois, Ellen (NIH/OD) [E] [mailto:gadboisel@od.nih.gov]
Sent: Wednesday, May 01, 2013 8:27 AM
To: 'parsons@SDRMI.org'; 'parsons@xcelthera.com'
Cc: HESCREGISTRY (NIH/OD)
Subject: your email to Dr. Francis Collins

Dear Dr. Parsons,

Your recent email dated April 17, to Dr. Francis Collins, Director of the National Institutes of Health (NIH), regarding stem cell research funding, was referred to me for reply. I appreciate the opportunity to respond to your email. 

Across NIH, stem cell research is a high priority. As you know, NIH funds a range of stem cell research, using human and non-human adult stem cells, embryonic stem cells, and induced pluripotent stem cells. NIH-funded research is exploring potential applications in regenerative medicine, drug screening, and the study of the molecular pathways in biological development and human disease. There is no budget set for stem cell research overall or in specific categories; the individual institutes and centers at NIH make their decisions on awarding grants and contracts based on considerations of scientific merit and relevance to their mission, programs, and priorities.

You state that NIH has cut funding for research with human embryonic stem cells under the current administration. That is not correct--NIH has actually increased support by $58.4 million between fiscal year 2008 ($88.1 million awarded) and fiscal year 2012 ($146.5 million awarded). You can find additional details about NIH stem cell research funding at http://stemcells.nih.gov/research/funding/pages/Funding.aspx. 

You may also be interested in reading the NIH Guidelines for Human Stem Cell Research (Guidelines), posted at http://stemcells.nih.gov/policy/pages/2009guidelines.aspx. NIH has approved 209 human embryonic stem cell lines for use in NIH-funded research under the Guidelines. Information on these lines is available at http://grants.nih.gov/stem_cells/registry/current.htm. If you have human embryonic stem cell lines that you think meet the requirements of the Guidelines, I encourage you to submit your documentation for consideration by NIH.

Finally, it is of utmost importance to NIH to conduct high quality peer review. NIH has established a peer review appeal system (see NOT-OD-11-064) to provide investigators and applicant organizations the opportunity to seek reconsideration of the initial review results if, after consideration of the summary statement, they believe the review process was flawed as outlined below. Additional details of this appeals process can be found at http://grants.nih.gov/grants/peer_review_process.htm#Appeals. 

Thank you again for your interest in stem cell research.

Sincerely,

Ellen L. Gadbois, Ph.D.

Senior Policy Analyst

Office of Science Policy

Office of the Director

National Institutes of Health