NINDS Advisory Council Meeting Minutes, May 27, 2010

Department of Health and Human Services 
Public Health Service
National Institutes of Health
National Advisory Neurological Disorders and Stroke Council

Summary of Meeting[1]
May 27, 2010

The National Advisory Neurological Disorders and Stroke (NANDS) Council was convened for its 178th meeting on May 27, 2010, at Building 31, Conference Room 10, Bethesda, Maryland. Dr. Story Landis, Director of the National Institute of Neurological Disorders and Stroke (NINDS), served as Chairperson.

In accordance with Public Law 92-463, the meeting was:

Council members present were:

Council member absent was:

Ms. Katherine Hood

Council Roster (Attachment 1)

Ex Officio Member present:

Dr. Robert Ruff, Department of Veterans Affairs

Ex Officio Member absent:

Dr. Geoffrey Ling, Department of Defense

Members of the public present for portions of the open meeting included:

Ms. Michelle Rodrigues, SRI
Ms. Amy Rick, The Parkinson Alliance
Ms. Erica Froyd, Lewis-Burke Associates

NINDS employees present for portions of the meeting included:

Other Federal employees present for portions of the meeting included:

Dr. Peter Guthrie, CSR
Dr. Patricia Manos, CSR
Dr. Suzan Nadi, CSR
Dr. Rene Etcheberrigaray, CSR
Dr. Mary Custer, CSR
Dr. Alexander Yakovlev, CSR
Dr. Cate Bennett, CSR
Dr. Alice Luo Clayton, NIMH

I. Council Consideration of Pending Applications

This portion of the meeting, involving specific grant review, was closed to the public. The Council gave special attention to applications from foreign institutions and other applications which needed specific discussion. Prior to the discussion of the grants, Dr. Finkelstein reminded Council regarding conflict of interest and confidentiality as follows:

Conflict of Interest

The regulations concerning conflict of interest were reviewed. Council members were reminded that materials furnished for review purposes and discussion during the closed portions of the meeting are considered privileged information. All Council members present signed a statement certifying that they had not been involved in any conflict of interest situations during the review of grant applications.

Confidentiality

During the closed session, any information that is discussed and the outcome of any recommendation are considered privileged information. They may not be discussed outside of the closed session. If an applicant requests support for his or her application from a Council member, the Council member must respond that he/she is not permitted to discuss the application. Any inquiry should be referred to Dr. Robert Finkelstein, the Council Executive Secretary, who will then refer the questions to the appropriate staff member for response.

Research Training and Career Development Programs

The Council reviewed a total of 95 research career development and institutional training grant applications; of this total, 56 applications had primary assignment to NINDS, and 37 of them (66.1 percent) were recommended for support in the amount of $5.2 million first-year direct costs. It is anticipated that, of the research career development and institutional training grant applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $1.7 million.

Research Project and Center Awards

The Council reviewed a total of 2,404 research project and center applications; of this total, 1,278 applications had primary assignment to NINDS, and 748 of them (58.5 percent) were recommended for support in the amount of $210.0 million first-year direct costs. It is anticipated that, of the research grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $67.3 million.

Senator Jacob Javits Neuroscience Investigator Awards

The Senator Jacob Javits Neuroscience Investigator Awards are made to distinguished investigators who have a record of scientific excellence and productivity, who are actively pursuing an area of research of strategic importance, and who can be expected to continue to be highly productive for a seven-year period. Candidates are nominated and selected at each Council meeting. At this meeting, no Javits awards were recommended.

Small Business Innovation Research and Small Technology Transfer Award Programs

The Council reviewed a total of 208 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 139 applications had primary assignment to NINDS and 96 of them (69.1 percent) were recommended for support in the amount of $19.9 million first-year direct costs. It is anticipated that, of the SBIR and STTR applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $1.9 million.

II. Call to Order and Opening Remarks

Dr. Landis, Director, NINDS, welcomed Council members, visitors, and staff to the 178th meeting of the National Advisory Neurological Disorders and Stroke Council meeting.

Dr. Landis announced that Council member Katie Hood would be unable to attend this meeting but would be in attendance at the September Council meeting.

This is the last meeting for five Council members whose terms expire on July 31: Susan Axelrod, Lucie Bruijn, Ralph Dacey, Edgar Kenton, and Gary Westbrook. Dr. Landis thanked the members for their contributions to NINDS and would more formally acknowledge their service at that evening’s Council dinner. Dr. Landis presented Susan Axelrod and Gary Westbrook with plaques since they would not be in attendance at the Council dinner. A letter and certificate from Secretary Sebelius will be forwarded to the five members in a few weeks.

Dr. Landis stated that the Council slate to replace these members had been submitted to the Department.

III. Report of the Associate Director for Extramural Research, NINDS

Approval of Council Minutes -- Dr. Finkelstein requested, and the Council voted approval, for the February 4, 2010, Council meeting minutes.

The following future Council meeting dates were confirmed

• September 23-24, 2010 - (Thursday and Friday)
• February 3-4, 2011 - (Thursday and Friday)
• May 26-27, 2011 - (Thursday and Friday)
• September 15-16, 2011 - (Thursday and Friday)
• February 9-10, 2012 - (Thursday and Friday)
• May 24-25, 2012 - (Thursday and Friday)
• September 20-21, 2012 - (Thursday and Friday)

Expedited Review Process -- A subset of Council members, prior to the meeting, approve applications with scores within the payline for which there are no unresolved issues. For this round, there were 140 applications eligible to be expedited for payment of which 117 awards had been issued.

DER Announcements - Dr. Finkelstein introduced Dr. Rod Corriveau and Dr. Amelie Gubitz, new program directors in the Neurodegeneration Cluster, and Dr. Katrina Gwinn, a new program director in the Neurogenetics Cluster.

IV. Concept Clearance for FY 2011 Proposed Initiatives

Dr. Danilo Tagle, Program Director, Neurogenetics Cluster, discussed a proposed Administrative Supplement program to conduct Whole Genome Deep Sequencing of Neurological Disorders with Small Cohorts to advance gene discovery for Mendelian disorders that are not amenable to whole genome analysis approaches such as GWAS, but that can benefit from more targeted approaches.

Dr. Finkelstein requested, and was granted, a motion to move forward with this initiative.

V. Report of the Director, NIH

Dr. Francis Collins, Director, NIH, presented an overview of a number of important themes that will help guide the momentum and scientific opportunities of NIH moving forward. Beforecontinuing, Dr. Collins reflected on the excitement associated with the visit of President Obama and Secretary Sebelius to the NIH in September 2009, and noted the words of the President which positioned the scientific enterprise as an important part in providing solutions for many of the problems that face our Nation and the world. Themes described (Science 1 January 2010: Vol. 327. no. 5961, pp. 36 – 37) by Dr. Collins that provide both scientists and NIH with exceptional scientific opportunity include: 1) applying high throughput technologies (e.g., imaging, nanotechnology, computational biology, small molecule screening, DNA sequencing) to understand fundamental biology and to uncover the causes of specific diseases; 2) translating basic science discoveries into new and better treatments, and to empower basic science investigators to play a larger role in translational research; 3) putting science to work for the benefit of health care reform (e.g., comparative effectiveness research, personalized medicine, pharmacogenomics research, and research on health disparities); 4) encouraging a greater focus on global health; and 5) reinvigorating and empowering the biomedical research enterprise.

NIH’s overall goals are captured by its two-fold mission statement, the first part of which, "Science in pursuit of fundamental knowledge about the nature and behavior of living systems," encapsulates the basic research enterprise. Dr. Collins noted that over the years, the NIH has excelled in this endeavor, supporting the research of over 131 Nobel Prize winners as well as many other seminal and important basic research findings. To illustrate, Dr. Collins pointed to a recently published NINDS-supported finding which identified over 800 genes involved in the song learning behavior of the male zebra finch. Applying these basic research findings is the second piece of the NIH mission "…application of that knowledge to extend healthy life and reduce the burdens of illness and disability," towards which significant advances have been made. These advances are made particularly evident by the decline of death and disability rates in the United States over the past 30 years.

To capitalize on the opportunities to translate basic research findings into therapies for disease, the NIH has developed a number of programs to empower academic researchers to conduct drug discovery research. The NIH Molecular Libraries Program helps researchers take a promising target and develop a high-throughput screening assay. The NIH TRND (Therapeutics for Rare and Neglected Diseases) and NIH RAID (Rapid Access to Interventional Development) provides investigators with the tools to bridge the "valley of death" and conduct the preclinical research (e.g., medicinal chemistry, pharmacology, toxicology) necessary to develop a "druggable" agent from a lead compound. Following agent development, the NIH Clinical Center is poised, now more than ever, to facilitate clinical trials, particularly for rare diseases. Dr. Collins also commented that the newly developed NIH-FDA Joint Leadership Council which will help foster a relationship between the two agencies to improve translational research and to make NIH finding more "regulatory review ready." Another translational research effort that emerged as part of the Health Care Reform bill is the Cures Acceleration Network (CAN), the goal of which is to dramatically advance the development of new treatments and cures for debilitating and life-threatening diseases by reducing barriers between laboratory discoveries and clinical trials. The bill provides the NIH with the authority to utilize flexible funding mechanisms and research authority; however, activation of these authorities requires a specific appropriation for CAN, which has not yet been approved.

Lastly, Dr. Collins reported that the NIH budget has been flat between FY03 and FY08, and that while ARRA (the American Recovery and Reinvestment Act) provided much-needed relief to this drought of funding, challenging economic times may cause the success rates for obtaining NIH funding to fall to historic lows. Dr. Collins encouraged the audience to "Make the Case for NIH" by educating others about the importance of biomedical research and by inspiring passion for science in the next generation through events such as "National Lab Day."

VI. Report of the Director, NINDS

The 5 Opportunities

Dr. Landis reported that the 5 Opportunities for NIH outlined by Dr. Collins are reflected in a number of new and ongoing Common Fund projects including: Knockout Mouse Phenotyping (KOMP), the Library of Integrated Network-based Cellular Signatures (LINCS), Translational Applications of Stem Cells, Science of Behavior Change, the HMO Collaboratory, and Health Economics. In addition, Dr. Landis noted that FY10 budgets of the NIH ICs were partially determined based on the FY08 IC spending on these priorities.

The Big Think

Dr. Landis reported on The Big Think, a meeting convened by Dr. Collins on May 7, 2010, with about 50-60 experts to brainstorm and discuss potential topics for future NIH Common Fund projects in the following thematic areas: High Throughput Approaches, Translation, and the Science of Health Reform. A number of ideas were generated in each of these areas including: developing protein affinity reagents beyond monoclonal antibodies, identifying generalizable methods for assessing gene function (e.g., metabolic signatures), advancing tissue-specific targeting of small molecules, accessing "failed" compounds from the private sector for potential repurposing, conducting a systematic assessment of known genes/pathways involved in rare diseases, developing Centers of Excellence in chronic disease management, and designing a study to assess effects of different provider incentive models on cost and health care outcomes.

Financial Conflicts of Interest (FCOI)

In response to a number of Congressional inquiries regarding the impact of financial conflicts of interest on the conduct and reporting of federally-funded research, the NIH issued a Notice of Proposed Rulemaking: Responsibility of Applicants for Promoting Objectivity in Research for Which Public Health Service Funding is Sought and Responsible Prospective Contractors which was published in the Federal Register on May 21, 2010 (http://edocket.access.gpo.gov/2010/pdf/2010-11885.pdf). The Notice will be available for Public Comment until July 20, 2010, and addresses such issues as: 1) Significant Financial Interest, 2) Investigator disclosure requirements, 3) Public disclosure, 4) Management of an identified FCOI by the Institutions, 5) Information on an identified FCOI reported by the Institution to the PHS funding component, 6) Timing of reporting of an identified FCOI to the PHS-funding component, 7) Scope of the Regulation, 8) Investigator training, and 9) HHS authority to inquire about FCOI.

Health Care Reform: The Patient Protection and Affordable Care Act (PL 111-148)

On March 22, 2010, President Obama signed H.R. 3590, the Patient Protection and Affordable Care Act into law (PL 111-148). Provisions of this legislation that are of particular interest to NIH include: formation of the Cures Acceleration Network, Comparative Effectiveness Research (establishes a non-profit institute called the Patient-Centered outcomes Research Institute, which is authorized to set research priorities and a research agenda), Pain Research (convenes an IOM panel to evaluate the adequacy of diagnosis treatment and management of pain and establishes an FACA-sanctioned Interagency Pain Research Coordinating Committee to identify gaps in basic and clinical research), Emergency Medicine Research, and the designation of the National Center on Minority Health and Health Disparities (NCMHD) as an Institute.

NINDS Strategic Planning

NINDS is in the final stages of completing an Institute-wide Strategic Planning effort that commenced in 2006. Rather than mandating what science should be supported by NINDS, this planning exercise charged four external advisory panels with addressing more global questions associated with how NINDS should support science and manage scientific investments. The reports of these four panels were presented at the February 2009 meeting of the NANDS Council, and a summary of these reports is available on the NINDS website (http://www.ninds.nih.gov/about_ninds/plans/NINDS_strategic_plan.htm ) for Public Comment until May 28, 2010. An area that remains to be covered is Workforce Diversity and Health Disparities. A fifth panel has been established to address this topic, which held its first meeting May 12-13, 2010. Finally, Dr. Landis reported that a number of the recommendations made by the Basic, Translational, Clinical and Disease panels have been implemented, including: 1) modification of NINDS’s R21 policy, 2) release of an RFP for a medicinal chemistry contract, and 3) initiation of a planning effort on global health.

ARRA Support for New Faculty Recruitment

Dr. Landis provided an update on an ARRA initiative (RFA-OD09-005) designed to provide two years of Institutional support to hire, provide appropriate start-up packages, and develop pilot research projects for newly independent investigators, with the goal of augmenting and expanding the institution’s community of multidisciplinary researchers focusing on areas of biomedical research relevant to NIH. NIH-wide, 141 awards were made; NINDS funded 18 awards to create 28 positions.

NIH Blueprint Neurotherapeutics Grand Challenge: New Drugs for Nervous System Disorders

Dr. Landis provided the Council with an update on the Neurotherapeutics Grand Challenge, spearheaded by the NIH Blueprint for Neuroscience, a cooperative network of 16 NIH Institutes, Centers and Offices that support neuroscience research. This initiative (RFA-NS-11-002) is an effort to facilitate the movement of investigator-initiated ideas for new drugs for nervous system disorders through the therapeutic pipeline. Funded investigators will be provided with industry-standard infrastructure and expertise through a series of contracts for medicinal chemistry, preclinical toxicology, and industry advisors and consults with the goal of moving projects through the drug development pipeline to create licensing opportunities for industry handoff. It is anticipated that 20 projects will be selected for initial funding, with the goal of licensing 2 successes to industry at the end of 5 years.

VII. Council Subcommittee Reports

Clinical Trials Subcommittee — Dr. Thomas Brott/Dr. Timothy Pedley, Co-Chairs

Dr. Pedley reported on a presentation by Dr. Petra Kaufmann, Associate Director of the NINDS Office of Clinical Research, updating the subcommittee on a number of active NINDS supported clinical trials and detailing a number of steps that are being taken by the Institute to facilitate the success of new and ongoing trials (e.g., Common data elements project). In addition, the subcommittee discussed new program announcements designed to coordinate Phase III trials with pilot trials and ancillary studies. Dr. Brott noted that the overriding theme of the subcommittee’s discussions was on the difficulties of patient recruitment for trials, and the strategies being taken to overcome these challenges.

Basic and Preclinical Programs Subcommittee — Dr. John Povlishock, Chair

Dr. Povlishock reported on a discussion of the Basic and Preclinical Programs Subcommittee of the NINDS investment in Research Resources, defined as tools, collections or facilities to advance neuroscience research. This discussion was prompted by recommendations made by the Basic Research Strategic Planning module, and was facilitated by an analysis of four NINDS-supported resource programs performed by the DER-OSPP Analysis working group. Culminating from this analysis was a series of recommendations for the management of Research Resources moving forward (e.g., RFI to assess community need for new resources, Annual solicitation for resource applications, Milestone assessment, Evaluation of resource prior to resubmission).

Training, Career Development and Special Programs Subcommittee — Dr. Gary Westbrook, Chair

The Committee did not meet this Council round.

VIII. Overview, Division of Intramural Research (DIR)

Dr. Alan Koretsky, Scientific Director, NINDS, reported on the progress of infrastructure development within the Intramural Research Program, much of which was due to an influx of funds from the American Recovery and Reinvestment Act. In particular, it is anticipated that the second phase of the Porter Neuroscience Center, completion of which has been stalled for several years, will be finished in 2013. This facility houses 83,000 square feet of space that will be integrated across all of the neuroscience institutes, facilitating an increased collaborative effort.

IX. Scientific Presentations

Dr. Russell Lonser, Chair, Surgical Neurology Branch, DIR, gave a talk entitled, "Surgical Neurology Branch Overview" and "Convection-Enhanced Delivery for Pharmacologic Neurosurgery."

Despite the recent development of new therapeutic compounds for neurologic disorders that have shown promise in vitro, translation of these agents into effective clinical therapies is limited by the properties associated with existing delivery techniques including systemic, intrathecal or intraventricular, and drug-impregnated polymer delivery. Systemic delivery of putative therapeutics agents is limited by the blood-brain barrier, systemic toxicity, and non-specific distribution. Diffusion-driven delivery methods including intrathecal or intraventricular administration and drug-impregnated polymer implantation, result in homogeneous distribution over severely limited tissue volumes (2 to 4 mm from drug exposed surface). To overcome these limitations, the Surgical Neurology Branch has an ongoing effort using convection-enhanced delivery (CED) to distribute therapeutic molecules in the CNS for translational/clinical studies. Driven by a small hydrostatic pressure gradient, CED directly distributes infusate to targeted regions at an infusion cannula tip within the interstitial spaces of the CNS bypassing the blood-brain barrier. Because CED does not rely on diffusion for distribution, convective delivery distributes both small and large molecules reliably, safely, and homogeneously over clinically relevant volumes. Moreover, recent development of co-infused surrogate imaging tracers now permits for accurate real-time monitoring of drug distribution using computed tomography and magnetic resonance imaging. By exploiting the properties of CED, we are developing new research and treatment paradigms for CNS disorders in translational and clinical studies. Specifically, we are examining the use of image-guided convective delivery of factors to manipulate and expand endogenous stem cell populations, to treat malignant brainstem gliomas in children, to better define epileptic foci and predict side effects of surgical resection, to gain insight into the pathophysiology of Parkinson’s disease and predict surgical therapeutic success, and to develop viral-based gene therapy strategies for regeneration in Parkinson’s disease patients.

Next, Dr. Richard J. Youle, Senior Investigator, Biochemistry Section, Surgical Neurology Branch, DIR, gave a talk entitled "Mitochondrial Quality Control and the Etiology of Familial Parkinson's Disease." To explore the etiology of Parkinson's disease, our lab has investigated the molecular mechanism of the link identified in prior genetic studies between mitochondria and the E3 ubiquitin-ligase, Parkin that ismutated in autosomal recessive Parkinson's disease. We found that Parkin changes subcellular location upon mitochondrial damage and accumulates from the cytosol onto uncoupled mitochondria. Interestingly, Parkin selectively tagged only the damaged mitochondria within a cellular milieu of respiring mitochondria. Following Parkin recruitment and ubiquitination of proteins on the mitochondrial surface, the tagged organelles become engulfed by autophagosomes and eliminated. This suggested that Parkin mediates a long known but mechanistically mysterious quality control program that helps maintain the fidelity of our population of mitochondria. These results further suggested that certain forms of familial Parkinson's disease are caused by defects in mitochondrial quality control.

How Parkin is recruited selectively to impaired mitochondria was recently revealed by our group. Pink1, a mitochondrial outer membrane kinase, originally found mutated in families with autosomal recessive Parkinson's disease, was previously shown to function genetically upstream of Parkin. Corroborating their model that defects in mitochondrial quality control may cause parkinsonism, we found that Pink1 and its kinase activity are strictly required for Parkin recruitment to and elimination of damaged mitochondria. Furthermore, mutations in Parkin and Pink1 occurring in patients with Parkinson's disease were defective at various stages in this mitochondrial elimination process. We also identified a novel mechanism of Pink1 signaling mitochondrial damage to Parkin. Pink1 is rapidly synthesized and imported into all cellular mitochondria and immediately degraded by proteases to maintain a low level of expression and scant Parkin recruitment to healthy mitochondria. When a mitochondrion is damaged and loses membrane potential, Pink1 degradation (but not synthesis) stops allowing the rapid accumulation of Pink1 selectively on the damaged mitochondria within a population and thereby organelle-specific Parkin recruitment and mitophagy. This unanticipated mechanism of regulating Pink1 expression on select populations of mitochondria is proposed to mediate the quality control process.

X. Review of the Division of Intramural Research Board of Scientific Counselors’ Reports

In closed session, Dr. Koretsky presented the findings and recommendations of the Board of Scientific Counselors based on their review of specific DIR laboratories/units during 2009. The Council discussed the reports of the Board and accepted them.

XI. Adjournment

The meeting was adjourned at 5:50 p.m. on Thursday, May 27.

We certify that, to the best of our knowledge, the foregoing minutes and attachments are accurate and complete.

Robert Finkelstein, Ph.D.
Executive Secretary
National Advisory Neurological Disorders and Stroke Council

Director, Division of Extramural Research
National Institute of Neurological Disorders and Stroke

Story C. Landis, Ph.D.
Chairperson
National Advisory Neurological Disorders and Stroke Council

Director
National Institute of Neurological Disorders and Stroke

These minutes will be formally considered by the Council at its next meeting. Corrections or notations will be incorporated in the minutes of that meeting.