BASIC AND CLINICAL RESEARCH ON RETT SYNDROME AND MECP2

RELEASE DATE:  April 8, 2003 (see correction NOT-NS-03-014)

PA NUMBER:  PA-03-097 (This program announcement is being replaced by PAS-05-024)

EXPIRATION DATE:  November 26, 2004

National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov)  

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:  93.173 (NICHD), 93.853 (NINDS)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The National Institute of Neurological Disorders and Stroke (NINDS) and the 
National Institute of Child Health and Human Development (NICHD) invite 
research grant applications aimed at understanding or treating Rett Syndrome 
(RTT).  The recent demonstration that mutations in the MeCP2 gene cause most 
cases of RTT has created new opportunities for both basic and clinical 
research.  Included within the scope of this PA are developmental, molecular 
genetic, and pathophysiological research, therapy development projects and 
clinical studies.  Studies of the role of MeCP2 in basic biological processes 
or in the etiology of other neurological or neurobehavioral disorders are also 
appropriate.  

RESEARCH OBJECTIVES

RTT is a severely disabling neurodevelopmental disorder that affects 1 in 10-
15,000 females.  Until recently, little progress had been made in 
understanding the cause of RTT or in developing approaches for its treatment.  
However, the demonstration that mutations in the MeCP2 gene cause RTT (Amir et 
al., Nat. Genetics 2:185-8, 1999) suggests new avenues for research and 
therapy development.  The goal of this Program Announcement is to accelerate 
RTT research by capitalizing on these opportunities.  

RTT is unlike any other pediatric neurological disorder in that it cannot be 
classified simply as a degenerative condition, storage disease, or 
developmental malformation.   Although MeCP2 mutations are now known to cause 
RTT, the function of this gene during development is not known.  The MeCP2 
protein was originally identified by its ability to bind specifically to CpG-
methylated DNA, and it has been shown to repress transcription in a 
methylation-dependent fashion.  However, its precise mechanism of action has 
not been determined.  There is currently no clear pathophysiological or 
neurodevelopmental model to explain how MeCP2 mutations cause the symptoms 
associated with this devastating disease.  Understanding the etiology of RTT 
will be critical for developing rational therapeutic interventions.

MeCP2 mutations have recently been implicated in several disorders in addition 
to RTT.  These include X-linked recessive mental retardation, autism, Angelman 
syndrome, and neonatal onset encephalopathy.  The MeCP2 gene may account for a 
significant fraction of cases of mental retardation in the general population, 
as well as for other broadly expressed phenotypes.  Progress in RTT research 
will therefore be important for understanding and treating a variety of other 
brain disorders.

Applications submitted in response to this PA should focus on a topic related 
to understanding or treating RTT.  Studies of the involvement of MeCP2 in 
other neurological or neurobehavioral disorders, which may shed light on RTT, 
are also appropriate.  Possible areas of investigation include, but are not 
limited to:

o Developmental, neuroanatomical, electrophysiological, and imaging studies 
intended to identify specific abnormalities in RTT patients or in animal 
models of RTT.

o Studies of the role of the MeCP2 gene product in basic cellular processes 
(e.g. transcription, chromatin structure).  Novel hypotheses are encouraged 
and may be particularly suited to the R21 grant mechanism (see Mechanisms of 
Support below). Structure/function analyses of MeCP2 are also appropriate. 

o Investigation of the role of MeCP2 in other neurological or neurobehavioral 
disorders, and studies of other conditions and clinical abnormalities that co-
occur in the families of individuals with RTT.

o Identification and analysis of genes misexpressed in RTT patients or RTT 
animal models.

o Development of more sophisticated animal models for RTT.  Such models could, 
for example, permit spatial or temporal regulation of MeCP2 expression during 
development or be useful for testing candidate therapeutics.

o Neurodevelopmental and longitudinal studies of RTT patients that investigate 
the neuropathological progression and inherent variability of the disease.  
Studies that will facilitate the future development of clinical trials are 
particularly encouraged.

o Identification of potential molecular targets for drug therapy of RTT.

o Pre-clinical screening of potential therapeutic agents in cellular or animal 
models of RTT.

o Clinical studies of the problems that afflict children with RTT, including 
autonomic disorders and difficulties with literacy and communication.
  
o Clinical trials of therapeutic agents for the treatment or management of 
RTT.
 
MECHANISMS OF SUPPORT 

This PA will use the NIH research project grant (R01) and 
exploratory/developmental grant (R21) award mechanism(s).  As an applicant, 
you will be solely responsible for planning, directing, and executing the 
proposed project.  Applicants are encouraged to contact program staff for 
advice about choosing the appropriate grant mechanism.

The R21 mechanism is intended to encourage new exploratory/developmental 
research projects by providing support for the early stages of their 
development.  For example, such projects could assess the feasibility of a 
novel area of investigation or a new experimental system that has the 
potential to enhance health-related research.  These studies may involve 
considerable risk but may lead to a breakthrough in a particular area, or to 
the development of novel techniques, agents, methodologies, models or 
applications that could have major impact on a field of biomedical, 
behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those 
supported through the traditional R01 mechanism.  For example, long-term 
projects, or projects designed to increase knowledge in a well-established 
area will not be considered for R21 awards.  Applications submitted under 
this mechanism should be exploratory and novel.  These studies should break 
new ground or extend previous discoveries toward new directions or 
applications.

R21 applications may request a project period of up to two years with a 
combined budget for direct costs of up $275,000 for the two year period.  For 
example, you may request $100,000 in the first year and $175,000 in the 
second year.  The request should be tailored to the needs of your project.  
Normally, no more than $200,000 may be requested in any single year.  

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.

Competing continuation applications submitted in response to this PA will 
compete with all investigator-initiated applications and be referred and 
reviewed according to the customary peer review procedures.  Responsibility 
for the planning, direction, and execution of the proposed project will be 
solely that of the applicant.  The earliest anticipated award date is April 
1, 2004.  

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
  and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Applicants proposing therapy 
development projects or clinical studies are particularly encouraged to 
consult program staff prior to submission.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues. 

o Direct your questions about scientific/research issues to:

Robert Finkelstein, Ph.D.
Neurogenetics Cluster
NINDS
6001 Executive Boulevard, Room 2143
Bethesda, MD 20892-9527
Telephone:  (301) 496-5745
FAX:  (301)  402-1501
Email:  rf45c@nih.gov

Dr. Mary Lou Oster-Granite
Mental Retardation and Developmental Disabilities Branch
Center for Research for Mothers and Children 
NICHD
6100 Executive Boulevard, Rm 4B09D, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 435-6866
FAX: (301) 496-3791
E-mail: mo96o@nih.gov

o Direct inquiries regarding fiscal matters to:

Kathleen Howe
Grants Management Branch
NINDS
6001 Executive Boulevard, Room 3266
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  howek@ninds.nih.gov

Dianna Bailey
Grants Management Branch
NICHD
6100 Executive Boulevard, Room 8A17C
Bethesda, MD  20892-7510
Telephone:  (301) 435-6978
FAX:  (301) 402-0915
Email:  baileyd@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SUPPLEMENTAL INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) 
must be followed, with these exceptions:

o   Research Plan

For R21 applications only, items a – d of the Research Plan (Specific 
Aims, Background and Significance, Preliminary Studies, and Research 
Design and Methods) may not exceed a total of 15 pages.  No preliminary 
data is required for R21 proposals, but may be included if it is 
available.  Please note that a Progress Report is not needed for R21 
awards; competing continuation applications for an 
exploratory/developmental grant will not be accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 
398 except that for R21 applications, no more than 5 manuscripts, 
previously accepted for publication, may be included.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study;

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 
available at http://grants.nih.gov/grants/funding/women_min/guidelines_
amended_10_2001.htm. The amended policy incorporates: the use of an NIH 
definition of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language governing 
NIH-defined Phase III clinical trials consistent with the new PHS Form 398; 
and updated roles and responsibilities of NIH staff and the extramural 
community. The policy continues to require for all NIH-defined Phase III 
clinical trials that: a) all applications or proposals and/or protocols must 
provide a description of plans to conduct analyses, as appropriate, to 
address differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) investigators must report annual accrual and 
progress in conducting analyses, as appropriate, by sex/gender and/or 
racial/ethnic group differences. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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