GENE THERAPY FOR NEUROLOGICAL DISORDERS
Release Date: July 19, 2001
RFA: RFA-NS-02-007
National Institute of Neurological Disorders and Stroke
National Institute of Child Health and Human Development
National Institute on Aging
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Deafness and Other Communications Disorders
Letter of Intent Receipt Date: October 15, 2001
Application Receipt Date: November 16, 2001
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. USE THE MODULAR
BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 (REVISION 5/2001)
AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html.
PURPOSE
The goal of this Request for Applications (RFA) is to accelerate the
translation of gene transfer methodologies into the clinic. Gene therapy
holds tremendous promise for the treatment of neurological disorders.
Despite recent advances in this area however, specific scientific,
technological, and safety goals must be achieved before gene transfer becomes
a viable therapeutic alternative. Current needs include more effective
methods for controlling the expression of therapeutic transgenes in the
brain, better strategies for vector delivery and monitoring transgene
expression, more studies addressing the toxicity of specific vector/transgene
combinations, and greater knowledge of the long term effects of expressing
specific transgenes in the nervous system. This RFA is intended to encourage
research projects that address these or related translational issues in the
context of specific neurological disorders.
RESEARCH OBJECTIVES
Background
Gene transfer methodologies may ultimately be used to treat a broad spectrum
of diseases that affect the nervous system. These include neurodegenerative
disorders (Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral
sclerosis, Huntington’s disease, etc.), stroke, epilepsy, and many genetic
diseases (lysosomal storage disorders, muscular dystrophies,
neurofibromatosis, etc.). There is also significant potential for the
application of gene therapy to the neural periphery, such as the auditory
system, since a number of genes that cause sensorineural deafness have been
isolated. For all these disorders, gene therapy could be used to supply gene
products that prevent disease onset or progression. Gene therapy also holds
great promise for the treatment of injury to the brain or spinal cord, as
well as for the amelioration of chronic pain.
The brain and nervous system present unique challenges to achieving
successful gene transfer. Because the brain contains many distinct cell
types and is regionally heterogeneous, determining how to deliver therapeutic
genes effectively is critical. The presence of the blood-brain barrier,
limited access to the brain, and the post-mitotic state of brain cells make
introducing genes and ensuring that they are correctly expressed difficult.
Finally, although the brain is comparatively isolated from immunological
surveillance, immune and inflammatory responses can occur, thereby damaging
neural tissue.
Recent studies indicate that, despite these problems, gene transfer has great
potential as a therapeutic modality. Through genetic manipulation, the
identification of spontaneous mutations, and drug treatment, investigators
have developed animal models for a variety of neurological disorders. Using
modified viral vectors, liposomes, genetically-modified cells, or direct DNA
transfer, researchers have delivered a variety of therapeutic genes into
these animal models. Among these have been genes encoding growth factors,
enzymes, anti-apoptotic proteins, anti-oxidant molecules, and anti-
angiogenesis factors. Researchers have attempted gene replacement therapy in
animals lacking a particular gene product, and have used antisense or
ribozyme technologies to reduce the expression of dominantly acting gene
products. Many of these pre-clinical experiments have been extremely
successful. For example, in a recent NINDS-sponsored workshop (Gene Therapy
for Neurological Disorders, October 23-24, 2000), investigators described the
successful treatment of animal models of Parkinson’s disease and of specific
lysosomal storage disorders. A summary of this meeting has been published
(see Molecular Therapy 3: 3-7, 2001).
Scope
This RFA is intended to encourage projects that, if successful, will overcome
obstacles blocking the translation of gene transfer techniques into the
clinic. Proposed projects should relate directly to a neurological disorder
relevant to the research missions of NINDS, NICHD, NIA, NIDCD or NIDDK.
These missions are described at:
http://www.ninds.nih.gov/about_ninds/plans/strategic_plan.htm (NINDS)
http://www.nichd.nih.gov/strategicplan/cells (NICHD)
http://www.nih.gov/nia/research/extramural/neuroscience/programs.htm and
http://www.nih.gov/nia/strat-plan/2001-2005/ (NIA),
http://www.nidcd.nih.gov/about/plans/strategic/health_disp.asp (NIDCD)
http://www.niddk.nih.gov/fund/program/topicslist.htm (NIDDK)
Projects should focus on specific scientific, technological, or safety issues
that must be addressed prior to the initiation of clinical trials.
Possible scientific/technological goals include, but are not limited to:
O The development of improved inducible vectors that permit effective
temporal control over transgene expression.
O The design of vectors with regulatory elements that permit gene expression
to be targeted to specific brain regions, peripheral neural tissues, or to
other cell types of therapeutic interest.
O The development of methods that achieve higher transduction efficiencies
and high-level, stable transgene expression in the nervous system.
O The development of techniques that permit improved focal or global delivery
of vectors into the brain or peripheral neural tissues.
O The development of improved methods for monitoring transgene expression in
the brain.
Safety issues, because of their paramount importance, should be addressed in
all projects. Possible safety-related goals include, but are not limited to:
O Toxicology studies and the determination of optimal dosage regimens for
specific vector/transgene constructs.
O The investigation of the long-term effects of expression of specific
therapeutic transgenes.
O The development of viral vectors that overcome problems of toxicity and
immune response.
O The use of large animal models to address safety issues.
SPECIAL REQUIREMENTS
Plan for Dissemination of Data and Biomaterials
Sharing of data and biological materials in a timely manner is essential for
the rapid progress of biomedical research. NIH policy requires that
investigators make unique research resources readily available for research
purposes to qualified individuals within the scientific community when they
have been published (see the NIH Grants Policy Statement at
http://grants.nih.gov/grants/guide/notice-files/not96-184.html)
To promote the dissemination of research results, applicants who respond to
this RFA must propose plans for sharing data and biomaterials generated
through the grant. Rapid sharing of data and biomaterials is strongly
encouraged. The Initial Review Group will evaluate the proposed sharing plan
and comment on its adequacy in an administrative note in the summary
statement. NIH staff will consider the adequacy of the plan in selecting
grants to be awarded.
National Gene Vector Laboratories
An obstacle facing gene transfer investigators is obtaining high quality
vectors and evaluating their safety. The National Gene Vector Laboratories
(NGVLs) were established in 1995 by the NIH to produce clinical grade vectors
for human gene transfer protocols and perform toxicology studies using these
vectors. Where appropriate, investigators are encouraged to utilize the
NGVLs (for further information, see http://www.iupui.edu/~iucc/ngvl/).
MECHANISM OF SUPPORT
This RFA will use the NIH individual research project grant (R01) and
exploratory/developmental grant (R21) mechanisms. For this solicitation,
participating NIH Institutes will use the NINDS guidelines for the R21
mechanism, which can be found at
http://www.ninds.nih.gov/funding/r21guidelines.htm. As described in these
guidelines, R21 proposals should have the potential for groundbreaking
impact, be restricted to a maximum of $125,000/year (direct costs), and
limited in duration to a maximum of two years. Applicants are encouraged to
contact program staff for advice about choosing the appropriate grant
mechanism.
For all competing individual research project grant applications
requesting up to $250,000 direct costs per year, specific application
instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME"
streamlining efforts being examined by NIH. Complete and detailed
instructions and information on Modular Grant applications can be found at:
http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that
request more than $250,000 in any year must use the standard PHS 398 (rev.
5/01) application instructions.
The total project period for an application submitted in response to this RFA
may not exceed five years.
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant. This RFA is a one-time
solicitation. Future unsolicited competing continuation applications will
compete with all investigator-initiated applications and be reviewed
according to the customary peer review procedures. The earliest anticipated
award date is July 1, 2002.
For administrative reasons, all applications received in response to this
solicitation will be assigned initially to NINDS. After discussions among
the participating Institutes following review, applications will be
reassigned to the Institute(s) that are programmatically most appropriate.
Because the scope of the research proposed in response to this RFA
encompasses the interests of several NIH Institutes, applications may receive
dual assignments based on the established PHS guidelines. Awards will be
made and managed by one of the participating NIH institutes.
FUNDS AVAILABLE
The participating Institutes intend to commit a total of approximately
$5,000,000 in FY 2002 to fund approximately 8 to 12 new grants submitted in
response to this RFA. Because the nature and scope of the research proposed
may vary, it is anticipated that the size of each award will also vary.
Although the financial plans of the Institute provide support for this
program, awards pursuant to this RFA are contingent upon the availability of
funds and the receipt of a sufficient number of meritorious applications.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Investigators from foreign institutions
are encouraged to contact program staff before preparing applications.
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Dr. Robert Finkelstein
NINDS
Neuroscience Center, Rm 2143
6001 Executive Blvd.
Bethesda, MD 20892-9527
Telephone: (301) 496-5745
FAX: (301) 402-1501
Email: finkelsr@ninds.nih.gov
Dr. Mary Lou Oster-Granite
Mental Retardation and Developmental Disabilities Branch
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
Dr. Bradley C. Wise
Neuroscience and Neuropsychology of Aging Program
NIA
Gateway Building, Suite 3C307
7201 Wisconsin Avenue MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
Email: WiseB@nia.nih.gov
Dr. Thomas M. Johnson
Scientific Programs Branch
NIDCD
Executive Plaza South-400C
6120 Executive Blvd.
Bethesda, MD 20892-7180
Telephone: 301-402-3461
FAS: 301-402-6251
Email: tj65y@nih.gov
Dr. Catherine McKeon
Division of Diabetes, Endocrinology and Metabolic Diseases
NIDDK
6707 Democracy Blvd.
Rm 6103, MSC 5460
Bethesda, MD 20892-5460
Telephone: (301) 594-8810
FAX: (301) 480-3503
Email: Catherine.McKeon@nih.gov
Direct inquiries regarding review issues to:
Dr. Lillian Pubols
Scientific Review Branch
NINDS
Neuroscience Center, Rm 3208
Bethesda, MD 20892
Telephone: (301) 496-9223
FAX: (301) 402-0182
Email: LP28E@nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Tina Carlisle
Grants Management Branch
NINDS
6001 Executive Boulevard, Rm 3290
Bethesda, MD 20892
Telephone: (301) 496-3938
Email: carlislt@ninds.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of the RFA in
response to which the application may be submitted. Although a letter of
intent is not required, is not binding, and does not enter into the review of
a subsequent application, the information that it contains allows IC staff to
estimate the potential review workload and plan the review.
The letter of intent is to be sent to Dr. Robert Finkelstein (see Inquiries)
by the date listed below.
SCHEDULE SUMMARY
Letter of Intent Receipt Date: October 15, 2001
Application Receipt Date: November 16, 2001
Peer Review Date: February, 2002
Council Review: May, 2002
Earliest Anticipated Start Date: July 1, 2002
APPLICATION PROCEDURES
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and NIH
staff. The research grant application form PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in
applying for these grants, with modular budget instructions beginning on page
13 of the application instructions. Applicants are permitted, however, to
use the 4/1998 revision of the PHS 398 for scheduled application receipt
dates until January 9, 2002. If you are preparing an application using the
4/1998 version, please refer to the step-by-step instructions for Modular
Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm
.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The
just-in-time concept allows applicants to submit certain information only
when there is a possibility for an award. It is anticipated that these
changes will reduce the administrative burden for the applicants, reviewers
and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in
applying for these grants, with the modifications noted below. Applicants
are permitted, however, to use the 4/1998 revision of the PHS 398 for
scheduled application receipt dates until January 9, 2002. If you are
preparing an application using the 4/1998 version, please refer to the step-
by-step instructions for Modular Grants available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
The RFA label available in the PHS 398 (rev. 5/2001) application form
(http://grants.nih.gov/grants/funding/phs398/labels.pdf) must be affixed to the
bottom of the face page of the application. Type the RFA number on the label.
Failure to use this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In addition,
the RFA title and number must be typed on line 2 of the face page of the
application form and the YES box must be marked.
Submit a signed, typewritten original of the application, including the
Checklist, and three 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)
At the time of submission, two additional copies of the application must be
sent to:
Dr. Lillian M. Pubols
Scientific Review Branch, NINDS
6001 Executive Blvd.
NSC Rm 3208, MSC 9529
Bethesda, MD 20892-9529
(for courier delivery use: Rockville, MD 20852)
Applications must be received by the application receipt date listed in the
heading of this RFA. If an application is received after that date, it will
be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA 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 substantial
revisions of applications already reviewed, but such applications must
include an introduction addressing the previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by NIH staff. Incomplete and/or non-responsive applications
will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated
for scientific and technical merit by an appropriate peer review group
convened by the NINDS Scientific Review Branch in accordance with the review
criteria stated below. As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally the top
half of the applications under review, will be discussed, assigned a priority
score, and 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 the application in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of these goals. Each
of these criteria will be addressed and considered in assigning the overall
score, weighting them as appropriate for each application. Note that the
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, an investigator 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 this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
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? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
(3) Innovation: Does the project employ novel concepts, approaches or
method? Are the aims original and innovative? Does the project challenge
existing paradigms or develop new methodologies or technologies?
(4) Investigator: Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?
(5) Environment: Does the scientific environment in which the 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?
(6) Sharing plan: Has the investigator proposed an adequate plan to make all
data and biological materials collected and produced as a result of the
proposed research accessible in a timely manner to the biomedical research
community?
(7) R21 applications only: Does this project have the potential for
groundbreaking impact? If successful, will this project achieve at least one
of the following goals: 1) generate pilot data to assess the feasibility of a
novel avenue of investigation? 2) involve high risk experiments that could
lead to a breakthrough in a particular field? or 3) demonstrate the
feasibility of new technologies that could have major impact in a specific
area?
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o 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.
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities
o adequacy of proposed sharing plan
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
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 biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are 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 research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html);
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to 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) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH 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 was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
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. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
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 RFA 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.
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. This policy announcement is found in the NIH Guide for Grants and
Contracts Announcement dated June 5, 2000, at the following website:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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 Request for
Applications (RFA), Gene Therapy for Neurological Disorders, is related to
many 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 No.
93.853 (NINDS), 93.865 (NICHD), 93.866 (NIA), 93.173 (NIDCD), and 93.847
(NIDDK). Awards are made under authorization of Sections 301 and 405 of the
Public Health Service Act as amended (42 USC 241 and 284) and administered
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts
74 and 92. This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-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.
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