Research (OER)
9000 Rockville Pike
Bethesda, Maryland 20892
and Human Services (HHS)
GENE THERAPY IN DUCHENNE MUSCULAR DYSTROPHY
NIH GUIDE, Volume 23, Number 7, February 18, 1994
PA NUMBER: PA-94-040
P.T. 34
Keywords:
Neuromuscular Disorders
Gene Therapy+
National Institute of Neurological Disorders and Stroke
National Institute of Arthritis and Musculoskeletal and Skin Diseases
PURPOSE
The National Institute of Neurological Disorders and Stroke (NINDS)
and the National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS) encourage the submission of research grant
applications to investigate the potential for gene therapy in
Duchenne muscular dystrophy. Responses to this program announcement
may include studies in appropriate animal models of gene replacement
using viral vectors, myoblast transfer, or other means of dystrophin
enhancement.
HEALTHY PEOPLE 2000
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention goals of "Healthy People 2000," a
PHS-led national activity for setting priorities. This program
announcement, Gene Therapy in Duchenne Muscular Dystrophy, is related
to the priority area chronic disabling conditions. Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
No. 017-001-00474-0, or Summary Report: Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government. Foreign institutions
are eligible to apply for only regular research project grants (R01).
Applications from minority individuals and women are encouraged.
MECHANISMS OF SUPPORT
The support mechanisms for grants in this area will be the
investigator-initiated research project grant (R01), the First
Independent Research Support and Transition (FIRST) award (R29), the
program project grant (P01), and the center grant (P50). The
Principal Investigator or program director, as well as any
participating investigators, will plan, direct, and perform the
research. Applicants for program project grants are requested to
contact the NINDS representative listed below as early as possible in
the planning stages.
RESEARCH OBJECTIVES
Duchenne muscular dystrophy (DMD) is the most common inherited
neuromuscular disease, affecting approximately one in 3,500 male
births. The disease is characterized by muscle necrosis and
regeneration. Eventually, the regeneration cannot keep up with the
necrosis, resulting in progressive muscle fiber loss. Affected boys
are usually wheelchair-bound by age 12, with death occurring in the
third decade. A milder variant, Becker muscular dystrophy, occurs
once in 30,000 male births. Isolation of the X-linked DMD gene led
to the discovery of dystrophin, the protein that is missing or
defective in Duchenne muscular dystrophy and abnormal in Becker
muscular dystrophy. Dystrophin is a 427-kd protein and an essential
component of the inner surface of the sarcolemmal membrane. The
full-length gene for dystrophin is huge, 2.4 megabases, and most
mutations are frame-shift deletions (Duchenne) or internal in-frame
deletions (Becker).
The most frequently studied animal model of Duchenne muscular
dystrophy is the mdx mouse, in which the homologous mutation also
results in a lack of dystrophin. Like affected humans, the mdx mice
have recurrent muscle fiber necrosis; regeneration, however, is very
efficient, and the mice do not suffer generalized muscle fiber loss
and weakness. A dog model with a similar mutation may be a superior
model of DMD because its size and symptoms are much closer to humans.
Unfortunately, the dog model has several disadvantages compared to
the mouse, including slow breeding rate, scarcity, and expense.
Among the potential genetic therapy approaches to dystrophin
replacement that have been considered are direct injection of DNA,
vector-mediated delivery, and myoblast transfer. These approaches
all present major obstacles that must be overcome.
The full-length dystrophin gene with its associated promoters and
other regulatory elements may be too large to routinely introduce
into muscle fibers directly or using a viral vector. Human cDNA,
length about 14 kb, has been isolated, and a partial cDNA of only 6.3
kb has been cloned from a patient with only very mild symptoms,
suggesting that such a smaller "minigene" could protect DMD muscles
from necrosis. A gene of this size could be accommodated in an
adenovirus or retrovirus vector.
Myoblast transfer studies in mice have been reported, with the
percentage dystrophin positive host muscle fibers varying widely.
Several groups of investigators have also performed similar
experiments in Duchenne muscular dystrophy boys. The procedure
appears to be safe, but so far there is little evidence of increased
strength or the production of dystrophin in the host muscle.
This announcement solicits applications for any study whose ultimate
goal is the successful genetic therapy of Duchenne muscular
dystrophy. Examples are given below, but applications are not
limited to these areas of research:
o Improve methods to express dystrophin cDNAs in viral vectors,
including adenovirus and retrovirus.
o Develop techniques to increase the penetration of gene constructs
into the muscle cells and their nuclei and to enhance the dispersion
of injected gene constructs or myoblasts.
o Develop strategies to enhance the efficiency of myoblast transfer
therapy.
o Investigate the feasibility of the 6.3 kb cDNA for genetic
therapy.
o Find alternative mechanisms to increase levels of existing
dystrophin.
o Assess the feasibility of injecting DNA directly into muscle
cells.
STUDY POPULATIONS
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis must be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them. This policy is
intended to apply to males and females of all ages. If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale must be provided.
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group. In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study. This information must be included in the form PHS 398 in
Sections 1-4 of the research plan AND summarized in Section 5, Human
Subjects. Applicants are urged to assess carefully the feasibility
of including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics). The rationale for
studies on single minority population groups must be provided.
For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.
The usual NIH policies concerning research on human subjects also
apply. Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded. However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants. For
foreign awards, the policy on inclusion of women applies fully; since
the definition of minority differs in other countries, the applicant
must discuss the relevance of research involving foreign population
groups to the United States' populations, including minorities.
If the required information is not contained within the application,
the review will be deferred until the information is provided.
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed and the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.
All applications for clinical research submitted to NIH are required
to address these policies. NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.
APPLICATION PROCEDURES
Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) according to instructions contained in the
application kit. Application kits are available from most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301-710-0267.
Check "YES" in item 2a on the face sheet of the application and type
"Gene Therapy in Duchenne Muscular Dystrophy."
FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.
Applicants for the P01 or P50 should use the application format as
described in the NINDS pamphlet, NINDS GUIDELINES: PROGRAM PROJECT
AND RESEARCH CENTER GRANTS (rev. June 1992). Deadlines for the
receipt of applications are February 1, June 1, and October 1. The
completed original application and five exact copies must be sent or
delivered to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
If the application is for a program project or center grant, submit
the original and three copies to the Division of Research Grants. An
additional two copies must be sent to Dr. Nichols at the address
listed under INQUIRIES to expedite processing applications for
multidisciplinary efforts.
REVIEW CONSIDERATIONS
Applications will be assigned on the basis of established PHS
referral guidelines. Applications will be judged on scientific merit
and program relevance in accordance with NIH policy and procedures
involving peer review. An initial review will be made by an
appropriate study section of the Division of Research Grants for
regular research grants and FIRST awards, and by an appropriate
institute committee for program projects and centers. A second level
of review will be made by an appropriate national advisory council.
AWARD CRITERIA
Applications will compete for available funds with all other approved
applications. The following will be used in making funding
decisions:
o Quality of the proposed project as determined by peer review
o Availability of funds
o Program balance among research areas of the announcement
INQUIRIES
Written and telephone inquiries are encouraged. The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Paul L. Nichols, Ph.D
Developmental Neurology Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8C08
Bethesda, MD 20892
Telephone: (301) 496-5821
Richard W. Lymn, Ph.D.
Muscle Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 403
Bethesda, MD 20892
Telephone: (301) 594-9959
Bitnet: LYM@NIHCU
Direct inquiries regarding fiscal matter to:
Patricia P. Driscoll
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 10A14
Bethesda, MD 20892
Telephone: (301) 496-9231
Carol Clearfield
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 726
Bethesda, MD 20892
Telephone: (301) 594-9973
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic
Assistance No. 93.853 ("Clinical Research Related Neurological
Disorders") and 93.854 ("Biological Basis Research in the
Neurosciences"). Awards are made under authorization of the Public
Health Service Act, Title IV, Part A (Public Law 78-410, as amended
by Public Law 99-150, 42 USC 241 and 285) and administered under PHS
grant policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.
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