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 301-435-0714.



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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