Full Text HD-94-010


NIH GUIDE, Volume 22, Number 43, November 26, 1993

RFA:  HD-94-010

P.T. 34

  Gene Therapy+ 
  Mental Retardation 
  Metabolic Diseases 

National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  November 26, 1993
Application Receipt Date:  March 25, 1994


The Mental Retardation and Developmental Disabilities Branch (MRDD),
Center for Research for Mothers and Children (CRMC), National
Institute of Child Health and Human Development (NICHD), invites
program project grant applications to develop new technologies, or
improve existing ones, for gene therapy targeted toward disorders
causing mental retardation.  For the purpose of this Request for
Applications (RFA), the diseases of interest are restricted to
genetic conditions in which mental retardation is the primary
clinical manifestation.  Genetic disorders causing mental retardation
include defects of amino acid metabolism, urea cycle defects, organic
acidemia, carbohydrate metabolism (e.g., galactosemia), peroxisomal
disorders, trace metal defects, lysosomal storage diseases, and
disorders of purine metabolism (e.g., Lesch-Nyhan syndrome).
Whatever organs are necessary to target for gene transfer to correct
or prevent mental retardation could be considered in response to this
RFA.  Four to five P01s may be funded under this grant solicitation.
Assignment of grants to appropriate Institutes will be based on
current National Institutes of Health (NIH) referral guidelines.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Gene Therapy for Disorders Causing Mental Retardation, is related to
the priority area of chronic disabling conditions.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone


Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, and units of State or local governments, and
eligible agencies of the Federal government.  Applicants may
collaborate, through consultation or contractual arrangements, with
foreign investigators.  Applications from minority individuals and
women are encouraged.


This RFA will use the NIH program project grant mechanism (P01).  The
applications should be prepared in a manner consistent with the
information presented in the publication P01 PROGRAM PROJECT
from  NICHD program staff listed under INQUIRIES.  Responsibility for
the planning, direction, and execution of the proposed project will
be solely that of the applicant.  The total project period for
applications submitted in response to this RFA may not exceed five
years.  The anticipated date of award is September 30, 1994.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and will be reviewed according to
the customary NIH peer review procedures.


It is estimated that program project applications submitted in
response to this RFA will compete for approximately $3 million in
direct costs that will be made available for the first year of
support.  It is anticipated that four to five awards will be made.
The number of awards depends on the overall scientific merit of the
applications and the availability of funds in fiscal year 1994.


The MRDD Branch supports research that relates to the biological,
behavioral, and social processes that contribute to, or influence the
development of, mental retardation and developmental disabilities.
Prevention of MRDD and amelioration of the clinical manifestations of
those afflicted constitute areas of special emphasis within the
Branch.  To accomplish its mission, the Branch uses the mechanisms of
research grants, supports special core facilities in the Mental
Retardation Research Centers, provides contract support for
development of new research resources, and disseminates information
to the scientific community and the public.

Genetic disorders have become increasingly prominent in the etiology
of mental retardation, particularly in severe cases, i.e., I.Q. <50.
In a survey of 122 severely mentally retarded children in Sweden, 36
percent were found to have demonstrable chromosome abnormalities, and
5 percent were caused by mutant genes.  In addition, 20 percent had
multiple congenital anomaly syndromes, and 16 percent had perinatal
or unidentified prenatal causes.  Since a large proportion of the
multiple congenital anomaly syndromes, especially those that affect
the central nervous system, and some of the unidentified prenatal
causes are genetically determined, it is likely that genetic causes
accounted for more than 50 percent of the total.  With aggressive use
of antimicrobial agents to treat infectious diseases, widespread
immunization programs to protect against bacterial and viral
infectious agents, better nutrition, and surgical correction of
congenital abnormalities, increasing numbers of mentally retarded
children, including those with genetic defects, who otherwise would
have succumbed, are able to survive and live longer.

Significant progress has been made in several areas of research
relevant to gene therapy.  The concepts have evolved quite rapidly
from in vitro cellular and molecular studies, preclinical studies on
an expanding list of animal models for human genetic disorders, to
actual clinical gene therapy involving human subjects.  The number of
cloned and characterized genes is increasing rapidly; we now have a
better understanding of the nature of disease-producing mutations,
and gene regulation; a much improved and growing list of gene
delivery systems are available; and various methods can now be
applied to develop animal models for genetic disorders.  In addition,
the limited number of approaches that are currently available to
treat some genetic disorders, such as dietary restriction, and enzyme
replacement, are not completely successful and require life-long

This RFA solicits applications that will address methods to
efficiently transfer foreign genes into human and other mammalian
systems, including transfer of genetically modified cells to
recipient tissues, organs, or animal models; develop methods for
sustained survival, and controlled expression of transferred foreign
genes in vivo by developing and using appropriate enhancers and other
regulatory sequences; develop genetic animal models of human diseases
by homologous recombination, gene knockout, and other methods; and
initiate human clinical trials for conditions that cause mental
retardation.  Proposed projects should evaluate the efficacy,
long-term effects, safety and, in human trials, neuropsychological


Note concerning FDA regulation of human gene therapy and somatic cell

Human gene therapy and somatic cell therapy involve the
administration to patients of materials considered biological
products, and thus subject to regulation by the Center for Biologics
Evaluation and Research (CBER), FDA. Investigational new drug (IND)
applications are filed concerning clinical use of such products.
Investigators planning clinical studies in these areas or preclinical
and animal studies in support of future applications should inform
themselves concerning the types of preclinical studies that are
appropriate for such biological products.

CBER has prepared a document entitled "Points to Consider in Human
Somatic Cell Therapy and Gene Therapy (1991)," which provides
guidance in this area. Other relevant Points to Consider documents
should also be consulted.  These may include:

Points to Consider in the Production and Testing of New Drugs and
Biologicals Produced by Recombinant DNA Technology (1985)

Points to Consider in the Characterization of Cell Lines Used to
Produce Biologicals (1987)

Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (1987)

Points to Consider in the Collection, Processing, and Testing of
Ex-Vivo-Activated Mononuclear Leukocytes for Administration to Humans

Copies of Points to Consider documents are available from:

Division of Congressional and Public Affairs
Center for Biologics Evaluation and Research
1401 Rockville Pike, Suite 200N
Rockville, MD  20852-1448

CBER staff are also available for questions about which types of
therapies are covered, for consultation, or for arrangement of
pre-IND meetings at (301) 594-5114.

Note Concerning Institutions with NIH-funded GCRC

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator could be included
with the application.



NIH policy requires applicants for NIH grants that have a clinical
research component 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 and
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 must 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
(rev. 9/91) 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).  In that case,
the rationale for studies on single minority population groups should
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 the applicants.
If the required information is not contained within the application,
the application will be returned.

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 reflected
in assigning the priority score to the application.  In addition, NIH
funding components will not award grants or cooperative agreements
that do not comply with these policies.


Prospective applicants are asked to submit, by November 26, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, titles of the component subprojects and the principal
investigator, core facilities, when applicable, and the director of
each core, names 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 subsequent applications, the information
that it contains allows NICHD staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.

The letter of intent is to be sent to Dr. Felix F. de la Cruz at the
address listed under INQUIRIES.


The applicant is to submit the application using PHS 398 (rev. 9/91).
Application kits containing this form and the necessary instructions
are available in 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.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
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 2a 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:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Susan C. Streufert, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E-03
Bethesda, MD  20892

Applications must be received by March 25, 1994.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) 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 DRG 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.


Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness to the RFA by the NICHD staff.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA,
NICHD staff will contact the applicant to determine whether to return
the application to the applicant or submit it for review in
competition with unsolicited applications at the next review cycle.

Under certain circumstances, applications may be triaged by a peer
review group on the basis of relative competitiveness.  If so, the
NIH will withdraw from further competition those applications judged
to be non-competitive for an award and notify the applicant Principal
Investigator and institutional official.  Applications judged to be
competitive will undergo further scientific merit review.
Applications that are complete and responsive will be evaluated for
scientific and technical merit by a review panel convened solely for
this purpose by the Division of Scientific Review, NICHD.  The second
level of review will be provided by the National Advisory Child
Health and Human Development Council.

Review Criteria

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance of the application;

o  appropriateness and adequacy of the experimental approaches
proposed to carry out the research;

o  coordination, interrelationship, cohesiveness, and synergism among
the individual research projects and core components; relationship of
the program objectives to the common theme; the advantages of
pursuing the proposed research as a P01 rather than through
individual research grants;

o  qualifications and research experience of the Principal
Investigator for the entire program, and the principal investigators
for the component projects;

o  participation of a suitable number of responsible, experienced

o  the specific scientific objectives of each project that will
benefit from, depend upon, or contribute to collaborative
interactions with the other component projects within the P01 (i.e.,
objectives that can be accomplished with greater effectiveness,
and/or economy of effort, etc.);

o  an appropriate organizational and administrative structure for
effective attainment of program objectives;

o  arrangements for internal quality control of ongoing research, the
allocation of funds, day-to-day management, contractual agreements,
and internal communication and cooperation among program

o  availability and quality of resources and research environment;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  when applicable, quality of proposed core facilities;

o  adequacy of plans for the protection of human subjects;

o  adequacy of plans to protect against or minimize adverse effects
on animals; and

o  inclusion of women and minority subjects in research.


In addition to the scientific and technical merit of the application,
other factors will be considered in making the awards.  Among these

o  relevance to mental retardation;
o  access to unique populations; and
o  institutional commitment and support.

The anticipated date of award is September 30, 1994.


Written and telephone inquiries regarding this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants are welcome.

Requests for the program project guidelines, the letter of intent,
and inquiries regarding programmatic and scientific issues may be
directed to:

Felix F. de la Cruz, M.D., M.P.H.
Mental Retardation Developmental Disabilities Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B-09
Bethesda, MD  20892
Telephone:  (301) 496-1383

Fiscal and administrative inquiries may be directed to:

Mr. E. Douglas Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A-17
Bethesda, MD  20892
Telephone:  (301) 496-1303


This program is described in the Catalog of Federal Domestic
Assistance No. 93.865, Research for Mothers and Children.  Awards are
made under authorization of the Public Health Service Act, Title IV,
Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC
241 and 285) and administered under PHS grants 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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