CHARACTERIZATION AND TREATMENT OF GENETIC METABOLIC DISEASES

NIH GUIDE, Volume 23, Number 7, February 18, 1994



PA NUMBER:  PA-94-036



P.T. 34



Keywords:

  Metabolic Diseases 

  Genetics 

  Pathophysiology 

  Treatment, Medical+ 



National Institute of Diabetes and Digestive and Kidney Diseases



PURPOSE



The purpose of this program announcement is to encourage research

grant applications studying the mechanisms underlying the

pathophysiology of genetic metabolic diseases.  Research should be

aimed at elucidating the genetic defects, examining their metabolic

consequences, and devising and testing possible therapies for this

group of devastating diseases.



HEALTHY PEOPLE 2000



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 Program

Announcement, Characterization and Treatment of Genetic Metabolic

Diseases, 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 202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by for-profit and non-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 not eligible for First Independent Research Support and

Transition (FIRST) (R29) awards and program projects (P01).

Applications from minority individuals and women are encouraged.



MECHANISM OF SUPPORT



Support of this program will be through the NIH research project

grant (R01), FIRST (R29) awards, and program projects (P01).  All

investigators interested in submitting a program project will need to

discuss the application with NIDDK staff and obtain the NIDDK Program

Project Guidelines prior to applying for support via this mechanism.

The use of Interactive Research Project Grants (IRPG) is encouraged

for multi-disciplinary approaches to this complex problem.  Further

information on the IRPG mechanism is available in the NIH Guide, Vol.

22, No. 16, April 23, 1993.



RESEARCH OBJECTIVES



The National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) supports research on identifying and understanding the basic

defects in causing genetic metabolic diseases, identifying

alternative metabolic pathways, characterizing toxic metabolites and

the mechanisms of their effects on multiple organs, development of

animal models for these disorders, and treatment of these disorders

including enzyme replacement therapy, dietary therapy, drug therapy

and gene therapy.  The diseases of interest include disorders of

cellular transport, lysosome metabolism, peroxisome metabolism, amino

acid and organic acid metabolism, carbohydrate metabolism, purine and

pyrimidine metabolism, metal metabolism, lipid metabolism, and

mucopolysaccharide metabolism.



Background



The NIDDK has a continuing interest in supporting research in the

area of genetic metabolic diseases.  The Metabolic Diseases and Gene

Therapy Research Program has a large portfolio of regular research

and program project grants that study genetic metabolic diseases.

For many of these diseases, the enzyme defects have been identified

and the genes that are mutated have been cloned with grant support

from this program.  In addition, the NIDDK has recently funded three

core centers for gene therapy of cystic fibrosis and other genetic

diseases to accelerate progress in the development of this important

technology.



The diseases that historically have made up Garrod's inborn errors of

metabolism are due to defects in particular enzymes that result in

the use of alternative metabolic pathways, the production of abnormal

metabolites and frequently the aberrant storage of undigested

materials.  In many cases, it is the build up of these aberrant

metabolites that is toxic to several organ systems.  With extension

of the lifespan of patients with these diseases through therapy, it

has become increasingly evident that most metabolic diseases affect

several organ systems.  One such example is Galactosemia.  When this

life-threatening liver disease is prevented by dietary restrictions,

additional manifestations develop in other organs such as the ovarian

failure, which is unmasked by treatment.  Although treatment of

primary manifestations is an important approach with tremendous

therapeutic value, to adequately address the multisystemic nature of

these disorders it is important to develop methods to correct the

basic defect systemically.



Scope



Some examples of research topics that would be considered responsive

to this solicitation include, but are not limited to, the following:



o  Identification of Basic Defects:  This would include identifying

the protein or enzyme that is defective, isolating the gene that is

abnormal, identifying the mutations that cause the syndrome, and

studying the structural and functional properties of both the normal

and defective protein including X-ray crystallographic studies.

Another important area is the development or improvement of

diagnostic testing to enable earlier prenatal detection of metabolic

diseases.



o  Cellular and Animal Models of the Metabolic Diseases: Cellular and

animal models are particularly important for studying the underlying

metabolic disturbance and for testing potential therapies.  Cellular

models would include the culture of appropriate cell types that

manifest the defect for further study.  Animal models can include

identification and characterization of naturally occurring mutations,

the creation of a knock out mutant or the introduction of a point

mutation by homologous recombination, and the development of a

chemically induced model that mimics features of the disease.



o  Identification of Toxic Metabolites and their Mechanism of Action:

Enzyme deficiencies generate abnormal and/or excessive metabolites

that may then be shunted though alternative pathways for degradation.

In many cases, these metabolites are harmful to a variety of organ

systems.  For many metabolic diseases whose symptoms are attributed

to the production of toxic metabolites, the actual toxic metabolites

have not been identified nor has the mechanism of their detrimental

effects been fully elucidated.  For example, recent findings that

sphingosine, a sphingolipid breakdown product, inhibits the activity

of protein kinase C in vitro could help explain the mechanisms of

toxicity in the pathogenesis of the sphingolipidoses.  This mechanism

may result in a progressive dysfunction of the signal transduction

pathway vital for cell viability.  Research that focuses on such

elements in order to explain the pathophysiology of genetic metabolic

diseases is needed.



o  Identification of Genetic Modifiers:  As the genotypes of many

metabolic disorders are studied for their ability to predict severity

of disease, it is clear that genes other than those causing the

primary defect can modify the phenotype.  One classic example is that

the persistence of fetal hemoglobin gene expression modifies the

beta-thalassemia phenotype and, as a result, these patients have a

milder clinical course.  Identification of genes that modify the

phenotype of other common genetic mutations is needed to explain the

etiology of multiple phenotypes within a single genotype.



o  Development of Enzyme Replacement Therapy:  Enzyme replacement

therapy has been attempted for several metabolic diseases; however,

in most cases the enzyme is degraded prior to reaching the target

tissue.  Recently, two different protein modifications have led to

the development of enzyme replacement therapy for ADA deficiency and

Gaucher Disease.  Research is needed to develop methods for producing

large quantities of biologically active enzymes; modifications

directing targeting into organelles such as peroxisomes and into

specific tissues, for example, by ligand-mediated internalization

through cell surface receptors; and increasing protein half-life by

protein modification or genetic engineering of amino acids important

for signaling protein degradation.



o  Development of Dietary or Drug Therapy:  Current treatment for

most metabolic diseases consists of dietary restrictions, vitamin

supplementation and/or drug therapy to prevent the build up of toxic

metabolites.  Research into new or improved dietary or drug therapy

based on an understanding of the metabolic defect is needed.  One

area of research could be to develop drug therapy to prevent

aggregation of mutant proteins and to promote proper folding and

assembly of complex proteins.



o  Development of Gene Therapy:  The area of gene therapy for

metabolic diseases has evolved quickly.  In order to further

accelerate progress, many new directions must be evaluated for their

feasibility as approaches for gene therapy.  Studies of new viral

vectors, chimeric vectors, improved techniques for homologous

recombination and improvement in delivery vehicles such as liposomes

and receptor-mediated endocytosis are examples of areas in need of

further development.



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 are 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

(rev. 9/91) in Item 4 (Research Design and Methods) of the Research

Plan AND summarized in Item 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,

African Americans, 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 tissue

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) and will be accepted at the regular application

deadlines as indicated in the application kit. The receipt dates for

applications for AIDS-related research are found in the PHS 398

instructions.



Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Information, Division of Research Grants, National Institute of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

301/435-0714.  The title and number of this program announcement must

be typed in Section 2a on the face page of the application.



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 should be included

with the application.



For investigators applying for support through the FIRST award (R29),

three letters of references must be submitted with the application.

An applicant submitting a revised application in response to this RFA

must again submit reference letters.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institute of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Several other Institutes at the National Institutes of Health also

have an interest in supporting areas of research covered by this PA.

Applications will be assigned on the basis of established Public

Health Service referral guidelines and some applications may receive

dual assignments.  In the case of R01 and R29 applications, they will

be reviewed for scientific and technical merit by study sections of

the Division of Research Grants, NIH, in accordance with the standard

NIH peer review procedures and criteria.  Program project

applications will be reviewed by initial review groups organized by

the Institute to which the application is assigned.  Following

scientific-technical review, the applications will receive a

second-level review by the Institute's national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding

decisions:  quality of the proposed project as determined by peer

review; availability of funds; and 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.



Requests for the NIDDK Program Project Guidelines and inquiries

regarding programmatic issues may be directed to:



Dr. Catherine McKeon

Division of Diabetes, Endocrinology and Metabolic Diseases

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 621

Bethesda, MD  20892

Telephone:  (301) 594-7582

FAX:  (301) 594-9011



Direct inquiries regarding fiscal matters to:



Ms. Donna Huggins

Division of Extramural Activities

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 649

Bethesda, MD  20892

Telephone:  (301) 594-7543



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.847 . 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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