Full Text HL-95-012

LUNG SPECIFIC DRUG DELIVERY SYSTEMS FOR TUBERCULOSIS TREATMENT

NIH GUIDE, Volume 24, Number 1, January 13, 1995

RFA:  HL-95-012

P.T. 34

Keywords: 
  Pulmonary Diseases 
  0740022 
  Microbiology 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 24, 1995
Application Receipt Date:  April 7, 1995

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites grant
applications to encourage research on novel approaches to therapy,
adjuvants to therapy, and prophylaxis of tuberculosis (TB), using the
lung as the site of drug delivery.

The primary objective of this special grant program is to develop new
modalities of treatment for pulmonary TB based on delivery of the
therapeutic agent(s) directly to the lung.

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 Request
for Applications (RFA), Lung Specific Drug Delivery Systems for
Enhanced TB Treatment, is related to the priority area of
immunization and infectious diseases.  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 domestic and foreign for-profit and
non-profit institutions, public and private, such as universities,
colleges, hospitals, laboratories, units of state and local
governments and eligible agencies of the Federal government.  Foreign
institutions are not eligible for the First Independent Research
Support and Transition (FIRST) award (R29).  Applications from
minority individuals women and new investigators are encouraged.

All current policies and requirements that govern the research grant
programs of the NIH will apply to grants awarded under this RFA.
Awards under this announcement to foreign institutions will be made
only for research of very unusual merit, need, and promise, and in
accordance with Public Health Service policy governing such awards.

Among the disciplines and expertise that may be appropriate for this
research program are molecular pharmacology, physical chemistry, cell
biology, biochemistry, virology, molecular biology, molecular
immunology, infectious diseases, pathology, and pulmonary medicine.

MECHANISM OF SUPPORT

The support mechanism for this program will be the National
Institutes of Health (NIH), individual research grant (R01) and the
FIRST award (R29).  While multidisciplinary approaches are
encouraged, it is not the intent of this announcement to solicit
applications for large studies encompassing a variety of individual
subprojects, i.e., program projects.  If collaborative arrangements
through subcontracts with other institutions are planned, consult the
program staff listed under INQUIRIES.

Upon initiation of the program, the NHLBI will sponsor periodic
meetings to encourage exchange of information among investigators who
participate in this program.  In the budget for the grant
application, applicants should request travel funds for a one-day
meeting each year, most likely to be held in Bethesda, Maryland.
Applicants should also include a statement in their applications
indicating their willingness to participate in these meetings.

Applicants (who will plan and execute their own research programs)
are expected to furnish their own estimates of time required to
achieve the objectives of the proposed research project.  Up to five
years of support may be requested for R01s; five years are required
for FIRST awards.  Requested budgets for FIRST awards may not exceed
those specified in the FIRST award guidelines.  Because a variety of
approaches would represent valid responses to this RFA, it is
anticipated that there will be a range of costs among individual
grants awarded.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications may be submitted for peer review and
competition for support through the regular grant program of the NIH.
It is anticipated that support for this program will begin in
September 1995.  Administrative adjustments in project period and/or
amount may be required at the time of the award.

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 the GCRC
program director and principal investigator should be included with
the application.

The National Institute of Allergy and Infectious Diseases (NIAID)
also has interest in developing new delivery systems and new
therapeutic agents for the treatment of tuberculosis.  Therefore,
applications that are of mutual interest are likely to be given a
secondary assignment to NIAID in accordance with the NIH referral
guidelines.

FUNDS AVAILABLE

Although financial plans for fiscal year 1995 include approximately
$2,500,000 for the total cost of the program for the first year,
award of grants pursuant to this RFA is contingent upon receipt of
funds for this purpose.  It is anticipated that no more than 10
awards will be issued under this program.  The specific number to be
funded will, however, depend on the merit and scope of the
applications received and the availability of funds.

RESEARCH OBJECTIVES

Background

The spread of tuberculosis (TB) has reemerged as an urgent health
problem.  Rates for this disease have been increasing since the mid
1980s in association with the HIV epidemic.  Recent projections of TB
rates made by the Centers for Disease Control suggest that,
worldwide, the current high rate of new TB cases in the population is
likely to increase over the next 10 years.  For industrialized
countries, including the United States TB case rates are expected to
remain stable or perhaps increase slightly over the next decade.  The
number of new active cases of TB reported annually in the U.S.
population is now approximately 10/100,000 (new cases/100,000 people
in the general population), with extremely high rates in HIV infected
study populations, about 800/100,000.

Current methods of treatment are far from optimal and better ones are
being sought to overcome the increasing spread of TB and the problem
of incompletely treated TB that contributes to the emergence of drug
resistant strains.  Since many patients with TB may have significant
social problems, compliance with drug therapy is frequently
difficult.

The development of targeted drug delivery to the lungs as a means of
treating TB is desirable for several reasons.  Although TB is a
systemic disease that can potentially affect any organ system, the
lung is the major portal of entry for Mycobacterium tuberculosis
(Mtb) and thereby the site of the initial immune response as well as
an important site of reactivation disease.  Technology for lung
specific drug delivery systems is now at a point where aerosols and
aerosols combined with liposomes and possibly timed-release
methodology may offer advantages for more effective treatment and
prevention of TB.

Conventional antituberculous medications frequently have serious side
effects.  Although single drugs can be effective for prophylactic
treatment of skin test converters, active disease must be treated
using combinations of three or four drugs over a period of at least
six to nine months to insure that disease will not recur after
treatment is discontinued and to prevent the emergence of resistant
strains.  Targeted delivery of new formulations, directly to the
lungs, could result in high pulmonary levels relative to systemic
levels.  Thus, increasing effectiveness and decreasing toxicity.
Supplementing the dose of agent delivered to the diseased lung, when
it is the only clinically involved organ, could make it possible to
decrease the duration of treatment in these cases.  Because the
systemic dose will not be increased, undesirable toxicities would be
avoided.

Another advantage is that this mode of delivery might make it easier
to provide prolonged treatment.  It should be possible to design
biopolymers or nanoparticles which slowly dissolve and therefore
slowly release their drugs to the pulmonary environment.  Improved
targeted delivery approaches combined with development of new
antituberculous drugs or with timed release formulations may reduce
the frequency of dose delivery.  This would be a major benefit in
treating patients in whom it is hard to maintain effective compliance
with treatment regimens.  For example, longer intervals between
treatment would make it easier to deliver directly observed therapy,
which is an effective means of getting patients to complete a full
course of treatment.

Targeted drug delivery may be essential in carrying out future modes
of TB therapy such as gene therapy resulting in increased cytokine
expression or antisense oligonucleotide therapy blocking protein
synthesis.

Objectives and Scope

The objective of this initiative is to encourage basic research aimed
at developing new modalities of treatment for TB, using the lung as
the site of drug delivery.

Delivery of antituberculous agents to the lung might be used as a
means of increasing local concentrations of drug to augment existing,
conventional therapy or perhaps the lung could be used as the route
of delivery for agents that are intended to work both locally and
systemically.  It is thought that lowered systemic toxicity provided
by this approach would permit much more flexibility for treatment
regimens such that smaller, more effective doses may be employed.
Conversely, if a lung delivery system is intended as the only route
for drug delivery, it would be essential to demonstrate that systemic
levels of drug are adequate to treat TB elsewhere in the body.

Drugs could be targeted to the lung as opposed to other organs, to
airways of a specific size within the lungs, or perhaps to injured or
diseased areas as compared to normal ones.  Specific cells such as
macrophages, endothelial cells, or epithelial cells might be targeted
and it should even be possible to deliver drugs to specific
organelles within a cell.

Potential drug delivery sites could include the alveolar surface
itself, or cells on the surface such as macrophages, lymphocytes, or
neutrophils.  Other targets might include cells and extracellular
matrix beneath the epithelium.  The nature of the material will
affect its fate.  For example, insoluble particulate material will
largely be taken up by resident alveolar macrophages.  Some
surfactant phospholipids will be recycled into Type II epithelial
cells.  Soluble molecules will enter and pass through or between
epithelial cells into the extracellular matrix. Some proteins will be
found in phagocytic cells in the connective tissue and lymph nodes.

Aerosol delivery of therapeutic agents to the lung has been used for
many years in the treatment of airways obstructive diseases.  Since
the 1980s the aerosol application of interferon-alpha (INF-`) has
been examined by several groups of investigators for the treatment of
various types of lung cancer.  Interferon-gamma has also been given
to human subjects to activate alveolar macrophages.  In general, it
seems possible to deliver fairly high concentrations of these agents
to the epithelial lung surface and minimize the systemic dose and
toxicity.

Drugs used in the treatment of TB including rifampin and streptomycin
can be encapsulated in liposomes.  Drugs such as these could be
delivered to the lung in conjunction with antituberculous therapy
(administered by mouth or parenterally) to augment therapy or given
to replace conventional therapy, if adequate levels can be achieved
in all parts of the body.

Liposomal preparations of drugs or agents capable of potentiating
immune responses may have enhanced uptake by lung cells.
Furthermore, it appears to be possible to deliver liposomes by the
aerosol route.  Surfactant which may be useful as a vehicle for the
delivery of other agents can be aerosolized and delivered to the
lung.

Research topics that could be applicable to the goals of this RFA
might include, but are not limited to, the following areas:
mechanisms of treatment, drug formulation issues, delivery strategies
to get agents to the respiratory tract, targeting strategies to reach
particular sites, evaluation of drug delivery and especially,
evaluation of effectiveness of lung targeted drug delivery.  These
issues could be studied at a variety of levels including laboratory
modeling animal testing, and human studies.

Both animal studies and innovative studies involving human subjects
or using human cells or tissues are encouraged. Research involving
humans should be formulated in the context of mechanistic studies and
should address specific hypotheses.  Large scale clinical studies are
beyond the scope of this RFA.  Pharmacologic agents currently used in
antituberculous regimens and agents that appear to show promise for
future use are of interest.

SPECIAL REQUIREMENTS

Applications that propose descriptive studies and do not contain
hypothesis driven studies directed at developing lung specific drug
delivery systems to aid in the treatment of tuberculosis will not be
acceptable.  Treatment strategies must be clearly linked to the lung
and to specific mechanisms of mycobacterial disease.  This program
will not support studies directed at development of animal models
alone, therefore the models must be applied to the study of lung
specific drug delivery strategies for use in the treatment of
mycobacterial disease.  This RFA is not intended to support in vitro
studies of drug screening. Studies to verify that drug in an active
state reaches the site intended for deposition should be included.
Applications that focus on molecular pharmacologic approaches are of
particular interest.

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 subpopulations must be included in all NIH supported
biomedical and  behavioral research projects involving human
subjects, unless a clear and compelling rationale and justification
is provided that inclusion is inappropriate with respect to the
health of the subjects or the purpose of the research.  This new
policy results from the NIH Revitalization Act of 1993 (Section 492B
of Public Law 103-43) and supersedes and strengthens the previous
policies (Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 24, 1995, 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 subsequent applications, the information
that it contains allows NIH staff to estimate the potential review
workload and to avoid conflict of interest in the review.  The letter
of intent is to be sent to Dr. C. James Scheirer, at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, The Westwood Building, Room 449, Bethesda, MD 20892,
telephone (301) 435-0714.  Use the conventional format for research
project grant applications and ensure the points identified in the
section REVIEW CONSIDERATIONS are fulfilled.  To identify the
application as a response to this RFA, check "YES" on item 2a of page
1 of the application and enter the title "Lung Specific Drug Delivery
Systems for Enhanced TB Treatment" HL-95-012.

The RFA label found in form PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form PHS 398.  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.

Send or deliver the completed application and three signed
photocopies in one package to:

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

Send two additional copies of the application to the Chief, Review
Branch, DEA at the address listed under INQUIRIES.  It is important
to send these two copies at the same time as the original and three
copies are sent to the Division of Research Grants.  Otherwise the
NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by April 7, 1995.  If an application is
received after this date, it will be returned to the applicant
without review.  The 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness to this RFA by the NHLBI.  Incomplete
applications will be returned without further consideration.  If the
application is not responsive to the RFA, DRG staff may 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.  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 Division of Extramural Affairs, NHLBI in accordance with the
review criteria stated below.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.

Review Criteria.  The factors to be considered in the evaluation of
scientific merit of each application will be similar to those used in
the review of traditional research project grant applications
including the novelty, originality, and feasibility of the approach;
the training, experience, and research competence of the
investigator(s); the adequacy of the experimental design; the
suitability of the facilities; the appropriateness of the requested
budget to the work proposed and the adequacy of plans to include both
genders and minorities and their subgroups as appropriate for the
scientific goals of the research.  Plans for the recruitment and
retention of subjects will also be evaluated.  The initial review
group will also examine the provisions for the protection of human
and animal subjects and the safety of the research environment.

AWARD CRITERIA

The anticipated date of award is September 29, 1995.  In addition to
the scientific merit of the applications, awards will be based on
responsiveness to the RFA and the availability of resources.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A09
Bethesda, MD  20892
Telephone:  (301) 594-7425
FAX:  (301) 594-7487
Email:  hpv%nihhwb1.bitnet@cu.nih.gov

Direct inquiries regarding review matters to:

C. James Scheirer, Ph.D.
Division of Extramural Activities
National Heart, Lung, and Blood Institute
Westwood Building, Room 557
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407
Email:  james_scheirer%nihhwb1.bitnet@cu.nih.gov

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17
Bethesda, MD  20892
Telephone:  (301) 594-7420
FAX:  (301) 594-7492
Email:  raymond_zimmerman%nihhwb1.bitnet@cu.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.838.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410,
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 to review by a Health
Systems Agency.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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