Full Text AI-93-013

GENE THERAPY FOR HIV-1 INFECTION:  PRECLINICAL DEVELOPMENT

NIH GUIDE, Volume 22, Number 20, June 4, 1993

RFA:  AI-93-013

P.T. 34

Keywords: 
  AIDS 
  Viral Studies (Virology) 
  Gene Therapy+ 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  July 1, 1993
Application Receipt Date:  September 8, 1993

PURPOSE

This Request For Application (RFA) is designed to support applied
preclinical development studies for gene therapy systems targeting HIV;
such studies are vital for the transition from basic research to
experimental clinical evaluation in infected individuals.  Studies in
response to this RFA may propose to refine: viral vectors for in vivo
delivery; physical methods for in vivo transduction (liposomes,
receptor-ligand, naked DNA); expression of anti-HIV genes or
anti-cellular factors (negative transdominants, RNA-decoys, ribozymes)
for maximal virus inhibition in PBL challenged with clinical HIV
isolates.  Studies listed above are examples only, and are not intended
to be exclusive or comprehensive.

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 RFA, Gene
Therapy for HIV-1 Infection: Preclinical Development, is related to the
priority area of HIV Infection.  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 organizations, private and public institutions such as
universities, colleges, hospitals, laboratories, units of State and
local governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The support mechanism for this program is the individual research
project grant (R01) award.  It is the responsibility of the applicants
to plan, direct, and execute the proposed projects in accord with their
ongoing commitment to the development of gene therapy as a treatment
for HIV infected individuals.  Because the nature and scope of the
research proposed in response to this RFA may vary, it is anticipated
that the size of the awards will also vary.  The anticipated award date
is March 1994.  This RFA is a one-time solicitation.  Future
unsolicited applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review
procedures.

FUNDS AVAILABLE

The National Institute of Allergy and Infectious Diseases (NIAID) has
set aside $0.6 million (total costs) for first year funding of
applications received in response to this RFA.  Three to four awards
are anticipated.  The final number and specific amounts of awards to be
made will depend on the scientific quality, merit and scope of the
applications received, on relevance to programmatic priorities, and on
the availability of funds.  The total project period for applications
submitted in response to this RFA may not exceed four years.

RESEARCH OBJECTIVES

Background

Acquired Immune Deficiency Syndrome (AIDS) is a disease that destroys
the body's capacity to mount an effective immune response against a
variety of infections.  As of March 31, 1993, 289,320 cases of AIDS had
been reported in the United States by the Centers for Disease Control
(CDC) and more than 182,275 of these patients (63%) had died.  Recent
projections indicate that between 1,000,000 to 1,200,000 persons in the
United States may already be infected with HIV, the infectious virus
associated with AIDS.  To date, three drugs, AZT, ddI, and ddC, all
targeted to the viral reverse transcriptase, have been approved by the
FDA for HIV therapy.  Despite the advances in treating HIV infection
with nucleoside analogues, these agents have a limited duration of
activity; further, the emergence of drug-resistant isolates upon
prolonged treatment limit their indefinite use.  Several drugs,
including non-nucleoside reverse transcriptase inhibitors (NNRTI) and
those targeted against unique steps in HIV replication (protease
inhibitors, Tat-inhibitor) are currently undergoing clinical
evaluation.  Not with standing these efforts, the rapid emergence of
HIV resistant variants to certain NNRTI in vitro and in clinical
trials, reports of in vitro emergence of resistant isolates to protease
inhibitors, and uncertainties regarding the efficacy of newer drugs,
point to the urgent need to develop anti-HIV therapeutic strategies
based on state-of-the-art technological advances.  While these may
involve greater research risk than traditional antiviral approaches,
they offer the potential to effect long lasting therapeutic benefit.

Gene therapy - the process by which new genetic information is
introduced into patients' cells with a resulting therapeutic benefit -
is a cutting-edge strategy potentially applicable for the treatment of
HIV infection.  Gene therapy is not a single antiviral strategy but
rather a conglomerate of discrete, yet diverse manipulative steps
resulting in the endowment of target cells with an antiviral
'protective' capability.  Principal steps involved in an anti-viral
gene therapy strategy include:

o  Selecting the target for intervention (viral or host function);

o  Designing, constructing, and expressing the inhibitory gene (RNA
decoys, transdominant negative gene product, catalytic RNA, others);

o  Selecting the vehicle for gene delivery:  defective viral vectors
[retroviral (retV), HIV, adenoassociated virus (AAV), others];
liposomes; receptor-ligand mediated; other;

o  Selecting the mode of intervention:  ex vivo modification and
manipulation of target cells or direct injection of genetic information
('naked' DNA) into accessible tissue for augmenting immune responses.

Comprehensive preclinical studies for gene therapy strategies in vitro
are already underway.  Moreover, a clinical trial that uses one form of
gene therapy is in progress:  HIV patients with AIDS-associated
lymphomas which have received allogeneic bone marrow are treated post
transplantation with a combination of chemoradiotherapy, AZT, and
adoptive transfer of modified CD8+ T cells [containing fused genes of
herpes virus thymidine kinase (tk) and bacterial hygromycin (hgh)] to
minimize infection of donor- derived cells.  In most cases, however,
once a promising gene therapy strategy is identified at the basic
research level, funding to support preclinical development work
essential for the transition to applied clinical phase is lacking.
This initiative will support applied, advanced preclinical development
studies of gene therapy for HIV, thereby bridging the gap between the
early basic research ('discovery' phase) and applied clinical phases.

[Concomitant with strategies to abate HIV gene expression/replication,
there is an urgent need for therapeutic strategies that augment/restore
immune functions in the immune compromised individual.  These two
facets of HIV infection - viral gene expression/replication and a
gradual deterioration of the immune system - must be controlled to
prevent the onset/exacerbation of AIDS.  A separate RFA (AI-93-12) for
'Complete Immune Reconstitution of HIV-1 Infected Individuals' focuses
on hematopoietic stem cell biology that may be exploited to restore
immune functions to HIV positive subjects.

Research objectives and scope

The objective of this RFA is to support 'post discovery' HIV gene
therapy studies and to propel promising, state-of-the-art therapies
closer to clinical evaluation.  The many aspects in this transition
process are responsive to this RFA, including optimization of
intracellular delivery/expression of antiviral genes as well as
optimization of in vivo transduction methods capable of enhancing
immune parameters in HIV infected individuals.  Studies to be funded
under this RFA are restricted to investigators with ongoing gene
therapy projects which are directly related to HIV infection.
Investigators must demonstrate a commitment to the advanced preclinical
development and translation of a defined gene approach to clinical
evaluation.  Applications proposing a unique strategy for gene delivery
are responsive to the RFA provided the proposed preclinical
optimization studies focus on application to HIV infection.

Examples of advanced preclinical development projects responsive to
this RFA include:

o  Optimization of existing viral vectors [retV, HIV, AAV, herpes
simplex virus (HSV), others] for antiviral gene delivery to target
cells.  This includes gene stability, expression levels, tissue
specific promoters if required, purity and yield of recombinant vector
stock, stringent assessment for "leakiness" of helper-free virus, and
other parameters relevant to vector design and application.

o  Optimization of non-viral delivery vehicle
(liposomes,receptor-ligand, other);

o  Comparative assessment in relevant in vitro and/or animal models of
different anti-HIV genes, cis-acting regulatory elements, or cellular
functions critical for HIV gene expression for maximal virus
inhibition.  Examples of intracellular molecular inhibitors include:
transdominant negative mutants (tat, rev, gag, others); RNA decoys
(RRE, TAR, psi); multivalent ribozymes; antisense molecules;
transdominant mutants of NFkB; and Tat, Rev, TAR and RRE binding
proteins.  Multi-pronged targeting of unique viral functions for
enhanced inhibition and reduction of viral load are encouraged.

o  Refinement of vectors that provide stable, persistent expression in
mature and stem cell derived differentiating cells susceptible to HIV
infection;

o  Development of efficient and safe methods to enhance infection of
target cells (T-cells, stem cells, other) by recombinant vectors and
reduce ex vivo manipulations;

o  Development of anti-HIV strategies for the induction of cytolytic T
lymphocytes (CTL) and humoral response in HIV infected individuals.
Encouraging data in animal models using in vivo delivery of HIV-gp120
gene suggest the feasibility of inducing MHC-dependent CTL response as
a form of immune augmentation in HIV infected individuals;

o  Safety assessment of HIV gene therapy strategies in appropriate
animal models including toxicity studies.

Relationship to Ongoing Programs

A complementary RFA for immune reconstitution of HIV-infected patients
with multi-potent stem cells engineered to resist HIV infection is
available.  Studies on gene therapy for the treatment of HIV infection
funded or supported under other RFAs or other programs, which have
overlapping specific aims or objectives, are not responsive to this
RFA.

SPECIAL REQUIREMENTS

The NIAID will organize one to two meetings a year to which the
Principal Investigators and other key personnel will be invited to
attend.  This meeting will serve to promote interaction/collaboration
among awardees, discuss scientific issues bearing on
preclinical/clinical development of gene therapy strategies, and
feasibility of planned approaches. Other investigators with ongoing
programs in gene therapy strategies for HIV infection will be invited
to further promote exchange of information and ideas.  Funds for travel
to this meeting should be included in the budget.  For budgetary
purposes, applicants should assume travel costs for one meeting to the
Washington DC area or vicinity.

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 should 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 should
be provided.  The composition of the proposed study populations must be
described in terms of gender and racial/ethnic group, together with a
rationale for its choice.  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 should 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).  The rationale for studies on single minority population
groups should be provided.

For the purpose of this policy, clinical research includes 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 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 populations
groups to the United States' populations, including minorities.

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 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
that do not comply with these policies.

NOTE:  Peer review groups need adequate information about the
composition of proposed study populations in all applications involving
human subjects.  To avoid delays in review of such applications, the
NIAID therefore requires that, as a minimum, the application must
contain demographic data about the clinic and/or in-patient population
from which study subjects (including clinical samples, materials, or
fluids) will be drawn:  average hospital admissions and/or clinic
visits per year; percentage distribution of black/hispanic/other
minority/non-minority populations; gender; etc.  Studies using
non-hospital populations, such as community-based studies, should
provide similar data about populations in the area or region from which
the study subjects will be drawn.  In the absence of current data,
historical demographic information and/or previous recruitment data for
similar studies from the proposed study sites should be provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 1, 1993 a letter of
intent that includes a descriptive title of the proposed research, the
names and affiliation(s) of the Principal Investigator and other key
personnel, and the number and title of this RFA.  Although the letter
of intent is not required, is not binding, and does not enter into
subsequent peer review deliberation, it provides NIAID staff with
information on the number and scope of applications to be expected,
allows estimation of the potential review workload, and avoids conflict
of interest in the review.  The letter of intent is to be sent to Dr.
Madelon Halula 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 Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, Telephone
(301) 710-0267.  The deadline for receipt of application in response to
this RFA is September 8, 1993.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center of Research Resources
may wish to identify the Center as a resource for conducting the
proposed research.  If so, a letter of agreement from the GCRC Program
Director must be included in the application material.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page.  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 'Gene Therapy for HIV-1 Infection:  Preclinical
Development' and number (RFA AI-93-013) must be typed on line 2a of the
face page of the application, and the 'Yes' box marked.

Submit, in one package, a signed typewritten original of the
application including the Checklist, and three signed, exact
single-sided photocopies, to:

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

At the time of submission to DRG, two additional, exact copies must be
sent to Dr. Madelon Halula at the address indicated under INQUIRIES,
below.

Applications received after the receipt date will be returned without
review.  Alternatively, late applicants will be contacted and given the
option of having the application returned or  having it submitted for
review in competition with unsolicited applications for the next DRG
cycle.

The DRG will not accept an application in response to this RFA which is
essentially the same as one pending initial review, unless the
applicant withdraws the pending application.  DRG will not accept an
application which is essentially the same as one already reviewed.
This does not preclude the submission of a revised application already
reviewed. Revised application, however, must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Applications and supporting material will be reviewed by DRG for
completeness, and by NIAID staff to determine administrative and
programmatic responsiveness to this RFA.  If the application is judged
to be not responsive, NIAID staff will contact the applicant and
present the same options for handling the application as in late
submission, above.

Applications may be triaged by an NIAID peer group on the basis of
relative competitiveness among applications responsive to this RFA.
The NIH will withdraw from further competition those applications
judged to be non-competitive for award and notify the Principal
Investigator and institutional official.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an appropriate
review committee convened by the NIAID.  The second level of review
will be provided by the National Advisory Allergy and Infectious
Diseases Council.

Review Criteria

Review criteria for assessing the merit of submitted applications
include:

o  documented primary observations of an identified gene therapy
strategy with high potential for development of effective anti-HIV
therapy (e.g., use of specific antiviral gene);

o  preliminary data indicating feasibility of the strategy to be
developed;

o  likelihood for high therapeutic potential payoff that justifies
greater than usual risk level;

o  originality and adequacy of the experimental approach for developing
the identified strategy;

o  scientific and technical merit of the proposed research;

o  qualification and research experience of the Principal Investigator
and staff, specifically but not exclusively in the area of gene
therapy;

o  availability of resources necessary to perform the studies;

o  appropriateness of the proposed budget and duration in relation to
the proposed budget.

AWARD CRITERIA

The anticipated date of award is March 1994

The primary criterion for award is the scientific and technical merit
of the application as judged by peer reviewers and reflected in
priority score.  Additional award criteria are the availability of
funds, receipt of a sufficient number of scientifically meritorious
applications that are responsive to this RFA, and overall programmatic
relevance and priority.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged; the
opportunity to clarify issues and questions from prospective applicants
is welcome.

Direct inquiries concerning the programmatic and scientific aspects of
this RFA to:

Nava Sarver, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C11
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8197
FAX:  (301) 402-3211

Direct inquiries regarding matters pertaining to the review of
applications and address the letter of intent to:

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building,  Room 4C10
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 402-2636
FAX:  (301) 402-2638
Email:  MHalula@exec.niaid.pc.niaid.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building,  Room 4B22
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:  July 1, 1993
Application Receipt Date:       September 8, 1993
Scientific Review Date:         November 1993
Advisory Council Date:          February 1994
Anticipated Award date:         March 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases Research and
93.855 - Immunology, Allergic and Immunological Diseases Research.
Grants are awarded under the authority of the Public Health Service
Act, Section 301 (42 USC 241) and administered under the PHS grants
policies and Federal Regulations, most specifically at 42 CFR Part 52
and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of the Executive Order 12372 or
Health Systems Agency review.

.

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