DEVELOPMENT OF NEW GENE THERAPY VECTORS AND DELIVERY SYSTEMS 
NIH GUIDE, Volume 25, Number 32, September 27, 1996
 
P.T. 34

Keywords:
  Gene Therapy+ 
  0740022 
 
National Heart, Lung, and Blood Institute
 
Annual Receipt Dates:  April 1, August 1, and December 1 for STTR
                       April 15, August 15, and December 15 for SBIR
 
PURPOSE
 
The purpose of this notice is to emphasizes the importance of this
research topic to the National Heart, Lung, and Blood Institute
(NHLBI), National Institutes of Health (NIH).  Collaboration between
small business concerns and research institutions, including colleges
and universities, is encouraged to design and develop gene therapy
vectors and delivery systems for cardiovascular, pulmonary and
hematologic gene therapy.  Such collaboration is essential in order
to qualify for support under the Small Business Technology Transfer
(STTR) program and is permissible under the Small Business Innovation
Research (SBIR) program.
 
The "development of new gene therapy vectors and delivery systems" is
a research topic of special interest to the NHLBI, NIH, and is
identified in the OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF
HEALTH FOR STTR GRANT APPLICATIONS (PHS 95-4) on pages 78-81,
subtopics NN and E.  It is identified also in the OMNIBUS
SOLICITATION FOR SBIR GRANT APPLICATIONS (PHS 96-2) on pages 122-127,
subtopics JJJ, BB, Q,and Y.
 
The solicitations are available electronically through the NIH,
Office of Extramural Research "Small Business Funding Opportunities"
Home Page located at: HTTP://WWW.NIH.GOV/GRANTS/FUNDING/SBIR.HTM.  In
addition, a limited number of hard copies of the solicitations have
been produced.  Subject to availability, they may be obtained from
the PHS STTR/SBIR Solicitation Office, phone (301) 206-9385; fax:
(301) 206-9722; e-mail: a2y@cu.nih.gov.
 
RESEARCH OBJECTIVES
 
Background
 
Gene therapy or the introduction of genetic material into human cells
with successful expression of the inserted gene is a historic
technological advance.  It allows the development of novel strategies
for prevention, control, and treatment of disease through the use of
gene transfer.  However, gene therapy is still in its infancy and
faces many difficult biotechnical hurdles before it can achieve
widespread clinical application.
 
Somatic gene therapy entails two critical steps: delivery of the gene
to the appropriate cells and its subsequent maintenance and
expression.  In order to deliver the gene to the appropriate cell,
there must be a vehicle, or vector that will enter the cell and
transfer the genetic material into the host genome without adverse
effects.  To date, several vector systems such as RNA viruses
(retroviruses), DNA viruses (adenoviruses, adeno-associated viruses,
herpesviruses, and poxviruses), and naked or complexed DNA have been
developed.  However, none of these vectors are entirely satisfactory.
 
Presently, retroviruses and adenoviruses are the most extensively
employed vectors in clinical protocols.  However, both have
advantages and disadvantages.  Most retroviruses are efficient in
entering cells and integrating the transferred material into the host
genome but only if the cells are dividing.  In addition, their
preparation is cumbersome, titer yields are often low and they have a
limited carrying capacity for added genetic material.  On the other
hand, adenoviruses can enter dividing or nondividing cells, have high
titers and levels of expression, and relative ease of handling.
Their major drawback is that they may elicit immunogenic responses
from the host.  Experience with other DNA viral or nonviral systems
is less extensive and in its infancy.
 
Expanded and new research in collaboration with industry will enhance
the development of gene transfer technology.  Development of novel
vectors, modifications of existing vectors, and production of GMP-
grade vectors for clinical testing are areas particularly suited to
industry/academia collaborations.  Modern biotechnology and
pharmaceutical companies have important attributes: (1) skill in
translational research and the development of drug products; (2)
significant experience in meeting high manufacturing and quality
control standards; (3) professional staffs expert in regulatory and
clinical issues; and(4) high level of scientific and technical
expertise.  Involvement of industry in gene therapy technology will
facilitate the transfer of technology from the bench to the bedside
and bring products into the marketplace and into clinical practice at
the most rapid rate.
 
The potential of gene transfer to treat cardiovascular diseases is
substantial.  However, there are unique features of cardiovascular
diseases that require special gene transfer approaches.  For example,
the focal nature of coronary artery disease and restenosis may
require direct delivery of therapeutic genetic material to specific
myocardial or vascular sites.  Additional challenges encountered with
cardiovascular cells include the non-dividing nature of some cell
types, such as heart myocytes.  Strategies for other cardiovascular
diseases might include gene transfer to: treat myocardial ischemia by
promoting collateral circulation; modify vascular smooth muscle
contractility to reduce the total peripheral vascular resistance
observed to occur in hypertensive patients; and prevent cardiac
transplantation rejection by altering the cell surface properties to
deter an immune response.
 
There are many opportunities for application of gene transfer
techniques to prevention and treatment of pulmonary disorders.
Although there have been several promising advances in the use of
gene transfer approaches for cystic fibrosis, major barriers for this
and other pulmonary diseases to further progress exist.  Mechanisms
that underlie the immune response to viral vectors need to be
elucidated. The development and characterization of more efficient
gene transfer delivery systems need to be established.  The use of
gene transfer to ameliorate or prevent inflammatory lung disorders
such as ARDS and asthma is just beginning to be explored.  Gene
transfer to the pulmonary vasculature is also largely unexplored.
The role of this approach to treating pulmonary thrombosis, pulmonary
hypertension, or other conditions needs to be evaluated.
Bronchopulmonary dysplasia, pulmonary fibrosis, and chronic
obstructive pulmonary disease are other potential targets for the use
of gene transfer.
 
Many of the problems and needs relevant to gene transfer in the
cardiovascular and pulmonary areas are generally applicable to
hematologic genetic diseases such as hemophilia, sickle cell disease,
and thalassemia.  Choice of the appropriate target cell ranges from
important to critical for hematologic disorders.  In the case of
hemophilia, the normal site of production of factors VIII and IX is
believed to be the liver; however, other target cells such as
myoblasts and fibroblasts have been used in preliminary experiments.
Studies of mechanisms of development and suppression of immunity to
newly expressed gene products will also be an important issue.  Thus,
although much progress has been made, many basic issues crucial to
clinical success remain.
 
Objectives
 
This program is open to all approaches for effective gene therapy
vector designs and delivery methods.  Research needs include, but are
not limited to, the following:
 
Gene Expression:  The transferred gene must be expressed in
sufficient amounts and in a physiologically correct manner.
 
Gene Delivery and Transfer:  Studies might involve viral, physical,
chemical and fusion techniques to develop improved packaging and more
effective gene delivery.  Recent developments in controlled drug
release technology, including the use of biodegradable polymers in
the form of layers or microspheres and containing the desired gene,
may be applicable to gene delivery.
 
Target Cells:  Appropriate target cell population for gene transfer
of cardiovascular, pulmonary, and hematologic diseases should be
identified.
 
Cellular and Humoral Immunity:  Interventions to suppress the immune
response are in need of exploration, as well as the development of
novel vector systems that selectively minimize or repress the immune
response of the host organism.
 
Model Systems:  Model systems (in vivo and in vitro) need to be
developed to assess the safety and efficacy of viral and nonviral
vector systems.
 
INQUIRIES
 
Eligibility requirements, definitions, application procedures, review
considerations, application forms and instructions, and other
pertinent information (including policy information, for example,
Inclusion of Women and Minorities in Research Involving Human
Subjects) are contained in the STTR and SBIR solicitations identified
in ~Purpose~ above.
 
Inquiries concerning this notice are encouraged. Direct inquiries
regarding programmatic issues to:
 
Sonia Skarlatos, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10186, MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550
FAX:  (301) 480-2848
Email:  ss90g@nih.gov
 
Susan Banks-Schlegel, Ph.D.
Division of Lung Diseases
National Heart, Lung and Blood Diseases
6701 Rockledge Drive, Suite 10220, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email:  ss141w@nih.gov
 
Carol Letendre, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung and Blood Diseases
6701 Rockledge Drive, Room 10162, MSC 7950
Bethesda, MD  20892-7950
Telephone:  (301) 435-0080
FAX:  (301) 480-0867
Email:  cl44m@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Marie Willett
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7128, MSC 7128
Bethesda, MD  20892-7128
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  mw48f@nih.gov
 
.