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 .