- Email: [email protected]
Cardiac Directed Human Gene Therapy
cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. I'\at Med 1999; 5:434-438. 26. Takeshita S, Pu LQ, Stein LA, et al. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation 1994; 9O:II228-II234. 27. Takeshita S, Weir L, Chen D, et al. Therapeutic angiogenesis following arterial gene transfer of vascular endothelial grmvth factor in a rabbit model of hindlimb ischemia. Biochem Biophys Res Commun 1996; 227:628-635. 28. Watt D], Lambert K, Morgan]E, Partridge TA, Sloper Je. Incorporation of donor muscle precursor cells into an area of muscle regeration in the host mouse. ] l\eurol Sci 1982; 57:319-331.
11:20 am Cardiac Directed Human Gene Therapy Ronald G. Crystal, .tID New York Presbyterian Hospital New York, New York 1:00 pm Gene Therapy: A perspective from the NHLBI Vascular Research Program David M. Robinson. DVM, PhD National Heart and Lung, and Blood Institute Bethesda. Maryland In recent years, progress has been rapid in the development of vector design, and new strategies for gene therapy have gradually emerged to the extent that,within a decade, clinical practice is likely to be established at least for certain monogenic diseases, and for some pathologic conditions such as restenosis, in which short-term ex-
pression of a transferred gene may confer sufficient clinical benefit. The situation with such complex entities as hypertension and atherosclerosis, however, is far from clear. What is needed in all cases is the opportunity to translate findings from basic science to human clinical studies with maximal timeliness and effectiveness. Substantial resources and trained investigators are necessary for the objective and critical evaluation of work leading to gene therapy, and the creation of the kind of environment that will foster and encourage such approaches is vital. The Vascular Research Program at the I'\HLBI supports a substantial amount of research in gene therapy and the basic science that underlies it. Special programs are in place, designed to accelerate progress, and new ideas are constantly being incorporated. This talk will provide a snapshot of current activities, and will invite discussion of future prospects.
1:20 pm Clinical Trials of Local Drug Delivery Stephen R. Bailey, MD
430
University of Texas Health Science Center San Antonio. Texas 1:45 pm Gene Therapy of Metabolic Disease: OTC Deficiency, a Paradigm Ziv]. Haskal, lvfD New York Presbyterian Hospital New York, New York 2:05 pm Endovascular Molecular Therapy: Exploring the Delivery of Biologic Factors Alichael D. Dake, MD Stanford University Hospital Stanford, California Learning objectives: Upon completion of this presentation. the attendee should be able to: 1) list three disadvantages that limit viral-mediated gene delivery; 2) Give an example of an early physiologic control point that can be targeted to alter local responses to vascular wall injury; 3) Discuss a controlled release strategy and how it has produced a safer and more precise solution to a vascular problem. Our laboratory employs the tools of bioengineering and molecular medicine to alter local in vivo responses to injury. We typically employ viral-mediated gene delivery for initial evaluation and proof of principle, and, where possible, develop controlled-release strategies to more precisely and more safely manage the targeted disease state. Our general strategy is to target early physiologic control points to alter local responses. Following this approach, we have demonstrated that local thrombosis, inflammatory infiltrate, and neointima formation after balloon injury can be targeted through a single pathway. In other experiments targeting inflammatory-mediated damage alone, we have achieved improved postangioplasty, vein-graft, and transplant outcomes in animal models. A number of disadvantages limit viral-mediated gene delivery, however. Concerns over safety include toxicity, replication competence, and mutagenicity for integrating therapies. Additionally, levels of factor production and precise distribution of viral-mediated expression are highly variable and difficult to predict a priori. As a result, we develop nonviral gene delivery or strategies for controlled release of the desired factors themselves wherever possible. With use of combinations of rigid and gel-based degradable systems, we have found that we can deliver a factor of interest at a defined dose for a defined time course in vivo. Together with collaborators in several disciplines, we have applied this strategy to a variety of problems, ranging from guided arterial remodeling to enhanced local angiogenesis to a breast implant that is replaced by vascularized fat as it degrades. This type of approach allows us to ask precisely controlled in vivo
11:20 am Cardiac Directed Human Gene Therapy Ronald G. Crystal, .tID New York Presbyterian Hospital New York, New York 1:00 pm Gene Therapy: A perspective from the NHLBI Vascular Research Program David M. Robinson. DVM, PhD National Heart and Lung, and Blood Institute Bethesda. Maryland In recent years, progress has been rapid in the development of vector design, and new strategies for gene therapy have gradually emerged to the extent that,within a decade, clinical practice is likely to be established at least for certain monogenic diseases, and for some pathologic conditions such as restenosis, in which short-term ex-
pression of a transferred gene may confer sufficient clinical benefit. The situation with such complex entities as hypertension and atherosclerosis, however, is far from clear. What is needed in all cases is the opportunity to translate findings from basic science to human clinical studies with maximal timeliness and effectiveness. Substantial resources and trained investigators are necessary for the objective and critical evaluation of work leading to gene therapy, and the creation of the kind of environment that will foster and encourage such approaches is vital. The Vascular Research Program at the I'\HLBI supports a substantial amount of research in gene therapy and the basic science that underlies it. Special programs are in place, designed to accelerate progress, and new ideas are constantly being incorporated. This talk will provide a snapshot of current activities, and will invite discussion of future prospects.
1:20 pm Clinical Trials of Local Drug Delivery Stephen R. Bailey, MD
430
University of Texas Health Science Center San Antonio. Texas 1:45 pm Gene Therapy of Metabolic Disease: OTC Deficiency, a Paradigm Ziv]. Haskal, lvfD New York Presbyterian Hospital New York, New York 2:05 pm Endovascular Molecular Therapy: Exploring the Delivery of Biologic Factors Alichael D. Dake, MD Stanford University Hospital Stanford, California Learning objectives: Upon completion of this presentation. the attendee should be able to: 1) list three disadvantages that limit viral-mediated gene delivery; 2) Give an example of an early physiologic control point that can be targeted to alter local responses to vascular wall injury; 3) Discuss a controlled release strategy and how it has produced a safer and more precise solution to a vascular problem. Our laboratory employs the tools of bioengineering and molecular medicine to alter local in vivo responses to injury. We typically employ viral-mediated gene delivery for initial evaluation and proof of principle, and, where possible, develop controlled-release strategies to more precisely and more safely manage the targeted disease state. Our general strategy is to target early physiologic control points to alter local responses. Following this approach, we have demonstrated that local thrombosis, inflammatory infiltrate, and neointima formation after balloon injury can be targeted through a single pathway. In other experiments targeting inflammatory-mediated damage alone, we have achieved improved postangioplasty, vein-graft, and transplant outcomes in animal models. A number of disadvantages limit viral-mediated gene delivery, however. Concerns over safety include toxicity, replication competence, and mutagenicity for integrating therapies. Additionally, levels of factor production and precise distribution of viral-mediated expression are highly variable and difficult to predict a priori. As a result, we develop nonviral gene delivery or strategies for controlled release of the desired factors themselves wherever possible. With use of combinations of rigid and gel-based degradable systems, we have found that we can deliver a factor of interest at a defined dose for a defined time course in vivo. Together with collaborators in several disciplines, we have applied this strategy to a variety of problems, ranging from guided arterial remodeling to enhanced local angiogenesis to a breast implant that is replaced by vascularized fat as it degrades. This type of approach allows us to ask precisely controlled in vivo