Robert Montgomery - US grants

All solid organ allografts are maintained for some period of time outside of the body. While unwelcome ischemic injury results from this ex vivo phase, it does offer a unique window for focused and efficient gene transfer that could improve graft and recipient survival. Delayed graft function and primary nonfunction remain recalcitrant problems in transplantation and have been associated with late graft failure due to chronic rejection. Ischemia/reperfusion injury (IRI) is an important antigen-independent factor that can contribute to the pathogenesis of these clinical entities. We have developed a chimeric expression vector that generates abundant antisense/ribozyme regulatory molecules in situ and has proven efficacy. The goal of this work is to establish the conditions for the selective inactivation of individual genes responsible for IRI through the efficient ex vivo delivery of our chimeric transgene into allografts. The adhesion molecule ICAM-1 has been chosen as a model target gene to develop this gene therapy strategy because there is compelling evidence that it is an important trigger molecule for cascades of proinflamatory mediators responsible for IRI. Our hypothesis is that the ex vivo delivery of a chimeric transgene designed to produce anti- ICAM-1 regulatory molecules will inhibit the expression of ICAM-I in endothelial cells and abrogate or ameliorate IRI in an ischemic organ. Using a rational approach to designing chimeric constructs and testing them in vitro, we hope to establish the requirements and conditions for inhibition of ICAM-1 and other important molecules in the IRI pathway in transplanted allografts. Both viral and nonviral approaches to delivering effective ICAM-1 inhibitory transgenes will be developed for use in a rat renal IRI model. Because this method of inhibition is based on technology that is more potent and specific than strategies previously employed, it possess great potential as both a powerful therapeutic agent and a surrogate genetic tool for interrogating gene function. This work has important implications for the selective inactivation of gene function in allografts through ex vivo gene transfer.

DESCRIPTION (provided by applicant): Summary This application addresses broad Challenge Area (07) Enhancing Clinical Trials and specific Challenge Topic, 07-DK-103: Support for Registries. Live donor kidney transplantation is the best treatment for kidney failure, doubling life expectancy and significantly improving quality of life. However, it is estimated that 2000-4000 patients every year find a healthy, willing live donor but are relegated to forego the benefits of live donor renal transplantation because they are ABO or HLA incompatible with their donor. Some of these patients might find compatible matches through kidney paired donation, but those with broad HLA sensitization or hard-to-match blood types (over 50% of incompatible pairs) will not find matches through paired donation. Without incompatible kidney transplantation (IKT), the only other option for these patients is to join the 80,000-patient deceased donor waiting list, where waiting times average 5-7 years and death rates on dialysis exceed 10% per year. IKT is an emerging practice in which patients can receive kidney transplants across antibody barriers through the use of various desensitization techniques. Approximately 200 of these transplants are performed annually in the United States, of which approximately one-third are performed by a handful of high-volume centers and two-thirds are scattered across approximately 90 other very low-volume centers. However, two major challenges currently limit future growth in the field of IKT. First, there is a great need to study and validate specific components of the current protocols and develop best practice. This can only be accomplished if sufficient, detailed data from multiple centers can be collected in a prospective fashion;to date, only single-center studies have been available for analysis. Second, because IKT can be hard to implement due to its reliance on new technology in immunogenetics and pathology, there is a great need for mentoring of new provider teams by more experienced centers. This is currently limited by the inability to readily share detailed, integrated, longitudinal clinical, histological, radiographic, and immuogenetics data. In an effort to better understand IKT and mentor new centers building these programs, we propose to develop a National Incompatible Kidney Transplant Registry. We will design this registry based on a systematic set of in-depth interviews with personnel currently involved in this procedure, and then extend currently existing relational patient management software to accommodate the needs of this registry. We will then pilot test the registry on retrospective cases at our center, prospective cases at our center, and prospective cases from a handful of centers around the country. Finally, we will develop a long-term plan for sustainability. For sensitized patients, IKT is often the only viable treatment option, providing a significant (more than 3- fold) survival benefit to these patients when compared to the next-best available option, namely waiting on the deceased donor waiting list for a compatible donor. Expanding this treatment modality will not only save lives, decrease the long waiting list, and save the US healthcare system significant costs, but will also stimulate the expansion of transplant centers, tissue typing labs, and pathology labs nationwide. Although live donor kidney transplantation is the best treatment for kidney failure, thousands of patients each year have a healthy, willing donor but are relegated to forego the benefits of live donor transplantation because they are incompatible with their donor. Incompatible kidney transplantation is an emerging practice in which patients can receive kidney transplants from their incompatible donors, but this field has thus far been limited to single-center experiences where protocols cannot be validated, best practice cannot be developed, and mentorship of new centers by more experienced centers cannot be accomplished. The goal of this project is to create a detailed, integrated, National Incompatible Kidney Transplant Registry that will link clinical, biopsy, radiology, and antibody data from multiple centers throughout the United States in a way that will greatly improve and expand incompatible kidney transplantation.