U01AI170056

Lymph Node Delivery in Transplantation - Abstract

The transplantation field has witnessed many major breakthroughs, including the development of immunoregulatory molecules (IRMs), which have been key to the success of organ transplantation. However, the use of IRMs is hindered by lack of efficiency and toxicity, and it is implicated in the pathogenesis of organ failure and accelerated cardiovascular disease, which is the leading cause of death in transplant recipients.

Therefore, a substantial unmet medical need exists to develop novel strategies to increase the efficacy and reduce the toxicity of IRMs. The existing drugs are often adequately potent when directed specifically to their intended sites, so methods of targeted drug delivery could potentiate their safety and efficacy profiles significantly, while reducing the need for creating new drugs, a process that can be extremely expensive, labor-intensive, and time-consuming.

Although targeted drug delivery using nanotechnology represents a highly promising and innovative strategy for site-specific drug delivery, its application to transplantation remains to be developed.

The overall goal of this proposal is to develop a targeted drug delivery system for IRMs in transplantation, with the ultimate goal of increasing their efficacy and diminishing their toxicity.

In transplantation, presentation of donor allo-antigens to recipient T cells in the draining lymph nodes (DLNs) is fundamental to the generation of alloreactive T cells that traffic to the allografts and cause allograft rejection.

The overall hypothesis of this proposal is that targeted delivery of IRMs to the DLN would not only increase their efficacy, but also decrease their toxicity by significantly reducing systemic dosage.

In Aim 1, we plan to devise a clinically applicable active targeted method of delivering IRMs to the DLNs to promote heart allograft acceptance. We will focus primarily on murine heart allograft survival by devising a combinatorial therapeutic strategy with our targeted delivery platform to address the immediate unmet need for safer and more efficacious therapies in transplantation.

In Aim 2, we plan to evaluate the mechanism of prolongation of heart allograft survival by our active targeted delivery platform to DLNs. Mechanistic studies will also permit improvement of the design of our targeted delivery method. These experiments will employ murine heart transplant models, established functional assays, and sophisticated imaging studies to better understand the biodistribution of IRMs and their nanocarriers.

In Aim 3, we plan to pursue our preliminary data to generate proof-of-concept data in devising a method of targeting IRMs to DLNs in non-human primates. This multidisciplinary, collaborative approach sets forth a novel targeted delivery platform that could potentially shift the paradigm of the approach to immunosuppressive therapy in transplantation.

Brigham & Womens Hospital

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

Emerging Science and Technology in Transplantation (U01 Clinical Trial Not Allowed) (RFA-AI-21-016)

Amendment Since initial award the total obligations have increased 384% from $482,750 to $2,334,750.