Immunoengineering of donor lungs to optimize long-term graft function

Active Project Grant Awarded Last action

Award ID
R01AI173319
Recipient
Awarding agency
Obligated
$2,944,874

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 56% complete
Place of performance
2323 Riverside Dr., Ottawa, ON K1H 1A1, Canada

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Lung transplantation is the only treatment option for patients with end-stage lung disease. However, transplant outcomes are significantly limited by the development of primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD), and complete organ rejection. With increasing lung transplant activity around the world, new advancements are urgently needed to improve patient survival and quality of life. At university health network (UHN), our team pioneered the toronto EX vivo lung perfusion (EVLP) system-a breakthrough technology whereby donor lungs are preserved in a functional physiological state at 37°C and provided oxygen, nutrients, and other critical resources prior to transplantation. This enables donor lungs to "breathe" outside of the body for up to 12 hours. Using EVLP, transplant teams can more objectively assess marginal donor lungs and apply novel repair therapies. To this end, our project will leverage EVLP to develop novel somatic cell gene editing (SCGE) therapeutic strategies that can be applied to further enhance donor lungs. In preliminary research, we have shown that: 1) upregulation of an anti-inflammatory cytokine called interleukin (IL)-10 improves lung quality and post- transplant outcomes; and 2) recipient regulatory T cells (TREGS) that are resistant to tacrolimus (TAC) improve the regulatory microenvironment in the transplanted organ. Our hypothesis is that applying SCGE techniques during EVLP will enhance IL-10 gene and treg cell therapies, which will immunomodulate the donor organ and lessen the risk of transplant rejection. In aim 1, we will engineer new crispr editing technologies for use during EVLP and assess the feasibility and therapeutic potential of this approach using pre-clinical in vivo models. In aim 2, we will confer TAC resistance in treg cells using base editing and assess treg efficacy in vivo using a human skin xenograft model. In aim 3, we will conduct proof-of-concept translational studies and assess the efficacy of our combined therapies using clinically declined human lungs on EVLP, representing the closest approximation prior to clinical application. In our continued leadership of the field, we will enhance our strategic collaboration with massachusetts general hospital to explore this multidisciplinary approach to long-term transplant tolerance. Our project goal to combine SCGE and EVLP strategies will enable a grander pursuit of our long-term ambition: to 'design' better lungs that will last a lifetime in the transplant recipient. Achievement of our proposed objectives will result in novel clinical applications and a paradigm shift in how we treat lung transplant recipients-away from a life of immunosuppressive medications and towards self-sustaining and long-term graft tolerance.

Transactions

Action Obligated Date
Amendment $602,867
Amendment $584,781
Amendment $60,387
Amendment $60,387
Amendment $545,484
Amendment $545,484
Original award $545,484

Quick answers

Who received award R01AI173319?

R01AI173319 was awarded to University Health Network by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 12, 2024.

How much is award R01AI173319 worth?

$2,944,874 has been obligated on R01AI173319.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login