Key Dates

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
NOT-AI-21-067 Notice of Special Interest (NOSI): Somatic Cell Gene Editing Therapies To Improve Transplantation Outcomes
NOT-AI-21-081 - Notice of Early Expiration of NOT-AI-21-067, Notice of Special Interest (NOSI): Somatic Cell Gene Editing Therapies To Improve Transplantation Outcomes

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

The National Institute of Allergy and Infectious Diseases (NIAID) is interested in supporting research that applies somatic cell gene editing (SCGE) approaches to improve graft survival and outcomes for recipients of allogenic solid organ, pancreatic islet, or vascularized composite allograft (VCA) transplants in animal models or human tissues or organs excluded from clinical use. This Notice of Special Interest (NOSI) replaces NOT-AI-21-067, which was rescinded with the issuance of this Notice.

Background

Despite progress made in immunosuppressive and supportive therapies, improvements in allograft and patient survival are needed. Current clinical strategies to prevent acute and chronic allograft rejection rely on lifelong immunosuppression, the adverse effects of which include susceptibility to infection, nephrotoxicity, malignancy, diabetes, and cardiovascular disease. While immune tolerance to an allograft would alleviate the need for lifelong immunosuppression, tolerance induction strategies are not ready for widespread use in humans.

With the recent expansion and refinement of SCGE techniques that utilize zinc finger nucleases (ZFNs), transcription activator-like effectors (TALENs), and CRISPR/Cas9 editors, the number of clinical trials evaluating SCGE for the treatment of human diseases has grown rapidly and now includes clinical trials to treat cancers, confer resistance to HIV, and correct genetic abnormalities associated with hemophilia, sickle cell anemia, and thalassemia. The Somatic Cell Genome Editing Program launched in 2018 by the NIH Common Fund has generated new insights and tools, and continues to support efforts to improve the efficacy and specificity of gene editing approaches to help reduce the burden of common and rare diseases.

Advances in SCGE are primed for application to allotransplantation, which could derive significant benefits from these promising new technologies. Recent studies have identified many genes and genetic pathways involved in transplant outcomes that could serve as rational targets for gene editing-based therapies. These include genes encoding prominent alloantigens driving rejection, donor MHC class I and II; proinflammatory cytokines, chemokines, and chemokine receptors that attract and expand immune cells at sites of injury; and proteins driving ischemia reperfusion injury, inflammation, and graft dysfunction.

Research Objectives and Scope

This NOSI aims to stimulate multidisciplinary research collaborations that utilize cutting-edge technologies to apply progress made in SCGE to transplantation research. Research funded by this NOSI may utilize various models, including human tissues or organs excluded from clinical use and/or rodent, porcine, or nonhuman primate models. The research should address unmet needs in VCA, islet, or organ allotransplantation, such as the prevention or treatment of rejection; achievement of transplant tolerance; prolongation of allograft survival; protection from the toxicities of pharmacologic immunosuppression; and improvements in the organ/cellular function of transplanted grafts.

Areas of Interest

NIAID Areas of Interest:

The goal of NIAID transplantation research is to improve the long-term success of organ, tissue, and cell transplantation by understanding the role the immune system plays in transplant success or failure and modifying the immune response in a way that will improve long-term transplant survival and reduce the need for broadly immunosuppressive medications, which can cause significant side effects.

SCGE approaches may include ex vivo or in vivo targeting of donor or recipient organs, tissues, or cells designed to reduce graft immunogenicity and/or improve allograft survival and function. Applicants are encouraged to explore new or established SCGE platforms that have minimal intrinsic immunogenicity and infrequent off-target effects.

Particular areas of interest include but are not limited to:

• Disruption of deleterious genes that contribute to ischemia reperfusion injury, cellular rejection, or antibody-mediated rejection
• Insertion or amplification of protective genes to prevent drug-related toxicities or promote robust transplant tolerance
• Generation of gene-edited cellular therapies to regulate immune responses to the graft, expand the pool of suitable donor organs, or repair recipient organ or tissue damage to partially restore function as a bridge to transplant

NHLBI Areas of Interest:

NHLBI provides global leadership for a research, training, and education programs to promote the prevention and treatment of heart, lung, and blood diseases and sleep disorders and enhance the health of all individuals so that they can live longer and more fulfilling lives. Participation in this NOSI directly addresses the NHLBI strategic goals related to a desire to better understand human health and resilience, to stimulate discoveries in the diagnosis and prevention of disease and to facilitate the translation of discoveries from basic research into clinical practice.

NHLBI encourages research projects that propose technologies and approaches that include, but are not limited to:

• Studies that utilize SCGE technology to uncover immune-mediated mechanisms of graft rejection that can be therapeutically targeted to improve and/or extend the life of an allograft.
• Development/improvement of SCGE-based predictive animal models of the human immune response to transplantation.
• Development of sensitive, robust, assays for monitoring or predicting graft acceptance or rejection following SCGE-based interventions that can be adapted for clinical use.
• Studies that interrogate mechanisms related to coagulopathy and fibrinolysis.

The intent of this research is to encourage novel collaborations across disciplines and enhance research outcomes in a dynamic, technically challenging, and potentially high-risk/high-reward area. Ideally, such partnerships will have a lasting impact and drive the field forward beyond the lifetime of this NOSI.

For both NIAID and NHLBI, the research areas below will NOT be supported through this NOSI:

• Clinical trials
• Gene editing approaches that are not in the context of allotransplantation or stabilization of a recipient as a bridge to transplantation
• Hematopoietic stem cell or bone marrow transplantation unless performed in the context of VCA, islet, or organ transplantation
• Germline gene editing
• Xenotransplantation research (exception: use of humanized mouse models as a tool to evaluate SCEG platforms is allowed)

Application and Submission Information

Applicants must select the IC and associated funding opportunity announcement (FOA) to use for submission of an application in response to this NOSI. The selection must align with the IC requirements listed in order to be considered responsive to that FOA. Non-responsive applications will be withdrawn from consideration for this initiative. In addition, applicants using NIH Parent Announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those FOAs are acceptable and based on usual application-IC assignment practices.

NOTE: NHLBI will only accept applications submitted to the NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) PA-20-185 target FOA and will not accept applications that are submitted via the NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed) PA-20-195 target FOA. See table below.

This Notice applies to due dates on or after February 5, 2022 and subsequent receipt dates through January 7, 2025.

Submit applications for this initiative using one of the following FOAs or any reissues of these announcements through the expiration date of this Notice.

All instructions in the SF424 (R&R) Application Guide and the listed funding opportunity announcements must be followed, with the following additions:

• For funding consideration, applicants must include NOT-AI-21-080 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Scientific/Research Contact(s)

Nasrin Nabavi, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3538
Email: [email protected]

Rahul Gautam Thakar, Ph.D.
National Heart, Lung, And Blood Institute (NHLBI)
Telephone: 301-496-1740
E-mail: [email protected]

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Tamia Powell
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2982
Email:[email protected]

Leslye Fulwider
National Heart, Lung, And Blood Institute (NHLBI)
Telephone: 301-480-9544
E-mail: [email protected]