Key Dates

Related Announcements

• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.
• May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185.

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Purpose

The National Institute of Allergy and Infectious Diseases (NIAID) is interested in supporting research that applies somatic cell gene editing (SCGE) approaches in animal models or human tissues or organs excluded from clinical use to improve graft survival and outcomes for recipients of allogenic or xenogeneic solid organ or pancreatic islet transplants, or vascularized composite allografts (VCA).

This Notice of Special Interest (NOSI) replaces NOT-AI-21-080, which expires with the issuance of this Notice.
 

Background

Despite progress made in immunosuppressive and supportive therapies, improvements in transplant recipient 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 a graft would alleviate the need for lifelong immunosuppression, immune tolerance induction strategies are not ready for widespread use in humans. The use of SCGE therapies for treatment of human diseases has seen exciting progress in recent years, with multiple therapeutic approaches now in clinical trials to treat cancers, confer resistance to HIV, and correct genetic abnormalities associated with hemophilia, sickle cell anemia, and thalassemia; however, application of SCGE to improve transplantation outcomes has received little attention.

The Somatic Cell Genome Editing Program, launched in 2018 by the NIH Common Fund, generated new insights and tools for the development of somatic cell gene editing approaches. The program continues to support efforts to improve the efficacy and specificity of these approaches to help reduce the burden of common and rare diseases. With the expansion and refinement of SCGE techniques that utilize zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR/Cas9 editing, the number of clinical trials evaluating SCGE for the treatment of human diseases has grown rapidly. Ex vivo, SCGE approaches are used to engineer chimeric antigen receptor (CAR)-T cells that combat cancer and CCR5 co-receptor mutations that produce HIV-resistant T cells. In vivo, SCGE approaches are used to correct protein secretion defects in diseases like hemophilia B and mucopolysaccharidosis types I and II. Recent studies have identified many genes and genetic pathways involved in transplant outcomes that could serve as rational targets for gene editing-based therapies, including genes encoding prominent alloantigens driving rejection, donor major histocompatibility complex (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. Advances made in SCGE are primed for application to allo- and xeno- transplantation, which could derive significant benefits from these promising technologies.
 

Research Objectives and Scope

The objective of this NOSI is to stimulate multidisciplinary collaborations between transplant immunologists and gene editing experts that explore the use of SCGE technology to address unmet needs in transplantation, 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 organ/cellular function of transplanted grafts.

This NOSI encourages applications that will utilize cutting-edge technologies and employ interdisciplinary collaborations to apply progress made in SCGE to transplantation research. Applications should propose studies that test approaches in human tissues or organs excluded from clinical use and/or employ animal models of vascularized composite allograft (VCA), islet, or organ transplantation, including rodent, porcine, or nonhuman primates. Approaches may include ex vivo or in vivo modifications of donor or recipient organs, tissues, or cells to reduce graft immunogenicity and/or improve allograft survival and function through, for example, the disruption of deleterious genes or insertion of protective or regulatory genes to modulate immune responses, mitigate ischemia reperfusion injury, and/or repair organ damage.

The intent of this NOSI 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.
 

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 to expand the pool of suitable donor organs, reduce graft immunogenicity, improve graft survival and function, and/or repair recipient organ or tissue damage to partially restore function as a bridge to transplant. Applicants are encouraged to explore new or established SCGE platforms that have minimal intrinsic immunogenicity and infrequent off-target effects.

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.

NIDDK Areas of Interest:

The mission of the NIDDK is to conduct and support medical research on diabetes and other endocrine and metabolic diseases; digestive, hepatobiliary, pancreatic, nutritional disorders and obesity; and kidney, urologic, and hematologic diseases, to improve people’s health and quality of life.

Through this NOSI initiative, NIDDK will only accept R01 applications. NIDDK encourages research projects that propose technologies and approaches that include, but are not limited to:

• Optimizing SCGE technology to confer long-term protection from allogeneic immune rejection and autoimmune destruction of pancreatic islets or stem cell-derived islet-like cells.
• Development and refinement of preclinical testing platforms to assess the safety and efficacy of SCGE approaches to mitigate human transplant immune responses.
• Development of SCGE approaches to allow reporting of islet transplant graft viability and functional mass that can be applied in the clinical setting.
• Development of SCGE approaches to repair injured kidneys prior to transplantation, for example, targeting cells or pathways implicated in fibrosis.

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

• Clinical trials (all phases).
• Gene editing approaches that are not in the context of allo- or xeno- transplantation 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 (e.g., for tolerance induction).
• Germline gene editing.

Application and Submission Information

This notice applies to due dates on or after February 5, 2025 and subsequent receipt dates through November 16, 2027.

Applicants must select the IC and associated notice of funding opportunity (NOFO) 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 NOFO. Non-responsive applications will be withdrawn from consideration for this initiative.

Applicants using NIH Parent Announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those NOFOs are acceptable and based on usual application-IC assignment practices.

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

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AI-24-085” (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

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

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

Albert J. Hwa, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-1525
Email: [email protected]

Financial/Grants Management Contact(s)

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

Craig E. Bagdon, MPA
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: (301) 594-2115
Email: [email protected]