Key Dates

Related Announcements

NOT-AI-24-027 - Notice of Early Expiration of "Notice of Special Interest (NOSI): Molecular and Genetic Characterization of Inborn Errors of Immunity", NOT-AI-21-082.

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-22-006 - Notice of Early Expiration of PAR-19-079

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to advance the experimental validation and functional characterization of genetic variants in coding or non-coding genomic regions that result in inborn errors of immunity/primary immunodeficiency diseases and to elucidate the molecular, cellular, and immunological mechanisms of these disorders. Understanding the genetic basis of primary immunodeficiency disorders is essential for their diagnosis, prognosis, and the development of precision therapeutics.

Inborn errors of immunity/primary immunodeficiency diseases result largely from inherited genetic defects that perturb immune regulation or function; they are often severe in nature; and are characterized by highly diverse phenotypes such as infection, autoimmunity, auto-inflammation, allergy, and malignancy. Genomic analysis and experimental validation of genetic variants have been instrumental in the identification of numerous inborn errors of immunity/primary immunodeficiencies to date. More than 400 inborn errors of immunity have been identified in both coding and non-coding regions of the genome, as noted in the "Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082301/.

In silico prediction models suggest that mutations in more than 3000 coding regions may cause hitherto unrecognized inborn errors of immunity, while numerous mutations in non-coding regions also are expected to cause disease, underlining the public health significance in understanding the genetic basis of primary immunodeficiency disorders and reinforcing the notion that hundreds to thousands of these disorders remain unidentified. Furthermore, since these disorders are characterized by a high degree of phenotypic heterogeneity, understanding their genetic basis is essential for appropriate diagnosis, prognosis, and treatment.

The biochemical and functional characterization of genetic defects discovered through genomic investigation enabled not only the molecular characterization of numerous known and novel inborn errors of immunity but, importantly, also revealed defects in immunoregulatory pathways responsible for the disease phenotype. Significantly, the molecular diagnosis of inborn errors of immunity/primary immunodeficiency diseases has paved the way for the development of precision medicine therapeutics.

Research Objectives and Scope

Research areas supported by this NOSI include, but are not limited to, the experimental validation and immunological characterization of:

• Single nucleotide variants (inherited or de novo) in coding or non-coding regions of the genome that cause inborn errors of immunity;
• Insertions or deletions (indels) in coding or non-coding regions of the genome that cause inborn errors of immunity;
• Digenic/polygenic mutations that cause inborn errors of immunity;
• Structural variations (large insertions or deletions, translocations, inversions, or copy-number variations) that cause inborn errors of immunity.

State-of-the-art technologies and approaches (e.g., iPSC technology, CRISPR/Cas9 gene editing, multi-omics such as transcriptomics, proteomics, epigenetics etc) used to accomplish the objectives of this NOSI are strongly encouraged.

The prioritization of putative disease-causing variant(s) is expected to be finalized by the time applications are submitted. For the genetic variant(s) that are chosen to be investigated further according to the objectives of this NOSI, preliminary data should be presented to support causality between the variant(s) and disease phenotype.

The clinical and laboratory phenotype of the patients should be well defined and relevant medical history should be available. Information about the patient cohort(s) or family pedigree(s) should be provided. For single patient studies, adherence to the guidelines established for genetic studies in single patients is strongly encouraged.

Use of relevant cell types isolated from the patient(s) and appropriate controls (e.g., unaffected family members, healthy subjects of the same ethnic origin etc) are strongly encouraged for the delineation of the functional consequences of the mutations under investigation. If animal models are used to elucidate the mechanism of disease, a clear correlation between human and animal disease phenotypes should be established. In all cases, preliminary data should demonstrate that the genotype/phenotype correlation recapitulates the patient’s clinical disease.

This NOSI will NOT support:

• Studies that propose the use of targeted gene sequencing panels, which analyze specific mutations known to cause inborn errors of immunity/primary immunodeficiency diseases, since they will not aid in the identification of novel disease-causing mutations;
• Characterization of somatic mutations;
• Phenocopies of inborn errors of immunity/primary immunodeficiency diseases;
• Applications that focus on HIV/SIV/AIDS.

Application and Submission Information

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 funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

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)

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

• For funding consideration, applicants must include "NOT-AI-21-082" (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 not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Maggie A. Morris Fears, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-5444
Email: maggie.morrisfears@nih.gov