February 2, 2024
National Institute of Allergy and Infectious Diseases (NIAID)
National Center for Advancing Translational Sciences (NCATS)
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI) April 11, 2024 Participation Added (NOT-HL-24-012)
National Institute of Neurological Disorders and Stroke (NINDS) April 12, 2024 Participation Added (NOT-NS-24-068)
The purpose of this notice of special interest (NOSI) for Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) grants (Phase 1 or Phase 2) is to advance and accelerate the future clinical translation of RNA-based therapeutics to treat or prevent human diseases using non-viral technologies. To accomplish this goal, the NOSI will support the pre-clinical testing and evaluation of non-viral technologies to deliver RNA-based therapeutics or RNA-based vaccines to disease-relevant somatic cells and tissues in vivo.
RNA-based therapeutics (e.g., small interfering RNA (siRNA), messenger RNA (mRNA), micro-RNA (miRNA)) recently received wide-spread publicity due to the approval of mRNA-based COVID vaccines. The technology has moved to the forefront of biomedical research because it can manipulate gene expression, induce or suppress immune responses, or produce therapeutic proteins, making these agents suitable for pathologies with established genetic targets, including infectious diseases, cancers, cardiovascular disease, immune-mediated diseases, and neurological disorders. In addition, the rapid growth of technologies to analyze gene expression at the single-cell level is driving an exponential discovery of new targets for gene therapies. With the recent successes in RNA-based cancer vaccine trials and the rapid, flexible, and adaptable manufacturing of RNA-based therapeutics, these molecules are now pragmatic candidates in the implementation of precision medicine treatments. This has led to an unmet need for a parallel development of delivery methods to meet the exponential growth of RNA-based therapeutics.
To protect the RNA from degradation and maximize delivery to on-target cells, diverse non-viral synthetic materials such as polymers, lipids, and lipid nanoparticles (LNPs) have been developed. To date, only the following RNA-based therapeutics and vaccines are FDA approved, and these use lipid nanoparticles and N-acetylgalactosamine (GalNAC) conjugation as the main non-viral delivery platforms:
Despite these clinical advances, there remain several critical challenges associated with the RNA molecule itself and its delivery aspect (e.g., extracellular, and intracellular barriers). These challenges are common to mRNA, siRNA, and miRNA, the RNA types most actively investigated by academia and industry. Major limitations include the lack of efficient delivery methods, efficient delivery to organs other than liver, considerable off-target effects, and unwanted or excessive (in case of vaccines) immunogenicity of the delivery platform. Other major hurdles involve a lack of organ-specific or cell-specific RNA delivery, limited administration routes aside from systemic delivery, and endocytic pathway dependency of intracellular delivery methods. Therefore, this NOSI aims to support the development and pre-clinical assessment of innovative delivery approaches to effectively deliver RNA-based therapeutics or vaccines for sustained expression and/or activity at the target somatic cells, within the desired tissues and organs. This NOSI supports the development of emerging platforms for delivery of existing RNA-based therapeutics (includes either experimental or FDA approved RNA-based therapeutics) targeting specific cell populations, tissues and/or organs.
The current NOSI builds upon previous NIH funding opportunities that supported the development of technologies for the delivery of nucleic acid-based therapeutics and genome editors, including trans-NIH initiatives (PAR-20-109: Non-Viral Technologies for in vivo Delivery of Genome Editors (R41/R42 Clinical Trial Not Allowed)) and PAR-17-036: Platform Delivery Technologies for Nucleic Acid Therapeutics (R41/R42).
In the context of this announcement, ‘RNA-based therapeutics refers to the following types of RNA:
This funding opportunity aims to support the development and/or pre-clinical studies of non-viral technologies to deliver RNA-based therapeutics into disease-relevant cells and tissues in vivo. Projects may focus on a single or multiple cells or tissues. Emphasis will be placed on organs, tissues and cell types that are clinically relevant but for which no effective in vivo delivery technologies are currently available.
Disease models that could be used to evaluate delivery technologies may include but are not limited to:
Emphasis will be placed on delivery technologies with demonstrated potential for substantial improvements in clinical applications, including but not limited to:
This funding opportunity is limited to non-viral technologies. These may include, but are not limited to the following:
For proof-of-concept studies, investigators can choose one or more RNA-based therapeutics and one or more disease targets. Programmable delivery systems are encouraged. Optimally, proposed delivery technologies would be applicable to different RNA-based cargoes or types of genome editors.
Applicants can propose studies using tracers as cargo, and relevant human cell systems including organoids, xerographs, and/or micro physiological systems as platforms to demonstrate proof of concept in phase 1 projects. However, for phase 2 projects, all applications must include plans to test delivery systems of RNA-based therapeutic(s) and/or genome editors in vivo in healthy animals, and/or in animal models of disease. As noted above, the primary goal of this NOSI is not to develop new targets for specific diseases, but to develop or improve delivery systems to target specific cells and tissues that are of relevance to different diseases in vivo.
NIAID
Immune-mediated diseases, solid organ transplantation, and vaccine platforms/formulations:
Infectious diseases:
Methods for specific delivery of nucleic acid/RNA-based therapeutics to the specific sites of infection, such as specific cell types, organelles, glands, organs (e.g., lung, liver, brain, testes, granulomas, specific cell types harboring pathogens, or lymph nodes) relevant for the treatment of viral, fungal, bacterial, and parasitic infections.
Human Immunodeficiency Virus (HIV):
Methods for specific delivery of RNA-based therapeutics to HIV reservoir sites (e.g., specific cell types, lymph nodes, gut-associated lymphoid tissue, central nervous system, etc.) and/or specific sites of infection (e.g., specific cell types, lung, liver, brain, granulomas, etc.) relevant for the treatment of HIV and HIV-associated co-infections (Tuberculosis, HBV, or HCV).
NCI
Delivery methods that enable specific targeting to the primary tumor, metastatic sites and/or draining lymph nodes; delivery methods that allow encapsulation and delivery of multiple different RNA preventive or therapeutic molecules (e.g., neoantigen vaccines); delivery strategies that enable the specific expression or activation of RNA-based therapeutics at the target organ/tissue/cells of interest; delivery methods that explore the synergistic effects of combining mRNA-encoding tumor suppressors with other therapeutics (e.g., chemotherapeutics drugs and immune checkpoint inhibitors) to enhance therapeutic outcomes; delivery methods to overcome resistance to miRNA and siRNA-based cancer therapies, controlled targeting technologies that avoid delivery to normal cells but allow delivery to target cancer cells (smart delivery methods); novel delivery strategies that overcome resistance to miRNA and siRNA-based cancer therapies; assessment of non-invasive RNA delivery routes beyond systemic delivery (e.g., inhalable or oral RNA delivery).
NCATS
Delivery of RNA therapeutics and/or genome editors for the treatment of rare diseases; broad spectrum delivery technologies for RNA therapeutics and/or genome editors that go to multiple tissues; technologies to target RNA therapeutics and/or genome editors to specific cells and tissues; delivery technologies based on phages.
Applications proposing the following will NOT be supported by this NOSI:
This notice applies to due dates on or after April 5, 2024 and subsequent receipt dates through January 5, 2027.
Submit applications for this initiative using the following notice of funding opportunity (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 funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
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)
Jain Krotz, Ph.D.
Innovation and Commercialization Office
Division of Extramural Research Activities
National Heart Lung and Blood Institute (NHLBI)
Telephone: 301-435-7677
Email: jain.krotz@nih.gov
Michael Minnicozzi, PhD
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3532
Email: minnicozzim@niaid.nih.gov
Kien Nguyen, PhD
Division of Microbiology and Infectious Disease
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-351-6229
Email: kien.nguyen@nih.gov
Roger Ptak, PhD
Division of AIDS
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7424
Email: roger.ptak@nih.gov
Xing-Jian Lou, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5226
Email: Loux@mail.nih.gov
Philip J. ("Pj") Brooks, PhD
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-443-0513
Email: pj.brooks@nih.gov
Financial/Grants Management Contact(s)
Jason Lundgren
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2973
Email: Jason.Lundgren@nih.gov
Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: Hines@mail.nih.gov