Notice of Special Interest (NOSI)

Xing-Jian Lou, PhD

Contact Xing-Jian Lou to learn more about this program.

Notice Number: NOT-AI-24-007

RNA Delivery Technologies to Allow Specific Tissue Target Homing (RNA-DASH)

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.

Background

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:

Onpattro for polyneuropathy of hATTR amyloidosis
Givlaari for acute hepatic porphyria
Oxlumo for primary hyperoxaluria Type 1
Leqvio for primary hypercholesterolemia
Amvuttra for polyneuropathy of hereditary transthyretin
Comirnaty and Spikevax for COVID-19.

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.