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Nasal Delivery of CNS Therapeutics (R41/R42)


Section I. Funding Opportunity Description

   Less than 2% of small molecule pharmacotherapeutics effectively cross the blood brain barrier (BBB) . Larger molecules, such as peptides or antibodies, are virtually impenetrable. Direct routes of administration (e.g., epidural-, intracerebral- or intracerebral ventricular delivery) are invasive, costly and impractical for repeated dosing into the CNS. These difficulties significantly limit the development of therapeutics to treat substance use disorders (SUDs).

Nasal delivery of therapeutics may offer several advantages. It is thought that therapeutics, large or small, can directly enter the central nervous system (CNS) and/or CSF through the olfactory nerve via extracellular diffusion, axonal transport and/or other unknown mechanism(s). Thus, inhaled drugs do not face the same pharmacokinetic (PK) challenges as do systemically administered drugs. PK issues such as gastric-acid mediated destruction, intestinal absorption, first-pass metabolism, circulatory stability, BBB penetrability, etc. can be minimized or obviated. Nasal administration has been noted to delivery therapeutics into the CNS in a matter of minutes (e.g., nasal NarcanĀ® for opioid overdose). The development of nasal delivery formulations would, theoretically, reduce resources needed for chemical synthesis, iterative pharmacophore modifications, and scale up production. Non-systemic administration may limit the formation of unwanted active metabolites, while allowing for an effective, less harmful dosing strategy. Novel nasal delivery technologies would likely open the door for the development of several a wide variety of novel therapeutic options, such as peptides, antibodies, RNAi, stem cells, or small molecule pharmacotherapeutics. 

Nasal administration of CNS therapeutics is not without problems. Due in part to non-optimal administrative techniques and/or formulations, only 1-7% of a therapeutic dose enters the brain on a consistent basis. Therefore, the purpose of this RFA is to develop a nasal delivery formulation that reliably delivers of a therapeutic (e.g., peptides, antibodies, RNAi, or pharmacotherapeutics), at a physiologically relevant concentration, into the CNS.

Formulations that incorporate novel technologies such as, co-polymer micelles, viral vectors, and nanoparticles, are particularly encouraged.


Small Business Technology Transfer (STTR) Phase I --

A proof-of-concept project should demonstrate:

(i) CNS bioavailability (e.g., radiolabeling, fluorescence) AND

(ii) therapeutic efficacy in an animal model of SUD.

Small Business Technology Transfer (STTR) Phase II --

Topics that are more appropriate for Phase II awards would include, for example:

(i) reproducibility assessments,

(ii) formulation optimization,

(iii) benefits analyses of nasal- vs. other common routes of administration (e.g., oral, IP, IV), and/or (iv) safety/toxicity assessments.  

This RFA will NOT support applications aimed at chemical discovery or in vitro assay development.

Long-term, it is envisioned that the development of a nasal delivery technology could be marketed successfully to industry and/or academia. The FDA's Orange Book currently only lists three approved CNS-related nasal sprays. The global market for direct-to-CNS-delivery technologies is reported to grow to $450 million by 2019, and has increased by 50% per year since 2013.


See Section VIII. Other Information for award authorities and regulations.

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