The purpose of this funding opportunity announcement (FOA) is to support in vivo research to elucidate the chemical features of non-native molecules that facilitate passage across the blood-testis and/or blood-epidydimal barriers.
Many validated and putative male contraceptive targets are localized to the adluminal compartment of the seminiferous epithelium or reside in/on sperm within the epidydimal tubule lumen. These targets are not fully exposed to the systemic circulation due to the semi-permeable nature of the blood-testis barrier (BTB) and blood-epididymal barrier (BEB). The identification and successful development of small molecule therapeutics that modulate contraceptive targets residing in these areas are hindered by a lack of understanding of the characteristics of non-native molecules and molecular mechanisms that regulate transport across the BTB and/or BEB. The discovery and successful development of new chemical entities would be facilitated by a greater understanding of the chemical features of non-native molecules that cross the BTB and/or the BEB. This research may also provide insight into the basic biology of BTB and BEB molecular transport mechanisms.
In addition to contraception development, findings from this research may impact the development of therapeutics for other indications where passage to the immuno-privileged compartments of the testis or epididymis would be beneficial (e.g., anti-infectives).
Phased Innovation Awards:
This funding opportunity will use the R61/R33 phased award mechanism. Support will be provided for? up to two years for the R61 phase, and up to three years of support may follow for the R33 phase.? No less than two months before the completion of the R61 phase, awardees may submit an R33 transition package, which includes the R61 progress report describing in detail the progress towards the R61 milestones, and a description of how research proposed for the R33 phase will be supported by the completion of the R61 phase milestones. These materials will be evaluated by NIH Program staff. R33 funding decisions will be based on the original R61/R33 peer review recommendations, successful completion of transition milestones, Program priorities, and availability of funds. Grants receiving a positive R33 funding decision will be transitioned to an R33 award without the need to submit a new application. It is anticipated that not all R61 awardees will be transitioned into the R33 phase. Applicants should be aware that use of a no-cost extension at the end of the R61 period could jeopardize the award of the R33.
Research Objectives and Scope
This FOA is designed to stimulate milestone-driven research that will lead to an improved understanding of the chemical features of non-native molecules that mediate passage across the BTB and/or BEB. Projects must be focused on a rational approach to study multiple, chemically unrelated series of compounds to elucidate how the differing chemical structures relate to transport efficiency. Studies must be designed to demonstrate that tested compounds do not perturb the permeability of the BTB and/or the BEB.
Applications for this staged mechanism must include approaches to correlate chemical structure of compounds with passage across the BTB and/or BEB. In addition, studies may be designed to understand the molecular mechanism(s) of transport of those molecules across the BTB and/or BEB. Applications that include studies involving testis-specific transporters active within the BTB and/or BEB are of interest. However, determining the mechanism of transport is secondary to identifying chemical characteristics related to transport.
It is anticipated that studies will compare systemic PK to intraluminal (e.g. rete testis and/or epididymal tubule lumen) compound concentrations and utilize appropriate controls to ensure that the test compounds do not perturb the BTB and/or BEB.
Applications must be focused on:
- In vivo studies of BEB and/or BTB permeability of small molecular weight compounds with drug-like characteristics to identify chemical features that mediate and facilitate passage across the BTB and/or BEB.
In addition, applications may also include studies to:
- Evaluate transport mechanisms for molecules demonstrated to cross the BTB and/or BEB.
- Identify transporters within the BTB and/or BEB that transport chemical entities.
Applications that utilize any of the following research strategies are out of scope for this FOA:
- Applications that use in vitro systems to model the BTB and/or BEB;
- Applications that propose to catalog transporters without thorough evaluation of the structural characteristics of molecules that facilitate passage across the BTB and/or BEB;
- Applications that focus on a single chemical scaffold;
- Applications that propose the use of BTB and/or BEB disruptors;
- Applications proposing only the R61 mechanism, or only the R33 mechanism;
- Applications that do not provide proposed milestones and a clear path to transition from the R61 to the R33 phase of the award.
It is expected that proposed milestones will be both quantitative and unique for each project depending on its position within the development process. The following are examples of potential milestones for the R61 phase:
- Selection of three or more chemical series for initial evaluation;
- Development of analytical methods for the specific detection of molecules selected for preliminary testing;
- Determination of the molecular mechanism that one of the chemicals/chemical series utilize to cross the BTB and/or BEB;
- Initial testing of one chemical series including rational-based chemical modifications
Deadlines: November 27, 2018, November 27, 2019, November 27, 2020 (letters of intent due 30 days prior to deadline)
Filed Under: Funding Opportunities