Antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection. However, individuals on suppressive antiretroviral therapy develop a wide range of pathologies, including HIV-Associated CNS dysfunction. While ART has resulted in a reduction of the most severe forms of neurological and neurocognitive disorders, milder forms are prevalent in a sizable proportion of patients and have significant impact on quality of life.
HIV enters the CNS as early as 8 days after infection. The CNS is an important HIV reservoir, with cells that can support continuous viral replication, contributing to HIV-associated CNS dysfunction, and can be a source of virus after treatment interruption in suppressed individuals. Viral escape in the Cerebrospinal Fluid (CSF) has been described in patients on ART with undetectable blood HIV RNA, but with neurological damage, indicating the importance of the CNS as a viral reservoir. Residual viremia in the CNS drives immune activation/inflammation, contributing to mild to moderate forms of HIV-associated CNS dysfunction.
Reaching adequate drug concentrations in CNS is essential in treatment. Due to the unique structure of the Blood-Brain Barrier (BBB) and the existence of efficient efflux mechanisms, many of the current antiretrovirals have restricted entry into the CNS that might be a contributing factor to inadequate treatment of HIV infection in CNS.
The ability of antiretrovirals to penetrate the BBB and reach therapeutic concentrations in the CNS compartments depends on their physicochemical properties. Pharmacological profiles of current drugs differ significantly and result in notable differences in their ability to suppress HIV in CNS. Thus, enhancements of drug concentrations in the CNS compartments might potentially lead to more effective treatment and sustained remission of HIV via (1) depletion of HIV in the CNS, (2) minimizing possibility of drug resistance and (3) improvements in neurocognitive functioning. At the same time, careful monitoring of the drug-associated toxicities should be in place as some drugs (such as Efavirenz) can aggravate HIV-associated CNS pathology.
Understanding of the BBB and drug transport has improved over the years, and drug delivery technologies, including CNS-targeted platforms, have become one of the key focus areas of modern science. This solicitation is specifically designed to address CNS-targeted drug delivery for HIV and reflects the long-term goals of the National Institutes of Health to develop next generation HIV therapies.
Purpose and Research Objectives
This Funding Opportunity Announcement (FOA) will support non-clinical product development for innovative CNS-targeted drug delivery strategies capable of suppressing or eradicating HIV in the CNS. The research activities must be guided by critical assessments of both efficacy in the CNS and neurotoxicity to ensure that enhanced drug concentrations in the CNS compartments do not adversely affect product safety.
The FOA is focused on marketed and clinical-stage therapeutic agents with sufficient efficacy, pharmacological and toxicological data.
Investigators are encouraged to use multidisciplinary approaches and involve scientists with complementary expertise in chemistry, drug delivery, virology, animal disease models, pharmacology, toxicology, drug development, and other disciplines to ensure success and productivity.
Specific areas of interest include the development of:
- CNS targeting formulations of existing antiretrovirals known to have poor CNS penetration. Formulations may involve polymers, nanoparticles, liposomes, and other agents that will increase concentrations of antiretrovirals in CNS compartments and provide an acceptable balance between efficacy and safety.
- Formulations with the ability to carry large molecules (e.g., broadly neutralizing antibodies, bi-specific antibodies, etc.) to the CNS for HIV inactivation or for purging of the CNS reservoir.
- Drug delivery platforms that use current antiretrovirals in combination with transporters, immunomodulators, and other agents that will result in improvements in activity in the CNS.
The following activities will not be supported:
- Discovery of new drugs or biologics for HIV
Deadlines: January 7, 2019; January 7, 2020; January 7, 2021
Filed Under: Funding Opportunities