Advancing Technologies to Improve Delivery of Pharmacological, Gene Editing, and other Cargoes for HIV and SUD Mechanistic or Therapeutic Research (R01 Clinical Trial Optional)

The purpose of this funding opportunity is to develop technologies to improve the delivery of pharmacological, gene editing, or other cargoes for HIV and SUD or mechanistic or therapeutic research. The development of combination antiretroviral therapy (ART) for HIV has transformed HIV/AIDS into a chronic disease by suppressing viral replication to undetectable levels. However, even with effective ART, HIV reservoirs reside within the body (gut, bone marrow, brain, and other tissues), where cells harboring HIV provirus could reestablish active HIV infection with poor adherence or cessation of ART. Thus, no cure has been found for HIV infection and no effective vaccine for HIV exists. While progress has been made in developing antiretroviral formulations that are longer acting and with improved compliance, problems related to toxicity, bioavailability, and reservoir penetration remain. Effective long term sustained delivery is needed among people with substance use disorders (SUDs) where compliance with an ART regimen may be problematic. To address these issues, the development of improved reagents or technologies that enable targeted delivery of reagents (e.g., small molecules, biologics, gene editing reagents, etc.) to specific central nervous system (CNS) regions or cell types is needed. Such delivery systems would improve our ability to monitor or manipulate HIV and SUD processes and could serve as the foundation for improved future therapeutics for HIV and/or SUD. Targeted delivery of gene editing constructs, such as clustered regularly interspaced short palindromic repeats (CRISPR), to HIV reservoirs has the potential to eradicate and/or disable the virus, leading to a cure for HIV. The efficacy of gene editing technology may be enhanced by activating or inhibiting endogenous genes, combination therapy with long-acting antivirals, and other innovative strategies to improve reservoir penetrance, such as nano formulations and increasing blood brain barrier permeability. It is important to understand the effects of substances with addictive potential on these therapeutic strategies as many people living with HIV (PLWH) are exposed to these substances. It remains unclear how gene editing technology and other therapeutic cure strategies are altered in people with SUDs and HIV comorbidity. Research Objectives: The purpose of this notice of funding opportunity (NOFO) is to support milestone-driven preclinical research that will advance the development of new technology or tools to improve the delivery of pharmacological, gene editing, or other cargoes for HIV and SUD therapeutic and mechanistic research. Some examples of research project appropriate for this NOFO include, but are not limited to: Development of a new technology or tool to improve the delivery of pharmacological, gene editing, or other cargoes for HIV and SUD therapeutic and mechanistic research. Nano formulations to reduce toxicity, improve bioavailability, and provide vehicles for sustained delivery of pharmacological, gene editing, or other cargoes to the CNS. Strategies to selectively permeabilize the blood brain barrier for delivery of novel HIV therapies. Strategies to identify and selectively target brain cells harboring HIV provirus. Strategies to target and regulate neuroinflammation and neurotoxic immune cell phenotypes, independent of the HIV status of the cell. Research to test and generate evidence for effectiveness of non-opioid pain management strategies in aging adults living with HIV. Technologies or tools to optimize HIV and SUD care that minimizes the risks of polypharmacy among PLWH. In order to be responsive to the NOFO, applicants MUST: Propose to develop or significantly improve technologies for the delivery of cargoes for HIV and SUD research, as the major thrust of the work. Include at least one aim involving either (1) opioid, cannabinoid, nicotinic, dopaminergic, or other signaling pathways relevant to addictive substance use, or (2) exposure to addictive substances, or (3) analysis of samples from patients that have used addictive substances or have SUDs. Substances of interest include: nicotine, cocaine, methamphetamine, stimulants, xylazine, opioids, addictive prescription drugs, cannabinoids, or combinations of these drugs. Studies proposing long term exposure to addictive substances are encouraged. Focus on brain, tissues or cells relevant to the CNS OR well-justified studies using blood or lymphoid systems. Include one aim or sub-aim on humans or primates, animals with humanized immune systems and/or cells (including organoids) derived from human or primates. Other application considerations Despite the use of the R01 activity code, this NOFO supports high-risk/high-payoff projects. Applicants may wish to propose high-risk/high-payoff projects with a more limited scope, in which case they should align the proposed budget and/or project period with the proposed scope. The research strategy must include a timeline with quantitative SMART (Specific, Measurable, Achievable, Realistic, and Timely) milestones that will be achieved yearly. Investigators should consider milestones to be Go/No-Go decision points that are used to determine if the proposed approaches are feasible and attainable during the award period. The application must include well-defined milestones: e.g., critical steps to achieving development of the new technology, sequential assessment criteria for success of new technology, expected quality performance measures to be reached each year. If selected for funding, applicants will work with NIH staff to develop more granular milestones which will be included in their Notice of Award. Progress towards completion of these milestones will be assessed yearly. Patient samples should be well-characterized for stage/trajectory of SUD, type(s) of drug used, co-occurring conditions, gender, and age. Newly formed collaborations or teams to foster sharing of expertise between the fields of HIV, SUDs, and other research areas are encouraged. Studies leveraging biospecimens from other studies including National Institute on Drug Abuse (NIDA)-supported cohorts are encouraged. Applications Not Responsive to this NOFO The following types of applications will be considered non-responsive and will be withdrawn prior to review: Projects that don't propose to develop or significantly improve technologies for the delivery of cargoes for HIV and SUD research. Applications that don't include substances of interest and those focused solely on alcohol exposure. Proposed projects using tissues or cells relevant to cardiac, kidney, liver, or lung systems. Applications that don't include one aim or sub-aim on humans or primates, animals with humanized immune systems and/or cells (including organoids) derived from human or primates. Design, Analysis, and Sample Size for Studies to Evaluate Group-Based Interventions: Investigators who wish to evaluate the effect of an intervention on a health-related biomedical or behavioral outcome may propose a study in which (1) groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention, or (2) participants are assigned individually to study arms but receive at least some of their intervention in a real or virtual group or through a shared facilitator. Such studies may propose a parallel group- or cluster-randomized trial, an individually randomized group-treatment trial, a stepped-wedge design, or a quasi-experimental version of one of these designs. In these studies, special methods may be warranted for analysis and sample size estimation. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions. Additional information is available at https://researchmethodsresources.nih.gov/. Plan for Enhancing Diverse Perspectives (PEDP) This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV). Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.