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East Africa International Epidemiology Database to evaluate AIDS (IeDEA) Regional Consortium

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National Institute of Allergy and Infectious Diseases (NIAID)

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Project Summary/Abstract: Our primary goal continues to be the provision of answers to questions that clinicians, governments, programs and international organizations consider central to the evolution and sustainability of their long term HIV care and treatment strategies for achieving the UNAIDS 2030 targets of 95-95-95 in the midst of the SARS-CoV-2 pandemic and changes in public health funding priorities. Our central hypothesis is that retention in the HIV care cascade and treatment outcomes are influenced by patient-level demographic, clinical, developmental, and behavioral factors, as well as, factors within the ambient health care and broader contextual environment. We will leverage our strengths, including robust working relationships with HIV treatment programs, a substantial harmonized regional database, plus broad experience in sampling-based methodologies and novel analytical approaches. Over the course of this research we will: SA-1: Describe movement through the HIV care cascade with a focus on identifying broader and health care environment contextual factors that influence optimal retention in care and viral suppression, in the face of global disruption due to the COVID-19 pandemic and changes in donor funding priorities. The Post COVID-19 Double-Sampling Cohort (Post COVID) will address the impact of broader contextual factors (COVID-19) while the Telehealth and Structural Adaptations project will address the impact of health care structure. SA-2: Examine the impact of developmental stage and behavioral factors on retention in the cascade and subsequent outcomes. The multiregional Adolescent and Young Adult Network of IeDEA (AYANI) and regional Measuring Adverse Pregnancy and Newborn Congenital Outcomes (MANGO) cohorts will assess the impact of developmental stage on the cascade, while the Syndemics cohort will address the impact of mental health on the cascade.SA- 3: Examine the immediate and long-term outcomes of people diagnosed with Tuberculosis (TB) with a focus on identifying and addressing factors associated with patient outcomes. The multiregional TB Sentinel Research Network (TB-SRN) will focus on understanding TB outcomes and long-term pulmonary complications including associated factors. SA-4: Explore the use of new technologies, including eHealth and machine (deep) learning to diagnose and manage HIV-associated cancers with a focus on Kaposi’s Sarcoma (KS) and Cervical Cancer. The KS Project will assess implementation of a Dermatology Telehealth Program and the Cervical Cancer Project will assess the implementation of cervical image capture with machine learning for cancer diagnoses and management. SA-5: Examine the epidemiology of NCD comorbidities and ART complications with a focus on the oldest and youngest-age groups affected by HIV. The multi-regional Sentinel Research Network (SRN) will address non-communicable diseases in people living with HIV (PLHIV) > 40 years and the regional MANGO Cohort will address complications of ART/HIV exposure on HIV-Exposed Infants.

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East Africa International Epidemiology Database to evaluate AIDS (IeDEA) Regional Consortium

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
Project Summary/Abstract: Our primary goal continues to be the provision of answers to questions that clinicians, governments, programs and international organizations consider central to the evolution and sustainability of their long term HIV care and treatment strategies for achieving the UNAIDS 2030 targets of 95-95-95 in the midst of the SARS-CoV-2 pandemic and changes in public health funding priorities. Our central hypothesis is that retention in the HIV care cascade and treatment outcomes are influenced by patient-level demographic, clinical, developmental, and behavioral factors, as well as, factors within the ambient health care and broader contextual environment. We will leverage our strengths, including robust working relationships with HIV treatment programs, a substantial harmonized regional database, plus broad experience in sampling-based methodologies and novel analytical approaches. Over the course of this research we will: SA-1: Describe movement through the HIV care cascade with a focus on identifying broader and health care environment contextual factors that influence optimal retention in care and viral suppression, in the face of global disruption due to the COVID-19 pandemic and changes in donor funding priorities. The Post COVID-19 Double-Sampling Cohort (Post COVID) will address the impact of broader contextual factors (COVID-19) while the Telehealth and Structural Adaptations project will address the impact of health care structure. SA-2: Examine the impact of developmental stage and behavioral factors on retention in the cascade and subsequent outcomes. The multiregional Adolescent and Young Adult Network of IeDEA (AYANI) and regional Measuring Adverse Pregnancy and Newborn Congenital Outcomes (MANGO) cohorts will assess the impact of developmental stage on the cascade, while the Syndemics cohort will address the impact of mental health on the cascade.SA- 3: Examine the immediate and long-term outcomes of people diagnosed with Tuberculosis (TB) with a focus on identifying and addressing factors associated with patient outcomes. The multiregional TB Sentinel Research Network (TB-SRN) will focus on understanding TB outcomes and long-term pulmonary complications including associated factors. SA-4: Explore the use of new technologies, including eHealth and machine (deep) learning to diagnose and manage HIV-associated cancers with a focus on Kaposi’s Sarcoma (KS) and Cervical Cancer. The KS Project will assess implementation of a Dermatology Telehealth Program and the Cervical Cancer Project will assess the implementation of cervical image capture with machine learning for cancer diagnoses and management. SA-5: Examine the epidemiology of NCD comorbidities and ART complications with a focus on the oldest and youngest-age groups affected by HIV. The multi-regional Sentinel Research Network (SRN) will address non-communicable diseases in people living with HIV (PLHIV) > 40 years and the regional MANGO Cohort will address complications of ART/HIV exposure on HIV-Exposed Infants.

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Program for Resistance, Immunology, Surveillance & Modeling of Malaria in Uganda (PRISM) Renewal

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National Institute of Allergy and Infectious Diseases (NIAID)

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Summary/Abstract Malaria remains one of the most important global health challenges, with an estimated 247 million cases and 619,000 deaths in 2021, of which 95% of cases and 96% of deaths were in the WHO Africa region. The scale up of proven control interventions resulted in significant reductions in the burden of malaria following the turn of the century. However, since 2015 progress has stalled and even reversed course in some of the highest burden countries of Africa. Indeed, a myriad of challenges, including the spread of insecticide resistance, changes in vector composition and behavior, the emergence of artemisinin partial resistance, and the COVID- 19 pandemic have created a precarious situation. Our program called “PRISM” has been based in Uganda, representing the East African region for the International Centers of Excellence for Malaria Research network. Uganda is emblematic of the challenges faced by high burden countries, where routine surveillance systems are inadequate to assess trends in the burden of malaria or to monitor the impact of control interventions. Through PRISM we have implemented a comprehensive malaria surveillance program including enhanced health facility-based surveillance and detailed longitudinal studies. Complementary laboratory-based studies include surveillance for markers of antimalarial drug and insecticide resistance and serologic measures of malaria exposure. These studies have greatly improved our understanding of the epidemiology of malaria in Uganda and of the impact of control interventions. In this renewal application we propose to continue key components of our health facility and community-based malaria surveillance to strategically focus on quantifying the impact of malaria control interventions, working in close collaboration with our partners at the Uganda National Malaria Control Division (NMCD). We will utilize specimens collected from our surveillance system to generate genomic and serologic data to address key questions about malaria epidemiology, transmission, diagnostics, and antimalarial drug and insecticide resistance. The central theme of our program will be to improve malaria surveillance to better assess the impact of malaria control interventions and guide evidence-based utilization of existing and novel interventions to reduce the malaria burden using an adaptive approach. The program will consist of three research projects linked together in an integrated manner to maximize scientific discovery. Research Project 1 (Surveillance and Impact Evaluation Project) will utilize health facility and community-based malaria surveillance data from sites with varied transmission intensity and control interventions to monitor trends, estimate the impact of interventions, and provide clinical data and specimens for our other research projects. Research Project 2 (Resistance Project) we will characterize the evolution of genotypic markers of drug and insecticide resistance and assess the impacts of resistance on malaria transmission. Research Project 3 (Molecular Epidemiology Project) will characterize key parasite and vector genomic traits and human serological responses.

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With this R13 application, we request funding to support, in part, the costs for planning, publicizing, and hosting the 42nd, 43rd, and 44th Annual Symposia on Nonhuman Primate Models for AIDS. For more than four decades, this symposium has served as the premier scientific forum for the exchange of information, including new research findings and scientific perspectives, among HIV/AIDS investigators whose research includes studies in nonhuman primates (NHPs). Disseminating the latest research findings in NHP models of AIDS while also facilitating discussion and exchange of information between basic scientists and clinicians remains a priority, as do focusing on emerging technologies to accelerate translation of NHP studies into the clinic and engaging a broader and more diverse group of researchers in HIV/AIDS research in NHP models. This meeting, the only one of its kind in the world, convenes an international group of scientists whose research focuses on the study of natural and experimental immunodeficiency virus infections in NHPs, as well as on the development of novel therapeutics, prophylactic vaccines for HIV, and curative approaches. Emerging topics in related infectious diseases (such as COVID-19 pathogenesis, vaccines and treatment) may also be included. The seven National Primate Research Centers (NPRCs) host this meeting in rotation, and upcoming symposia hosts will be the Wisconsin (2025), Southwest (2026), and Washington (2027) NPRCs. We plan a hybrid format with most participants attending in person and others joining online to access oral and poster sessions. The conference will begin on day 1 with registration, a keynote address by a leading HIV/AIDS researcher, and an evening reception. The following two and a half days will include scientific presentations from invited speakers and accepted oral abstracts. Each symposium scientific committee will select session topics and speakers to highlight new and cutting-edge technologies in their respective fields. Each session will open with a 30-minute talk by an invited chair. Individuals whose abstracts are accepted for oral presentations will give the remaining session talks. A poster session will occur on the evening of day 2, and there will be a banquet on the evening of day 3. As is traditional for this symposium, the Journal of Medical Primatology will publish all poster and oral abstracts in a special issue. In partnership with the HIV Vaccine Trials Network (HVTN), the NHP AIDS Symposium will also host a pre-symposium meeting for early-stage investigators (ESI). This meeting will be open to the attendees of a linked ESI Conference the HVTN sponsors. ESI attendees and mentors will focus on grant writing, budgeting, and networking, and will participate in a Q&A with NIH Program Officers. We believe bringing together researchers from a variety of diverse backgrounds will generate future collaborations and scientific advances. Knowledge shared and gained at upcoming Annual Nonhuman Primate Models for AIDS Symposia will further the continued, effective use of NHP models to maintain long term control of HIV replication in the absence of antiretroviral therapy and to design interventions to prevent or eradicate HIV infection.

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United States National Institutes of Health

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Hijacking the neonatal Fc receptor: the novel biology of arterivirus entry, transmission, and persistence

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National Institute of Allergy and Infectious Diseases (NIAID)

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Understanding novel mechanisms by which animal viruses enter cells, evade immunity, and cause disease has scientific and public health importance. Arteriviruses are an understudied family of RNA viruses (related to coronaviruses) that infect a wide variety of mammals. The host and viral factors that determine arterivirus disease, persistence, and cross-species transmission remain unknown and unpredictable. This lack of understanding has implications for predicting/thwarting arterivirus emergence in humans, as some arteriviruses have been shown to infect human cells. Macrophages are exclusively infected by most arteriviruses, but the subpopulation(s) of macrophages that support arterivirus replication remain poorly defined. The process by which arteriviruses enter cells is highly novel and also poorly understood. Each virion displays an unusually large set of surface glycoproteins (7-11 depending on the virus) that are unlike any known viral fusion machinery. The macrophage-specific molecule CD163 is a required arterivirus receptor, yet CD163 by itself is insufficient to mediate arterivirus entry. We recently identified the neonatal Fc receptor (FcRn) as an important entry factor that arteriviruses use together with CD163 to gain entry into cells. Aim 1 of this project builds upon this discovery to define the molecular details of the arterivirus:FcRn interaction. In Aim 1a, we will map the site(s) on FcRn that are critical for arterivirus engagement by creating chimeric FcRn molecules that incorporate features of arterivirus-permissive and -resistant FcRn orthologs, with the goal of defining the domains, motifs, and residues involved in arterivirus/FcRn interactions. In Aim 1b, we will generate chimeric arteriviruses that contain combinations of glycoproteins from different arteriviruses, seeking to define the viral glycoproteins, domains, motifs, and residues involved in FcRn engagement. In Aim 1c, we will continue to develop our understanding of the host factors required for arterivirus entry by performing screens to identify additional host factors that are functionally redundant with FcRn for the viral entry process. In Aim 2, we will use the murine arterivirus (lactate dehydrogenase-elevating virus, LDV), which causes life-long viremia in adult mice, to understand several aspects of arterivirus infection in vivo. In Aim 2a, we will use a nanoluciferase-expressing LDV to perform body-wide imaging and identify the tissues that support LDV infection over time. In Aim 2b, we will hone in key tissues and identify the macrophage populations within these tissues that support LDV infection and determine how persistent arterivirus infection impacts recovery of target cell populations. Finally, in Aim 2c we will use FcRn-knockout mice to determine whether arteriviruses hijack FcRn’s physiologic role in placental biology, potentially explaining the high efficiency with which arteriviruses transmit vertically. This project will provide insights into novel mechanisms of viral entry, macrophage infection and dysfunction, viral persistence, and vertical transmission through the study of the neglected “pre-emergent” family of mammalian viruses, the arteriviruses.

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Clustered Regularly Interspaced Short Palindromic Repeats

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National Institute of Allergy and Infectious Diseases (NIAID)

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Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus from the Henipavirus genus that causes severe respiratory disease and encephalitis in humans. To date, no antivirals have been approved for treatment or prevention of these infections. We will develop and test peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO)-based compounds as anti-NiV therapeutics. Phosphorodiamidate morpholino oligomers (PMO) are water soluble, nucleic-acid-like antisense agents having nuclease resistance. They form stable duplexes with complementary RNA, affecting function. PMOs are FDA-approved to treat forms of Duchenne muscular dystrophy. PMOs can be conjugated to a cell-penetrating peptide to produce peptide-PMO (PPMO) which enter cells without the need for transfection. Aqueous solutions of PPMOs have shown considerable antiviral efficacy against a number of RNA viruses. We evaluated the anti-henipavirus potential of PPMOs using the non-pathogenic henipavirus Cedar virus (CedV) at BSL2. We designed PPMOs to target the start codons for the mRNAs encoding the three viral proteins essential for viral RNA synthesis- nucleoprotein (N), phosphoprotein (P) and large protein (L). These exhibited low micromolar activity versus CedV replication in Vero cells. A pilot test of PPMO targeting NiV N and P demonstrated anti-NiV activity in cell culture. That the P gene is a viable target is notable because the NiV P gene also encodes two critical virulence factors, V and W, which disable the type I interferon response. Because V and W share the same N-terminus as the P protein, an inhibitor of P translation will also block V and W expression. Therefore, a single P-targeting PPMO could disable viral RNA synthesis and simultaneously promote antiviral IFN-I responses, potentially enhancing antiviral activity. Building on these data, we will design PPMOs to target NiV N, P and L mRNAs. These will be tested for inhibition against live NiV at BSL4 and mechanism of action assessed by using a BSL2 NiV minigenome assay. We will test the hypotheses that antiviral activity of PPMOs correlates with suppression of translation of the targeted mRNA and determine whether targeting the P start codon will augment PPMO antiviral effects by suppressing expression of V and W. We will then test the best performing PPMO in vivo, using a hamster model. We will use airway administration because (1) Respiratory symptoms are a significant component of NiV infection. (2) In hamsters, infection can spread from the airway to the central nervous system (CNS) via the olfactory bulb. (3) Prior studies have used respiratory delivery and respiratory NiV challenge to test therapeutic candidates. (4) We recently demonstrated that PPMOs delivered directly to the airway at a 1 mg/kg dose reduced SARS-CoV-2 lung titers by >104 infectious units per gram lung tissue, and our Preliminary Data demonstrates that intranasal delivery to mice results in sustained PPMO effects throughout the upper airway and extending into the olfactory bulb. The in vivo studies will include assessment of tolerability, tissue distribution and efficacy against NiV of the top performing PPMO. We expect these efforts to yield a candidate PPMO for further development.

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National Institute of Allergy and Infectious Disease

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Advancing Analytical Tools to Quantify and Mitigate the Risk for Transitioning from Episodic to Endemic Transmission for Emerging Infections

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National Institute of Allergy and Infectious Diseases (NIAID)

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This project will develop and apply computational tools for assessing the risk that diseases with episodic transmission become established in the general population. Our project is relevant to emerging zoonoses, re-emerging vaccine-preventable diseases, and healthcare-associated infections. Timely identification and control of such diseases could have significantly altered the course of mpox, SARS-CoV-2, and antimicrobial resistance. It is therefore important to have methods available to monitor and fully elucidate the transmission patterns of infectious diseases that can develop increased burden through pathogen evolution, reduced population immunity, or other sociodemographic changes. Any such method needs to consider patchy surveillance and differences in risk among those who are exposed to the disease. Furthermore, diseases that cause episodic outbreaks might require specific control strategies that are different from those that apply to epidemic or endemic diseases. Existing models that explore some of these aspects typically omit key factors, rely on untested assumptions, or are validated in a circular fashion using simulations based on the same assumptions they aim to test. This limits their reliability for real-world applications. To address this gap, we will combine statistical inference with simulation approaches to address key questions in quantifying and mitigating the risk from infectious diseases. We will extend methods for inference using branching process models to take into account imperfect observations and heterogeneity in both transmission and susceptibility. We will apply these methods to a range of applications to improve our ability to learn from data describing sporadic infection clusters. We will also use mobility and demographic data to construct synthetic populations representing situations where infections cause occasional outbreaks. This will permit stress-testing of inference methods and evaluation of control strategies. Our iterative approach will allow us to refine model assumptions, improve inference robustness, and identify the most informative data types for public health surveillance and control. The work will result in a greater understanding of how public health agencies can best use data from episodic disease transmission and computational tools for applying this understanding to coming threats. To demonstrate the breadth of applicability, we will apply our methodological advancements to (1) quantify the transmissibility of H5N1 influenza, (2) determine the probability of large measles outbreaks occurring annually, and (3) evaluate control strategies for reducing transmission of virulent, healthcare-associated MRSA strains. To promote scientific reproducibility, we will produce user-friendly software that integrates with existing packages and share synthetic population data. Our team is well-positioned to conduct this work since we have developed many existing tools and paradigms for analyzing episodic transmission, including branching process models and outbreak simulations in synthetic populations. By advancing the science of disease transmission and equipping public health agencies with actionable results, this work will reduce the risk of future pandemics.

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A systems biology approach to identifying mechanisms underlying enhanced reactogenicity after mRNA-based vaccination

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LOUIS STOKES CLEVELAND VA MEDICAL CENTER

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Signiﬁcance to the VA: Vaccine hesitancy toward COVID-19 mRNA vaccines remains a signiﬁcant challenge. Identifying ways to reduce hesitancy is a key objective of these studies. Reactogenicity refers to adverse events (AEs) that occur shortly after vaccination as a physical manifestation of the inﬂammatory response. Understanding which reactogenic mechanisms are most closely linked to enhanced immunogenicity is crucial for designing interventions that mitigate negatively perceived side eKects without compromising the protective immune response. The veteran population includes a high proportion of older, multimorbid individuals who are particularly susceptible to severe morbidity and mortality from SARS-CoV-2 and RSV, both of which have approved mRNA vaccines, and inﬂuenza, for which an mRNA vaccine is anticipated soon. As the use of mRNA vaccine platforms increases, eKorts to facilitate their acceptance and utilization are essential for veteran health. Innovation and Impact: To our knowledge, no NIH-supported studies are investigating mRNA vaccine reactogenicity using systems biology approaches, particularly in VA priority cohorts, as indicated by NIH RePORTER and ClinicalTrials.gov. No comprehensive systems biology studies have focused on identifying speciﬁc pathways and molecules associated with AEs from mRNA vaccines. This innovative approach can help VA providers explain vaccine use and AEs, increasing uptake. Additionally, our ﬁndings could inform strategies to reduce AEs while maintaining protective immune responses. Speciﬁc Aims: Aim 1: Determine the mechanisms underlying reactogenicity by assessing local and systemic AEs following mRNA COVID-19 vaccination. Hypothesis: The development of AEs is associated with interferome and inﬂammasome pathway activation, leading to increased inﬂammatory cytokine and chemokine levels and enhanced immune activation. Additionally, pre-existing metabolic pathway perturbations may exacerbate AEs and serve as potential therapeutic targets. Aim 2: Identify mechanisms speciﬁc to reactogenicity versus protective immune response or those common to both. Hypothesis: Some mechanisms linked to severe AEs are also associated with stronger vaccine-induced immune responses. Aim 3: Model the impact of age and sex on mRNA COVID-19 vaccine-induced reactogenicity and immune response. Hypothesis: Older individuals, due to higher baseline inﬂammatory signatures, exhibit altered AE development and vaccine-speciﬁc immune responses following mRNA vaccination. Methodology: Veterans and, if necessary, some non-veterans will be enrolled to meet study targets. Participants will receive standard-of-care Pﬁzer or Moderna mRNA COVID-19 vaccines. Reactogenicity will be assessed clinically, and blood samples will be analyzed for cellular and transcriptomic changes, as well as vaccine-speciﬁc immune responses. Comprehensive systems biology analysis will compare individuals with high versus low AEs. Path to Translation/Implementation: Vaccine education interventions enhance trust in CDC recommendations and address concerns about rapid vaccine development and side eKects. Understanding the mechanisms driving reactogenicity will provide essential information to health care providers for patient education. Additionally, our ﬁndings may inform therapies or vaccine modiﬁcations to reduce AEs while preserving immune protection.

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United States National Institutes of Health

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N Protein Nexus: Rewiring Host Translation Machinery for SARS-CoV-2's Early Replicative Advantage

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National Institute of Allergy and Infectious Diseases (NIAID)

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ABSTRACT: Dependence on host-cell machinery for protein synthesis poses a significant challenge to coronavirus replication, particularly at the onset of infection when viral genomic RNA must compete with an abundance of host mRNAs for translation. To overcome this hurdle, viruses have evolved sophisticated strategies to commandeer the host translation machinery. While multiple mechanisms by which SARS-CoV-2 hijacks host translation have been elucidated, almost all involve non-structural viral proteins. This raises a fundamental question: how does SARS- CoV-2 establish a translational foothold during the early stages of infection, before non-structural proteins are synthesized? The viral nucleocapsid (N) protein is the primary viral factor present at this early stage of infection and has been shown to manipulate cell machinery to facilitate infection. We have found that N protein physically and functionally interacts with the human translation machinery, facilitating preferential viral translation. Moreover, our results suggest that the viral genome's 5ʹ untranslated region exploits high-affinity N protein binding to potentiate selective viral RNA recognition for translation. We hypothesize that N protein is a key mediator of viral translational hijacking in early SARS-CoV-2 infection, establishing a new paradigm within the N- protein functional repertoire. This proposal now seeks to elucidate the molecular mechanisms of host protein- synthesis modulation by N protein for viral benefit during early infection. Through two specific aims, we will (1) identify the viral determinants responsible for the impact of N protein on viral RNA translation and (2) delineate the roles of host factors in N protein viral-translation enhancement. By combining biochemical, biophysical, and genetic approaches, we will establish a comprehensive understanding of unanticipated host-virus interactions that govern SARS-CoV-2 pathogenesis, uncovering novel viral vulnerabilities that can be exploited to develop targeted antiviral therapy. Ultimately, this study will provide new insights for innovative therapeutic strategies that can be extended to other viruses with RNA-binding proteins, offering a promising avenue for smothering infection at its onset. 3

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miR-10b Gene Editing Therapy for Glioblastoma

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National Institute of Neurological Disorders and Stroke (NINDS)

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Malignant glioma, particularly glioblastoma (GBM), remains among the most lethal forms of cancer and represents a significant unmet need in current medicine. The median survival of GBM patients is approximately 15-20 months with highly aggressive standard care, and the five-year survival rate is about 5%. There are no effective therapies for the disease. Over the years, we accumulated evidence that GBM growth and invasiveness are closely regulated by microRNAs, small regulatory molecules that control gene expression and strongly contribute to gliomagenesis. We demonstrated that this class of molecules holds great promise as therapeutic targets for neuro-oncology. Our work led us to focus on miR-10b, a unique growth and invasion-promoting miRNA and common molecular target for GBM in adults (otherwise a highly heterogeneous class of brain malignancies). We identified miR-10b, essential for glioma growth, as a top and common therapeutic target for GBM. Inhibition of miR-10b using different strategies reduced tumor growth in all tested glioma cell and animal models. CRISPR/Cas9 gene-editing of miR-10b emerged as the most potent therapeutic strategy in mice, and it holds great promise for GBM patients. We developed potent and safe lipid nanoparticle (LNP) -based miR-10b editing formulation as a new class of precision medicine for GBM. Our objective is to advance this miR-10b editing drug (called miRTED) into a “first-in-human” clinical trial in subjects with GBM. The Specific Aims of this project are, in UG3 component (Discovery phase): 1) Finalize the efficacy of miRTED administration using diverse orthotopic GBM models, 2) Assess the toxicity and off-target effects of miRTED administration using human and rodent neuroglial cells, brain organoids, and mouse models to establish dosing guidelines, and during UH3 component (Development phase): 3) Partner with BPN team and selected contract research organization to manufacture preclinical and then GMP-grade clinical lots of the LNP, 4) Partner with BPN team and selected contract research organization to conduct IND-enabling mouse toxicology and biodistribution studies, and 5) Finalize the writing and filing of the IND application with the FDA. Due to glioma “addiction” to miR-10b, the new strategy is expected to be highly efficacious for most, if not all, GBM patients despite the heterogeneity of the disease. This approach is principally different from other gene therapies proposed for the GBM- that all target only a subpopulation of patients. It can be used in combination with, or ultimately replace, the current standard care. In addition, the LNP formulations developed in this project could provide a platform technology for precision medicine targeting other tumor vulnerabilities. Notably, the recent success of COVID mRNA vaccines and in vivo gene editing trials provide POCs for the efficacy, safety, and scalability of mRNA/LNPs and CRISPR/Cas9 components in humans.