Grants

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Radiation induced lymphopenia (RIL) occurs in approximately one-half of cancer patients receiving external beam radiotherapy and this post-therapy condition has been shown to greatly reduce five-year survival rates. It is theorized that RIL is induced by direct lymphocyte cell kill, suggesting that assessment of the radiation dose to lymphocytes during radiotherapy is a necessary requirement for their consideration as a dose avoidance structure. In order to facilitate the computation of radiation dose to circulating lymphocytes, their supporting structures must be modeled in patient anatomic models used in tissue dosimetry. Currently, there exists no intra- organ blood vasculature nor lymphatic vasculature nor specialized lymphoid tissue structures within the International Commission on Radiological Protection’s (ICRP) reference computational phantoms – commonly used as a digital model of medical patients. Additionally, there exists major inaccuracies in the inter-organ whole- body blood vessels of these reference phantoms, and no modeling of microscale vasculature of blood or lymph has been yet undertaken to account for their large portion blood and lymph within the human body. Additionally, in applications of radiopharmaceutical therapy, blood self-dose, which is substantial for short-range radiations such as alpha particles and lower-energy electrons, emitted by many common radiopharmaceuticals, cannot be entirely quantified due to the lack of intra-organ vasculature in the ICRP phantoms. Dose to lymphatic vessels, additionally can be computed for the first time in RPT applications with these models in place. Therefore, this project hypothesizes that the development of a comprehensive model of blood and lymphatic vessels and corresponding lymphoid tissues will facilitate the computation of blood and lymphocyte radiation dose for the first time and will subsequently allow for consideration of circulating and non-circulating lymphocytes as organs-at- risk in radiotherapy treatment planning. The proposed project will be achieved by the completion of four Specific Aims: Aim 1: develop whole-body adult mesh models with intra-organ and inter-organ vasculature. Aim 2: develop corresponding lymphatic tissue and vessel models. Aim 3: develop organ specific microscale blood and lymph vasculature models. Aim 4: compute organ radionuclide S values for radiopharmaceutical therapy and lymphocyte dosimetry for external beam radiotherapy. Completion of these aims will greatly improve the computational models used as tools in reference medical dosimetry for a new assessment of dose to blood, as well as set the stage for adaptation of these models via deformable registration to expand to patient-specific modeling and personalized dosimetry.

Up to $44K

Rolling

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Development of molecular tools and mouse models to study neglected Sindbis virus genotypes and their epidemic potential

NIAID - National Institute of Allergy and Infectious Diseases

Title: Development of molecular tools and mouse models to study neglected Sindbis virus genotypes and their epidemic potential PROJECT SUMMARY Sindbis virus (SINV) is a mosquito-borne alphavirus with a single-stranded positive-sense RNA genome. SINV is transmitted between mosquitoes and birds which serve as reservoir hosts for the virus but can cause spillover infections in other vertebrate hosts including humans. SINV can be classified into distinct genotypes (G1-G6) which aligns with their zoogeographical distribution. SINV causes frequent epidemic outbreaks of polyarthritis disease in Northern Europe and has also been associated with outbreaks in Africa. Epidemics in both these regions are caused by G1 viruses. SINV is widely distributed geographically but is not associated with epidemics elsewhere in the world. Despite being prevalent in mosquito populations in Australia, the SINV strains in this region (G2/3 and G6) have never been associated with epidemics of polyarthritis disease here, though isolated human cases have been reported, and serological data shows the occurrence of human infections. The Australian genotypes of SINV (G2/3, G6) are significantly divergent from the G1 viruses which cause frequent epidemics, suggesting that genetic differences between these genotypes may explain why G1 viruses have a propensity to cause epidemics but other genotypes do not. Most of the genetic tools available to study SINV are derived from G1 viruses, and there is only a single non-G1 cDNA clone (for the G4 virus XJ-160). There currently exists no molecular clones for studying other genotypes of SINV, including the divergent Australian G2 and G6 viruses. In this R03 we propose to construct cDNA clones for G2 and G6 SINV and characterize the in vitro replication properties of these clones and compare pathogenesis profiles of virus derived from these clones versus characterized G1 strains in a small animal model. We have established a subcutaneous model of SINV infection and shown that replicating virus can be detected in the skin and joints of adult mice, which reflects the pathogenesis observed in humans. Thus, this serves as a good model for examining the genetic determinants that underlie the epidemic potential of neglected SINV genotypes. These tools will be available to the research community and thus aid in further investigations of other key aspects of arbovirus transmission and pathogenesis including virus-mosquito interactions, species-specific determinants of transmission, and viral immunity.

Up to $78K

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Development of Muscle Optimized Non-viral Gene Editors

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary Duchenne muscular dystrophy is a severe X-linked genetic disorder characterized by progressive muscle degeneration and weakness caused by the loss of dystrophin protein. There are no curative therapies for DMD, and recently approved micro-dystrophin gene therapies have shown modest clinical benefit. Adeno-associated virus (AAV) delivered CRISPR gene editing strategies have achieved high rates of corrective gene editing in mouse and canine models of DMD but rely on dangerously high doses of AAV and result in constitutive expression of immunogenic gene editors. Lipid nanoparticles (LNPs) have emerged as a promising non-viral delivery strategy for gene editing but have lower delivery efficiency in skeletal muscle than AAV. Significant effort has been put towards improving delivery efficiency of LNPs, however, the factors that limit gene editing in skeletal muscle after delivery have not been addressed. Gene editing efficiency is not only determined by the entry of the delivery vehicle into the cell but also by the ability of the gene editor protein to populate all the myonuclei of the myofiber. Myofibers have hundreds or thousands of myonuclei that must be edited to achieve therapeutic benefit, but our preliminary data show that gene editor proteins cannot propagate to myonuclei distant from the site of transfection/transduction. In addition to the issue of low myonuclear propagation, low mRNA stability prevents the accumulation of sufficient levels of gene editor protein to edit most myonuclei. The objective of this project is to develop a muscle-optimized gene editor that can increase gene editing efficiency after non-viral delivery. This objective will be achieved by developing an in-vitro myotube based screening platform to identify modifications to the ABE8e adenine base editor that improve myonuclear propagation. An in-vivo pooled LNP screen will be performed to identify UTRs and codon optimization strategies that improve base editor mRNA stability in skeletal muscle. Modifications identified in these screens will be combined into a muscle-optimized base editor that will be used in LNP-delivered editing of a humanized mouse model of DMD. Completion of these studies will contribute to the development of a non-viral curative therapy for DMD. The insight gained from these studies will provide a basis for developing other muscle-optimized gene therapy cargos. These studies will be carried out in the laboratory of Dr. Eric Olson, PhD at University of Texas Southwestern Medical Center. All studies and career development will be performed under the mentorship of Dr. Olson and Dr. Ning Liu, PhD, pioneers in the field of skeletal muscle gene editing.

Up to $76K

2028-11-30

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Development of Nav channel targeting antisense oligonucleotides as chronic pain therapeutics using an integrated platform based on machine learning and optical electrophysiology

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary: Development of Nav channel targeting antisense oligonucleotides as chronic pain therapeutics using an integrated platform based on machine learning and optical electrophysiology Effective treatment of chronic pain, including severe neuropathic pain conditions, such as erythromelalgia (EM) and small fiber neuropathy (SFN), remains a significant unmet medical need. Current therapies often lack full efficacy or come with serious risk, such as addiction associated with opioids. Antisense oligonucleotides (ASOs) offer a promising solution by knocking down specific mRNA transcripts with a long duration of action (~3 months) for sustained relief. ASOs have been successfully applied to patients to treat severe neurological disease. Here, we propose to develop an ASO therapeutic targeting the voltage-gated sodium channel, Nav1.7, which is highly expressed in dorsal root ganglion (DRG) neurons. Nav1.7 is a target with strong human genetics validation in pain transmission, including neuropathic pain. Reduction of channel expression via a therapeutic ASO may overcome the challenges of small molecules by mimicking the mechanism for congenital insensitivity to pain (CIP) resulting from hNav1.7 loss-of-function mutations. Administering the ASO via intrathecal (IT) injection will enable precise knockdown of Nav1.7 expression in DRG tissues in a state-independent manner with minimal risks for autonomic side effects, paving the way for an effective and targeted chronic pain therapy. To enable the selection of a Nav1.7 specific ASO with the desired profiles, Quiver has developed breakthrough technologies: (i) high throughput readout of neuronal excitability based on all-optical electrophysiology, (ii) combination of patient genetics and state-of-the-art human iPSC sensory neuron differentiation protocol for pain therapeutics validation in patient-based models, and (iii) a machine learning-guided ASO design and discovery platform for identifying the best ASO candidates with maximum therapeutic index. As an entry point, Quiver has identified a potent and selective hNav1.7 lead ASO (QV-2421) with confirmed activity in primary DRG neurons from relevant species and a clean in vivo CNS tolerability profile through in sillico prediction and empirical validation. In the UG3 phase, we will apply our breakthrough technology in combination with well-established preclinical assays to optimize the ASO lead. Quiver will collaborate with Boston Children's Hospital (BCH) to validate the functional impact of the lead ASO in sensory neurons derived from EM/SFN patients with neuropathic pain conditions. We will also evaluate long term in vivo tolerability and investigate translational biomarker approaches. Based on these studies, we aim to select one optimized ASO lead candidate with an acceptable tolerability profile and in vivo NHP PK/PD data profile by the end of the UG3 phase. In the UH3 phase, we will conduct dose-range finding toxicology studies, establish clinical biomarkers, perform large-scale manufacturing of the ASO candidate for IND-enabling studies, and initiate a Phase I clinical trial in young adult EM patients. The UH3 phase will conclude with the identification of an ASO candidate with an acceptable toxicology and preclinical profile that is advanced through IND-submission to enable the initiation of Phase I clinical trial. Our ultimate goal is to deliver a much-needed, non-opioid therapy to patients suffering from severe, chronic pain.

Up to $2.0M

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Development of Neuromedin Receptor 2 antagonists as Novel Analgesics

NINDS - National Institute of Neurological Disorders and Stroke

Abstract Chronic pain affects millions of individuals globally, profoundly impacting their quality of life and imposing a significant burden on healthcare systems. While opioids have been the gold standard for treating moderate to severe pain, their serious adverse effects, such as dependency and tolerance, limit their clinical utility. Consequently, there is a critical need to explore new therapeutic targets for more effective and safer pain management strategies. Neuromedin U (NMU) is a neuropeptide that modulates various physiological functions, including pain perception, through its interaction with Neuromedin U Receptor 2 (NMUR2). Emerging evidence suggests that NMUR2 plays a crucial role in the transmission and modulation of pain signals within the central nervous system, and blocking this receptor could potentially alleviate pain. This proposal aims to establish a comprehensive structure-activity relationship (SAR) for two chemical series of NMUR2 antagonists, with the goal of optimizing their potency, selectivity, and drug-like properties. Upon completion of this project, we aim to provide structure-activity relationship data for compound optimization, early-stage ADME and pharmacokinetic information, laying the foundation for developing NMUR2 targeting tool compounds and drug candidates for chronic pain treatment.

Up to $231K

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Development of new genetic tools for selective targeting plasma cells

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Plasma cell (PCs) antibody production is at the core of humoral immunity and inherently critical to the success of almost all existing vaccines. Their ability to persist and secret antibodies long after pathogen exposure or immunization provides long term sometimes lifelong immune protection against future encounter of the pathogens. What are the molecular pathways dictating the lifespan of PCs during their generation and subsequent maintenance remain largely unknown. Equally unknown are the regulators that control the diversity and activity of PCs reside in various lymphoid and non-lymphoid tissues. Cell lineage specific gene targeting and tracing (GT&T) with the Cre/LoxP system has been proven vital to understand the biology and regulation of various types of cells, especially rare cell populations such as PCs. However, existing mouse models for PC selective GT&T have significant drawbacks due to leakiness in either closely related cell lineage such as germinal center B cells or functionally intertwined cell lineage such as germinal center T cells. To improve selectivity in genetic dissection of PCs, we searched for genes that display high level expression in PCs but absent in the rest of lymphoid lineages. We found a single gene that fulfills this criterion and thus a good candidate for developing new mouse models with high selectivity and efficiency to drive Cre/CreERT2 expression in PCs. We propose to develop new Cre and CreERT2 models for GT&T studies in PCs. The proposed mouse model will address the immediate need for genetic and molecular investigations aimed at understanding longevity and behaviors of PCs in various tissues in response to infection or immunization.

Up to $162K

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Development of next generation spectinomycin analogs that evade modifying enzyme-based resistance and show enhanced potency against multidrug-resistant pathogens.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Multi-drug resistance is rapidly emerging among carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. With increasing frequency, these pathogens often prove untreatable or treatable only with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. Spectinomycin is a novel tricyclic aminocyclitol antibiotic approved for treatment of N. gonorrhoeae. It has an excellent safety profile in humans. Unlike other aminoglycoside antibiotics, it is neither ototoxic nor renal toxic. It also remains active in the presence of widely circulating ribosomal methylases. However, it is covalently inactivated at a single site by circulating adenylases. It also does not efficiently penetrate the outer membrane of gram-negative ESKAPE pathogens; and, therefore, these pathogens are relatively resistant to achievable drug levels. However, experiments performed in combination with membrane-permeabilizing agents, strains with defects in the outer membrane, and with in vitro translation extracts indicate that gram-negative pathogens are susceptible to this antibiotic if outer membrane penetration is facilitated. Recently, molecular properties that enhance penetrance into gram-negatives have been defined. Based on intrinsically compelling properties of spectinomycin, we propose to use structure- and molecular property-guided de novo asymmetric glycochemistry in combination with streptamine semi-synthesis in the design of spectinomycin analogs with enhanced penetrance and that escape modification by aad-class adenylases and thereby evade circulating resistance. The underlying goal will be to identify analogs that have broad-spectrum activity against resistant gram-negative pathogens and fill a critical unmet medical need. There are no previously published modern efforts along the lines proposed targeting gram-negative ESKAPE pathogens, and, therefore, the proposed work is both novel and innovative. Importantly, the analogs will be profiled in a series of complementary functional studies. These will include both in vitro and in vivo measurements that will distinguish effects of penetrance and intrinsic translational inhibition; activity spectrum studies; assessment of metabolic stability; and proof-of-principle in vivo efficacy experiments that together will inform future intensive exploration of lead candidates. The near-term goal of this two-year, exploratory R21 proposal is to identify tractable, potent, broad-spectrum spectinomycin analogs worthy of further exploration.

Up to $494K

2028-06-30

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Development of Novel Antimicrobial Peptides, Pdi1-Derived Translation Termination Inhibitors

NIAID - National Institute of Allergy and Infectious Diseases

Abstract The urgent need for new antibacterial agents is well recognized, as the rapid emergence of resistance continues to outpace current drug development efforts. To address this challenge, the Moore and Mankin/Vázquez-Laslop labs are collaborating to advance the development of translation termination inhibitors, a novel antibacterial mechanism observed only in the Class II subset of proline-rich antimicrobial peptides (PrAMPs). Apidaecin (Api) and drosocin (Dro), both Class II PrAMPs, share this unique mechanism despite having distinct sequences and binding modalities. Recently, the Mankin/Vázquez-Laslop lab identified Pdi1, an insect-derived translation termination inhibitor with similarity to Api. This proposal outlines a plan to leverage Pdi1 and the structurally distinct Dro to design and optimize novel hybrid translation termination inhibitors with enhanced potency and metabolic stability. Pdi1’s similarity to Api also provides a framework to investigate the role of secondary structure in this mechanism of action. Notably, Api’s bioactive conformation includes polyproline type II (PPII) features. Incorporating proline derivatives into Pdi1 will constrain the amide bond conformation and provide a systematic approach to study how PPII structure influences the peptide’s antimicrobial activity. The results of this work will be fundamental to the development of FDA-approvable translation termination inhibitors.

Up to $50K

2027-07-15

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Development of Novel Biomarkers for Diagnosis of Malignant Pleural Effusion

NCI - National Cancer Institute

Abstract /Summary: Malignant pleural effusion (MPE) affects 200,000 individuals in the United States annually and lung cancer is the most common cancer to metastasize to the pleura. Unfortunately, cytologic examination of the pleural fluid (PF) obtained during thoracentesis only has a diagnostic sensitivity of ~50% with marginal increase upon serial sampling and limited by the need to detect malignant cells which are sparse in the PF. More invasive procedures such as thoracoscopic pleural biopsy are often required, but these procedures are associated with potential complications, hospital stay and delayed diagnosis and treatment. There is an urgent need to develop novel approaches to complement PF cytology. To address this need, we examined the potential of tumor cell products, specifically extracellular vesicles (EVs) and non-vesicular particles, for MPE diagnosis. In previous studies, we have detected and characterized EVs in PF and have identified and validated distinct EV microRNA (miRNA) signatures discriminating cytology-positive (C+) lung adenocarcinoma induced MPE (LA-MPE) from non-malignant pleural effusion (non-MPE). Additionally, because epithelial-derived surface markers are not native in the pleural space, we analyzed the expression of epithelial cell adhesion molecule (EpCAM), in cell- free PF of LA-MPE to identify tumor-derived EVs. We showed significantly higher EpCAM expression in (C+) LA-MPE compared to non-MPE. An essential next step is the evaluation of extracellular miRNA and proteins within the cytology-negative (C-) MPE populations, where current tests fail or are highly invasive. To Accomplish this goal, we will leverage samples from a diverse PF biorepository (current n=313) including (C+) and (C-) MPE and non-MPE with 35% African/Black participants and detailed tumor-specific and clinical data. Specific Aims will: 1) identify differentially expressed extracellular miRNA among patients with (C-) LA-MPE and non-MPE and validate the identified miRNA signature in an independent validation cohort, 2) identify differentially expressed extracellular proteins (particularly epithelial-derived proteins) among patients with (C-) LA-MPE and non-MPE. In addition, we will identify protein expression in (C+) and (C-) MPE due to breast cancer and compare protein expression among groups. We will evaluate the combined discriminating role of protein and miRNA expression among (C-) LA-MPE and non-MPE. Development of a diagnostic classifier, using a cell-free biofluid enriched with tumor-cell products that requires drainage and is underutilized is paradigm shifting and a crucial missing step in our MPE management which will be addressed through our proposal. Most biomarkers to date are examined in (C+) MPEs of heterogeneous populations and lack reproducibility or confirmation in (C-) MPE groups. We aim to close this gap and focus on (C-) LA-MPE populations where our findings could be clinically relevant and practice changing. This work will lead to an R01- level grant focusing on PF tumor-derived EVs and EV cargo in diagnosis, disease monitoring and prognosis of metastatic cancers of varying tissue type to the pleura.

Up to $450K

2028-04-30

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Development of novel malaria vaccine antigen targeting multiple stages of the Plasmodium lifecycle.

NIAID - National Institute of Allergy and Infectious Diseases

Development of a novel malaria vaccine antigen targeting multiple stages of the Plasmodium lifecycle. Project summary Previously, using a phage peptide display library technique, our group identified mimotope peptides that mimic the conformation of Plasmodium sporozoite ligands essential for liver infection. Notably, these small peptides elicit protective immunity by inducing antibodies that neutralize sporozoites. Using a similar approach, we identified two peptides, FG1 and MG1, which structurally mimic ligands employed by male and female gametes to facilitate parasite fertilization in the mosquito midgut. Antibodies generated against each peptide specifically bind to their corresponding gametes and markedly inhibit fertilization, thereby blocking mosquito transmission. Using the anti-MG1 antibody, we further identified the Plasmodium Heat-Shock- Protein 90 N’-terminal ATPase domain (HSP90N’) as the female gamete fertilization ligand and a potential transmission-blocking vaccine (TBV) antigen. We propose to 1) evaluate the transmission-blocking efficacy of the HSP90N’ domain and the MG1 peptide to select an optimal female-targeting antigen, and then fuse it with the male-targeting FG1 peptide to generate a dual-target TBV antigen; and 2) develop a multiple-stage vaccine antigen by linking the dual epitope TBV construct with our recently developed triple-epitope liver-stage vaccine antigen. The final fusion vaccine antigen will comprise: (i) a female gamete antigen (HSP90N’ or MG1), (ii) the FG1 peptide targeting male gametes, (iii) the PfCSP NPNA repeat peptide, (iv) the P39 peptide targeting sporozoite–Kupffer cell traversal, and (v) the HP1 peptide targeting sporozoite–hepatocyte invasion. We anticipate that this strategy will enhance malaria control by eliciting broad protective immunity through a single antigen targeting multiple essential epitopes across the Plasmodium life cycle.

Up to $230K

2028-06-30

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Development of novel neoantigen-based spherical nucleic acid immunotherapeutics

NCI - National Cancer Institute

PROJECT SUMMARY Triple negative breast cancer (TNBC) is a highly invasive form of breast cancer with a dismal outcome, accounting for a staggering 25% of all breast cancer associated deaths despite comprising only 10-15% of cases. The standard of care for TNBC includes aggressive surgery, followed by radiation therapy and continued chemoimmunotherapy yet often results in a high rate of recurrence, formation of tumor resistance mechanisms, and metastasis, leading to poor patient outcomes. Current therapies are limited due to the lack of clear molecular targets, genomic instability, and the suppressive tumor microenvironment. Thus, there is an overwhelming need for targeted, effective, and safe therapeutics to combat TNBC. Flashpoint Therapeutics and the Gillanders Laboratory at Washington University School of Medicine (WUSM) proposed solution leverages the combined expertise of both teams to develop a targeted, personalized neoantigen cancer immunotherapeutic for TNBC using a structural nanomedicine platform. Cancer neoantigens represent a potentially optimal target to combat cancer as tumor-specific mutations can be utilized to selectively prime a specific immune response to target and destroy cancer cells while sparing healthy tissue. Additionally, delivery of RNA through lipid nanoparticles (LNPs) decorated with immunostimulatory spherical nucleic acids (SNA) has shown drastic improvement over conventional approaches. Having already demonstrated proof-of-concept feasibility for the safety and efficacy of TNBC personalized neoantigens and proven immunostimulatory RNA LNP SNA properties, we are poised to develop a patient-specific neoantigen-based personalized nanoparticle immunotherapeutic (PNI), termed P-SNA, for TNBC patients. In this Academic-Industrial Partnership R01 application we first aim to evaluate the efficacy and mechanism of action of our lead P-SNA candidate through in vivo preclinical breast cancer mouse models (Aim 1.1), and by use of fluorescently labeled constructs to determine biodistribution, immune activation, and immune priming (Aim 1.2). We will then chemically optimize our lead candidate to improve therapeutic properties using a rigorous Design of Experiments approach (Aim 2.1) and test the efficacy and mechanism of action of optimized candidates in vivo (Aim 2.2). As there is no model which can accurately or completely reproduce the complex immune and non-immune interactions that occur between the host and a tumor, even in the absence of vaccination, the only way to understand the impact of the P-SNA therapeutics are to test in well characterized animal models. Finally, we will develop GMP manufacturing protocols for the production of our optimized P-SNA lead GMP-compliant facilities (Aim 3.1) and complete FDA recommended IND-enabling studies (Aim 3.2). Together, these steps will enable the delivery of a lead P-SNA therapeutic for TNBC, fully characterized and optimized for efficacy and ready for clinical evaluation. Additionally, this work will establish a versatile platform for the development of P-SNAs for other cancer subtypes, increase our knowledge of immune mechanisms to fight cancer, and elucidate important aspects critical for rational PNI design and development.

Up to $563K

2031-07-01

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Development of novel RPS23 inhibitors for the treatment of leukemia

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) remains a lethal disease despite recent therapeutic advances, including the BCL2 inhibitor venetoclax. Most patients ultimately develop relapsed or refractory disease, underscoring the urgent need for new therapies, particularly agents that synergize with venetoclax. One promising strategy is to target the integrated stress response (ISR), a conserved pathway that modulates protein synthesis through phosphorylation of eIF2á by one of four stress-sensing kinases: GCN2, PKR, PERK, or HRI. This phosphorylation reduces global cap-dependent translation while selectively increasing translation of transcripts such as ATF4, which drive adaptive or pro-apoptotic programs depending on context. Leukemia stem cells rely on chronic ISR activity to withstand metabolic stress, suggesting that further ISR activation could tip the balance toward apoptosis. Consistent with this idea, we found that venetoclax itself activates the ISR via HRI, and its efficacy in preclinical models depends on this mechanism. We discovered novel ISR modulators using our integrated platform that combines high-throughput phenotypic screening with rapid target deconvolution. Through this approach, we identified ligands of RPS23, a 40S ribosomal subunit protein, that activate the ISR through GCN2 by a mechanism distinct from venetoclax and known ribosome binders. These ligands trigger apoptosis in leukemia cells and prolong survival in aggressive AML mouse models with minimal toxicity to normal hematopoietic cells. We hypothesize that RPS23 ligands represent a novel therapeutic strategy for AML and may act synergistically with venetoclax to overcome resistance. The discovery of this ISR-inducing target, together with a bioavailable compound showing preclinical efficacy, highlights the significance and innovation of our approach and provides a strong foundation for clinical translation. To advance this therapeutic strategy, our Specific Aims will define the mechanism by which RPS23 ligands activate the ISR and evaluate their on-target toxicities and efficacy alone and in combination with venetoclax in disease-relevant models of AML. No validated in vitro or computational model currently recapitulates the integrated immune, vascular, and metabolic interactions required to evaluate therapeutic efficacy and toxicity in vivo.

Up to $688K

2031-05-31

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Development of Online Launch Calendar, Phase III

National Park Service

Development of Online Launch Calendar, Phase III

$28K

rolling

sciencetechnology

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Development of Overmountain Victory Trail interpretive exhibits at the new Lake James State Park Visitor Center

National Park Service

The purpose of this Cooperative Agreement is to partner with the state park to develop, build, and install a permanent interpretive exhibit within the visitor center to interpret the significance and history of the trail and connect visitors to the trail for public education and recreational enjoyment.

$1 – $93K

rolling

Education

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Development of polarizable Gaussian multipole force field for biomolecular simulations based on in-solution electrostatics

NIGMS - National Institute of General Medical Sciences

Project Summary Physics-based molecular modeling methods have played important roles in biochemical and biophysical sciences. This investigator has led a team of investigators in the development of Amber polarizable force fields with long-term goals to develop force fields that can reproduce biological structure, dynamics and interactions without sacrificing the computational efficiency necessary to reach biologically relevant temporal and size scales. Furthering the advances, this investigator proposes to develop parameters and simulation methodologies that are part of the foundation of molecular simulation platform to push the “Amber” polarizable force field efforts to the next level. A key focus is to not only develop general, reliable and widely applicable polarizable force fields for proteins, nucleic acids and drug-like molecules, but to validate the force fields via vigorous testing using experimental and high-level quantum mechanical data on a variety of molecular systems and at all stages of the development. This proposal is broad reaching in that successes will have positive impact in broad range of scientific and technological areas. The proposed work is broadly categorized in the following areas: 1) Development of polarizable force fields, including parameterization of charges, permanent dipoles, van der Waals and torsion potentials; 2) Critical validation and refinement of polarizable force field parameters for non-trivial model systems; 3) Development of a continuum solvent method for polarizable force fields for efficient calculations of binding free energies; 4) Develop novel methods for improved modeling of charge transfer and atomic quadrupoles.

Up to $342K

2030-02-28

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Development of Polygenic Risk Scores for Diabetes and Complications across the Life-Span in Populations of Multiple Ancestries

NHGRI - National Human Genome Research Institute

Abstract Large-scale genome wide association studies (GWAS) have identified a large number of genetic variants associated with complex diseases. The aggregation of all the variants that are known to contribute to the disease in the form of polygenic risk scores (PRS) improves the prediction of a range of complex diseases. Most PRS have been developed within European ancestry study samples and have shown to perform poorly in other ancestry groups, further exaggerating differences in treatment quality across ancestries. As genetic approaches for precision medicine become more popular, there is a critical need to responsively and proactively expand access to accurate PRS. Specifically, diabetes, and its associated complications are one of the biggest health problems of the 21st century. In fact, type 1 and type 2 diabetes (T1D and T2D), gestational diabetes (GDM) and related complications are excellent disease models to study the utility of PRS for predicting heterogenous and complex health outcomes in a setting where differences in access to healthcare exist. Not only are PRS useful to predict T1D and T2D, but they can distinguish between T1D and T2D, and between T2D subtypes. The wealth of existing GWAS data from diabetes subtypes, complications, and quantitative traits recently generated provides a unique opportunity for constructing highly transferable PRS across populations. To address the differences in accuracy in PRS across ancestries, we have assembled a multi-disciplinary team to aggregate and analyze the largest existing genetic data from more than 1.8 M individuals (49% non-European) with T1D, T2D, GDM and glycemia-related complications and quantitative traits to improve the PRS prediction of diabetes and progression across lifespan in multiple ancestries with these Aims: (1) Collection, harmonization and integration of large-scale, multi-ancestry cohorts with diabetes traits across the life-span and genomics for development, training and testing PRS for multiple ancestries; (2) Development of methods to improve PRS prediction in non-European populations by using Bayesian approaches that allow integration of linkage disequilibrium and summary statistics from several ancestries. (3) Development, testing, and comparing performance of PRS for each trait, development of risk prediction tools that integrate clinical and genetic risk factors, and assessment of scenarios where PRS improve the prediction. Accomplishing the aims of this proposal will demonstrate how genomic data can inform more efficient and targeted preventive strategies within healthcare systems and across multiple populations. Findings are expected to advance precision care of patients with diabetes and related conditions in people of multiple ancestral backgrounds and serve as a paradigm for many other complex diseases.

Up to $876K

2027-03-31

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Development of Precision Genome Editing Tools for the Functional Characterization of Genetic Variants

OD - NIH Office of the Director

Summary Over half of the genetic variants identified through clinical sequencing are variants of uncertain significance (VUS), posing a significant challenge to accurate genetic diagnosis and effective patient care due to the unknown functional impact of these single-nucleotide variants (SNVs). Current genome editing methods lack the efficiency, specificity, and scalability required for high-throughput functional validation in vivo, presenting challenges such as bystander mutations, insertions/deletions, and limited targeting coverage in zebrafish, an ideal model organism for human disease genetics. This proposal aims to establish a high-throughput, cost-effective platform for in vivo functional validation of human disease-associated genetic variants using the zebrafish model. The central hypothesis is that optimized CRISPR editors, when paired with zebrafish-specific computational tools, will enable efficient and precise modeling of single-nucleotide variants (SNVs). Three integrated aims will be pursued: (1) Develop high-fidelity base editors with expanded genomic targeting to model SNVs with minimal bystander mutations and enhanced editing efficiency; (2) Create a deep learning model to design optimized guide RNAs for CRISPR base editing, improving variant editing accuracy; and (3) Engineer next-generation prime and Click Editors for precise in vivo editing. This innovative approach introduces zebrafish-optimized CRISPR tools, a novel deep learning model, and pioneering Click Editing, overcoming specificity and scalability barriers. The platform will accelerate VUS interpretation, reduce diagnostic delays, and be extended to other aquatic models, advancing therapeutic development and supporting the goals of PAR-23-039.

Up to $806K

2030-03-31

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Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required)

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).

Healthhealthcare

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Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required)

National Institutes of Health

Health

Free to search & build · $99 one-time to unlock the application pack · No subscription

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required)

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to two years of support for evaluation of target engagement and establishment of intervention parameters, and up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).

Healthhealthcare

Free to search & build · $99 one-time to unlock the application pack · No subscription

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required)

National Institutes of Health

Health

Free to search & build · $99 one-time to unlock the application pack · No subscription

Development of Research-based Educational Outreach Materials

NCA Contracting

Development of Research-based Educational Outreach Materials

Rolling

Educationresearch

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Development of Selective Antiviral RNA-Degrading Chimeras Mimicking Ribonuclease Activity

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Endogenous ribonucleases (RNases) are an important component of the host immune response to viral infections. Mimicking the RNase function, RNA-degrading chimeras (RDC) are a class of molecules that selectively bind RNA and recruit RNases, typically RNase L, to cleave the viral RNA. However, RNase L- dependent RDCs typically achieve only ~75% RNA knockdown, insufficient for complete viral clearance. To overcome this limitation, we propose to develop a novel class of direct-acting antivirals: RDCs that cleave RNA directly through general acid–general base catalysis, more faithfully mimicking the mechanism of natural ribonucleases. Additionally, we will improve the selectivity of RNA-binding scaffolds by targeting a conserved viral RNA structure and developing a high-throughput synthesis and screening pipeline. Importantly, we will implement a second-generation chemical-guided SHAPE sequencing (cgSHAPE-seq) technology for activity- based RNA profiling. This platform will enable competitive, transcriptome-wide evaluation of ligand binding specificity in live cells. We will demonstrate the effectiveness of this new approach to antiviral design in the context of Zika virus (ZIKV), a mosquito-borne flavivirus associated with severe neurological disorders, including Guillain-Barré syndrome and microcephaly. We hypothesize that our optimized RDCs will significantly reduce ZIKV RNA levels both in vitro and in ZIKV-infected human neural progenitor cells. This project represents the first application of RDCs to directly degrade ZIKV RNA and introduces a generalizable strategy for RNA-targeting antiviral development. By establishing robust methods for RNA binding optimization and transcriptome-wide selectivity profiling, this work has the potential to revolutionize antiviral drug discovery and provide a scalable approach to combat emerging RNA viral threats. 1

Up to $442K

2028-05-31

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Development of Self-Assembling Pyrrole-Imidazole Polyamides for the Treatment of Friedreich’s Ataxia and Prostate Cancer Using Proximity-Induced Bioorthogonal Chemistry

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Developing a new drug typically takes over a decade and costs over $500 millions dollars. Despite this, 90% of drug candidates fail in clinical trials, often due to undesired off-target effects or poor pharmacokinetic (PK) properties. One promising strategy that could overcome these issues and provide a new level of control over therapeutic activity would be the in-situ assembly of a drug at the site of interest. Rather than administering a single compound, two smaller, inactive fragments can be delivered that selectively combine at the target site to furnish the active drug. Lower molecular weight compounds display enhanced PK properties, such as high membrane permeability, due to their smaller size and could avoid off-target effects by only combining at the site of disease. This approach could address PK issues that are inherently associated with the growing demand for large bifunctional molecules that break Lipinski’s rule of five, such as proteolysis-targeting chimeras. This strategy has seldom been explored as identifying a bioorthogonal reaction that will selectively unite the fragments—present only in low concentrations in a cell—remains challenging. The studies described in this proposal seek to develop strategies for the design of self-assembling pyrrole- imidazole polyamides (Py-Im PA), small molecules that can bind DNA and control gene expression, potentially stopping disease at its root. Numerous Py-Im PAs have been developed to treat different diseases yet there are no FDA-approved Py-Im PA pharmaceuticals, in part due to their poor PK properties. By leveraging the natural binding of these compounds to DNA to generate a high local concentration and template a proximity-induced bioorthogonal reaction, one could achieve their selective in situ self-assembly. In Aim 1, a self-assembling linear Py-Im PA that targets the DNA triplet repeats that cause the incurable neurodegenerative disease Friedreich’s ataxia will be designed and evaluated. This PA previously showed promise in cellulo yet suffered from poor membrane permeability due to its high molecular weight. In Aim 2, a proximity-induced azide-alkyne cycloaddition for the in situ synthesis of hairpin polyamides from their linear fragments will be developed. A hairpin Py-Im PA that binds the prostate-specific antigen promoter androgen response element for the treatment of prostate cancer will be prepared. Performing this research in Prof. Bertozzi’s group at Stanford aligns well with their success with developing bioorthogonal chemistry (2022 Nobel prize) and will augment my prior training in organic synthesis to prepare me for a future academic career as a professor. Overall, the proposed research is significant because it could unlock the therapeutic potential of Py-Im PAs for the treatment of Friedreich’s ataxia and prostate cancer by improving their PK properties. This proposal is unique as it represents the first in-situ self-assembly of PAs in cellulo from more bioavailable components. More broadly, this proposal represents a novel approach to addressing PK issues in drug design and could be expanded to solve long-standing challenges encountered by other drug candidates.

Up to $76K

2029-02-15