•ATF4 does not protect nigral dopamine neurons against α-synuclein induced pathology.•Up-regulation of the ATF4 in nigral neurons increases caspase 3/7 activity.•Overexpression of the ATF4 leads to ...severe nigra-striatal degeneration.
Activating transcription factor 4 (ATF4) is a member of the PERK signaling pathway, which directly binds endoplasmic reticulum stress target genes and plays a crucial role in both adaptations to stress and activation of apoptosis. Previous publications demonstrated conflicting evidence on the role of ATF4 in the pathogenesis of neurodegenerative disorders. In this study, we used recombinant adeno-associate virus (rAAV)-mediated gene transfer to investigate if the sustained up-regulation of ATF4 launches a pro-survival or pro-death trend in the dopamine (DA) cells of the substantia nigra pars compacta in a rat model of Parkinson-like neurodegeneration induced by human alpha-synuclein (αS) overexpression. We showed that ATF4 does not protect nigral DA neurons against an αS-induced pathology. Moreover, the rAAV-mediated overexpression of ATF4 resulted in severe nigra-striatal degeneration via activation of caspases 3/7.
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BackgroundGene-fusion genetic aberrations present unique challenges in cancer diagnosis and management. Current treatment strategies often yield low efficiency due to their non-specific targets ...leading to adverse side effects. Personalized immunotherapies targeting these genetic aberrations can potentially improve therapeutic outcomes. We proposed to create messenger RNA nanoparticles designed to target fusion-driven malignancies, aiming to enhance treatment specificity and minimize classic immunotherapeutic adverse effects.MethodsWe are developing a pipeline to identify gene-fusions, design amplification primers, and classify fusions for treatment using messenger RNA nanoparticles cancer vaccine.1–5 The immunogenicity and safety of this approach are to be evaluated using murine models and spontaneous canine and feline tumors.ResultsWe demonstrated the synthesis of fusion-specific mRNA and identified common fusion breakpoints in various tumor types, such as Ewing sarcoma, glioblastoma, ependymoma, non-small cell lung carcinoma, and clear cell sarcoma. Importantly, we established two primary approaches for our fusion-based messenger RNA nanoparticles: 1) off-the-shelf gene-fusion immunotherapy vaccines, and 2) personalized vaccines developed for rare fusions.ConclusionsPreliminary findings suggest that our formulation can target gene fusions with potentially improved treatment.ReferencesSayour EJ, Grippin A, De Leon G, Stover B, Rahman M, Karachi A, et al. Personalized Tumor RNA Loaded Lipid-Nanoparticles Prime the Systemic and Intratumoral Milieu for Response to Cancer Immunotherapy. Nano Lett. 2018.Sayour EJ, De Leon G, Pham C, Grippin A, Kemeny H, Chua J, et al. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. OncoImmunology. 2016:e1256527.Sanchez-Perez LA, Choi BD, Archer GE, Cui X, Flores C, Johnson LA, et al. Myeloablative temozolomide enhances CD8(+) T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS One. 2013;8(3):e59082.Mitchell DA, Fecci PE, Sampson JH. Immunotherapy of malignant brain tumors. Immunol Rev. 2008;222:70–100.Badapanda C. Suppression subtractive hybridization (SSH) combined with bioinformatics method: an integrated functional annotation approach for analysis of differentially expressed immune-genes in insects. Bioinformation. 2013;9(4):216–21.Ethics ApprovalAll animal experiments were conducted following protocols approved by the Institutional Animal Care and Use Committee at the University of Florida (protocol number 202009685).
While immune-cell infiltrated tumors, such as human papillomavirus positive (HPV+) ororpharyngeal squamous cell carcinomas (OPSCC) have been associated with an improved clinical prognosis, there is ...evidence to suggest that OPSCCs are also subjected to increased immunoregulatory influence. The objective of this study was to assess whether patients with clinically aggressive OPSCC have a distinct immunosuppressive immune signature in the primary tumor.
This retrospective case-control study analyzed 37 pre-treatment tissue samples from HPV+ and HPV-negative OPSCC patients treated at a single institution. The cases were patients with known disease recurrence and the controls were patients without disease recurrence. An mRNA-expression immune-pathway profiling was performed, and correlated to clinical outcomes. The TCGA head and neck cancer database was utilized to make comparisons with the institutional cohort.
In our cohort, HPV-negative and HPV+ patients with known disease recurrence both had significantly increased suppressive monoctyte/macrophage and granulocyte cell-expression-profile enrichment. Similar findings were found in the TCGA cohort when comparing HPV-negative to positive patients.
our study demonstrates that patients with recurrent HPV+ OPSCC had suppressive monocyte/macrophage and granulocyte immune-cell enrichment, similar to those seen in the more aggressive HPV-negative OPSCC.
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The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent ...patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRβ repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.
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In this study, Ogando-Rivas and colleagues generated SARS-CoV-2 specific T cells using human APCs transduced with full length structural antigen encoding mRNAs. The manufactured T cells also recognized immunogenic hypomutated regions within the Spike gp in healthy donors and COVID-19 recovered donors, suggesting protection against ancient and new variants.
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Current urban vector control strategies have failed to contain dengue epidemics and to prevent the global expansion of Aedes-borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in ...sustaining effective ABV control emerges from the paucity of evidence regarding the epidemiological impact of any Aedes control method. A strategy for which there is limited epidemiological evidence is targeted indoor residual spraying (TIRS). TIRS is a modification of classic malaria indoor residual spraying that accounts for Aedes aegypti resting behavior by applying residual insecticides on exposed lower sections of walls (< 1.5 m), under furniture, and on dark surfaces.
We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). The trial will be conducted in the city of Merida, Yucatan State, Mexico (population ~ 1million), where we will prospectively follow 4600 children aged 2-15 years at enrollment, distributed in 50 clusters of 5 × 5 city blocks each. Clusters will be randomly allocated (n = 25 per arm) using covariate-constrained randomization. A "fried egg" design will be followed, in which all blocks of the 5 × 5 cluster receive the intervention, but all sampling to evaluate the epidemiological and entomological endpoints will occur in the "yolk," the center 3 × 3 city blocks of each cluster. TIRS will be implemented as a preventive application (~ 1-2 months prior to the beginning of the ABV season). Active monitoring for symptomatic ABV illness will occur through weekly household visits and enhanced surveillance. Annual sero-surveys will be performed after each transmission season and entomological evaluations of Ae. aegypti indoor abundance and ABV infection rates monthly during the period of active surveillance. Epidemiological and entomological evaluation will continue for up to three transmission seasons.
The findings from this study will provide robust epidemiological evidence of the efficacy of TIRS in reducing ABV illness and infection. If efficacious, TIRS could drive a paradigm shift in Aedes control by considering Ae. aegypti behavior to guide residual insecticide applications and changing deployment to preemptive control (rather than in response to symptomatic cases), two major enhancements to existing practice.
ClinicalTrials.gov NCT04343521 . Registered on 13 April 2020. The protocol also complies with the WHO International Clinical Trials Registry Platform (ICTRP) (Additional file 1).
National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID).
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BackgroundMelanoma is an increasing public health concern. Immune checkpoint inhibitors (ICI) has revolutionized the treatment of advanced melanoma. Unfortunately, in the adjuvant setting, up to 30% ...of subjects have disease recurrence within 1 year of treatment. Previous studies have shown that subjects who progress while on adjuvant ICI, or soon after completion, have a more aggressive course of disease that responds poorly to subsequent immunotherapy. One reason for the failure of ICI in the post adjuvant setting is the immune suppressive nature of the tumor microenvironment (TME) and lack of professional APC activation. These APCs remain in an inert state unable to present tumor antigens for immune detection due to lack of innate immune activation and inhibition from myeloid derived suppressor cells (MDSCs). We have developed a novel RNA-lipid particle (RNA-LP) vaccine that simultaneously penetrates and reprograms the TME while inducing a tumor specific adaptive response (figure 2). This vaccine utilizes novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle ‘onion-like’ package along with pp65 full length lysosomal associated membrane protein (LAMP1) mRNA (figure 2). These RNA-LPs localize to the TME and activate multiple innate pathways thereby activating APCs and suppressing the function of MDSCs (figure 3). In this study we propose the use of subject derived RNA-LP vaccine in patients who progress on, or soon after completion of adjuvant ICI. We propose that through re-priming of the antitumor immune response and alteration of the TME we can restore the efficacy of ICI therapy. If effective, this treatment will revolutionize the management of this aggressive subset of melanoma. This study will also gather information into the mechanisms of early ICI resistance, identify novel biomarkers of innate resistance and response to treatment, and provides a cutting edge, personalized immunology approach to melanoma treatment.MethodsWe have designed a 3+3 design phase I clinical trial (NCT05264974) assessing the manufacturing feasibility, safety, and maximum tolerated dose of RNA-LP vaccines in melanoma patients with early adjuvant ICI failure. Patients will receive a 3-part vaccine series, 2 weeks apart at time of progression then resume ICI therapy (figure 4). Major eligibility criteria include progression on ICI therapy or within 6 months of completion of adjuvant therapy. A minimum of 6 and maximum of 18 subjects will be treated. Secondary endpoints include overall response rate (ORR) and progression free survival rate (figure 5). Exploratory analysis will investigate the TME through single cell analysis pre and post vaccine series.Trial RegistrationNovel RNA-nanoparticle Vaccine for the Treatment of Early Melanoma Recurrence Following Adjuvant Anti-PD-1 Antibody Therapy ClinicalTrials.gov Identifier: NCT05264974Ethics ApprovalThis trial has been approved by the University of Florida Institutional Review Board IRB202200462 Novel RNA-nanoparticle vaccine for the treatment of early melanoma recurrence following adjuvant anti-PD-1 antibody therapy- UF-CUT-001.Abstract 772 Figure 1Different RNA loaded lipid-particle formulations. LPs or liposomes have been developed to protect nucleic acid delivery in vivo. (Left) RNA lipoplexes were first developed with mRNA persevered in the lipid core and a net positive charge located on the outer surface. (Middle) Alternatively, anionic lipoplexes have been developed with an excess of RNA tethered to the surface of bi-lamellar liposomes. (Right) Our lab has developed multi-lamellar RNA-LPs with several layers of mRNA contained inside a tightly coiled liposome with alternating layers of positive/negative charge. This design maximizes the amount of mRNA that can be loaded into each particle.Abstract 772 Figure 2Generation of personalized tumor mRNA loaded LPs: From as few as 100–500 biopsied tumor cells, total RNA is extracted and a cDNA library is generated from which copious amounts of mRNA (representing a personalized tumor specific transcriptome) can be amplified. Negatively charged tumor mRNA is then encapsulated into multi-lamellar LPs. LPs encapsulate and coil RNA through electrostatic interactions before intravenous delivery for uptake by DCs in lungs and in reticuloendothelial organs (i.e. liver, spleen and lymph nodes). The RNA is then translated and processed by a DC’s intracellular machinery for presentation of peptides onto MHC Class I and II molecules, which activate CD4 and CD8+ T cells.Abstract 772 Figure 3Multi-lamellar RNA-LP mediate increased DC activation and IFN-α release. RNA/anionic lipoplex (LPX) or RNA-LPs were administered once weekly (x3) and spleens were harvested one week later for assessment of activated DCs (left). Serum was drawn 6h after the first vaccine for IFN-α assessment by ELISA (right) (*p<0.05, Mann-Whitney test).Abstract 772 Figure 4Abstract 772 Figure 5
BackgroundDiffuse midline glioma (DMG) is a universal fatal glial brain cancer in children. We tested our novel multilamellar mRNA lipid particle aggregate vaccine (RNA-LPA, IND19304—Sayour),1 a ...tumor-agnostic treatment platform that encapsulates tumor specific RNA and delivers the payload in a highly immunogenic fashion, as an approach to treating this currently incurable cancer.MethodsUsing the K2 DMG model,2 we implant H3K27M-expressing DMG cells into the 4th ventricle of P1-P3 neonatal C57BL/6 mice. RNA-LPA generated from predicated human H3K27M epitopes or total-tumor mRNA are administered intravenously beginning at day 35. We performed multiparameter 3D geospatial fluorescent microscopy to characterize mRNA transduction. Immunologic responses to treatment were evaluated by multiparameter flow cytometry, microscopy, and cytokine profiling.ResultsMice developed clinical neurological signs of disease by day 30–35. RNA-LPAs targeting human H3K27M epitopes were found to be immunogenic in wild-type mice. Intriguingly, nonspecific enhanced green fluorescent protein (eGFP)-RNA-LPAs resulted in statistically significant survival benefits compared to mice treated with empty LPs. However, tumor-specific RNA-LPAs (either H3K27M-specific or total tumor mRNA-derived) also enhanced survival and additionally resulted in a subset of mice with long-term survival. This survival benefit was observed despite the development of clinical hydrocephalus in mice treated with RNA-LPAs. 3D microscopy established that tumors demonstrated invasive disease and microvascular erosion in mice. We found that mRNA transduces fibroblastic reticular cells (FRCs) in the spleen and lymph nodes, prompting widespread immune activation. Treatment with RNA-LPA led to massive increases in production inflammatory cytokines (i.e. TNF-α) and chemokines (i.e. CCL2), which led to recruitment of the majority of circulating monocytes and lymphocytes to secondary lymphoid organs.ConclusionsRNA-LPAs extend survival in our highly aggressive DMG model, including curative outcomes in cohorts treated with either total tumor or H3K27M RNA-LPs. These data suggest that RNA-LPs are capable of stimulating host adaptive immune responses against established DIPG tumors. Signs of hydrocephalus in treated mice may indicate pseudoprogression due to immunologic response, yet mice were frequently able to survive this development. Future studies will further characterize the immunologic response in these mice and support expansion of our existing IND for a multi-institutional phase I clinical trial for children with DMG, who currently have no curative options.AcknowledgementsWe appreciate funding from the ChadTough Defeat DIPG Foundation and the DIPG/DMG Research Funding Alliance. John Ligon and Elias Sayour contributed equally and are co-senior authors.ReferencesMendez-Gomez H, DeVries A, Castillo P, Stover B, Qdaisat S, Von Roemling C, Ogando-Rivas E, Weidert F, McGuiness J, Zhang D, Chung MC, Li D, Zhao C, Marconi C, Campaneria Y, Chardon-Robles J, Grippin A, Karachi A, Thomas N, Huang J, Milner R, Sahay B, Sawyer WG, Ligon JA, Silver N, Simon E, Cleaver B, Wynne K, Hodik M, Molinaro A, Guan J, Kellish P, Doty A, Lee J-H, Carrera-Justiz S, Rahman M, Gatica S, Mueller S, Prados M, Ghiaseddin A, Mitchell DA, Sayour EJ. mRNA aggregates harness danger response for potent cancer immunotherapy. medRxiv. 2023:2023.03.12.23287108. doi: 10.1101/2023.03.12.23287108.Misuraca KL, Cordero FJ, Becher OJ. Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma. Front Oncol. 2015;5:172. doi: 10.3389/fonc.2015.00172. PubMed PMID: 26258075; PMCID: PMC4513210.Ethics ApprovalWork approved under UF IACUC 202200000375
BackgroundPatients with relapsed and metastatic osteosarcoma have a 5 year overall survival <25%. Our group tested our novel multilamellar RNA lipid nanoparticle aggregate vaccine (RNA-LPA)1 as an ...approach to reprogram the immunosuppressive tumor microenvironment (TME)2 present in osteosarcoma, where immunotherapy has not yet been effective.MethodsTotal-tumor mRNA was amplified from tumor cell lines in mice or tumor biopsy in canines before complexation in lipid nanocarriers/cationic lipids, generating RNA-LPA for systemic administration. Preclinical murine models were generated using K7M2, KHOS or 143B osteosarcoma cells in either C57Bl/6, BALB/c or BALB/c SCID mice inoculated by tail vein injection to mimic minimal residual metastatic disease from pulmonary osteosarcoma. We treated client-owned canine patients (pet-dogs) with osteosarcoma through a comparative oncology clinical trial with the UF College of Veterinary Medicine (UF IACUC#202111376, PI: Milner). Using liquid-like solid (LLS) 3D tumoroid culture system,3 we established ex vivo models of murine, canine, and human osteosarcoma.ResultsTumor-specific RNA-LPAs elicited anti-tumor efficacy in the murine K7M2 model with long term survival (7/8 mice), with some survival benefit even with irrelevant pp65 RNA-LPAs (p<0.05); these findings correlated with an increase in intratumoral central memory T cells. Both tumor-specific and irrelevant RNA-LPAs reprogramed the innate immune microenvironment (decreased tumor associated macrophages and myeloid derived suppressor cells, p<0.01), but tumor-specific RNA-LPAs additionally resulted in activation of adaptive immunity (dendritic cells and T-cells). Five pet-dogs with osteosarcoma were safely treated with total-tumor RNA-LPAs, which were immunologically active, demonstrating changes in complete blood counts and serum cytokines within 6 hours of vaccine administration. One pet dog received 4 total RNA-LPAs every 2 weeks with initial objective radiographic resolution of pulmonary metastases, though this subject relapsed with new metastases. Osteosarcoma tumors from mice, canines, and human patients were used to successfully establish 3D tumoroid tissue culture for at least 32 days ex vivo.ConclusionsBoth tumor-specific and nonspecific ‘off the shelf’ RNA-LPA vaccines redirected immunosuppressive myeloid cells, a hallmark of the osteosarcoma TME.2 This agent, which is FDA-IND approved (BB-19304, Sayour) and in human clinical trials for patients with brain tumors (NCT04573140) will enter clinical trials for patients with osteosarcoma in the coming year (NCT04837547, not yet recruiting). Our 3D tumoroid system offers the opportunity to study the immune-modulating effect of RNA-LPAs and may be a meaningful correlate to both canine and human subjects enrolled on clinical trials.AcknowledgementsWe appreciate funding from the National Cancer Institute, the V Foundation, MIB Agents, Hyundai Hope on Wheels, and the Pediatric Cancer Research Foundation.Trial RegistrationNCT04573140ReferencesMendez-Gomez H, DeVries A, Castillo P, Stover B, Qdaisat S, Von Roemling C, Ogando-Rivas E, Weidert F, McGuiness J, Zhang D, Chung MC, Li D, Zhao C, Marconi C, Campaneria Y, Chardon-Robles J, Grippin A, Karachi A, Thomas N, Huang J, Milner R, Sahay B, Sawyer WG, Ligon JA, Silver N, Simon E, Cleaver B, Wynne K, Hodik M, Molinaro A, Guan J, Kellish P, Doty A, Lee J-H, Carrera-Justiz S, Rahman M, Gatica S, Mueller S, Prados M, Ghiaseddin A, Mitchell DA, Sayour EJ. mRNA aggregates harness danger response for potent cancer immunotherapy. medRxiv. 2023:2023.03.12.23287108. doi: 10.1101/2023.03.12.23287108.Ligon JA, Choi W, Cojocaru G, Fu W, Hsiue EH, Oke TF, Siegel N, Fong MH, Ladle B, Pratilas CA, Morris CD, Levin A, Rhee DS, Meyer CF, Tam AJ, Blosser R, Thompson ED, Suru A, McConkey D, Housseau F, Anders R, Pardoll DM, Llosa N. Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes. Journal for immunotherapy of cancer. 2021;9(5). doi: 10.1136/jitc-2020–001772. PubMed PMID: 34021032; PMCID: PMC8144029.Bhattacharjee T, Gil CJ, Marshall SL, Urueña JM, O’Bryan CS, Carstens M, Keselowsky B, Palmer GD, Ghivizzani S, Gibbs CP, Sawyer WG, Angelini TE. Liquid-like Solids Support Cells in 3D. ACS Biomater Sci Eng. 2016;2(10):1787–95. Epub 20160620. doi: 10.1021/acsbiomaterials.6b00218. PubMed PMID: 33440476.Ethics ApprovalStudies approved by UF IACUC 202111376 and 202009941, and UF IRB202001062
Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.
Here we analyze the role of Nolz1 during LGE ...development. We show that Nolz1 expression is high in proliferating neural progenitor cells (NPCs) of the LGE subventricular zone. In addition, low levels of Nolz1 are detected in the mantle zone, as well as in the adult striatum. Similarly, Nolz1 is highly expressed in proliferating LGE-derived NPC cultures, but its levels rapidly decrease upon cell differentiation, pointing to a role of Nolz1 in the control of NPC proliferation and/or differentiation. In agreement with this hypothesis, we find that Nolz1 over-expression promotes cell cycle exit of NPCs in neurosphere cultures and negatively regulates proliferation in telencephalic organotypic cultures. Within LGE primary cultures, Nolz1 over-expression promotes the acquisition of a neuronal phenotype, since it increases the number of β-III tubulin (Tuj1)- and microtubule-associated protein (MAP)2-positive neurons, and inhibits astrocyte generation and/or differentiation. Retinoic acid (RA) is one of the most important morphogens involved in striatal neurogenesis, and regulates Nolz1 expression in different systems. Here we show that Nolz1 also responds to this morphogen in E12.5 LGE-derived cell cultures. However, Nolz1 expression is not regulated by RA in E14.5 LGE-derived cell cultures, nor is it affected during LGE development in mouse models that present decreased RA levels. Interestingly, we find that Gsx2, which is necessary for normal RA signaling during LGE development, is also required for Nolz1 expression, which is lost in Gsx2 knockout mice. These findings suggest that Nolz1 might act downstream of Gsx2 to regulate RA-induced neurogenesis. Keeping with this hypothesis, we show that Nolz1 induces the selective expression of the RA receptor (RAR)β without altering RARα or RARγ. In addition, Nozl1 over-expression increases RA signaling since it stimulates the RA response element. This RA signaling is essential for Nolz1-induced neurogenesis, which is impaired in a RA-free environment or in the presence of a RAR inverse agonist. It has been proposed that Drosophila Gsx2 and Nolz1 homologues could cooperate with the transcriptional co-repressors Groucho-TLE to regulate cell proliferation. In agreement with this view, we show that Nolz1 could act in collaboration with TLE-4, as they are expressed at the same time in NPC cultures and during mouse development.
Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.
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