RESUMEN
The lack of tools to observe drug-target interactions at cellular resolution in intact tissue has been a major barrier to understanding in vivo drug actions. Here, we develop clearing-assisted tissue click chemistry (CATCH) to optically image covalent drug targets in intact mammalian tissues. CATCH permits specific and robust in situ fluorescence imaging of target-bound drug molecules at subcellular resolution and enables the identification of target cell types. Using well-established inhibitors of endocannabinoid hydrolases and monoamine oxidases, direct or competitive CATCH not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain but also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types, as well as dose-dependent target shifts across tissue, cellular, and subcellular compartments that are not accessible by conventional methods. CATCH represents a valuable platform for visualizing in vivo interactions of small molecules in tissue.
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Química Clic , Imagen Óptica , Animales , Encéfalo , Sistemas de Liberación de Medicamentos , Mamíferos , Ratones , Imagen Óptica/métodosRESUMEN
Antibody therapeutics are a large and rapidly expanding drug class providing major health benefits. We provide a snapshot of current antibody therapeutics including their formats, common targets, therapeutic areas, and routes of administration. Our focus is on selected emerging directions in antibody design where progress may provide a broad benefit. These topics include enhancing antibodies for cancer, antibody delivery to organs such as the brain, gastrointestinal tract, and lungs, plus antibody developability challenges including immunogenicity risk assessment and mitigation and subcutaneous delivery. Machine learning has the potential, albeit as yet largely unrealized, for a transformative future impact on antibody discovery and engineering.
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Anticuerpos , Neoplasias , Anticuerpos/química , Anticuerpos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Aprendizaje Automático , Neoplasias/tratamiento farmacológico , Ingeniería de ProteínasRESUMEN
Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
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Sistemas de Liberación de Medicamentos , Ingeniería Genética , Proteínas/uso terapéutico , Virión/genética , Animales , Secuencia de Bases , Ceguera/genética , Ceguera/terapia , Encéfalo/metabolismo , ADN/metabolismo , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Edición Génica , Células HEK293 , Humanos , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Proproteína Convertasa 9/metabolismo , Epitelio Pigmentado de la Retina/patología , Retroviridae , Virión/ultraestructura , Visión OcularRESUMEN
The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.
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Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Genómica , Humanos , Neoplasias/genética , Neoplasias/patología , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Vaccines are critical tools for maintaining global health. Traditional vaccine technologies have been used across a wide range of bacterial and viral pathogens, yet there are a number of examples where they have not been successful, such as for persistent infections, rapidly evolving pathogens with high sequence variability, complex viral antigens, and emerging pathogens. Novel technologies such as nucleic acid and viral vector vaccines offer the potential to revolutionize vaccine development as they are well-suited to address existing technology limitations. In this review, we discuss the current state of RNA vaccines, recombinant adenovirus vector-based vaccines, and advances from biomaterials and engineering that address these important public health challenges.
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Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Adenoviridae/genética , Animales , Antígenos Virales/genética , Materiales Biocompatibles , COVID-19/virología , Sistemas de Liberación de Medicamentos/métodos , Vectores Genéticos/inmunología , Humanos , Inmunogenicidad Vacunal , Liposomas , Nanopartículas , ARN Mensajero/síntesis química , ARN Mensajero/inmunología , Vacunas de ARNmRESUMEN
Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.
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Tratamiento Farmacológico de COVID-19 , Virus Interferentes Defectuosos/metabolismo , Replicación Viral/efectos de los fármacos , Animales , Antivirales/farmacología , COVID-19/metabolismo , Línea Celular , Chlorocebus aethiops , Medios de Cultivo Condicionados/farmacología , Virus Interferentes Defectuosos/patogenicidad , Sistemas de Liberación de Medicamentos/métodos , Células Epiteliales , Humanos , Masculino , Mesocricetus , Nanopartículas/uso terapéutico , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Células VeroRESUMEN
The first two vaccines proven to be effective for inhibiting COVID-19 illness were both mRNA, achieving 95% efficacy (and safety) among 74,000 participants (half receiving placebo) after intramuscular delivery of two shots, 3-4 weeks apart. To view this Bench to Bedside, open or download the PDF.
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Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , COVID-19/virología , Sistemas de Liberación de Medicamentos/métodos , Humanos , Liposomas , Nanopartículas , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Resultado del Tratamiento , Vacunas de ARNmRESUMEN
Off-target effects of systemically administered drugs have been a major hurdle in designing therapies with desired efficacy and acceptable toxicity. Developing targeting strategies to enable site-specific drug delivery holds promise in reducing off-target effects, decreasing unwanted toxicities, and thereby enhancing a drug's therapeutic efficacy. Over the past three decades, a large body of literature has focused on understanding the biological barriers that hinder tissue-specific drug delivery and strategies to overcome them. These efforts have led to several targeting strategies that modulate drug delivery in both the preclinical and clinical settings, including small molecule-, nucleic acid-, peptide-, antibody-, and cell-based strategies. Here, we discuss key advances and emerging concepts for tissue-specific drug delivery approaches and their clinical translation.
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Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Preparaciones Farmacéuticas/química , HumanosRESUMEN
Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness.
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Músculo Esquelético/metabolismo , Miosinas del Músculo Esquelético/efectos de los fármacos , Miosinas del Músculo Esquelético/genética , Adulto , Animales , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo , Línea Celular , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Masculino , Ratones , Contracción Muscular/fisiología , Fibras Musculares Esqueléticas/fisiología , Espasticidad Muscular/genética , Espasticidad Muscular/fisiopatología , Músculo Esquelético/fisiología , Miosinas/efectos de los fármacos , Miosinas/genética , Miosinas/metabolismo , Isoformas de Proteínas , Ratas , Ratas Wistar , Miosinas del Músculo Esquelético/metabolismoRESUMEN
Genomic studies of lung adenocarcinoma (LUAD) have advanced our understanding of the disease's biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD remain poorly understood. We carried out a comprehensive proteomics analysis of 103 cases of LUAD in Chinese patients. Integrative analysis of proteome, phosphoproteome, transcriptome, and whole-exome sequencing data revealed cancer-associated characteristics, such as tumor-associated protein variants, distinct proteomics features, and clinical outcomes in patients at an early stage or with EGFR and TP53 mutations. Proteome-based stratification of LUAD revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Further, we nominated potential drug targets and validated the plasma protein level of HSP 90ß as a potential prognostic biomarker for LUAD in an independent cohort. Our integrative proteomics analysis enables a more comprehensive understanding of the molecular landscape of LUAD and offers an opportunity for more precise diagnosis and treatment.
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Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Proteómica , Adenocarcinoma del Pulmón/genética , Pueblo Asiatico/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Sistemas de Liberación de Medicamentos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Fosfoproteínas/metabolismo , Análisis de Componente Principal , Pronóstico , Proteoma/metabolismo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genéticaRESUMEN
A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.
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Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Neoplasias/tratamiento farmacológico , Proclorperazina/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Presentación de Antígeno/efectos de los fármacos , Biopsia , Cetuximab/farmacología , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Antineoplásicos/genética , Endocitosis/efectos de los fármacos , Endocitosis/inmunología , Xenoinjertos , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células MCF-7 , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Neoplasias/genética , Neoplasias/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Trastuzumab/farmacologíaRESUMEN
Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these.
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Vesículas Extracelulares , Transporte Biológico , Biomarcadores/metabolismo , Comunicación Celular , Sistemas de Liberación de Medicamentos , Vesículas Extracelulares/metabolismoRESUMEN
Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.
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Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/ultraestructura , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/ultraestructura , Adamantano/análogos & derivados , Adamantano/metabolismo , Antituberculosos/química , Transporte Biológico , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Etilenodiaminas/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/ultraestructura , Compuestos de Fenilurea/metabolismo , Rimonabant/metabolismo , Tuberculosis/microbiologíaRESUMEN
A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.
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Proteína HMGB1/antagonistas & inhibidores , Infecciones/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Sistemas de Liberación de Medicamentos , Proteína HMGB1/metabolismo , Humanos , Inmunidad Innata , Infecciones/metabolismo , Inflamación/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in â¼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.
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Neoplasias Encefálicas , Exones , Glioblastoma , Mutación , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-met , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Sistemas de Liberación de Medicamentos , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Ratas Sprague-Dawley , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias/tratamiento farmacológico , Animales , Variación Biológica Individual , Ensayos Clínicos como Asunto , Sistemas de Liberación de Medicamentos , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Xenoinjertos , Humanos , Inmunoterapia , Trasplante de NeoplasiasRESUMEN
The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP.
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Neoplasias Encefálicas/patología , Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Glioma/patología , Ventrículos Laterales/patología , Invasividad Neoplásica/patología , Anciano , Animales , Neoplasias Encefálicas/metabolismo , Comunicación Celular , Niño , Sistemas de Liberación de Medicamentos , Femenino , Glioma/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Xenoinjertos , Humanos , Ventrículos Laterales/metabolismo , Masculino , Ratones , Trasplante de Neoplasias , Transducción de Señal , Proteínas de Unión al GTP rho/metabolismoRESUMEN
How the master regulator of cell growth, TOR, came to be identified and understood, from the perspective of its discoverer, Michael N. Hall.
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Inmunosupresores/aislamiento & purificación , Sirolimus/aislamiento & purificación , Serina-Treonina Quinasas TOR/fisiología , Antifúngicos/aislamiento & purificación , Sistemas de Liberación de Medicamentos , Resistencia a Medicamentos , Historia del Siglo XX , Humanos , Inmunosupresores/historia , Inmunosupresores/uso terapéutico , Polinesia , Sirolimus/historia , Sirolimus/uso terapéutico , Microbiología del Suelo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Knowledge of the parameters of drug development can greatly aid academic scientists hoping to partner with pharmaceutical companies. Here, we discuss the three major pillars of drug development-pharmacodynamics, pharmacokinetics, and toxicity studies-which, in addition to pre-clinical efficacy, are critical for partnering with Big Pharma to produce novel therapeutics.
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Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Farmacocinética , UniversidadesRESUMEN
The links between cellular and systemic metabolism and different pathologies, including cancer, are on the rise. Cell editor Lara Szewczak asked Doug Green, Ralph DeBerardinis, and Mark Febbraio about what the prospects are for being able to target metabolism therapeutically. An annotated excerpt of the conversation appears below, and the full conversation is available with the article online.