RESUMEN
Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or ß (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.
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Acidemia Propiónica , Propionil-Coenzima A Carboxilasa , ARN Mensajero , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto Joven , Administración Intravenosa , Relación Dosis-Respuesta a Droga , Acidemia Propiónica/genética , Acidemia Propiónica/terapia , Propionil-Coenzima A Carboxilasa/genética , Propionil-Coenzima A Carboxilasa/metabolismo , ARN Mensajero/administración & dosificación , ARN Mensajero/efectos adversos , ARN Mensajero/genética , ARN Mensajero/uso terapéuticoRESUMEN
BACKGROUND: Premature ovarian failure (POF) is a type of pathological aging, which seriously interferes with the fertility of affected women. Electroacupuncture (EA) may have a beneficial effect; however, its mechanism of action is unknown. The purpose of this study was to determine the effect of EA on ovarian function in ovarian granulosa cells (OGCs) in a cyclophosphamide (CTX)-induced mouse model of POF. METHODS: Mice were divided into three groups: wild type (WT) group, CTX group and CTX + EA group. EA was administered under isoflurane anesthesia at CV4, ST36 and SP6 for 30 min every 2 days, 2-3 times per week for a total of 4 weeks. Effects of EA on ovarian weight and level of estrogen were examined. The mRNA and protein expression levels of cell cycle-associated proteins were detected and mRNA modifications were analyzed. RESULTS: EA significantly increased ovarian weight and reduced the proportion of atretic follicles in mice with CTX-induced POF (p < 0.05). EA increased the level of estrogen in the peripheral blood of mice and inhibited the modification of total mRNA N4-acetylcytidine (ac4C). A significant increase in the expression of P16 and N-acetyltransferase 10 (NAT10) and a significant decrease in the expression of Cyclin D (CCND1) and cyclin-dependent kinase 6 (CDK6) were observed in the OGCs of POF mice (p<0.05). After EA, P16 and NAT10 expression was decreased, and CCND1 and CDK6 expression was increased. Finally, EA reduced the ac4C modification of P16 mRNA-specific sites in the OGCs of POF mice. CONCLUSION: This study demonstrated that EA promoted the repair of the ovarian microenvironment by inhibiting the ac4C modification of P16 mRNA to decrease its stability and expression intensity, and by altering the activity of the P16/CDK6/CCND1 axis in OGCs.
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Electroacupuntura , Insuficiencia Ovárica Primaria , Humanos , Femenino , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/genética , Insuficiencia Ovárica Primaria/terapia , ARN Mensajero/genética , ARN Mensajero/efectos adversos , Células de la Granulosa/metabolismo , Células de la Granulosa/patología , Estrógenos/efectos adversosRESUMEN
BACKGROUND: Amarogentin (AMA) is a secoiridoid glycoside extracted from Swertia and Gentiana roots and exhibits many biological effects such as antioxidative, anti-inflammatory, and antitumor activities. Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by disorders in the regulation of multiple inflammatory cytokines. No effective cure has been found for AD now. METHODS: We constructed the HaCat and splenocyte model and tested the inhibitory effect of AMA on IL-4, IL-6, and IL-13 secretions using enzyme-linked immunosorbent assay (ELISA). The AD mouse model was constructed and treated with AMA, the severity of skin lesions was observed, epidermal tissue was collected, and epidermal thickness and mast cell infiltration were observed using hematoxylin and eosin and toluidine blue staining, respectively. The expression of kallikrein-related peptidase 7 (KLK7) and filaggrin (FLG) was detected using immunostaining and Western blot analysis. The mRNA expression of KLK7 and FLG was detected using quantitative polymerase chain reaction (qPCR). Blood immunoglobulin E (IgE) secretion was detected. RESULTS: AMA inhibited IL-6 secreted by tumor necrosis factor (TNF)-α-induced HaCaT cells and reduced IL-4 and IL-13 secreted by phytohemagglutinin (PHA)-induced primary cells in the mice spleen. It was found that the treatment of AMA with 2,4-dinitrochlorobenzene-induced AD-like mice could promote the recovery of dermatitis, reduce the score of dermatitis severity and the scratching frequency, treat the skin lesions, reduce the epidermal thickness, decrease the infiltration of mast cells, reduce the IgE level in serum, decrease the expression levels of AD-related cytokines, increase protein and mRNA expression of FLG, and reduce the protein and mRNA expression of KLK7 in the skin tissues of AD-like mice. CONCLUSION: In conclusion, AMA inhibits inflammatory response at the cellular level, and AMA reduces the validation response of specific dermatitis mice, relieves pruritus, and repairs the damaged skin barrier.
Asunto(s)
Dermatitis Atópica , Animales , Ratones , Humanos , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Dinitroclorobenceno/efectos adversos , Interleucina-13/efectos adversos , Interleucina-6/efectos adversos , Células HaCaT/metabolismo , Células HaCaT/patología , Interleucina-4/efectos adversos , Citocinas/genética , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Antiinflamatorios/efectos adversos , Inmunoglobulina E/efectos adversos , ARN Mensajero/efectos adversosRESUMEN
Inflammation comprises alterations in glucocorticoids (in amphibians, corticosterone-CORT) and melatonin (MEL) levels, two hormones with immunomodulatory effects on cytokine production in several vertebrates. Cytokines mediate inflammation progress differently depending on their function. While some are secreted during the acute phase of the immune response, others prevail during the resolution phase. Major efforts have been made to understand the interaction of endocrine mediators and cytokine production in endotherms, but little is known for ectotherms so far. Characterizing the stages of inflammation and their interplay with endocrine mediators is crucial for an assertive and integrative approach to amphibian physiology and ecoimmunology. Herein, we investigated CORT and MEL plasma levels as well as splenic cytokine (IL-1ß, IL-6, and IL-10) mRNA levels during the progression of the inflammatory response in toads (Rhinella diptycha) in four time-points (1, 3, 6, and 18 h) after an immune challenge with lipopolysaccharide (LPS) using independent samples. Toads were responsive to LPS, with all hormones and cytokines affected by LPS. IL-1ß and IL-6 were up-regulated after 1 h, but IL-1ß decreased right after 3 h, while IL-6 sustained up-regulation throughout all time-points. IL-10 had not been detected until 6 h post-LPS-stimulation, when it showed up-regulation, along with a CORT increase at the same time-point. After 18 h, CORT levels were still high, and IL-1ß was up-regulated again, along with up-regulated IL-6 and an IL-10 decrease. We also found positive correlations between IL-1ß with IL-6 for LPS and saline groups. LPS-treated individuals showed an overall decrease in MEL plasma levels compared to saline counterparts. Our results showcase the early endocrine and molecular events of the amphibian immune response. We also report activation of the hypothalamus-pituitary-interrenal (HPI) axis during inflammation and increasing evidence for an immune-pineal axis to be described in amphibians.
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Citocinas , Lipopolisacáridos , Animales , Citocinas/genética , Citocinas/efectos adversos , Lipopolisacáridos/efectos adversos , Interleucina-10/efectos adversos , Interleucina-6/efectos adversos , ARN Mensajero/efectos adversos , Corticosterona , Inflamación/inducido químicamenteRESUMEN
Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 ( NCT03829384 ). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18-50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg-1, or two weekly doses at 0.3 mg kg-1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml-1) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg-1 (mean t1/2 approximately 69 d). A second 0.3 mg kg-1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.
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Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Virus Chikungunya/inmunología , Lípidos/química , ARN Mensajero/uso terapéutico , Adulto , Anticuerpos Monoclonales/genética , Anticuerpos Neutralizantes/genética , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas/química , Placebos , Prueba de Estudio Conceptual , ARN Mensajero/efectos adversos , ARN Mensajero/genética , ARN Mensajero/farmacocinética , Adulto JovenRESUMEN
The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.
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Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2/inmunología , Adulto , Anciano , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Femenino , Voluntarios Sanos , Humanos , Inmunización Secundaria/efectos adversos , Masculino , Persona de Mediana Edad , Datos Preliminares , ARN Mensajero/efectos adversos , ARN Mensajero/genética , ARN Mensajero/inmunología , SARS-CoV-2/genética , Resultado del Tratamiento , Estados Unidos , Vacunación/efectos adversosRESUMEN
SARS-CoV-2 infection and the resulting COVID-19 have afflicted millions of people in an ongoing worldwide pandemic. Safe and effective vaccination is needed urgently to protect not only the general population but also vulnerable subjects such as patients with cancer. Currently approved mRNA-based SARS-CoV-2 vaccines seem suitable for patients with cancer based on their mode of action, efficacy, and favorable safety profile reported in the general population. Here, we provide an overview of mRNA-based vaccines including their safety and efficacy. Extrapolating from insights gained from a different preventable viral infection, we review existing data on immunity against influenza A and B vaccines in patients with cancer. Finally, we discuss COVID-19 vaccination in light of the challenges specific to patients with cancer, such as factors that may hinder protective SARS-CoV-2 immune responses in the context of compromised immunity and the use of immune-suppressive or immune-modulating drugs.
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Vacunas contra la COVID-19 , Neoplasias/terapia , ARN Mensajero , SARS-CoV-2/inmunología , Vacunas Virales , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/genética , Vacunas contra la COVID-19/uso terapéutico , Estabilidad de Medicamentos , Humanos , Gripe Humana/epidemiología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Neoplasias/epidemiología , Neoplasias/inmunología , Pandemias , Estabilidad del ARN/fisiología , ARN Mensajero/administración & dosificación , ARN Mensajero/efectos adversos , ARN Mensajero/química , ARN Mensajero/genética , SARS-CoV-2/genética , Vacunación/métodos , Vacunas Virales/efectos adversos , Vacunas Virales/química , Vacunas Virales/genéticaRESUMEN
One year has elapsed since a team of Chinese scientists reported the first case of COVID-19 in Wuhan, China on January 8, 2020, after sequencing the first viral genetic material. Since then, many vaccines were rushed into testing, bypassing animal experimentations, with more than 200 pharma companies in different countries declaring the development of different vaccines, each with their own strategy for generating immunity, despite the arguments of many infectious disease experts that 18 months for a first vaccine is an incredibly aggressive schedule because it takes an average of 10 years to develop a vaccine. Ten vaccine candidates have already entered phase 3 clinical trials in humans. These vaccines rely on different types of technology, the most innovative of which use the genetic material messenger RNA. Many provocative questions and genuine concerns have been raised, such as short durations of efficacy and safety follow-ups, lack of identified correlates of protection, morbidity and mortality cases reported shortly after vaccination, uncertainties regarding the risk of enhanced disease on exposure to the virus in the long-term, the possibility of viral transmission after vaccination, the reported reduced efficacies of these vaccines against new variants, the efficacy and safety of these vaccines in the previously excluded subgroups (such as children, pregnant women, the frail elderly high-risk population, and immunocompromised individuals), the unknown risk of immunogenicity-induced autoimmune diseases, cancer and chronic inflammation, the risk of genome transformation (mainly in the presence of reverse transcriptase), and finally the potential coercion that may be imposed by either public or private sectors on citizens to receive the vaccine. Many plausible questions are apparent, with no clear and convincing answers.
Asunto(s)
Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Humanos , ARN Mensajero/efectos adversosRESUMEN
INTRODUCTION: Concerns are prevailing about the safety and side effects of the BNT162b2 mRNA vaccine for coronavirus disease 2019 (COVID-19). METHODS: A randomized, cross-sectional study was performed to investigate the side effects of the BNT162b2 vaccine using an independent online questionnaire gathering responses from healthcare workers (HCWs) with detailed review of organ systems. RESULTS: Of all HCWs, 87.98% (1245/1415) completed the survey. Of them, 64.5% (803/1245) received the BNT162b2 mRNA vaccine and reported at least one or more symptoms (classified based on organ systems and occurrence rate) post vaccination. Of these, 640/803 (79.7%) were able to continue activities of daily living (ADL), 103/803 (12.83%) had trouble temporarily to perform ADL, 99/803 (12.33%) took time off work temporarily, 20/803 (2.49%) required help from an outpatient provider, 5/803 (0.62%) required help from an emergency department and 2/803 (0.25%) required hospitalization. Despite this, 97.61% intended to have the second dose and 92.9% had already received it. CONCLUSIONS: Commonly reported symptoms (occurrence in descending order) were soreness, fatigue, myalgia, headache, chills, fever, joint pain, nausea, muscle spasm, sweating, dizziness, flushing, feelings of relief, brain fogging, anorexia, localized swelling, decreased sleep quality, itching, tingling, diarrhoea, nasal stuffiness and palpitations. Despite this, remarkable acceptance for the second dose of the BNT162b2 vaccine was found among HCWs.
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Vacunas contra la COVID-19/efectos adversos , ARN Mensajero/efectos adversos , Autoinforme , Actividades Cotidianas , Adulto , Vacuna BNT162 , Estudios Transversales , Fatiga/etiología , Personal de Salud/estadística & datos numéricos , Humanos , ARN Mensajero/genéticaRESUMEN
Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti-polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.
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Anafilaxia/inmunología , Vacunas contra la COVID-19/efectos adversos , COVID-19/inmunología , Hipersensibilidad a las Drogas/inmunología , Lípidos/efectos adversos , Nanopartículas/efectos adversos , ARN Mensajero/efectos adversos , SARS-CoV-2/inmunología , Vacuna nCoV-2019 mRNA-1273 , Anafilaxia/inducido químicamente , Animales , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , Hipersensibilidad a las Drogas/patología , Humanos , Lípidos/inmunología , Lípidos/uso terapéutico , Mastocitos/inmunología , Mastocitos/patología , Nanopartículas/uso terapéutico , ARN Mensajero/inmunología , ARN Mensajero/uso terapéutico , Factores de RiesgoAsunto(s)
Vacunas contra la COVID-19/uso terapéutico , COVID-19/terapia , Inmunoterapia Activa/efectos adversos , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vacuna BNT162 , COVID-19/epidemiología , Vacunas contra la COVID-19/efectos adversos , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/organización & administración , Ensayos Clínicos como Asunto/normas , Femenino , Estudios de Seguimiento , Humanos , Inmunoterapia Activa/métodos , Inmunoterapia Activa/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Pandemias , Seguridad del Paciente/normas , ARN Mensajero/efectos adversos , ARN Mensajero/uso terapéutico , SARS-CoV-2/genética , Resultado del Tratamiento , Adulto JovenAsunto(s)
Anafilaxia/inducido químicamente , Vacunas contra la COVID-19/efectos adversos , ARN Mensajero/inmunología , ARN Viral/inmunología , Anafilaxia/tratamiento farmacológico , COVID-19/prevención & control , Humanos , Inmunoglobulina E/inmunología , ARN Mensajero/efectos adversos , ARN Viral/efectos adversos , SARS-CoV-2/genéticaRESUMEN
Vaccines and therapeutics using in vitro transcribed mRNA hold enormous potential for human and veterinary medicine. Transfection agents are widely considered to be necessary to protect mRNA and enhance transfection, but they add expense and raise concerns regarding quality control and safety. We found that such complex mRNA delivery systems can be avoided when transfecting epithelial cells by aerosolizing the mRNA into micron-sized droplets. In an equine in vivo model, we demonstrated that the translation of mRNA into a functional protein did not depend on the addition of a polyethylenimine (PEI)-derived transfection agent. We were able to safely and effectively transfect the bronchial epithelium of foals using naked mRNA (i.e., mRNA formulated in a sodium citrate buffer without a delivery vehicle). Endoscopic examination of the bronchial tree and histology of mucosal biopsies indicated no gross or microscopic adverse effects of the transfection. Our data suggest that mRNA administered by an atomization device eliminates the need for chemical transfection agents, which can reduce the cost and the safety risks of delivering mRNA to the respiratory tract of animals and humans.
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Caballos , Rociadores Nasales , ARN Mensajero/administración & dosificación , Mucosa Respiratoria , Animales , Animales Recién Nacidos , Células Cultivadas , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/efectos adversos , Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/veterinaria , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Nebulizadores y Vaporizadores/veterinaria , Polietileneimina/administración & dosificación , Polietileneimina/química , ARN Mensajero/efectos adversos , ARN Mensajero/farmacocinética , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Transcripción Genética , Transfección/métodos , Transfección/veterinaria , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Vacunas de ADN/farmacocinéticaRESUMEN
The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c+ antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (Treg cell) populations. Notably, these Treg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.
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Efecto Espectador/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Terapia de Inmunosupresión/métodos , Esclerosis Múltiple/terapia , Vacunas Sintéticas/uso terapéutico , Animales , Células Presentadoras de Antígenos , Autoantígenos/genética , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Seudouridina/análogos & derivados , Seudouridina/química , ARN Mensajero/efectos adversos , ARN Mensajero/química , ARN Mensajero/genética , Linfocitos T Reguladores/inmunología , Vacunas Sintéticas/efectos adversos , Vacunas de ARNmRESUMEN
Despite various clinical modalities available for patients, heart disease remains among the leading causes of mortality and morbidity worldwide. Genetic medicine, particularly mRNA, has broad potential as a therapeutic. More specifically, mRNA-based protein delivery has been used in the fields of cancer and vaccination, but recent changes to the structural composition of mRNA have led the scientific community to swiftly embrace it as a new drug to deliver missing genes to injured myocardium and many other organs. Modified mRNA (modRNA)-based gene delivery features transient but potent protein translation and low immunogenicity, with minimal risk of insertional mutagenesis. In this review, we compared and listed the advantages of modRNA over traditional vectors for cardiac therapy, with particular focus on using modRNA therapy in cardiac repair. We present a comprehensive overview of modRNA's role in cardiomyocyte (CM) proliferation, cardiac vascularization, and prevention of cardiac apoptosis. We also emphasize recent advances in modRNA delivery strategies and discuss the challenges for its clinical translation.
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Terapia Genética , Cardiopatías/terapia , ARN Mensajero/uso terapéutico , Animales , Proliferación Celular , Técnicas de Transferencia de Gen , Terapia Genética/efectos adversos , Cardiopatías/genética , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , ARN Mensajero/efectos adversos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Recuperación de la Función , Regeneración , Factores de Riesgo , Resultado del TratamientoAsunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Desarrollo de Medicamentos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Vacunas Virales , Anticuerpos Neutralizantes/inmunología , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/inmunología , Colaboración Intersectorial , ARN Mensajero/administración & dosificación , ARN Mensajero/efectos adversos , ARN Mensajero/inmunología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Vacunas de ADN/inmunología , Vacunas Virales/administración & dosificación , Vacunas Virales/efectos adversos , Vacunas Virales/inmunologíaRESUMEN
Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.
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Diabetes Mellitus Tipo 2/terapia , Neovascularización Fisiológica/fisiología , ARN Mensajero/efectos adversos , ARN Mensajero/uso terapéutico , Piel/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Terapia Genética , Humanos , Inyecciones Intradérmicas , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , ARN Mensajero/genética , Flujo Sanguíneo Regional/genéticaRESUMEN
Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic-acid-based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose-dependent control of encoded protein expression. Inhaled delivery of IVT-mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g-1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE-mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT-mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.
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Células Epiteliales/metabolismo , Luciferasas/genética , Nanopartículas/química , Polímeros/química , ARN Mensajero/química , Administración por Inhalación , Animales , Composición de Medicamentos/métodos , Liberación de Fármacos , Células Epiteliales/citología , Femenino , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Concentración de Iones de Hidrógeno , Pulmón/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Modelos Animales , ARN Mensajero/administración & dosificación , ARN Mensajero/efectos adversos , ARN Mensajero/metabolismo , Distribución Tisular , Transfección/métodosRESUMEN
This chapter provides a brief introduction to nucleic acid-based vaccines and recent research in developing self-amplifying mRNA vaccines. These vaccines promise the flexibility of plasmid DNA vaccines with enhanced immunogenicity and safety. The key to realizing the full potential of these vaccines is efficient delivery of nucleic acid to the cytoplasm of a cell, where it can amplify and express the encoded antigenic protein. The hydrophilicity and strong net negative charge of RNA impedes cellular uptake. To overcome this limitation, electrostatic complexation with cationic lipids or polymers and physical delivery using electroporation or ballistic particles to improve cellular uptake has been evaluated. This chapter highlights the rapid progress made in using nonviral delivery systems for RNA-based vaccines. Initial preclinical testing of self-amplifying mRNA vaccines has shown nonviral delivery to be capable of producing potent and robust innate and adaptive immune responses in small animals and nonhuman primates. Historically, the prospect of developing mRNA vaccines was uncertain due to concerns of mRNA instability and the feasibility of large-scale manufacturing. Today, these issues are no longer perceived as barriers in the widespread implementation of the technology. Currently, nonamplifying mRNA vaccines are under investigation in human clinical trials and can be produced at a sufficient quantity and quality to meet regulatory requirements. If the encouraging preclinical data with self-amplifying mRNA vaccines are matched by equivalently positive immunogenicity, potency, and tolerability in human trials, this platform could establish nucleic acid vaccines as a versatile new tool for human immunization.
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ARN Mensajero/administración & dosificación , Vacunas/administración & dosificación , Animales , Antígenos/genética , Electroporación , Humanos , Nanopartículas/administración & dosificación , Nanopartículas/química , ARN Mensajero/efectos adversos , ARN Mensajero/genética , Vacunas/efectos adversos , Vacunas ViralesRESUMEN
BACKGROUND: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1). METHODS/DESIGN: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments. DISCUSSION: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41.