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1.
Mol Ther ; 30(5): 1897-1912, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34990810

RESUMO

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Cricetinae , Humanos , Lipossomos , Camundongos , Nanopartículas , RNA Mensageiro , Ratos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Distribuição Tecidual
2.
Sci Rep ; 14(1): 11573, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773172

RESUMO

GSK2838232 (GSK8232) is a second-generation maturation inhibitor (MI) developed for the treatment of HIV with excellent broad-spectrum virological profiles. The compound has demonstrated promising clinical results as an orally administered agent. Additionally, the compound's physical and pharmacological properties present opportunities for exploitation as long-acting parenteral formulations. Despite unique design constraints including solubility and dose of GSK8232, we report on three effective tunable drug delivery strategies: active pharmaceutical ingredient (API) suspensions, ionic liquids, and subdermal implants. Promising sustained drug release profiles were achieved in rats with each approach. Additionally, we were able to tune drug release rates through a combination of passive and active strategies, broadening applicability of these formulation approaches beyond GSK8232. Taken together, this report is an important first step to advance long-acting formulation development for critical HIV medicines that do not fit the traditional profile of suitable long-acting candidates.


Assuntos
Liberação Controlada de Fármacos , Animais , Ratos , Interações Hidrofóbicas e Hidrofílicas , Preparações de Ação Retardada , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Líquidos Iônicos/química , Ratos Sprague-Dawley , Masculino , Solubilidade , Infecções por HIV/tratamento farmacológico , Antirretrovirais/administração & dosagem , Antirretrovirais/química
3.
Cornea ; 21(8): 787-91, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12410038

RESUMO

PURPOSE: To evaluate the immunohistochemical profiles of the abnormal endothelial cells of posterior polymorphous dystrophy (PPMD) and congenital hereditary endothelial dystrophy (CHED). METHODS: Formalin-fixed, paraffin-embedded sections of seven corneas with the diagnosis of PPMD (seven patients), six corneas with the diagnosis of CHED (four patients), and five control corneas were stained with hematoxylin-eosin. Adjacent histologic sections were stained with monoclonal antibodies that react with pancytokeratin, AE1/AE3, cytokeratin (CK) 7, CK 20, CAM 5.2, and epithelial membrane antigen. The immunoreactivity of the corneal endothelium was assessed by light microscopy. RESULTS: The endothelial cells stained positive for pancytokeratin and CK 7 in seven of seven corneas of patients with PPMD and five of six corneas of patients with CHED; variable positivity was seen to AE1, AE3, and CAM 5.2. The endothelium was uniformly negative to staining by CK 20. The epithelium stained positive with pancytokeratin, AE1, and AE3. All control corneas were negative for pancytokeratin, CK 7, and CK 20. CONCLUSION: The abnormal endothelium in both PPMD and CHED expresses similar CKs, including CK 7, which is not present in normal endothelium or surface epithelium. This may indicate a shared developmental abnormality in these conditions, as previously suggested by ultrastructural studies and genetic mapping.


Assuntos
Distrofias Hereditárias da Córnea/patologia , Endotélio Corneano/patologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais , Pré-Escolar , Distrofias Hereditárias da Córnea/metabolismo , Endotélio Corneano/metabolismo , Feminino , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Lactente , Queratinas/metabolismo , Masculino , Pessoa de Meia-Idade , Mucina-1/metabolismo
4.
J Fam Psychol ; 23(5): 626-35, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19803599

RESUMO

This study examined whether (a) therapist behaviors thought to enhance family treatment predicted caregiver in-session responses, and (b) caregiver race, racial match between caregiver and therapist, and family financial hardship moderated the relationships between therapist and caregiver behavior. Observers coded caregiver and therapist behavior during one session of multisystemic therapy for substance abusing adolescents. Therapist teaching, focusing on strengths, making reinforcing statements, problem solving, and dealing with practical family needs predicted caregiver engagement and/or positive response, regardless of race, racial match, or financial hardship. Caregiver race, financial hardship, and therapist-caregiver racial match occasionally moderated the relationship between other therapist and caregiver behaviors. Findings suggest both commonalities and differences in how therapist behavior may function to engage caregivers in family treatment, depending on diversity-related factors.


Assuntos
Transtorno da Personalidade Antissocial/etnologia , Transtorno da Personalidade Antissocial/reabilitação , População Negra/psicologia , Cuidadores/psicologia , Terapia Familiar/métodos , Delinquência Juvenil/etnologia , Delinquência Juvenil/reabilitação , Motivação , Relações Profissional-Família , Psicotrópicos , Transtornos Relacionados ao Uso de Substâncias/etnologia , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Teoria de Sistemas , População Branca/psicologia , Adolescente , Adulto , Transtorno da Personalidade Antissocial/psicologia , Criança , Diversidade Cultural , Humanos , Delinquência Juvenil/psicologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Projetos Piloto , Pobreza/etnologia , Pobreza/psicologia , Resolução de Problemas , Ensaios Clínicos Controlados Aleatórios como Assunto , Reforço Verbal , Identificação Social , Transtornos Relacionados ao Uso de Substâncias/psicologia
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