Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
N Engl J Med ; 385(6): 493-502, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34215024

RESUMO

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).


Assuntos
Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/terapia , Sistemas CRISPR-Cas , Edição de Genes , Lipossomos/uso terapêutico , Nanopartículas/uso terapêutico , Pré-Albumina/genética , RNA Guia de Cinetoplastídeos/uso terapêutico , Feminino , Técnicas de Transferência de Genes , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pré-Albumina/análise , RNA Mensageiro
2.
J Infect Dis ; 212(11): 1719-25, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25977264

RESUMO

We studied preexisting respiratory syncytial virus (RSV)-specific serum and nasal antibodies and their correlation with infectivity, viral dynamics, and disease severity in a human experimental infection model. Higher preinoculation serum neutralizing antibody titers and nasal immunoglobulin (Ig) A predicted lower infectivity and lower measures of viral replication. However, once individuals were infected, no significant protective effect of preexisting antibodies was seen. Lack of correlation between serum and mucosal antibodies was observed, implying that they are independent co-correlates of protection against RSV infection. We suggest that protection from RSV infection is a function of a complex interplay between mucosal and serum humoral immune responses.


Assuntos
Anticorpos Antivirais/análise , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Adolescente , Adulto , Feminino , Humanos , Imunoglobulina A/análise , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Adulto Jovem
3.
ISRN Pediatr ; 2012: 721295, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22792479

RESUMO

Background. New aerosol drugs for infants may require more efficient delivery systems, including face masks. Maximizing delivery efficiency requires tight-fitting masks with minimal internal mask volumes, which could cause carbon dioxide (CO(2)) retention. An RNA-interference-based antiviral for treatment of respiratory syncytial virus in populations that may include young children is designed for aerosol administration. CO(2) accumulation within inhalation face masks has not been evaluated. Methods. We simulated airflow and CO(2) concentrations accumulating over time within a new facemask designed for infants and young children (PARI SMARTMASK(®) Baby). A one-dimensional model was first examined, followed by 3-dimensional unsteady computational fluid dynamics analyses. Normal infant breathing patterns and respiratory distress were simulated. Results. The maximum average modeled CO(2) concentration within the mask reached steady state (3.2% and 3% for normal and distressed breathing patterns resp.) after approximately the 5th respiratory cycle. After steady state, the mean CO(2) concentration inspired into the nostril was 2.24% and 2.26% for normal and distressed breathing patterns, respectively. Conclusion. The mask is predicted to cause minimal CO(2) retention and rebreathing. Infants with normal and distressed breathing should tolerate the mask intermittently delivering aerosols over brief time frames.

4.
Antiviral Res ; 77(3): 225-31, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18242722

RESUMO

Small interfering RNAs (siRNAs) work through RNA interference (RNAi), the natural RNA inhibitory pathway, to down-regulate protein production by inhibiting targeted mRNA in a sequence-specific manner. ALN-RSV01 is an siRNA directed against the mRNA encoding the N-protein of respiratory syncytial virus (RSV) that exhibits specific in vitro and in vivo anti-RSV activity. The results of two safety and tolerability studies with ALN-RSV01 involving 101 healthy adults (65 active, 36 placebo, single- and multiple dose, observer-blind, randomized dose-escalation) are described. Intranasal administration of ALN-RSV01 was well tolerated over a dose range up through 150mg as a single dose and for five daily doses. Adverse events were similar in frequency and severity to placebo (normal saline) and were transient, mild to moderate, with no dose-dependent trend. The frequency or severity of adverse events did not increase with increasing ALN-RSV01 exposure. All subjects completed all treatments and assessments with no early withdrawals or serious adverse events. Physical examinations, vital signs, ECGs and laboratory tests were normal. Systemic bioavailability of ALN-RSV01 was minimal. ALN-RSV01 appears safe and well tolerated when delivered intranasally and is a promising therapeutic candidate for further clinical development.


Assuntos
Antivirais/efeitos adversos , Antivirais/farmacocinética , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Administração Intranasal , Adolescente , Adulto , Antivirais/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...