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1.
Nucleic Acids Res ; 52(10): 5423-5437, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38742636

RESUMEN

Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence of oral dosage forms of peptide-based drugs in clinical settings. Antisense oligonucleotides (ASOs) have also been investigated for oral administration but despite the recent progress, the bioavailability remains low. Given the advancement with highly potent and durable trivalent N-acetylgalactosamine (GalNAc)-conjugated small interfering RNAs (siRNAs) via subcutaneous (s.c.) injection, we explored their activities after oral administration. We report robust RNA interference (RNAi) activity of orally administrated GalNAc-siRNAs co-formulated with permeation enhancers (PEs) in rodents and non-human primates (NHPs). The relative bioavailability calculated from NHP liver exposure was <2.0% despite minimal enzymatic degradation in the GI. To investigate the impact of oligonucleotide size on oral delivery, highly specific GalNAc-conjugated single-stranded oligonucleotides known as REVERSIRs with different lengths were employed and their activities for reversal of RNAi effect were monitored. Our data suggests that intestinal permeability is highly influenced by the size of oligonucleotides. Further improvements in the potency of siRNA and PE could make oral delivery of GalNAc-siRNAs as a practical solution.


Asunto(s)
Acetilgalactosamina , ARN Interferente Pequeño , Animales , Acetilgalactosamina/química , Acetilgalactosamina/metabolismo , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacocinética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Administración Oral , Ratones , Ratas , Interferencia de ARN , Masculino , Disponibilidad Biológica , Humanos , Ratas Sprague-Dawley , Macaca fascicularis , Hígado/metabolismo , Macaca mulatta
2.
PLoS One ; 8(2): e55785, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23409044

RESUMEN

Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.


Asunto(s)
Canales de Calcio/metabolismo , Calcio/metabolismo , Mitocondrias/metabolismo , Complejos Multiproteicos/metabolismo , Secuencia de Aminoácidos , Animales , Canales de Calcio/química , Canales de Calcio/genética , Señalización del Calcio , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Respiración de la Célula/genética , Células HEK293 , Células HeLa , Humanos , Hígado/metabolismo , Potencial de la Membrana Mitocondrial/genética , Ratones , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Familia de Multigenes , Unión Proteica , Estabilidad Proteica , Transporte de Proteínas , Interferencia de ARN , Alineación de Secuencia
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