RESUMEN
The approval of splice-switching oligonucleotides with phosphorodiamidate morpholino oligomers (PMOs) for treating Duchenne muscular dystrophy (DMD) has advanced the field of oligonucleotide therapy. Despite this progress, PMOs encounter challenges such as poor tissue uptake, particularly in the heart, diaphragm, and central nervous system (CNS), thereby affecting patient's prognosis and quality of life. To address these limitations, we have developed a PMOs-based heteroduplex oligonucleotide (HDO) technology. This innovation involves a lipid-ligand-conjugated complementary strand hybridized with PMOs, significantly enhancing delivery to key tissues in mdx mice, normalizing motor functions, muscle pathology, and serum creatine kinase by restoring internal deleted dystrophin expression. Additionally, PMOs-based HDOs normalized cardiac and CNS abnormalities without adverse effects. Our technology increases serum albumin binding to PMOs and improves blood retention and cellular uptake. Here we show that PMOs-based HDOs address the limitations in oligonucleotide therapy for DMD and offer a promising approach for diseases amenable to exon-skipping therapy.
Asunto(s)
Modelos Animales de Enfermedad , Distrofina , Ratones Endogámicos mdx , Morfolinos , Distrofia Muscular de Duchenne , Animales , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/metabolismo , Morfolinos/administración & dosificación , Morfolinos/genética , Ratones , Distrofina/genética , Distrofina/metabolismo , Empalme del ARN , Humanos , Exones/genética , Masculino , Músculo Esquelético/metabolismo , Terapia Genética/métodos , Oligonucleótidos/administración & dosificación , Oligonucleótidos/farmacocinéticaRESUMEN
A 60-year-old man was admitted to our hospital because of fever and mental status change. Neurological examination showed meningeal irritation and frontal sign. Cerebrospinal fluid (CSF) examination showed mild pleocytosis and elevated protein. Laboratory findings showed hyponatremia, elevated liver enzymes and creatine phosphokinase, and positive Legionella pneumophila antigen in urine. The chest computed tomographic scans showed consolidation in the left lower lobe lung. We diagnosed Legionnaires' pneumonia and started treatment with levofloxacin. Legionella pneumophila was isolated from culture of the bronchoalveolar lavage fluid, but Legionella culture and polymerase chain reaction in CSF were negative. We hypothesize that Legionella pneumophila could produce nerological symptoms by immune-mediated mechanism associated with elevated IgG index. The neurologist should recognize the presence of the meningo-encephalitis associated with Legionnaires' pneumonia lacking remarkable pulmonary symptoms.