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1.
Expert Opin Pharmacother ; 21(3): 307-315, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31973611

RESUMEN

Introduction: Spinal muscular atrophy (SMA) is one of the most common inherited neuromuscular disorders. It causes progressive muscle weakness and results in significant disability. Until recently, there were no drugs available for the treatment of SMA. Several phase 1-3 studies, including three double-blind randomized placebo-controlled studies have demonstrated the efficacy of disease-modifying approaches including gene replacement therapy, antisense oligonucleotides, and splicing modifiers.Areas covered: This article covers the publically available data on therapeutic strategies that address the underlying cause of SMA and clinical data available on approved treatments and drugs in the pipeline.Expert opinion: The newer therapeutic options in SMA have a good safety profile and deliver a therapeutic benefit in most patients. It is essential that the recommended standards of care are delivered along with the drugs for the best outcomes. No biomarkers to distinguish responders from non-responders are available; it is important that biomarkers be identified. Early treatment is essential for the maximum efficacy of the newly available treatments.


Asunto(s)
Terapia Genética/métodos , Atrofia Muscular Espinal/terapia , Oligonucleótidos Antisentido/uso terapéutico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
3.
DNA Cell Biol ; 39(2): 154-158, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31821021

RESUMEN

Antisense oligonucleotides (ASOs) are a relatively new therapeutic entity that utilizes short chemically modified strands of DNA in targeted interactions with RNA to modulate the type or amount of resultant protein. This brief review summarizes the preclinical, translational, and early clinical development of an ASO designed to reduce the production of the disease-causing protein in Huntington's disease, an inherited neurodegenerative disease.


Asunto(s)
Enfermedad de Huntington/tratamiento farmacológico , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Humanos , Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/metabolismo , Enfermedades Neurodegenerativas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo
5.
Adv Exp Med Biol ; 1185: 85-89, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31884593

RESUMEN

Inherited retinal diseases (IRD) encompass a wide spectrum of hereditary blindness with significant genetic heterogeneity. Therapeutics regulating gene expression on an RNA level have significant promise for treating IRD. In this review, we review the molecular basis of oligonucleotide therapeutics such as ribozymes, RNA interference (RNAi), antisense oligonucleotides (ASO), CRISPRi/a, and their applications to treatments of IRD.


Asunto(s)
ARN/uso terapéutico , Enfermedades de la Retina/terapia , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Humanos , Oligonucleótidos Antisentido/uso terapéutico , Interferencia de ARN , ARN Catalítico/uso terapéutico
6.
Drugs Today (Barc) ; 55(10): 627-639, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31720560

RESUMEN

Duchenne muscular dystrophy is the most common lethal X-linked genetic disorder, characterized by progressive muscle loss, with cardiac and respiratory complications. It is caused by a lack of dystrophin protein due to mutations in the DMD gene, which can disrupt the reading frame of the dystrophin primary transcript. Antisense oligonucleotides such as phosphorodiamidate morpholino oligomers (PMOs) can induce exon skipping during pre-mRNA splicing and restore the reading frame of the DMD primary transcript. The resulting dystrophin protein is internally deleted but partially functional. Viltolarsen, also known as NS-065/NCNP-01, is a PMO developed through comprehensive sequence optimization and is designed to skip exon 53 on the DMD primary transcript. Exclusion of exon 53 from the DMD primary transcript can treat 8-10% of DMD patients worldwide. This review paper summarizes the mechanism of action, pharmacokinetics and safety of viltolarsen from preclinical and clinical trials.


Asunto(s)
Morfolinos/uso terapéutico , Distrofia Muscular de Duchenne , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos/uso terapéutico , Ensayos Clínicos como Asunto , Distrofina , Exones , Humanos , Precursores del ARN
7.
Buenos Aires; CONETEC; nov. 2019. tab.
No convencional en Español | BRISA/RedTESA | ID: biblio-1025032

RESUMEN

INTRODUCCIÓN: La Atrofia Muscular Espinal (AME) es una enfermedad neuromuscular hereditaria caracterizada por la afectación de las células del asta anterior de la médula espinal (neuronas motoras), que cursa con debilidad proximal simétrica y atrofia progresiva de los grupos musculares. Es una patología poco frecuente, altamente discapacitante y con elevada mortalidad en sus formas más graves. Tiene una incidencia aproximada de 1 cada 6.000/10.000 nacidos vivos, y constituye la principal causa de mortalidad infantil por una enfermedad genética. Actualmente, no existe un tratamiento curativo para la AME; sólo se dispone de tratamiento sintomático para retrasar la progresión de la enfermedad y sus efectos discapacitantes, y tratamiento de sostén nutricional, ventilatorio y neuromuscular para mitigar sus complicaciones. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y políticas de cobertura de nusinersen para el tratamiento de la atrofia muscular espinal y el impacto presupuestario de su potencial inclusión en la cobertura del sistema de salud. DESCRIPCIÓN DE LA TECNOLOGÍA: Nusinersen (ISIS-SMNRx o ISIS 396443, SPINRAZANR) es un oligonucleótido antisentido, diseñado para alterar el empalme de ARN mensajero del gen SMN2 y aumentar la síntesis de proteína SMN funcional compensando así la ausencia de proteína SMN protectora, causada por el defecto en el gen SMN1, y la consecuente atrofia muscular. Se encuentra aprobado por FDA (Food and Drug Administration) y EMA (European Medicines Agency) para el tratamiento de AME6. BÚSQUEDA BIBLIOGRÁFICA: Se llevó a cabo una búsqueda bibliográfica utilizando las siguientes palabras claves: nusinersen (all) OR spinraza (all). Se exploraron las siguientes bases de datos: PubMed, Cochrane Library, Biblioteca Virtual en Salud, Biblioteca Central de Medicina (RIMA), Epistemonikos, Tripdatabase, Lilacs, NICE, National Guidelines Clearinghouse, Scielo, Clinical Trials, Orphanet. También se realizó búsqueda manual. Se encontraron 5 estudios8­12, todos ellos financiados por el productor de la tecnología, de los cuales se seleccionaron 2 estudios de fase 3.8,9 Se consideraron además documentos de aprobación de FDA13, EMA14y NHS15.Se revisó información aportada por el fabricante, que solicitó un registro especial. RESULTADOS: Existe evidencia de que el nusinersen para AME tipo I disminuye la mortalidad y el requerimiento de asistencia ventilatoria mecánica, así como también mejora la función motora permitiendo el desarrollo y la adquisición de ciertas habilidades (por ejemplo sentarse, permanecer de pie o caminar) hasta por lo menos los 13 meses de observación. Por otro lado, si bien existe evidencia sobre el uso de nusinersen en pacientes con AME tipo II que muestra una mejora en la función motora a los 15 meses de tratamiento, no se encontró evidencia sobre efectos en la mortalidad, el requerimiento de asistencia ventilatoria mecánica o la calidad de vida. No se encontró evidencia sobre el uso de nusinersen en pacientes con AME de inicio luego de los 20 meses de edad (la mayoría de los pacientes con diagnóstico de AME tipo III y todos los tipo IV). La incidencia global de Efectos Adversos (EAs) resultó similar en los grupos nusinersen y control, al igual que los EAs moderados o graves. Sin embargo, una comunicación de julio de 2018 del productor de la tecnología revela que se han notificado casos de hidrocefalia comunicante no asociada a meningitis ni a hemorragia en pacientes tratados con nusinersen. Varios de estos pacientes fueron tratados mediante la colocación de una Válvula de Derivación Ventriculoperitoneal (VDVP). La eficacia o riesgos de nusinersen tras la implantación de una VDVP se desconocen. No hay información fehaciente más allá del seguimiento publicado y a largo plazo. CONCLUSIONES: Existe evidencia proveniente de un único ensayo clínico aleatorizado con seguimiento a 13 meses que muestra que nusinersen para pacientes con Atrofia Muscular Espinal tipo I disminuye la mortalidad y el requerimiento de asistencia ventilatoria mecánica, así como también mejora la función motora permitiendo el desarrollo y la adquisición de ciertas habilidades (sentarse, permanecer de pie, caminar). Existe evidencia proveniente de un único ensayo clínico sobre la utilización de nusinersen en pacientes con Atrofia Muscular Espinal tipo II, que muestra una mejora en la función motora a los 15 meses de tratamiento en el subgrupo de pacientes con edad de comienzo menor a los 20 meses, aunque no se encontró evidencia sobre efectos en la mortalidad, el requerimiento de asistencia ventilatoria mecánica o la calidad de vida. No se encontró evidencia sobre el uso de nusinersen en pacientes con Atrofia Muscular Espinal de inicio luego de los 20 meses de edad (la mayoría de los AME tipo III y todos los tipo IV).


Asunto(s)
Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Evaluación de la Tecnología Biomédica , Análisis Costo-Eficiencia
8.
N Engl J Med ; 381(17): 1644-1652, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31597037

RESUMEN

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).


Asunto(s)
Proteínas de Transporte de Membrana/genética , Mutagénesis Insercional , Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Lipofuscinosis Ceroideas Neuronales/genética , Oligonucleótidos Antisentido/uso terapéutico , Medicina de Precisión , Enfermedades Raras/tratamiento farmacológico , Biopsia , Niño , Desarrollo Infantil , Descubrimiento de Drogas , Drogas en Investigación/uso terapéutico , Electroencefalografía , Femenino , Humanos , Pruebas Neuropsicológicas , ARN Mensajero , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Piel/patología , Secuenciación Completa del Genoma
9.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-31470511

RESUMEN

Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNAs, aptamers, decoys, and CpG oligodeoxynucleotides. In this review, we provide an update on current research of nucleic acid-based therapies. Despite the challenging obstacles, we hope that nucleic acid drugs will have a significant impact on the treatment of pancreatic cancer. The combination of genetic diagnosis using next generation sequencing and targeted therapy may provide effective precision medicine for pancreatic cancer patients.


Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Oligodesoxirribonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , ARN Interferente Pequeño/uso terapéutico , Animales , Aptámeros de Nucleótidos/genética , Humanos , Oligodesoxirribonucleótidos/genética , Oligonucleótidos Antisentido/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , ARN Neoplásico/antagonistas & inhibidores , ARN Neoplásico/genética , ARN Interferente Pequeño/genética
10.
Nat Commun ; 10(1): 3882, 2019 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-31462641

RESUMEN

The ß-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/ß-catenin signaling induces HB tumor formation is unknown. Here we show that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/ß-catenin signaling in HB patients. GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFß signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of ß-catenin, YAP, and c-Met induces HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppresses marker gene expression and HB-like liver tumorigenesis, and instead enhances TGFß signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppress the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a target molecule of Wnt/ß-catenin signaling and required for HB progression.


Asunto(s)
Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/genética , Factor de Crecimiento Transformador beta/metabolismo , Vía de Señalización Wnt , Adolescente , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinogénesis , Línea Celular Tumoral , Proliferación Celular , Niño , Preescolar , Regulación Neoplásica de la Expresión Génica , Hepatoblastoma/genética , Humanos , Lactante , Recién Nacido , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , beta Catenina/metabolismo
11.
EBioMedicine ; 45: 630-645, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31257147

RESUMEN

Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle degeneration, caused by the absence of dystrophin. Exon skipping by antisense oligonucleotides (ASOs) has recently gained recognition as therapeutic approach in DMD. Conjugation of a peptide to the phosphorodiamidate morpholino backbone (PMO) of ASOs generated the peptide-conjugated PMOs (PPMOs) that exhibit a dramatically improved pharmacokinetic profile. When tested in animal models, PPMOs demonstrate effective exon skipping in target muscles and prolonged duration of dystrophin restoration after a treatment regime. Herein we summarize the main pathophysiological features of DMD and the emergence of PPMOs as promising exon skipping agents aiming to rescue defective gene expression in DMD and other neuromuscular diseases. The listed PPMO laboratory findings correspond to latest trends in the field and highlight the obstacles that must be overcome prior to translating the animal-based research into clinical trials tailored to the needs of patients suffering from neuromuscular diseases.


Asunto(s)
Distrofia Muscular de Duchenne/terapia , Enfermedades Neuromusculares/terapia , Oligonucleótidos Antisentido/uso terapéutico , Péptidos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Distrofina , Exones/genética , Terapia Genética , Humanos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/genética , Enfermedades Neuromusculares/genética , Oligonucleótidos Antisentido/genética , Péptidos/genética
12.
Int J Mol Sci ; 20(13)2019 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-31284594

RESUMEN

Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.


Asunto(s)
Oligonucleótidos Antisentido/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Aptámeros de Nucleótidos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , MicroARNs/uso terapéutico , ARN Interferente Pequeño/uso terapéutico
13.
EBioMedicine ; 45: 646-654, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31300345

RESUMEN

MicroRNA-134 is a brain-enriched small noncoding RNA that has been implicated in diverse neuronal functions, including regulating network excitability. Increased expression of microRNA-134 has been reported in several experimental epilepsy models and in resected brain tissue from temporal lobe epilepsy patients. Rodent studies have demonstrated that reducing microRNA-134 expression in the brain using antisense oligonucleotides can increase seizure thresholds and attenuate status epilepticus. Critically, inhibition of microRNA-134 after status epilepticus can potently reduce the occurrence of spontaneous recurrent seizures. Altered plasma levels of microRNA-134 have been reported in epilepsy patients, suggesting microRNA-134 may have diagnostic value as a biomarker. This review summarises findings on the cellular functions of microRNA-134, as well as the preclinical evidence supporting anti-seizure and disease-modifying effects of targeting microRNA-134 in epilepsy. Finally, we draw attention to unanswered questions and some of the challenges and opportunities involved in preclinical development of a microRNA-based oligonucleotide treatment for epilepsy.


Asunto(s)
Epilepsia/terapia , MicroARNs/genética , Neuronas/metabolismo , Convulsiones/terapia , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Epilepsia/genética , Epilepsia/patología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/uso terapéutico , Neuronas/patología , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/uso terapéutico , Convulsiones/genética
14.
Drugs ; 79(12): 1349-1354, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31301033

RESUMEN

Volanesorsen (Waylivra®), an antisense oligonucleotide inhibitor of apolipoprotein CIII (apoCIII) mRNA, is being developed by Ionis Pharmaceuticals through its subsidiary company, Akcea Therapeutics, to treat familial chylomicronemia syndrome (FCS), hypertriglyceridemia and familial partial lipodystrophy (FPL). In May 2019, volanesorsen was approved in the EU for the treatment of adult patients with FCS based on positive results from the multinational, phase III APPROACH and COMPASS studies. Other clinical trials are ongoing to assess its utility in hypertriglyceridemia, FPL and partial lipodystrophy. This article summarizes the milestones in the development of volanesorsen leading to this first approval as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.


Asunto(s)
Apolipoproteína C-III/antagonistas & inhibidores , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos/uso terapéutico , Apolipoproteína C-III/genética , Apolipoproteína C-III/metabolismo , Ensayos Clínicos Fase III como Asunto , Aprobación de Drogas , Europa (Continente) , Humanos , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hipertrigliceridemia/tratamiento farmacológico , Lipodistrofia Parcial Familiar/tratamiento farmacológico , Lipodistrofia Parcial Familiar/genética , Oligonucleótidos/administración & dosificación , Oligonucleótidos/efectos adversos , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/efectos adversos
15.
Nervenarzt ; 90(9): 891-897, 2019 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-31332452

RESUMEN

Alzheimer's disease is histopathologically characterized by aggregation of two proteins, namely amyloid-beta peptide and tau protein. Whereas former intervention trials focused particularly on the amyloid pathology, recent therapeutic approaches are directed against the tau pathology. This article summarizes recent progress in anti-tau therapies, especially therapies based on anti-tau immunization and antisense oligonucleotides (ASO).


Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/metabolismo , Humanos , Inmunoterapia , Oligonucleótidos Antisentido/uso terapéutico , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo
16.
PLoS One ; 14(6): e0219182, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31251792

RESUMEN

Cystic fibrosis (CF) is caused by mutations in the gene encoding the epithelial chloride channel CF transmembrane conductance regulator (CFTR) protein. The most common mutation is a deletion of three nucleotides leading to the loss of phenylalanine at position 508 (p.Phe508del) in the protein. This study evaluates eluforsen, a novel, single-stranded, 33-nucleotide antisense oligonucleotide designed to restore CFTR function, in in vitro and in vivo models of p.Phe508del CF. The aims of the study were to demonstrate cellular uptake of eluforsen, and its efficacy in functional restoration of p.Phe508del-CFTR both in vitro and in vivo. In vitro, the effect of eluforsen was investigated in human CF pancreatic adenocarcinoma cells and human bronchial epithelial cells. Two mouse models were used to evaluate eluforsen in vivo. In vitro, eluforsen improved chloride efflux in CF pancreatic adenocarcinoma cell cultures and increased short-circuit current in primary human bronchial epithelial cells, both indicating restoration of CFTR function. In vivo, eluforsen was taken up by airway epithelium following oro-tracheal administration in mice, resulting in systemic exposure of eluforsen. In female F508del-CFTR mice, eluforsen significantly increased CFTR-mediated saliva secretion (used as a measure of CFTR function, equivalent to the sweat test in humans). Similarly, intranasal administration of eluforsen significantly improved nasal potential difference (NPD), and therefore CFTR conductance, in two CF mouse models. These findings indicate that eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated CF and supported further development of eluforsen in human clinical trials, where eluforsen has also been shown to improve CFTR activity as measured by NPD.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Células Epiteliales/efectos de los fármacos , Oligonucleótidos Antisentido/uso terapéutico , Animales , Línea Celular Tumoral , Fibrosis Quística/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Oligonucleótidos Antisentido/farmacología
17.
Bull Exp Biol Med ; 167(1): 116-119, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31177453

RESUMEN

We propose an original method for controlling BP by administration of Si~ODN nanocomposites containing antisense oligonucleotides fixed on silicon-organic nanoparticles. ODN in nanocomposites are targeted to mRNA of the genes encoding angiotensin-converting enzyme (ACE1) and type 1 angiotensin-II receptor (AT1A). The experiments were performed on hypertensive ISIAH rats, a genetic model of hypertension. Single inhalation or intraperitoneal administration of the nanocomposites targeted to ACE1 mRNA or ATA1 mRNA, respectively, led to a pronounced decrease (by ~30 mm Hg) in systolic BP in ISIAH rats over a week. The use of scrambled ODN in the nanocomposites had no effect. A decrease in the expression of ACE1 and AT1A genes under the effect of the corresponding antisense ODN was demonstrated, which attested to directed effect of the test preparations.


Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Nanopartículas/química , Nanopartículas/uso terapéutico , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/uso terapéutico , Sistema de Transporte de Aminoácidos A/genética , Sistema de Transporte de Aminoácidos A/metabolismo , Animales , Presión Sanguínea/genética , Hipertensión/genética , Hipertensión/metabolismo , Masculino , Peptidil-Dipeptidasa A/genética , ARN Mensajero/metabolismo , Ratas , Silicio
18.
Nervenarzt ; 90(8): 781-786, 2019 Aug.
Artículo en Alemán | MEDLINE | ID: mdl-31165208

RESUMEN

Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy, Duchenne muscular dystrophy and transthyretin amyloidosis predict a robust future for ASOs in medicine. Perhaps the most significant advantage of ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of possible complementary oligonucleotide therapeutics. This review article describes the various types of ASOs, their therapeutic use and the current preclinical efforts to develop new ASO treatments.


Asunto(s)
Enfermedades Neurodegenerativas , Oligonucleótidos Antisentido , Terapia Genética , Humanos , Atrofia Muscular Espinal , Distrofia Muscular de Duchenne , Enfermedades Neurodegenerativas/terapia , Oligonucleótidos Antisentido/uso terapéutico
19.
Nat Biotechnol ; 37(6): 640-650, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31036929

RESUMEN

The molecular mechanisms of toxicity of chemically modified phosphorothioate antisense oligonucleotides (PS-ASOs) are not fully understood. Here, we report that toxic gapmer PS-ASOs containing modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2'-O-methoxyethyl (2'-MOE) bind many cellular proteins with high avidity, altering their function, localization and stability. We show that RNase H1-dependent delocalization of paraspeckle proteins to nucleoli is an early event in PS-ASO toxicity, followed by nucleolar stress, p53 activation and apoptotic cell death. Introduction of a single 2'-O-methyl (2'-OMe) modification at gap position 2 reduced protein-binding, substantially decreasing hepatotoxicity and improving the therapeutic index with minimal impairment of antisense activity. We validated the ability of this modification to generally mitigate PS-ASO toxicity with more than 300 sequences. Our findings will guide the design of PS-ASOs with optimal therapeutic profiles.


Asunto(s)
Oligonucleótidos Antisentido/química , Oligonucleótidos/química , Oligonucleótidos Fosforotioatos/química , Humanos , Hígado/efectos de los fármacos , Oligonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos Fosforotioatos/uso terapéutico , Unión Proteica/efectos de los fármacos , Ribonucleasa H/química , Ribonucleasa H/genética , Índice Terapéutico
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