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1.
Expert Opin Pharmacother ; 21(3): 307-315, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31973611

RESUMO

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.


Assuntos
Terapia Genética/métodos , Atrofia Muscular Espinal/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Adv Exp Med Biol ; 1185: 85-89, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884593

RESUMO

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.


Assuntos
RNA/uso terapêutico , Doenças Retinianas/terapia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Interferência de RNA , RNA Catalítico/uso terapêutico
5.
Drugs Today (Barc) ; 55(10): 627-639, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31720560

RESUMO

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.


Assuntos
Morfolinos/uso terapêutico , Distrofia Muscular de Duchenne , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Ensaios Clínicos como Assunto , Distrofina , Éxons , Humanos , Precursores de RNA
6.
Buenos Aires; CONETEC; nov. 2019. tab.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1025032

RESUMO

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).


Assuntos
Humanos , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Avaliação da Tecnologia Biomédica , Análise Custo-Eficiência
7.
N Engl J Med ; 381(17): 1644-1652, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31597037

RESUMO

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.).


Assuntos
Proteínas de Membrana Transportadoras/genética , Mutagênese Insercional , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão , Doenças Raras/tratamento farmacológico , Biópsia , Criança , Desenvolvimento Infantil , Descoberta de Drogas , Drogas em Investigação/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Testes Neuropsicológicos , RNA Mensageiro , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Pele/patologia , Sequenciamento Completo do Genoma
8.
Nat Commun ; 10(1): 3882, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462641

RESUMO

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.


Assuntos
Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/genética , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Adolescente , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Criança , Pré-Escolar , Regulação Neoplásica da Expressão Gênica , Hepatoblastoma/genética , Humanos , Lactente , Recém-Nascido , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , beta Catenina/metabolismo
9.
EBioMedicine ; 45: 646-654, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31300345

RESUMO

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.


Assuntos
Epilepsia/terapia , MicroRNAs/genética , Neurônios/metabolismo , Convulsões/terapia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/uso terapêutico , Neurônios/patologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Convulsões/genética
10.
Drugs ; 79(12): 1349-1354, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31301033

RESUMO

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.


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Apolipoproteína C-III/genética , Apolipoproteína C-III/metabolismo , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Europa (Continente) , Humanos , Hiperlipoproteinemia Tipo I/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Lipodistrofia Parcial Familiar/tratamento farmacológico , Lipodistrofia Parcial Familiar/genética , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos
11.
Int J Mol Sci ; 20(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284594

RESUMO

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.


Assuntos
Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Aptâmeros de Nucleotídeos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , MicroRNAs/uso terapêutico , RNA Interferente Pequeno/uso terapêutico
12.
EBioMedicine ; 45: 630-645, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31257147

RESUMO

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.


Assuntos
Distrofia Muscular de Duchenne/terapia , Doenças Neuromusculares/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Peptídeos/uso terapêutico , Animais , Modelos Animais de Doenças , Distrofina , Éxons/genética , Terapia Genética , Humanos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/genética , Doenças Neuromusculares/genética , Oligonucleotídeos Antissenso/genética , Peptídeos/genética
13.
Nervenarzt ; 90(9): 891-897, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31332452

RESUMO

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).


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Humanos , Imunoterapia , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
14.
Nervenarzt ; 90(8): 781-786, 2019 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-31165208

RESUMO

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.


Assuntos
Doenças Neurodegenerativas , Oligonucleotídeos Antissenso , Terapia Genética , Humanos , Atrofia Muscular Espinal , Distrofia Muscular de Duchenne , Doenças Neurodegenerativas/terapia , Oligonucleotídeos Antissenso/uso terapêutico
15.
Bull Exp Biol Med ; 167(1): 116-119, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177453

RESUMO

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.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Nanopartículas/química , Nanopartículas/uso terapêutico , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/uso terapêutico , Sistema A de Transporte de Aminoácidos/genética , Sistema A de Transporte de Aminoácidos/metabolismo , Animais , Pressão Sanguínea/genética , Hipertensão/genética , Hipertensão/metabolismo , Masculino , Peptidil Dipeptidase A/genética , RNA Mensageiro/metabolismo , Ratos , Silício
16.
Nat Biotechnol ; 37(6): 640-650, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31036929

RESUMO

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.


Assuntos
Oligonucleotídeos Antissenso/química , Oligonucleotídeos/química , Oligonucleotídeos Fosforotioatos/química , Humanos , Fígado/efeitos dos fármacos , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Fosforotioatos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ribonuclease H/química , Ribonuclease H/genética , Índice Terapêutico
17.
J Atheroscler Thromb ; 26(7): 583-591, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31061262

RESUMO

Lipoprotein(a) [Lp(a)], discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings.


Assuntos
Aterosclerose/sangue , Lipoproteína(a)/sangue , Apolipoproteínas B/sangue , Apolipoproteínas B/química , Aterosclerose/tratamento farmacológico , Biomarcadores/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteína(a)/química , Niacina/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase
18.
Chem Biol Interact ; 308: 206-215, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136735

RESUMO

Oligonucleotide-based therapies are advanced novel interventions used in the management of various respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). These agents primarily act by gene silencing or RNA interference. Better methodologies and techniques are the need of the hour that can deliver these agents to tissues and cells in a target specific manner by which their maximum potential can be reached in the management of chronic inflammatory diseases. Nanoparticles play an important role in the target-specific delivery of drugs. In addition, oligonucleotides also are extensively used for gene transfer in the form of polymeric, liposomal and inorganic carrier materials. Therefore, the current review focuses on various novel dosage forms like nanoparticles, liposomes that can be used efficiently for the delivery of various oligonucleotides such as siRNA and miRNA. We also discuss the future perspectives and targets for oligonucleotides in the management of respiratory diseases.


Assuntos
Portadores de Fármacos/química , Oligonucleotídeos Antissenso/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Dendrímeros/química , Humanos , Lipossomos/química , MicroRNAs/química , MicroRNAs/uso terapêutico , Nanopartículas/química , Oligonucleotídeos Antissenso/química , Interferência de RNA , RNA Interferente Pequeno/química , RNA Interferente Pequeno/uso terapêutico
20.
Molecules ; 24(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999681

RESUMO

Skin cancer has always been and remains the leader among all tumors in terms of occurrence. One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells. These mutations inactivate apoptosis, an event required to avoid the malignant transformation of healthy cells. Among these deadliest of cancers, melanoma and its 'younger sister', Merkel cell carcinoma, are the most lethal. The heavy toll of skin cancers stems from their rapid progression and the fact that they metastasize easily. Added to this is the difficulty in determining reliable margins when excising tumors and the lack of effective chemotherapy. Possibly the biggest problem posed by skin cancer is reliably detecting the extent to which cancer cells have spread throughout the body. The initial tumor is visible and can be removed, whereas metastases are invisible to the naked eye and much harder to eliminate. In our opinion, antisense oligonucleotides, which can be used in the form of targeted ointments, provide real hope as a treatment that will eliminate cancer cells near the tumor focus both before and after surgery.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma , Mutação , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Cutâneas , Raios Ultravioleta/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
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