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1.
Drugs Today (Barc) ; 56(8): 491-504, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33025945

RESUMO

Duchenne muscular dystrophy (DMD) is a life-shortening X-linked genetic disorder characterized by progressive wasting and weakening of muscles in boys. Loss-of-function mutations in the DMD gene, which codes for dystrophin, lead to this disease. The majority of mutations in this gene result in the exclusion of one or more exons from the transcript, eventually causing the remaining exons not to fit together correctly (i.e., out-of-frame mutations). Antisense oligonucleotides, e.g., phosphorodiamidate morpholino oligomers (PMOs), can induce therapeutic exon skipping during pre-mRNA processing to restore the reading frame of the primary transcript of DMD. As a result, truncated but partially functional dystrophin is produced, potentially slowing down the disease progression. Golodirsen is a provisionally approved PMO-based drug for approx. 8% of all DMD patients amenable to exon 53 skipping. This article summarizes golodirsen's pharmacology, efficacy and safety information. It also discusses some controversies that golodirsen met after the approval.


Assuntos
Distrofia Muscular de Duchenne/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Distrofina , Éxons , Humanos , Morfolinos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico
2.
J Pharmacol Sci ; 144(4): 204-211, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070839

RESUMO

The deficiency of survival motor neuron (SMN) protein can result in the onset of spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by a progressive loss of motor neurons and skeletal muscle atrophy. The mechanism underlying SMA pathology remains unclear. Here, we demonstrate that SMN protein regulates oxidative stress and inflammatory response in microglia. Antisense oligonucleotide, which increases SMN protein expression (SMN-ASO), attenuated SMA model mice phenotypes and suppressed the activation of microglia in the spinal cord. The expression of oxidative stress marker in microglia was decreased by SMN-ASO injection in SMA model mice. Increased reactive oxygen species production and subsequent antioxidative stress reaction was observed in SMN protein-depleted RAW264.7. Furthermore, nuclear factor kappa B (NFκB) and c-Jun amino terminal kinase (JNK) signaling, which mainly mediate the inflammatory response, are activated in SMN protein-depleted RAW264.7. Tumor necrosis factor-α (TNF-α) production is also increased in SMN protein-depleted RAW264.7. These findings suggest that SMN protein regulates oxidative stress and inflammatory response in microglia, supporting current claims that microglia can be an effective target for SMA therapy.


Assuntos
Inflamação/genética , Microglia/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Estresse Oxidativo/genética , Medula Espinal/citologia , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/fisiologia , Animais , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Atrofia Muscular Espinal/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Pharmacol Rev ; 72(4): 862-898, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32929000

RESUMO

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.


Assuntos
RNA/efeitos dos fármacos , RNA/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/uso terapêutico , Betacoronavirus , Técnicas de Química Analítica/métodos , Técnicas de Química Analítica/normas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/organização & administração , Descoberta de Drogas , Humanos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA/efeitos adversos , RNA Antissenso/farmacologia , RNA Antissenso/uso terapêutico , RNA Guia/farmacologia , RNA Guia/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/farmacologia , RNA Ribossômico/efeitos dos fármacos , RNA Ribossômico/farmacologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , RNA Viral/efeitos dos fármacos , Ribonucleases/metabolismo , Riboswitch/efeitos dos fármacos
4.
N Engl J Med ; 383(13): 1242-1247, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32877578

RESUMO

Hereditary angioedema is characterized by recurrent and unpredictable episodes of subcutaneous and mucosal swelling that can be life threatening. IONIS-PKK-LRx is a ligand-conjugated antisense oligonucleotide designed for receptor-mediated delivery to hepatocytes. In a compassionate-use pilot study, two patients with severe bradykinin-mediated angioedema were initially administered weekly subcutaneous injections of the unconjugated parent drug, IONIS-PKKRx, for 12 to 16 weeks, after which they received IONIS-PKK-LRx at a dose of 80 mg every 3 to 4 weeks for 7 to 8 months. Treatment was accompanied by a reduction in the angioedema attack rate. (Funded by Amsterdam UMC.).


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Pré-Calicreína/antagonistas & inibidores , Adulto , Angioedemas Hereditários/metabolismo , Bradicinina/metabolismo , Ensaios de Uso Compassivo , Feminino , Humanos , Injeções Subcutâneas , Oligonucleotídeos Antissenso/administração & dosagem , Projetos Piloto , Pré-Calicreína/metabolismo
5.
Nucleic Acids Res ; 48(19): 10615-10631, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32776089

RESUMO

Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.


Assuntos
Oligonucleotídeos Antissenso/uso terapêutico , Doenças Priônicas/terapia , Proteínas Priônicas/genética , Terapêutica com RNAi/métodos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Camundongos , Camundongos Endogâmicos C57BL , Oligonucleotídeos Antissenso/química , Proteínas Priônicas/metabolismo
6.
Arterioscler Thromb Vasc Biol ; 40(9): 2002-2017, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698685

RESUMO

Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.


Assuntos
Artérias/metabolismo , Aterosclerose/metabolismo , RNA Longo não Codificante/metabolismo , Lesões do Sistema Vascular/metabolismo , Animais , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/terapia , Constrição Patológica , Epigênese Genética , Marcadores Genéticos , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Placa Aterosclerótica , RNA Longo não Codificante/genética , RNA Longo não Codificante/uso terapêutico , Terapêutica com RNAi , Transdução de Sinais , Remodelação Vascular , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia , Lesões do Sistema Vascular/terapia
8.
Expert Opin Pharmacother ; 21(14): 1675-1684, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32646313

RESUMO

INTRODUCTION: Severe hypertriglyceridemia (sHTG) is a complex disorder of lipid metabolism characterized by plasma levels of triglyceride (TG) greater than 885 mg/dl (>10 mmol/L). The treatment of sHTG syndromes is challenging because conventional treatments are often ineffective in reducing TG under the threshold to prevent acute pancreatitis (AP). The inhibition of APOC3, which encodes a protein involved in triglyceride (TG)-rich lipoproteins (TGRLs) removal, has been reported to be a novel target for the treatment of sHTG. Volanesorsen is a second-generation antisense oligonucleotide inhibiting apoC-III transcription/translation that has been recently approved in Europe for Familial Chylomicronemia Syndrome (FCS) treatment. AREAS COVERED: This review summarizes the evidences on the efficacy and safety of volanesorsen for the treatment of sHTG syndromes. EXPERT OPINION: Volanesorsen effectively reduces TG in sHTG through a mechanism that is mainly LPL-independent, potentially decreasing the risk of AP. Some safety concerns have been raised with the use of volanesorsen, mainly represented by the occurrence of thrombocytopenia. Due to the potential severity of side effects, some caution is needed before affirming the long-term utility of this drug. Despite this, volanesorsen currently remains the only drug that has been demonstrated effective in FCS, which otherwise remains an untreatable disease.


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Hipertrigliceridemia/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Europa (Continente) , Humanos , Hiperlipoproteinemia Tipo I/tratamento farmacológico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/metabolismo , Lipoproteínas/sangue , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos , Pancreatite/induzido quimicamente , Pancreatite/prevenção & controle , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controle , Triglicerídeos/sangue
9.
Cardiovasc Pathol ; 49: 107243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32629211

RESUMO

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of cases of heart failure, which is the most common cause of hospitalization in US patients over the age of 65. HFpEF pathogenesis is increasingly believed to be due to pathological hypertrophy and fibrosis of the myocardium that may be a result of systemic inflammation from comorbid conditions such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, anemia, chronic kidney disease and others. It is believed that oxidative stress triggers a process of pathological hypertrophy and fibrosis in cardiac endothelial cells, which leads to increased left ventricle filling pressures and, eventually, symptoms of heart failure. Numerous recent major clinical trials that have examined various therapies aimed at improving mortality in HFpEF have emerged empty-handed and thus the search for effective management strategies continues. Over the last several years, there have been many new developments in the field of antisense oligonucleotide-based therapeutics, which involves using noncoding nucleic acid particles such as microRNA and small interfering RNA to repress the expression of specific messenger RNA. In this article, we review the concept of using oligonucleotide-based therapeutics to prevent or treat HFpEF by targeting a specific microRNA that has been implicated in the pathogenesis of myocardial fibrosis and hypertrophy, microRNA-21 (miR-21). We review the various evidence that implicates miR-21 in the process of myocardial fibrosis and discuss recent attempts to use antimiR-21 compounds to prevent fibrosis. We also discuss proposed methods for screening patients at high risk for HFpEF for diastolic dysfunction in order to determine which patients.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/terapia , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Volume Sistólico , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Animais , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , MicroRNAs/genética , MicroRNAs/metabolismo , Resultado do Tratamento , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
10.
Nucleic Acids Res ; 48(14): 7623-7639, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32644123

RESUMO

RNA therapeutics are a promising strategy to treat genetic diseases caused by the overexpression or aberrant splicing of a specific protein. The field has seen major strides in the clinical efficacy of this class of molecules, largely due to chemical modifications and delivery strategies that improve nuclease resistance and enhance cell penetration. However, a major obstacle in the development of RNA therapeutics continues to be the imprecise, difficult, and often problematic nature of most methods used to measure cell penetration. Here, we review these methods and clearly distinguish between those that measure total cellular uptake of RNA therapeutics, which includes both productive and non-productive uptake, and those that measure cytosolic/nuclear penetration, which represents only productive uptake. We critically analyze the benefits and drawbacks of each method. Finally, we use key examples to illustrate how, despite rigorous experimentation and proper controls, our understanding of the mechanism of gymnotic uptake of RNA therapeutics remains limited by the methods commonly used to analyze RNA delivery.


Assuntos
RNA/metabolismo , RNA/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Núcleo Celular/metabolismo , Citosol/metabolismo , Doenças Genéticas Inatas/tratamento farmacológico , Técnicas Genéticas , Humanos , MicroRNAs/uso terapêutico , Microscopia Eletrônica , Oligonucleotídeos Antissenso/uso terapêutico , RNA/química , RNA/farmacocinética , RNA Interferente Pequeno/uso terapêutico , Espectrometria de Fluorescência
11.
Nat Med ; 26(9): 1444-1451, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719489

RESUMO

CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1-3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20-30 years of life4-7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3∆ex7/8), creating a reading frameshift7,8. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3∆ex7/8 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.


Assuntos
Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Linhagem Celular , Códon sem Sentido/genética , Modelos Animais de Doenças , Mutação da Fase de Leitura/genética , Humanos , Camundongos
12.
Am J Cardiol ; 126: 94-102, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32336532

RESUMO

Lipoprotein (a) [Lp(a)] is a low-density, cholesterol-containing lipoprotein that differs from other low-density lipoproteins due to the presence of apolipoprotein(a) bound to its surface apolipoprotein B100. Multiple epidemiologic studies, including Mendelian Randomization studies, have demonstrated that increasing Lp(a) levels are associated with increased risk of heart disease, including atherosclerotic cardiovascular disease and calcific aortic stenosis. The risk associated with elevations in Lp(a) appears to be independent of other lipid markers. While the current treatment options for elevated Lp(a) are limited, promising new therapies are under development, leading to renewed interest in Lp(a). This review provides an overview of the biology and epidemiology of Lp(a), available outcome studies, and insights into future therapies.


Assuntos
Doenças Cardiovasculares/sangue , Lipoproteína(a)/sangue , Biomarcadores/sangue , Remoção de Componentes Sanguíneos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus/sangue , Predisposição Genética para Doença , Humanos , Lipoproteína(a)/genética , Oligonucleotídeos Antissenso/uso terapêutico , Doença Arterial Periférica/sangue , Prevenção Primária , Medição de Risco , Prevenção Secundária , Acidente Vascular Cerebral/sangue
13.
Nucleic Acids Res ; 48(9): 5065-5080, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32249312

RESUMO

Disabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13-13.5 (E13-13.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Surdez/congênito , Surdez/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Vestíbulo do Labirinto/fisiopatologia , Âmnio , Animais , Limiar Auditivo/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Surdez/genética , Surdez/fisiopatologia , Orelha Interna/efeitos dos fármacos , Orelha Interna/metabolismo , Feto , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/ultraestrutura , Camundongos , Microinjeções , Mutação , Oligonucleotídeos Antissenso/administração & dosagem , Processamento de RNA/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos
14.
Yonsei Med J ; 61(4): 273-283, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32233169

RESUMO

The reduction of survival motor neuron (SMN) protein causes spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease. Nusinersen is an antisense oligonucleotide, approved by the FDA, which specifically binds to the repressor within SMN2 exon 7 to enhance exon 7 inclusion and augment production of functional SMN protein. Nusinersen is the first new oligonucleotide-based drug targeting the central nervous system for the treatment of SMA. This review of nusinersen will discuss its action mechanism, cellular uptake, trafficking mechanisms, and administration approaches to cross the blood-brain barrier. Furthermore, nusinersen clinical trials will be assessed in terms of pharmacokinetics, tolerability and safety, the clinical outcomes of multiple intrathecal doses, and a discussion on the primary and secondary endpoints.


Assuntos
Éxons/genética , Atrofia Muscular Espinal/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Barreira Hematoencefálica , Humanos , Atrofia Muscular Espinal/genética
15.
Nervenarzt ; 91(4): 303-311, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32179957

RESUMO

In Germany at least 8000 and probably up to ca. 14,000 people currently suffer from clinically manifest Huntington's disease (HD). In addition, an estimated 24,000 Germans carry the HD mutation in the huntingtin (HTT) gene and will develop HD during their lifetime. Although HD is a rare neurodegenerative disease, it is currently in the focus of general medical interest: clinical trials have begun that provide a rational basis for hope to slow down the so far relentless progression of the disease, ultimately resulting in patients becoming entirely dependent on nursing care. If treatment is started early enough it may be possible to mitigate the clinical manifestation of HD. These innovative therapeutic approaches aim at inhibiting the de novo production of mutant HTT gene products. A first clinical drug trial to demonstrate the efficacy (phase III) of intrathecal antisense oligonucleotides (ASO, active substance RG6042) was started in 2019. Additional clinical studies on alternative treatment approaches with allele-selective ASOs as well as gene therapeutic approaches using RNA molecules and zinc finger repressor complexes are imminent. This article gives an overview of the current gene-selective therapeutic approaches in HD under discussion.


Assuntos
Terapia Genética , Doença de Huntington , Ensaios Clínicos como Assunto , Terapia Genética/tendências , Alemanha , Humanos , Proteína Huntingtina/genética , Doença de Huntington/terapia , Oligonucleotídeos Antissenso/uso terapêutico
18.
Nervenarzt ; 91(4): 318-323, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32076754

RESUMO

Gene-specific treatment for hereditary muscle diseases has made great progress in recent years. The pathomechanisms of many of these diseases could be decrypted using molecular genetic techniques, paving the way for disease-modifying treatment options. A milestone was undoubtedly the successful translation of the antisense oligonucleotide (ASO) technology into clinical practice, with gene-specific ASOs being approved for the first time in 2016 for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy. This article reviews recent developments in the field of antisense and gene therapies for hereditary muscle diseases.


Assuntos
Terapia Genética , Doenças Musculares , Oligonucleotídeos Antissenso , Terapia Genética/tendências , Humanos , Atrofia Muscular Espinal/terapia , Doenças Musculares/genética , Doenças Musculares/terapia , Distrofia Muscular de Duchenne/terapia , Oligonucleotídeos Antissenso/uso terapêutico
19.
Nervenarzt ; 91(4): 287-293, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32076756

RESUMO

Amyotrophic lateral sclerosis (ALS) is monogenic in up to 10% of cases. Various mutation types result in a loss of function, a gain of toxicity or a combination of both. Due to the continuous development of gene-specific approaches, the treatment of the various ALS forms is no longer a dream. Depending on the underlying mutation type and pathomechanism, different antisense oligonucleotide (ASO)-based or viral strategies are available. The SOD1 and C9ORF72 genes are the most frequently mutated ALS genes in Germany and their mutations most likely predominantly lead to a gain of toxicity. For both genes, specific ASOs were developed binding to the respective mRNAs and leading to their degradation and are now being tested in clinical trials after excellent efficacy in the related ALS mouse models, with promising interim results. For the sporadic form of ALS there are also gene-specific approaches that compensate pathomechanisms and are a promising therapeutic option. In this article, gene-specific therapeutic developments in ALS as well as possible pitfalls and challenges are discussed in detail.


Assuntos
Esclerose Amiotrófica Lateral , Terapia Genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/terapia , Animais , Proteína C9orf72/genética , Modelos Animais de Doenças , Terapia Genética/tendências , Alemanha , Camundongos , Mutação , Oligonucleotídeos Antissenso/uso terapêutico , Superóxido Dismutase-1/genética
20.
Nervenarzt ; 91(4): 312-317, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32076757

RESUMO

The pathological hallmarks of Alzheimer's disease are aggregation and accumulation of amyloid-ß and tau proteins. So far most interventional studies have focused on the removal of the toxic protein products, such as antibody-based immunotherapies targeted against amyloid-ß and tau proteins; however, the development of gene therapies targeting gene products involved in the disease has opened up new therapeutic strategies to reduce the development of toxic protein aggregates by inhibiting the translation of pathological Alzheimer genes using antisense oligonucleotides (ASO). This has a timely influence on development of the disease. This article gives an overview of new advances in ASO-based treatment strategies for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Terapia Genética , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/genética , Terapia Genética/tendências , Humanos , Imunoterapia/tendências , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas tau/metabolismo
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