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1.
Int J Mol Sci ; 25(9)2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38732027

RESUMO

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.


Assuntos
Doença dos Neurônios Motores , Oligonucleotídeos Antissenso , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/terapia , Animais , Atrofia Muscular Espinal/terapia , Atrofia Muscular Espinal/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia
2.
Cells ; 13(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38607040

RESUMO

Precision medicine is rapidly gaining recognition in the field of (ultra)rare conditions, where only a few individuals in the world are affected. Clinical trial design for a small number of patients is extremely challenging, and for this reason, the development of N-of-1 strategies is explored to accelerate customized therapy design for rare cases. A strong candidate for this approach is Stargardt disease (STGD1), an autosomal recessive macular degeneration characterized by high genetic and phenotypic heterogeneity. STGD1 is caused by pathogenic variants in ABCA4, and amongst them, several deep-intronic variants alter the pre-mRNA splicing process, generally resulting in the insertion of pseudoexons (PEs) into the final transcript. In this study, we describe a 10-year-old girl harboring the unique deep-intronic ABCA4 variant c.6817-713A>G. Clinically, she presents with typical early-onset STGD1 with a high disease symmetry between her two eyes. Molecularly, we designed antisense oligonucleotides (AONs) to block the produced PE insertion. Splicing rescue was assessed in three different in vitro models: HEK293T cells, fibroblasts, and photoreceptor precursor cells, the last two being derived from the patient. Overall, our research is intended to serve as the basis for a personalized N-of-1 AON-based treatment to stop early vision loss in this patient.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Oligonucleotídeos Antissenso , Humanos , Feminino , Criança , Doença de Stargardt/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Células HEK293 , Íntrons , Transportadores de Cassetes de Ligação de ATP/genética
3.
Artigo em Russo | MEDLINE | ID: mdl-38676690

RESUMO

Before the advent of pathogenetic therapy, the diagnosis of spinal muscular atrophy (SMA) meant the loss of all hopes for recovery and the patient's setting on the path of a steady decline in motor functions, a deterioration in the quality of life and, ultimately, inevitable early death. Currently, new methods of pathogenetic therapy with nusinersen and risdiplam, as well as etiological therapy with onasemnogene abeparvovec, are available in the Russia. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN2 gene to increase production of normal full-length motor neuron survival protein, which is deficient in SMA. The mechanism of action of Nusinersen is based on the activation of the disabled exon 7 of the SMN2 gene. The article describes an example of long-term effective treatment using pathogenetic therapy of a patient diagnosed with SMA type 3.


Assuntos
Oligonucleotídeos , Atrofias Musculares Espinais da Infância , Proteína 2 de Sobrevivência do Neurônio Motor , Humanos , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Atrofias Musculares Espinais da Infância/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Resultado do Tratamento , Masculino , Oligonucleotídeos Antissenso/uso terapêutico
4.
Lakartidningen ; 1212024 Apr 26.
Artigo em Sueco | MEDLINE | ID: mdl-38666665

RESUMO

We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.


Assuntos
Esclerose Lateral Amiotrófica , Progressão da Doença , Terapia Genética , Superóxido Dismutase-1 , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/terapia , Superóxido Dismutase-1/genética , Masculino , Pessoa de Meia-Idade , Mutação , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos/administração & dosagem
5.
Nature ; 628(8009): 818-825, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38658687

RESUMO

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.


Assuntos
Transtorno Autístico , Síndrome do QT Longo , Oligonucleotídeos Antissenso , Sindactilia , Animais , Feminino , Humanos , Masculino , Camundongos , Processamento Alternativo/efeitos dos fármacos , Processamento Alternativo/genética , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/genética , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo L/genética , Movimento Celular/efeitos dos fármacos , Dendritos/metabolismo , Éxons/genética , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/genética , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Organoides/efeitos dos fármacos , Organoides/metabolismo , Prosencéfalo/metabolismo , Prosencéfalo/citologia , Sindactilia/tratamento farmacológico , Sindactilia/genética , Interneurônios/citologia , Interneurônios/efeitos dos fármacos
6.
Int J Mol Sci ; 25(6)2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38542364

RESUMO

Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 PRPF31. The expression level of PRPF31 is linked to incomplete penetrance in affected families; mutation carriers with higher PRPF31 expression can remain asymptomatic. The current study explores an antisense oligonucleotide exon skipping strategy to treat RP11 caused by truncating mutations within PRPF31 exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a PRPF31 1205C>A nonsense mutation were investigated; PRPF31 transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in PRPF31 mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold PRPF31 mRNA upregulation in the RP11 patient fibroblasts. The level of PRPF31 upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased PRPF31 expression and retention of the nuclear translocation capability for the induced PRPF31 isoform. Future studies should evaluate the function of the induced PRPF31 protein on pre-mRNA splicing in retinal cells to validate the therapeutic approach for amenable RP11-causing mutations.


Assuntos
Oligonucleotídeos Antissenso , Precursores de RNA , Retinose Pigmentar , Humanos , Precursores de RNA/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Fases de Leitura Aberta , Mutação , Códon sem Sentido , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Linhagem
7.
Atherosclerosis ; 391: 117492, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38461759

RESUMO

BACKGROUND AND AIMS: Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. We reported that deficiency of Serum Amyloid A (SAA) significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. The aim of this study is to investigate whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice. METHODS: Male C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with AngII until the end of the study. Mice with at least a 25% increase in the luminal diameter of the abdominal aorta after 4 weeks of AngII infusion were stratified into 2 groups. The first group received a control antisense oligonucleotide (Ctr ASO), and the second group received ASO that suppresses SAA (SAA-ASO) until the end of the study. RESULTS: Plasma SAA levels were significantly reduced by the SAA ASO treatment. While mice that received the control ASO had continued aortic dilation throughout the AngII infusion periods, the mice that received SAA-ASO had a significant reduction in the progression of aortic dilation, which was associated with significant reductions in matrix metalloprotease activities, decreased macrophage infiltration and decreased elastin breaks in the abdominal aortas. CONCLUSIONS: We demonstrate for the first time that suppression of SAA protects obese C57BL/6 mice from the progression of AngII-induced AAA. Suppression of SAA may be a therapeutic approach to limit AAA progression.


Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Humanos , Masculino , Animais , Camundongos , Angiotensina II/farmacologia , Proteína Amiloide A Sérica/genética , Oligonucleotídeos Antissenso/uso terapêutico , Camundongos Endogâmicos C57BL , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/prevenção & controle , Aorta Abdominal , Obesidade , Modelos Animais de Doenças , Camundongos Knockout , Apolipoproteínas E
8.
J Lipid Res ; 65(3): 100514, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38309418

RESUMO

Human genetic evidence suggests a protective role of loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) for liver fibrotic diseases. Although there is limited preclinical experimental data on Hsd17b13 antisense oligonucleotide (ASO) or siRNA in a fibrosis model, several ASO and siRNA approaches are being tested clinically as potential therapies for nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the therapeutic potential of Hsd17b13 ASO in a preclinical advanced NASH-like hepatic fibrosis in vivo model. In vitro testing on primary hepatocytes demonstrated that Hsd17b13 ASO exhibited strong efficacy and specificity for knockdown of the Hsd17b13 gene. In choline-deficient, L-amino acid-defined, HFD (CDAHFD)-induced steatotic and fibrotic mice, therapeutic administration of Hsd17b13 ASO resulted in a significant and dose-dependent reduction of hepatic Hsd17b13 gene expression. The CDAHFD group exhibited considerably elevated liver enzyme levels, hepatic steatosis score, hepatic fibrosis, and increased fibrotic and inflammatory gene expression, indicating an advanced NASH-like hepatic fibrosis phenotype. Although Hsd17b13 ASO therapy significantly affected hepatic steatosis, it had no effect on hepatic fibrosis. Our findings demonstrate, for the first time, that Hsd17b13 ASO effectively suppressed Hsd17b13 gene expression both in vitro and in vivo, and had a modulatory effect on hepatic steatosis in mice, but did not affect fibrosis in the CDAHFD mouse model of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Modelos Animais de Doenças , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/metabolismo
9.
Curr Atheroscler Rep ; 26(4): 111-118, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38311667

RESUMO

PURPOSE OF REVIEW: Lipoprotein(a) is an important causal risk factor for cardiovascular disease but currently no available medication effectively reduces lipoprotein(a). This review discusses recent findings regarding lipoprotein(a) as a causal risk factor and therapeutic target in cardiovascular disease, it reviews current clinical recommendations, and summarizes new lipoprotein(a) lowering drugs. RECENT FINDINGS: Epidemiological and genetic studies have established lipoprotein(a) as a causal risk factor for cardiovascular disease and mortality. Guidelines worldwide now recommend lipoprotein(a) to be measured once in a lifetime, to offer patients with high lipoprotein(a) lifestyle advise and initiate other cardiovascular medications. Clinical trials including antisense oligonucleotides, small interfering RNAs, and an oral lipoprotein(a) inhibitor have shown great effect on lowering lipoprotein(a) with reductions up to 106%, without any major adverse effects. Recent clinical phase 1 and 2 trials show encouraging results and ongoing phase 3 trials will hopefully result in the introduction of specific lipoprotein(a) lowering drugs to lower the risk of cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Lipoproteína(a) , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Lipoproteína(a)/efeitos dos fármacos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Oligonucleotídeos Antissenso/uso terapêutico , Fatores de Risco
10.
Mol Cancer ; 23(1): 40, 2024 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-38383439

RESUMO

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.


Assuntos
Melanoma , RNA Longo não Codificante , Humanos , Camundongos , Animais , Melanoma/patologia , RNA Longo não Codificante/genética , Apoptose/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Linhagem Celular Tumoral , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo
11.
Nat Commun ; 15(1): 1880, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424098

RESUMO

Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5' splice site sequences, suggest that branaplam recognizes 5' splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.


Assuntos
Atrofia Muscular Espinal , Pirimidinas , Splicing de RNA , Humanos , Splicing de RNA/genética , Compostos Azo , Oligonucleotídeos/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Sítios de Splice de RNA , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética
12.
Curr Opin Endocrinol Diabetes Obes ; 31(2): 70-77, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38334488

RESUMO

PURPOSE OF REVIEW: The aim of this review is to present the clinical indications of apolipoprotein C-III (apoC3) inhibition in the therapeutic arsenal for the treatment of lipid disorders and associated risks and to compare the most advanced modalities of apoC3 inhibition currently available or in development, specifically APOC3 antisense oligonucleotides (ASO) and small interfering RNA (siRNA). RECENT FINDINGS: ApoC3 inhibition significantly decreases triglyceride levels by mechanisms coupling both lipoprotein lipase (LPL) upregulation and LPL-independent mechanisms. The main apoC3 inhibitors in advanced clinical development are the GalNAc-ASO olezarsen and the GalNAc-siRNA plozasiran. Clinical studies conducted with volanesorsen, the olezarsen precursor, showed a favorable effect on hepatic steatosis (nonalcoholic fatty liver disease, NAFLD). Olezarsen does not appear to be associated with the main side effects attributed to volanesorsen including thrombocytopenia. Plozasiran is in advanced clinical development and requires subcutaneous injection every 3 months and present to-date an efficacy and safety profile comparable to that of the monthly ASO. SUMMARY: Inhibition of apoC3 is effective across all the spectrum of hypertriglyceridemia, might have a favorable effect on hepatic steatosis (NAFLD) and the effect of apoC3 inhibition on cardiovascular risk is not limited to its effect on plasma triglycerides. APOC3 GalNAc-conjugated ASO and siRNA are both effective in decreasing plasma apoC3 and triglyceride levels.


Assuntos
Dislipidemias , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Apolipoproteína C-III/genética , Oligonucleotídeos Antissenso/uso terapêutico , Triglicerídeos , Dislipidemias/genética , Dislipidemias/terapia
13.
Mol Ther ; 32(4): 935-951, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38327047

RESUMO

Angelman syndrome (AS), an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal allele of the UBE3A gene is disrupted, since the paternal allele is silenced in neurons by the UBE3A antisense (UBE3A-AS) transcript. Given the importance of early treatment, we hypothesized that prenatal delivery of an antisense oligonucleotide (ASO) would downregulate the murine Ube3a-AS, resulting in increased UBE3A protein and functional rescue. Using a mouse model with a Ube3a-YFP allele that reports on-target ASO activity, we found that in utero, intracranial (IC) injection of the ASO resulted in dose-dependent activation of paternal Ube3a, with broad biodistribution. Accordingly, in utero injection of the ASO in a mouse model of AS also resulted in successful restoration of UBE3A and phenotypic improvements in treated mice on the accelerating rotarod and fear conditioning. Strikingly, even intra-amniotic (IA) injection resulted in systemic biodistribution and high levels of UBE3A reactivation throughout the brain. These findings offer a novel strategy for early treatment of AS using an ASO, with two potential routes of administration in the prenatal window. Beyond AS, successful delivery of a therapeutic ASO into neurons has implications for a clinically feasible prenatal treatment for numerous neurodevelopmental disorders.


Assuntos
Síndrome de Angelman , Animais , Camundongos , Síndrome de Angelman/terapia , Síndrome de Angelman/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Distribuição Tecidual , Encéfalo/metabolismo , Fenótipo , Ubiquitina-Proteína Ligases/genética , Modelos Animais de Doenças
14.
Mutagenesis ; 39(3): 157-171, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38332115

RESUMO

The therapeutic potential of the human genome has been explored through the development of next-generation therapeutics, which have had a high impact on treating genetic disorders. Classical treatments have traditionally focused on common diseases that require repeated treatments. However, with the recent advancements in the development of nucleic acids, utilizing DNA and RNA to modify or correct gene expression in genetic disorders, there has been a paradigm shift in the treatment of rare diseases, offering more potential one-time cure options. Advanced technologies that use CRISPR-Cas 9, antisense oligonucleotides, siRNA, miRNA, and aptamers are promising tools that have achieved successful breakthroughs in the treatment of various genetic disorders. The advancement in the chemistry of these molecules has improved their efficacy, reduced toxicity, and expanded their clinical use across a wide range of tissues in various categories of human disorders. However, challenges persist regarding the safety and efficacy of these advanced technologies in translating into clinical practice. This review mainly focuses on the potential therapies for rare genetic diseases and considers how next-generation techniques enable drug development to achieve long-lasting curative effects through gene inhibition, replacement, and editing.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Doenças Genéticas Inatas , Terapia Genética , Doenças Raras , Humanos , Doenças Raras/genética , Doenças Raras/terapia , Edição de Genes/métodos , Terapia Genética/métodos , Doenças Genéticas Inatas/terapia , Doenças Genéticas Inatas/genética , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , RNA Interferente Pequeno/genética , MicroRNAs/genética , Aptâmeros de Nucleotídeos/uso terapêutico
15.
Pharmacol Res ; 201: 107083, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38309383

RESUMO

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.


Assuntos
Diabetes Mellitus Tipo 2 , Cardiopatias , Doenças Metabólicas , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/genética , Oligonucleotídeos Antissenso/uso terapêutico
16.
Prog Mol Biol Transl Sci ; 203: 181-196, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38359998

RESUMO

The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.


Assuntos
Neuropatias Amiloides Familiares , Oligonucleotídeos Antissenso , Oligonucleotídeos , Humanos , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , RNA Mensageiro
17.
Prog Mol Biol Transl Sci ; 203: 41-63, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38360005

RESUMO

RNA therapy is one of the new treatments using small RNA molecules to target and regulate gene expression. It involves the application of synthetic or modified RNA molecules to inhibit the expression of disease-causing genes specifically. In other words, it silences genes and suppresses the transcription process. The main theory behind RNA therapy is that RNA molecules can prevent the translation into proteins by binding to specific messenger RNA (mRNA) molecules. By targeting disease-related mRNA molecules, RNA therapy can effectively silence or reduce the development of harmful proteins. There are different types of RNA molecules used in therapy, including small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamer, ribozyme, and antisense oligonucleotides (ASOs). These molecules are designed to complement specific mRNA sequences, allowing them to bind and degrade the targeted mRNA or prevent its translation into protein. Nanotechnology is also highlighted to increase the efficacy of RNA-based drugs. In this chapter, while examining various methods of RNA therapy, we discuss the advantages and challenges of each.


Assuntos
MicroRNAs , Humanos , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , RNA Mensageiro/genética
18.
Prog Mol Biol Transl Sci ; 203: 99-114, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38360008

RESUMO

Ribonucleic acid (RNA) therapeutics have significantly used RNA-based drugs to the prevention and treatment of diseases as effective messenger RNA-based vaccines in response to the COVID-19 pandemic. The RNA therapeutics with five classes including antisense oligonucleotide, small interfering RNA, microRNA, APTAMER and messenger RNAs are being quickly developed to treat various human diseases as neurological disease, cardiovascular disease, genetic and rare disease, cancer disease, coronavirus disease… which cannot be treated by other conventional drugs as small molecule-based drugs and antibodies. Therefore, the discovery of these RNA therapeutics created a new avenue for treatment of various human diseases. This chapter demonstrates the history of important discoveries in RNA biology and their impact on key developments in RNA therapeutics as well as the advantages of RNA therapeutics; RNA therapeutics describes the action mechanisms and examples of RNA-based drugs approved for treatment of various disease; and RNA therapeutics discusses delivery methods for RNA therapeutics to target organs and cells. In conclusion, this chapter is designed to offer an updated important development and advance of RNA therapeutics for the prevention and treatment of various human diseases.


Assuntos
MicroRNAs , RNA , Humanos , Pandemias , MicroRNAs/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Mensageiro
19.
Prog Mol Biol Transl Sci ; 203: 245-256, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38360001

RESUMO

The excretory system is responsible for removing wastes from the human body, which plays a crucial role in our lives. Current treatments for diseases related to this system have shown several limitations; therefore, there is a rising need for novel methods. In this circumstance, RNA-based therapeutics have rapidly emerged as new and promising candidates. In fact, to date, a handful of potential drugs have passed the development step and entered the clinical pipeline. Among them, one drug received FDA approval to enter the global market, which is Oxlumo (Lumasiran) for the treatment of primary hyperoxaluria type 1. For other excretory diseases, such as paroxysmal nocturnal hemoglobinuria, urothelial cancer or renal cancer, RNA-based candidates are also being tested under clinical trials. Currently, the most potential types of RNA therapeutics to treat disorders of the excretory system are those based on small interfering RNA (siRNA), antisense oligonucleotides (ASO) and messenger RNA (mRNA), Among them, siRNA therapeutics seem to be the most promising, including Oxlumo and two other developing drug candidates. This chapter will provide a general overview on the application of RNA therapeutics in disorders of the excretory system.


Assuntos
Oligonucleotídeos Antissenso , Humanos , RNA Interferente Pequeno/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Mensageiro
20.
Trends Mol Med ; 30(3): 252-262, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38216448

RESUMO

Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/terapia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Splicing de RNA
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