Patisiran for the treatment of patients with familial amyloid
polyneuropathy

Rizk, Malak

doi:10.1358/dot.2019.55.5.2958475

Cited by 10 publications

(8 citation statements)

References 0 publications

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“…While this is unachievable currently with small molecule inhibitors due to the untargetable nature of this unstructured protein, efficient genetic downregulation of BRD4-NUT is accomplished through siRNA knockdown of NUT 7 , 10 . Until recently, this was not a viable approach in vivo, but the development of lipid nanoparticles (LNP) has led to the FDA approval of an siRNA-based approach to treating hereditary ATTR amyloidosis 111 . This technological breakthrough may provide the groundwork for this approach in NC.…”

Section: Future Directionsmentioning

confidence: 99%

Supercharging BRD4 with NUT in carcinoma

Eagen

French

2021

Oncogene

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NUT carcinoma (NC) is an extremely aggressive squamous cancer with no effective therapy. NC is driven, most commonly, by the BRD4-NUT fusion oncoprotein. BRD4-NUT combines the chromatin-binding bromo- and extraterminal domain-containing (BET) protein, BRD4, with an unstructured, poorly understood protein, NUT, which recruits and activates the histone acetyltransferase (HAT) p300. Recruitment of p300 to chromatin by BRD4 is believed to lead to the formation of hyperacetylated nuclear foci, as seen by immunofluorescence. BRD4-NUT nuclear foci correspond with massive contiguous regions of chromatin co-enriched with BRD4-NUT, p300, and acetylated histones, termed ‘megadomains’ (MD). Megadomains stretch for as long as 2 MB. Proteomics has defined a BRD4-NUT chromatin complex in which members that associate with BRD4 also exist as rare NUT-fusion partners. This suggests that the common pathogenic denominator is the presence of both BRD4 and NUT, and that the function of BRD4-NUT may mimic that of wild-type BRD4. If so, then MDs may function as massive super-enhancers, activating transcription in a BET-dependent manner. Common targets of MDs across multiple NCs and tissues are three stem cell-related transcription factors frequently implicated in cancer: MYC , SOX2 , and TP63 . Recently, MDs were found to form a novel nuclear sub-compartment, called subcompartment M (subM), where MD-MD interactions occur both intra- and inter-chromosomally. Included in subM are MYC , SOX2 , and TP63 . Here we explore the possibility that if MDs are simply large super-enhancers, subM may exist in other cell systems, with broad implications for how 3D organization of the genome may function in gene regulation and maintenance of cell identity. Finally, we discuss how our knowledge of BRD4-NUT function has been leveraged for the therapeutic development of first-in-class BET inhibitors and other targeted strategies.

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Section: Future Directionsmentioning

confidence: 99%

Supercharging BRD4 with NUT in carcinoma

Eagen

French

2021

Oncogene

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“…Currently, no miRNA-based therapeutics for MDS and sAML are available. However, it is encouraging that the first small-interfering RNA (siRNA) drug Onpattro ® (patisiran), a therapy for the rare hereditary disease transthyretin-mediated amyloidosis in adult patients, was approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [ 196 , 197 ]. Furthermore, a number of miRNA vaccine therapies are currently in the clinical development or in phase I/II trials, while others were halted due to severe side effects [ 159 ].…”

Section: Therapeutic Possibilities Of Mirnas In Mds and Samlmentioning

confidence: 99%

Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins

Bauer

Vaxevanis

Heimer

et al. 2020

IJMS

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Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies.

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“…Lipid nanocarriers are some of the most promising nonviral tools for gene therapy. Currently, the only medicine approved by the FDA and European Medicines Agency (EMA) that uses nanostructures to deliver RNA is Onpattro ® (mentioned in section “Small Interfering RNAs (siRNAs)”); Onpattro ® is a lipid nanoparticle-based drug product that transports patisiran, an siRNA molecule for the treatment of TTR amyloidosis ( Rizk and Tuzmen, 2019 ).…”

Section: Nanomedicinementioning

confidence: 99%

Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease

et al. 2020

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Alternative splicing of pre-mRNA contributes strongly to the diversity of cell- and tissue-specific protein expression patterns. Global transcriptome analyses have suggested that >90% of human multiexon genes are alternatively spliced. Alterations in the splicing process cause missplicing events that lead to genetic diseases and pathologies, including various neurological disorders, cancers, and muscular dystrophies. In recent decades, research has helped to elucidate the mechanisms regulating alternative splicing and, in some cases, to reveal how dysregulation of these mechanisms leads to disease. The resulting knowledge has enabled the design of novel therapeutic strategies for correction of splicing-derived pathologies. In this review, we focus primarily on therapeutic approaches targeting splicing, and we highlight nanotechnology-based gene delivery applications that address the challenges and barriers facing nucleic acid-based therapeutics.

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Patisiran for the treatment of patients with familial amyloid polyneuropathy

Cited by 10 publications

References 0 publications

Supercharging BRD4 with NUT in carcinoma

Supercharging BRD4 with NUT in carcinoma

Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins

Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease

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