China
Africa
Explore chapters and articles related to this topic
Conventional and Molecular Cytogenetics of Ph-Negative Chronic Myeloproliferative Disorders
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Gene expression profiling as well as array CGH can identify candidate disease-specific gene(s) and molecular signature to aid in the diagnosis in addition to the pathophysiology of disease development. Some glimpses into the genes involved in the pathogenesis of PV were provided by microarray studies on isolated mature granulocytes or isolated CD34+ cells from over 70 PV patients using different platforms (64,65). Although different groups of genes were found upregulated and downregulated, so far the best analysis include nine genes that can distinguish PV patients from normal controls and they include: RNASE6, IRF8, MCL1, INHBC, SNRPE, KLF4, KLF2, ILF2, TRGV9, and LY86 (66). Many of these genes
Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Nidhi Jyotsana, Michael Heuser
Bifunctional oligonucleotides are hybrid ASOs that are linked to an additional binding or peptide sequence [124] to recruit specific splicing factors, which may enhance or suppress splicing [125]. Examples are exon-specific splicing enhancement by small chimeric effectors (ESSENCE), which are bifunctional reagents with a peptide effector domain and an antisense target domain mimicking the effect of SR proteins [126], and targeted oligonucleotide enhancer of splicing (TOES), which are bifunctional oligos that bind to SR proteins to induce exon inclusion [124,127]. For example, a bifunctional ASO was linked to a 2ʹdeoxy-2ʹfluoro nucleotide to recruit the interleukin enhancer binding factor 2/3 (ILF2/3) protein, that prevents the recruitment of hnRNP at that site. Administration of this 2ʹdeoxy-2ʹfluoro ASO at doses of 50 mg/kg body weight every 2nd day for 4 times resulted in increased transcripts that included exon 7 of SMN2 restoring SMN protein levels in spinal muscular atrophy [128].
Chromosomal 1q21 abnormalities in multiple myeloma: a review of translational, clinical research, and therapeutic strategies
Published in Expert Review of Hematology, 2021
Kamlesh Bisht, Brian Walker, Shaji K. Kumar, Ivan Spicka, Philippe Moreau, Tom Martin, Luciano J. Costa, Joshua Richter, Taro Fukao, Sandrine Macé, Helgi van de Velde
In the 1q21 amplicon, several genes have been associated with aggressive phenotypes (Figure 3) including CKS1B (associated with G1-S transition), PSMD4 (resistance to PI), ANP32E (epigenetic regulation), IL6R (promotion of cell growth), ADAR and ILF2 (RNA metabolism), MCL-1 (apoptosis control), those encoding SLAM family molecules, FCRL5 (encoding FcRH5), and CD1D (cluster differentiation 1D) [10,38,86,119]. Therapeutic targeting of candidate genes in the 1q21 amplicon might benefit patients who do not respond to current treatment [10].
Next steps for the optimization of exon therapy for Duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2023
Galina Filonova, Annemieke Aartsma-Rus
Wave Life Sciences in collaboration with Matthew Wood’s research group continues to investigate the effectiveness of the stereopure PS backbone. They synthesized and tested chimeric stereopure AONs with various 2OMe and 2’ F modification patterns. For the splice modulation approach for spinal muscular atrophy, it was shown that 2’ F-modified AONs forming a duplex with target pre-mRNA recruit interleukin enhancer-binding factors 2 and 3 (ILF2/3 proteins) and enhance alternative splicing of target transcripts [26]. Previously 2’ F technology was shown to enhance the effectiveness of AONs in DMD exon skipping in vitro, while AONs in vivo tolerability depended on the position of the 2’ F modification [27,28]. In addition to the 2’ F chemistry, the impact of phosphoryl guanidine (PN) linkages on the effectiveness of AONs with stereopure PS backbone was tested. Compared to PS linkages, neutral PN linkages reduce the overall charge of an oligonucleotide and are more resistant to the nuclease degradation [29]. Experiments showed that oligonucleotides comprising defined 2OMe and 2’ F patterns were well tolerated and more efficient compared to AONs with 2OMe modification only. While the focus of Wave Life Sciences is on their stereopure technology, it is likely that the increased efficiency they see in vitro and in vivo is also or primarily due to the 2’ F and PN modifications. AONs with PN linkages in clinically relevant doses increased dystrophin protein production in the diaphragm and heart and improved survival and respiratory functions in mdx/utrophin double knockout (dKO) mice with severe phenotype. In addition, exon skipping activity was improved in AONs with PN and stereopure PS compared to PN and stereorandom PS, suggesting that controlling stereochemistry allows to improve AONs effectiveness [29]. In September 2021 Wave Life Sciences initiated phase 1b/2a clinical trial of a stereopure oligonucleotide with PN backbone chemistry modification for exon 53 skipping (WVE-531) (https://clinicaltrials.gov/ct2/show/NCT04906460). The trial will evaluate the safety and tolerability of four escalating doses of WVE-531 [30].