Insulin/IGF Signaling in Early Brain Development
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
Functional Insulin-like Growth Factor (IGF) is also expressed early in development and plays a significant role in the proper formation of the central nervous system (20). Both isoforms of IGF, referred to as IGF-1 and IGF-2, have varying roles in development and adulthood, promoting the growth and survival of neuronal cells through their respective receptors, IGF-1R and IGF-2R and the hybrid Insulin/IGF-1 receptor. Using bovine embryos, a protective effect- of IGF-1 was noted in the early developing embryo. However, due to the anti-apoptotic effects of IGF-1, it was indicated that IGF-1 may inhibit neurulation via the downregulation of specific genes involved in this process (25, 26). On the other hand, additional studies in vertebrates have yielded insights pertaining to IGF-2. Interestingly, IGF-2 is shown to have a high affinity and ability to signal through the IR-A isoform and points toward dynamic crosstalk of the two signaling pathways in early development (21, 27). In zebrafish, there are two co-orthologs of IGF2, igf2a and igf2b. Found primarily in and near the notochord, igf2a and igf2b, play a role in neurulation. The use of an oligomer molecule called a morpholino can decrease gene expression and morpholino-mediated knockdown of either igf2a or igf2b results in defects in dorsal midline development. This is highlighted by changes in the rate of segmentation, notochord undulations, ectopic fusion of the nephron primordia, defects in ventral forebrain development and increased ventral curvature.
Investigational Antiviral Drugs
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
AVI-7287 and AVI-7288 are positively charged antisense phosphorodiamidate morpholino oligomers (PMOplus), which target the viral nucleoprotein gene, thereby blocking viral RNA synthesis. These drugs are being developed for parenteral use, specifically for treatment or prevention of Ebola and Marburg virus infections, respectively. In a study of cynomolgus macaques experimentally infected with Marburg virus, none (0/6) of the placebo group survived whereas 83–100% of infected monkeys survived when AVI-7288 treatment was initiated 1, 24, 48, or 96 hours after infection. The antisense treatment also reduced virus load in plasma and inflammatory cytokines in all treatment groups compared to vehicle controls. Human phase I trials have been completed (NCT01566877) (Warren et al., 2016; Iversen et al., 2012; Heald et al., 2015).
Drug Discovery: From Hits to Clinical Candidates
Divya Vohora in The Third Histamine Receptor, 2008
To improve brain receptor occupancy, scientists at J&J PRD have pursued their search of novel H3 antagonists belonging to their established dibasic pharmacophore and investigated linker rigidification (see also section Recent Advance in H3 Receptor Ligand Computer-Aided Drug Design). Indeed, SAR around the conformational restricted iso-propyl piperidin-4-oxyphenyl framework provided highly potent H3 antagonists, as exemplified by compounds 48a (hH3 pKi 8.7; pA2 9.3) and 48b (hH3 pKi 9.2; pA2 9.9) [90, 91]. On the basis of previous investigations, the profile of morpholino derivative 48a (JNJ-7737782) was more detailed, with high selectivity on a panel of 50 targets (CEREP, <18% inhibition at 1 μM) but with a lower binding affinity for the rH3R (pKi 7.8). JNJ-7737782 has demonstrated in vivo efficacy in a rat Electroencephalogram (EEG) EEG model of wakefulness, supporting the therapeutic use of H3 antagonists in sleep/wake disorders and narcolepsy.
Murine models of dengue virus infection for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Alana B. Byrne, Cybele C. García, Elsa B. Damonte, Laura B. Talarico
Diverse agents that interact with a specific region of the viral genome were able to induce a partial or total downregulation of DENV expression [92]. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), possessing a backbone of morpholine rings and phosphonodiamidite inter-subunit linkages of 18–22 bases length designed against either the 5’ terminal portion (5ʹSL) or the 3’ cyclization-sequence (3ʹCS) of the DENV-2 genome, blocked translation by pairing to the viral mRNA. When tested early in infection of AG129 mice these PPMOs only extended the survival time up to 8 days [93]. Small interfering RNA (siRNA) is another approach to regulate gene expression by cleavage of a specific mRNA that was intended for DENV inhibition. An siRNA targeting the 5ʹCS of the capsid gene also induced extension of survival time in an AG129 model of ADE infection [94]. Furthermore, viral load in tissues and levels of TNF, a cytokine mediating early death in this animal model, were reduced.
Antisense Oligonucleotide Therapy for Ophthalmic Conditions
Published in Seminars in Ophthalmology, 2021
Kevin Ferenchak, Iris Deitch, Rachel Huckfeldt
The phosphodiester backbone of single-stranded RNA and AON can easily degrade in a cell, which limited the practical applications of antisense therapy for many years. Since they were first described, modifications have developed, which make AON viable in vivo with a longer half-life, more resistant to degradation, and more likely to be taken up by cells. These modifications include changes such as the first generation phosphorothioate (PS) backbone, which improved nuclear uptake.23 A phosphoramidate morpholino has been investigated to improve stability, but its viability may be limited by quicker clearance.24,25 Common second generation modifications are a 2ʹO-methoxy ethyl (2MOE) or 2ʹO-methyl (2OME) group attached to the sugar residues of the PS backbone, which further increase stability and cellular uptake.26,27
New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges
Published in Expert Review of Clinical Pharmacology, 2019
Federica Ricci, Martina Vacchetti, Chiara Brusa, Liliana Vercelli, Chiara Davico, Benedetto Vitiello, Tiziana Mongini
A number of other drug candidates based on proprietary RNA-based technology and phosphorodiamidate morpholino oligomer chemistry are currently under development [62]. A phase 3 trial is ongoing for golodirsen, able to skip exon 53 (about 10% of DMD patients [63]), and casimersen for exon 45 skipping (about 9% of DMD patients [63]) (NCT02500381) [64]. A phase 2 trial on antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 (NCT02740972) showed favorable safety profile [65] and an open-label extension is now ongoing (NCT03167255). In December 2018, a biotechnology company announced that the safety and tolerability results of a phase 1 trial of suvodirsen, a high efficacy stereopure oligonucleotide, in DMD boys amenable to exon 51 skipping, supported the initiation of a phase 2/3 placebo-controlled efficacy and safety clinical trial (NCT03907072) [18]. More recently, however, additional data released by the company on the phase 1 trial show severe adverse events at high doses.
Related Knowledge Centers
- Gene Expression
- Gene Knockdown
- Molecular Biology
- Molecular Geometry
- Molecule
- Oligomer
- Rna
- Phosphoramidate
- Rna
- Reverse Genetics
- Nucleic Acid Analogue