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12. Antisense oligonucleotides for dominantly inherited hearing impairment DFNA9: from cells models to humanized mice.

Author

Aben, F., Verdoodt, D., de Bruijn, S., Oostrik, J., Venselaar, H., Sels, L., De Backer, E., Gommeren, H., Szewczyk, K., Van Camp, G., Ponsaerts, P., Van Rompaey, V., van Wijk, E., and de Vrieze, E.

Subjects
BIOLOGICAL models, CONFERENCES & conventions, NUCLEOTIDES, MICE, ANIMAL experimentation, HEARING disorders, GENETIC mutation
Abstract

The c.151C>T (p.P51S) mutation in COCH is highly prevalent in the Dutch/Belgian population and causes DFNA9 (hearing loss and vestibular dysfunction) in > 1500 individuals. The initial symptoms manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The clear non-haploinsufficiency disease mechanism indicates that blocking or reducing the p.P51S mutant cochlin protein levels may alleviate or prevent the DFNA9 phenotypes. Considering the broad expression of COCH by the fibrocytes of the inner ear, we designed "gapmer" antisense oligonucleotides (ASO) to specifically induce RNase H1-mediated degradation of COCH transcripts containing the c.151C>T mutation. We established several model systems to investigate the molecular efficacy of ASOs targeting the c. 151C>T mutation or low-frequency mutant allele-specific SNPs. Using overexpression models, we identified several ASOs that efficiently induce the degradation of mutant COCH transcripts. By introducing chemical modification to the oligonucleotide bases, we can alter the affinity and selectivity for the mutation transcript. We identified several ASOs with a strong preference for the mutant transcript in overexpression models. To investigate allele-specificity under physiological expression levels, we exposed patient-derived otic progenitor cells (iPCS-OPCs) to different ASOs for 8 days. In parallel, we developed a genetically humanized mouse model for DFNA9 in which human sequence-specific therapeutic strategies can be evaluated. Phenotypic follow-up of mice of all genotypes indicate that the genetic humanization has no adverse effects, and removal of the Cdh23ahl allele is mandatory to observe the late-onset auditory phenotype: the first signs of high-frequency hearing loss emerged at 12 months of age. Studies in iPSC-OPCs indicated that the ASOs identified in overexpression studies also effectively reduce mutant COCH transcript levels in patient-derived cells with physiological expression levels. Unfortunately, variation between replicate wells of OPC differentiation is relatively high, making it difficult to draw conclusions on allele-specificity. We selected a candidate ASO, directed against a rare mutant allele-spe-cific intronic SNP, for subsequent studies in our humanized mouse model. First intracochlear injections will be conducted in May 2024, after which we can collect the first in vivo data on gapmer ASO uptake and efficacy in fibrocytes of the mammalian inner ear. [ABSTRACT FROM AUTHOR]

Published
2024

13. Impact of aortic regurgitation on long-term outcomes in heart failure with preserved ejection fraction

Author

De Colle, C, primary, Paolisso, P, additional, Gallinoro, E, additional, Bertolone, D T, additional, Mileva, N, additional, Fabbricatore, D, additional, Valeriano, C, additional, Mancusi, C, additional, Collet, C, additional, Vanderheyden, M, additional, De Luca, N, additional, Van Camp, G, additional, Barbato, E, additional, Bartunek, J, additional, and Penicka, M, additional

Published
2022
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18. Performance of non-invasive myocardial work to predict the first hospitalization for de novo heart failure with preserved ejection fraction (HFpEF)

Author

Paolisso, P, primary, Gallinoro, E, additional, Mileva, N, additional, Moya, A, additional, Fabbricatore, D, additional, Esposito, G, additional, De Colle, C, additional, Spapen, J, additional, Heggermont, W, additional, Collet, C, additional, Van Camp, G, additional, Vanderheyden, M, additional, Barbato, E, additional, Bartunek, J, additional, and Penicka, M, additional

Published
2022
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21. Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats

Author

Verhaeghe, R. (Remy), Gao, V. (Vance), MORLEY-FLETCHER, S. (Sara), Bouwalerh, H. (Hammou), Van Camp, G. (Gilles), Cisani, F. (Francesca), Nicoletti, F. (Ferdinando), Maccari, S. (Stefania), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], and Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Subjects
Early life stress, Sex differences, Brain aging, Behaviors, Hormones
Abstract

Brain aging may be programmed by early-life stress. Aging affects males and females differently, but how perinatal stress (PRS) affects brain aging between sexes is unknown. We showed behavioral and neurobiological sex differences in non-stressed control rats that were strongly reduced or inverted in PRS rats. In particular, PRS decreased risk-taking behavior, spatial memory, exploratory behavior, and fine motor behavior in male aged rats. In contrast, female aged PRS rats displayed only increased risk-taking behavior and reduced exploratory behavior. PRS induced large reductions in the expression of glutamate receptors in the ventral and dorsal hippocampus and prefrontal cortex only in male rats. PRS also reduced the expression of synaptic vesicle-associated proteins, glucocorticoid receptors (GR), and mineralocorticoid receptors (MR) in the ventral hippocampus of aged male rats. In contrast, in female aged rats, PRS enhanced the expression of MRs and brain-derived neurotrophic factor (BDNF) in the ventral hippocampus and the expression of glial fibrillary acidic protein (GFAP) and BDNF in the prefrontal cortex. A common PRS effect in both sexes was a reduction in exploratory behavior and metabotropic glutamate (mGlu2/3) receptors in the ventral hippocampus and prefrontal cortex. A multidimensional analysis revealed that PRS induced a demasculinization profile in glutamate-related proteins in the ventral and dorsal hippocampus and prefrontal cortex, as well as a demasculinization profile of stress markers only in the dorsal hippocampus. In contrast, defeminization was observed only in the ventral hippocampus. Measurements of testosterone and 17-β-estradiol in the plasma and aromatase in the dorsal hippocampus were consistent with a demasculinizing action of PRS. These findings confirm that the brains of males and females differentially respond to PRS and aging suggesting that females might be more protected against early stress and age-related inflammation and neurodegeneration. Taken together, these results may contribute to understanding how early environmental factors shape vulnerability to brain aging in both sexes and may lay the groundwork for future studies aimed at identifying new treatment strategies to improve the quality of life of older individuals, which is of particular interest given that there is a high growth of aging in populations around the world.

Published
2021

28. Maternal stress programs accelerated aging of the basal ganglia motor system in offspring

Author

Marrocco, J., Verhaeghe, R., Bucci, D., Di Menna, L., Traficante, A., Bouwalerh, H., Van Camp, G., Ghiglieri, V., Picconi, B., Calabresi, P., Ravasi, L., Cisani, F., Bagheri, F., Pittaluga, A., Bruno, V., Battaglia, G., Morley-Fletcher, S., Nicoletti, F., Maccari, S., Rockefeller University [New York], Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Pharmacologie de la mort neuronale et de la plasticité cérébrale, IFR114-Université de Lille, Droit et Santé, Université de Genève (UNIGE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Istituto Neurologico Mediterraneo [NEUROMED I.R.C.C.S.], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], and Université de Genève = University of Geneva [UNIGE]

Subjects
Aging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nigrostriatal development, Motor behavior, Adenosine receptors, Synaptic proteins, Integrated study, lcsh:QP351-495, lcsh:RC346-429, lcsh:RC321-571, Settore MED/26 - NEUROLOGIA, lcsh:Neurophysiology and neuropsychology, Original Research Article, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system
Abstract

Early-life stress involved in the programming of stress-related illnesses can have a toxic influence on the functioning of the nigrostriatal motor system during aging. We examined the effects of perinatal stress (PRS) on the neurochemical, electrophysiological, histological, neuroimaging, and behavioral correlates of striatal motor function in adult (4 months of age) and old (21 months of age) male rats. Adult PRS offspring rats showed reduced dopamine (DA) release in the striatum associated with reductions in tyrosine hydroxylase-positive (TH+) cells and DA transporter (DAT) levels, with no loss of striatal dopaminergic terminals as assessed by positron emission tomography analysis with fluorine-18-l-dihydroxyphenylalanine. Striatal levels of DA and its metabolites were increased in PRS rats. In contrast, D2 DA receptor signaling was reduced and A2A adenosine receptor signaling was increased in the striatum of adult PRS rats. This indicated enhanced activity of the indirect pathway of the basal ganglia motor circuit. Adult PRS rats also showed poorer performance in the grip strength test and motor learning tasks. The aged PRS rats also showed a persistent reduction in striatal DA release and defective motor skills in the pasta matrix and ladder rung walking tests. In addition, the old rats showed large increases in the levels of SNAP-25 and synaptophysin, which are synaptic vesicle-related proteins in the striatum, and in the PRS group only, reductions in Syntaxin-1 and Rab3a protein levels were observed. Our findings indicated that the age-dependent threshold for motor dysfunction was lowered in PRS rats. This area of research is underdeveloped, and our study suggests that early-life stress can contribute to an increased understanding of how aging diseases are programmed in early-life.

Published
2020

47. Diagnosis of heart failure with preserved ejection fraction in patients with dyspnea and paroxysmal atrial fibrillation: a role of left atrial strain

Author

Katbeh, A, primary, De Potter, T, additional, Geelen, P, additional, Di Gioia, G, additional, Kodeboina, M, additional, Balogh, Z, additional, Albano, M, additional, Vanderheyden, M, additional, Bartunek, J, additional, Barbato, E, additional, Van Camp, G, additional, and Penicka, M, additional

Published
2020
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48. 468P PANIB 20139173: Randomized, multicentre phase II trial comparing fluorouracil, leucovorin and oxaliplatin (FOLFOX) plus panitumumab versus FOLFOX plus bevacizumab in patients with previously untreated, RAS wild-type (WT) metastatic colorectal cancer (mCRC)

Author

Janssens, K., primary, Fransen, E., additional, Rolfo, C.D., additional, Lybaert, W., additional, Demey, W., additional, Decaestecker, J., additional, Hendrickx, K., additional, Kalantari, H., additional, Op de Beeck, K., additional, Van Camp, G., additional, and Peeters, M., additional

Published
2020
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