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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 September 2023) | Viewed by 5836

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Dr. Victoria Campuzano

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Guest Editor

Biomedicine Department, University of Barcelona, 08036 Barcelona, Spain
Interests: rare diseases of conjuntive tissue; Williams syndrome; Marfan syndrome; oxidative stress

Special Issue Information

Dear Colleagues,

In this issue dedicated to advances in rare diseases, we would like to focus on those that have moved towards translational research. All of us who work in this field know that most rare diseases do not have an effective therapy, and in many of them, only palliative therapies can be applied once symptoms have developed.

In this issue, we want to highlight the research carried out in the search for new therapeutic agents, drug replacement, identification of therapeutic targets, gene therapy, cell therapy, and even the development of new diagnostic strategies towards the development of personalized medicine.

We hope that this Special Issue will be of interest to you.

Dr. Victoria Campuzano
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

rare diseases
disease model
diagnostics
therapeutic targets
therapy

Published Papers (4 papers)

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Research

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14 pages, 3338 KiB

Open AccessArticle

Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels

by Celeste Ferraguto, Yohan Bouleau, Thibault Peineau, Didier Dulon and Susanna Pietropaolo

Int. J. Mol. Sci. 2023, 24(14), 11863; https://doi.org/10.3390/ijms241411863 - 24 Jul 2023

Viewed by 1402

Abstract

Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calcium-activated potassium (BKCa) channels were proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their auditory alterations was not specifically addressed. Furthermore, studies on the acoustic phenotypes of FXS animal models mostly focused on central rather than peripheral auditory pathways. Here, we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of adult mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle phenotype with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs) compared to their wild-type (WT) littermates. BKCa expression was markedly reduced in the IHCs of KOs compared to WT mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to adult hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs. Full article

(This article belongs to the Special Issue New Advances in Rare Genetic Disorder)

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15 pages, 2453 KiB

Open AccessArticle

Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome

by Isaac Rodríguez-Rovira, Angela López-Sainz, Maria Encarnación Palomo-Buitrago, Belen Pérez, Francesc Jiménez-Altayó, Victoria Campuzano and Gustavo Egea

Int. J. Mol. Sci. 2023, 24(14), 11293; https://doi.org/10.3390/ijms241411293 - 10 Jul 2023

Cited by 1 | Viewed by 1230

Abstract

Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice (Fbn1^C1041G/+) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice. Full article

(This article belongs to the Special Issue New Advances in Rare Genetic Disorder)

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13 pages, 1266 KiB

Open AccessArticle

Dysfunctional Mitochondria in the Cardiac Fibers of a Williams–Beuren Syndrome Mouse Model

by Noura Abdalla, Ester Tobías-Baraja, Alejandro Gonzalez, Gloria Garrabou, Gustavo Egea and Victoria Campuzano

Int. J. Mol. Sci. 2023, 24(12), 10071; https://doi.org/10.3390/ijms241210071 - 13 Jun 2023

Viewed by 1003

Abstract

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors: on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria. Full article

(This article belongs to the Special Issue New Advances in Rare Genetic Disorder)

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Review

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19 pages, 2008 KiB

Open AccessReview

CAR-T State of the Art and Future Challenges, A Regulatory Perspective

by Lorenzo Giorgioni, Alessandra Ambrosone, Maria Francesca Cometa, Anna Laura Salvati and Armando Magrelli

Int. J. Mol. Sci. 2023, 24(14), 11803; https://doi.org/10.3390/ijms241411803 - 22 Jul 2023

Cited by 5 | Viewed by 1767

Abstract

This review is an outlook on CAR-T development up to the beginning of 2023, with a special focus on the European landscape and its regulatory field, highlighting the main features and limitations affecting this innovative therapy in cancer treatment. We analysed the current state of the art in the EU and set out a showcase of the field’s potential advancements in the coming years. For this analysis, the data used came from the available scientific literature as well as from the European Medicines Agency and from clinical trial databases. The latter were investigated to query the studies on CAR-Ts that are active and/or relevant to the review process. As of this writing, CAR-Ts have started to move past the “ceiling” of third-line treatment with positive results in comparison trials with the Standard of Care (SoC). One such example is the trial Zuma-7 (NCT03391466), which resulted in approval of CAR-T products (Yescarta™) for second-line treatment, a crucial achievement for the field which can increase the use of this type of therapy. Despite exciting results in clinical trials, limitations are still many: they regard access, production, duration of response, resistance, safety, overall efficacy, and cost mitigation strategies. Nonetheless, CAR-T constructs are becoming more diverse, and the technology is starting to produce some remarkable results in treating diseases other than cancer. Full article

(This article belongs to the Special Issue New Advances in Rare Genetic Disorder)

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