Methods and compositions for treating ocular diseases related to mithocondrial DNA maintenance

Inventors report heterozygous mutations in mitochondrial single-stranded DNA-binding protein SSBP1 in multiple unrelated families with non-syndromic dominant optic atrophy, associated in half of the cases by a striking occurrence of a foveopathy. SSBP1 is a key protein for the mtDNA replication machinery. Inventors have identified two mutations in SSBP1 in families with dominant optic atrophy and shown that SSBP1 mutation affects mtDNA replication. Patient fibroblasts displayed unstable formation of SSBP1 dimer/tetramer affecting mtDNA replication leading to a decrease of mtDNA copy-number. They provide evidences that SSBP1 deficiency in human results in a novel mtDNA syndrome resulting in an isolated visual defect. The present invention relates to a method for predicting the risk of having or developing ocular disease related to mtDNA maintenance by measuring at least one mutation in SSBP1. The invention relates also to treat ocular disease related to mtDNA maintenance by administering an inhibitor of SSBP1 gene expression or a vector which comprises a nucleic acid molecule encoding for SSBP1.Peer reviewedInstitut National de la Santé et de la Recherche Médicale, Université de Montpellier, Consejo Superior de Investigaciones Científicas (España), Radboud UniversityA1 Solicitud de patente con informe sobre el estado de la técnic

Rift Valley fever virus modulates apoptosis and immune response during infection of human astrocytes

International audienceRift Valley fever (RVF) is an arboviral disease of zoonotic origin that causes recurrent epidemics in Africa, the Arabic Peninsula, and islands of the South West of the Indian Ocean. RVF occurs mainly in livestock but also affects humans with severe clinical manifestations, including neurological disorders. However, human neuropathogenesis of Rift Valley fever virus (RVFV) is still poorly characterized. To study the interactions between RVFV and the central nervous system (CNS), we focused on RVFV infection of astrocytes, the major glial cells of the CNS that have several supporting roles including immune response regulation. We confirmed the permissiveness of astrocytes to RVFV infection and highlighted a strain-dependent infectivity. We showed that RVFV infection of astrocytes induced cell apoptosis and observed that the RVFV Non-Structural protein NSs, a known virulence factor, potentially delayed apoptosis by sequestrating activated-caspase 3 in the nucleus. Our study also showed that RVFV-infected astrocytes upregulated expression of genes associated with inflammatory and type I interferon responses at the mRNA level, but not at the protein level. This inhibition of immune response is potentially due to a NSs-dependent mechanism of mRNA nuclear export inhibition. Together, these results highlighted the direct impact of RVFV infection on the human CNS through the induction of apoptosis and a possible inhibition of early-onset immune responses that are crucial for the host survival

OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model

Abstract Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients

Evidence for circulation of Rift Valley fever virus in wildlife and domestic animals in a forest environment in Gabon, Central Africa.

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis caused by the Rift Valley fever virus (RVFV) that can infect domestic and wild animals. Although the RVFV transmission cycle has been well documented across Africa in savanna ecosystems, little is known about its transmission in tropical rainforest settings, particularly in Central Africa. We therefore conducted a survey in northeastern Gabon to assess RVFV circulation among wild and domestic animals. Among 163 wildlife samples tested using RVFV-specific RT-qPCR, four ruminants belonging to subfamily Cephalophinae were detected positive. The phylogenetic analysis revealed that the four RVFV sequences clustered together with a virus isolated in Namibia within the well-structured Egyptian clade. A cross-sectional survey conducted on sheep, goats and dogs living in villages within the same area determined the IgG RVFV-specific antibody prevalence using cELISA. Out of the 306 small ruminants tested (214 goats, 92 sheep), an overall antibody prevalence of 15.4% (95% CI [11.5-19.9]) was observed with a higher rate in goats than in sheep (20.1% versus 3.3%). RVFV-specific antibodies were detected in a single dog out of the 26 tested. Neither age, sex of domestic animals nor season was found to be significant risk factors of RVFV occurrence. Our findings highlight sylvatic circulation of RVFV for the first time in Gabon. These results stress the need to develop adequate surveillance plan measures to better control the public health threat of RVFV. [Abstract copyright: Copyright: © 2024 Becquart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

International audienc

List of wild animal species screened for the RVFV genome.

List of wild animal species screened for the RVFV genome.</p

Phylogenetic tree derived from nucleotide sequence data of the entire S segment.

The phylogenetic analyses were carried out after multiple alignments of the obtained sequences along with the GenBank reference sequences (including all published sequences). Maximum likelihood (ML) methods were used to construct trees based on full sequences of the S segment (1690 nt). The GenBank accession numbers for the S gene are OR528950, OR528951, OR528952, OR528953 for samples 7, 108, 120 and 166, respectively.</p

RVFV-specific IgG antibodies detection in livestock (sheep and goats) and dogs using ELISA according to sampled route and village.

RVFV-specific IgG antibodies detection in livestock (sheep and goats) and dogs using ELISA according to sampled route and village.</p

RVFV genome detection in wildlife using RT-qPCR according to sampled route and village.

RVFV genome detection in wildlife using RT-qPCR according to sampled route and village.</p

Map of the study area, Zadié Department, Gabon.

Gray dots indicate the sampled villages and red dots, the villages where hunters brought back Cephalophinae detected positive for RVFV.</p