Francesca Simonelli

Professor of Ophtalmology

Name Francesca
Surname Simonelli
Institution Università degli Studi della Campania Luigi Vanvitelli
E-Mail francesca.simonelli@unicampania.it
Address Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
Francesca Simonelli

Member PUBLICATIONS

  • CLINICAL PRESENTATION AND DISEASE COURSE OF USHER SYNDROME BECAUSE OF MUTATIONS IN MYO7A OR USH2A.

    Publication Date: 08/11/2016 on Retina (Philadelphia, Pa.)
    by Testa F, Melillo P, Bonnet C, Marcelli V, de Benedictis A, Colucci R, Gallo B, Kurtenbach A, Rossi S, Marciano E, Auricchio A, Petit C, Zrenner E, Simonelli F
    DOI: 10.1097/IAE.0000000000001389

    To evaluate differences in the visual phenotype and natural history of Usher syndrome caused by mutations in MYO7A or USH2A, the most commonly affected genes of Usher syndrome Type I (USH1) and Type II (USH2), respectively.

  • Renal phenotype in Bardet-Biedl syndrome: a combined defect of urinary concentration and dilution is associated with defective urinary AQP2 and UMOD excretion.

    Publication Date: 01/10/2016 on American journal of physiology. Renal physiology
    by Zacchia M, Zacchia E, Zona E, Capolongo G, Raiola I, Rinaldi L, Trepiccione F, Ingrosso D, Perna A, Di Iorio V, Simonelli F, Moe OW, Capasso G
    DOI: 10.1152/ajprenal.00224.2016

    The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min(-1)·1.73 m(-2) Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.

  • Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial.

    Publication Date: 13/08/2016 on Lancet (London, England)
    by Bennett J, Wellman J, Marshall KA, McCague S, Ashtari M, DiStefano-Pappas J, Elci OU, Chung DC, Sun J, Wright JF, Cross DR, Aravand P, Cyckowski LL, Bennicelli JL, Mingozzi F, Auricchio A, Pierce EA, Ruggiero J, Leroy BP, Simonelli F, High KA, Maguire AM
    DOI: 10.1016/S0140-6736(16)30371-3

    Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study.

  • Morphological and Functional Retinal Assessment in Epiretinal Membrane Surgery.

    Publication Date: 10/08/2016 on Seminars in ophthalmology
    by Donati S, Caprani SM, Semeraro F, Vinciguerra R, Virgili G, Testa F, Simonelli F, Azzolini C
    DOI: 10.1080/08820538.2016.1177097

    To analyze functional and morphological findings after surgery for idiopathic epiretinal macular membrane (IEMM).

  • Mulibrey nanism: Two novel mutations in a child identified by Array CGH and DNA sequencing.

    Publication Date: 01/08/2016 on American journal of medical genetics. Part A
    by Mozzillo E, Cozzolino C, Genesio R, Melis D, Frisso G, Orrico A, Lombardo B, Fattorusso V, Discepolo V, Della Casa R, Simonelli F, Nitsch L, Salvatore F, Franzese A
    DOI: 10.1002/ajmg.a.37770

    In childhood, several rare genetic diseases have overlapping symptoms and signs, including those regarding growth alterations, thus the differential diagnosis is sometimes difficult. The proband, aged 3 years, was suspected to have Silver-Russel syndrome because of intrauterine growth retardation, postnatal growth retardation, typical facial dysmorphic features, macrocephaly, body asymmetry, and bilateral fifth finger clinodactyly. Other features were left atrial and ventricular enlargement and patent foramen ovale. Total X-ray skeleton showed hypoplasia of the twelfth rib bilaterally and of the coccyx, slender long bones with thick cortex, and narrow medullary channels. The genetic investigation did not confirm Silver-Russel syndrome. At the age of 5 the patient developed an additional sign: hepatomegaly. Array CGH revealed a 147 kb deletion (involving TRIM 37 and SKA2 genes) on one allele of chromosome 17, inherited from his mother. These results suggested Mulibrey nanism. The clinical features were found to fit this hypothesis. Sequencing of the TRIM 37 gene showed a single base change at a splicing locus, inherited from his father that provoked a truncated protein. The combined use of Array CGH and DNA sequencing confirmed diagnosis of Mulibrey nanism. The large deletion involving the SKA2 gene, along with the increased frequency of malignant tumours in mulibrey patients, suggests closed monitoring for cancer of our patient and his mother. Array CGH should be performed as first tier test in all infants with multiple anomalies. The clinician should reconsider the clinical features when the genetics suggests this. © 2016 Wiley Periodicals, Inc.

  • Functional improvement assessed by multifocal electroretinogram after Ocriplasmin treatment for vitreomacular traction.

    Publication Date: 18/07/2016 on BMC ophthalmology
    by Rossi S, Testa F, Melillo P, Orrico A, Della Corte M, Simonelli F
    DOI: 10.1186/s12886-016-0284-3

    To evaluate the functional recovery of patients with symptomatic vitreomacular traction (VMT) after Ocriplasmin treatment.

  • En Face Spectral-Domain Optical Coherence Tomography for the Monitoring of Lesion Area Progression in Stargardt Disease.

    Publication Date: 01/07/2016 on Investigative ophthalmology & visual science
    by Melillo P, Testa F, Rossi S, Di Iorio V, Orrico A, Auricchio A, Simonelli F
    DOI: 10.1167/iovs.15-18751

    We investigated the progression of Stargardt disease (STGD1) over a multiyear follow-up by evaluating the macular lesion area as computed by an automatic algorithm from spectral-domain optical coherence tomography (SD-OCT).

  • Intrafamilial heterogeneity of congenital optic disc pit maculopathy.

    Publication Date: 08/06/2016 on Ophthalmic genetics
    by Rossi S, De Rosa G, D'Alterio FM, Orrico A, Banfi S, Testa F, Simonelli F
    DOI: 10.1080/13816810.2016.1188120

    Optic disc pit is a very rare clinical entity. The main complication of this condition is the maculopathy.

  • Rhodopsin targeted transcriptional silencing by DNA-binding.

    Publication Date: 14/03/2016 on eLife
    by Botta S, Marrocco E, de Prisco N, Curion F, Renda M, Sofia M, Lupo M, Carissimo A, Bacci ML, Gesualdo C, Rossi S, Simonelli F, Surace EM
    DOI: 10.7554/eLife.12242

    Transcription factors (TFs) operate by the combined activity of their DNA-binding domains (DBDs) and effector domains (EDs) enabling the coordination of gene expression on a genomic scale. Here we show that in vivo delivery of an engineered DNA-binding protein uncoupled from the repressor domain can produce efficient and gene-specific transcriptional silencing. To interfere with RHODOPSIN (RHO) gain-of-function mutations we engineered the ZF6-DNA-binding protein (ZF6-DB) that targets 20 base pairs (bp) of a RHOcis-regulatory element (CRE) and demonstrate Rho specific transcriptional silencing upon adeno-associated viral (AAV) vector-mediated expression in photoreceptors. The data show that the 20 bp-long genomic DNA sequence is necessary for RHO expression and that photoreceptor delivery of the corresponding cognate synthetic trans-acting factor ZF6-DB without the intrinsic transcriptional repression properties of the canonical ED blocks Rho expression with negligible genome-wide transcript perturbations. The data support DNA-binding-mediated silencing as a novel mode to treat gain-of-function mutations.

  • Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity.

    Publication Date: 01/02/2016 on Nature genetics
    by Saksens NT, Krebs MP, Schoenmaker-Koller FE, Hicks W, Yu M, Shi L, Rowe L, Collin GB, Charette JR, Letteboer SJ, Neveling K, van Moorsel TW, Abu-Ltaif S, De Baere E, Walraedt S, Banfi S, Simonelli F, Cremers FP, Boon CJ, Roepman R, Leroy BP, Peachey NS, Hoyng CB, Nishina PM, den Hollander AI
    DOI: 10.1038/ng.3474

    Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here we report the identification of heterozygous missense mutations in the CTNNA1 gene (encoding α-catenin 1) in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice demonstrated increased cell shedding and the presence of large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, indicates that CTNNA1 is involved in maintaining RPE integrity and suggests that other components that participate in intercellular adhesion may be implicated in macular disease.