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

  • Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15.

    Publication Date: 21/12/2017 on JCI insight
    by Botta S, de Prisco N, Marrocco E, Renda M, Sofia M, Curion F, Bacci ML, Ventrella D, Wilson C, Gesualdo C, Rossi S, Simonelli F, Surace EM
    DOI: 10.1172/jci.insight.96560

    The genome-wide activity of transcription factors (TFs) on multiple regulatory elements precludes their use as gene-specific regulators. Here we show that ectopic expression of a TF in a cell-specific context can be used to silence the expression of a specific gene as a therapeutic approach to regulate gene expression in human disease. We selected the TF Krüppel-like factor 15 (KLF15) based on its putative ability to recognize a specific DNA sequence motif present in the rhodopsin (RHO) promoter and its lack of expression in terminally differentiated rod photoreceptors (the RHO-expressing cells). Adeno-associated virus (AAV) vector-mediated ectopic expression of KLF15 in rod photoreceptors of pigs enables Rho silencing with limited genome-wide transcriptional perturbations. Suppression of a RHO mutant allele by KLF15 corrects the phenotype of a mouse model of retinitis pigmentosa with no observed toxicity. Cell-specific-context conditioning of TF activity may prove a novel mode for somatic gene-targeted manipulation.

  • Triple Vectors Expand AAV Transfer Capacity in the Retina.

    Publication Date: 05/12/2017 on Molecular therapy : the journal of the American Society of Gene Therapy
    by Maddalena A, Tornabene P, Tiberi P, Minopoli R, Manfredi A, Mutarelli M, Rossi S, Simonelli F, Naggert JK, Cacchiarelli D, Auricchio A
    DOI: 10.1016/j.ymthe.2017.11.019

    Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alström syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected full-length products along a number of aberrant transcripts. However, only the full-length transcripts are efficiently translated in vivo. We additionally showed that approximately 4% of mouse photoreceptors are transduced by triple AAV vectors and showed correct localization of recombinant ALMS1. The low-photoreceptor transduction levels might justify the modest and transient improvement we observe in the retina of a mouse model of ALMS. However, the levels of transduction mediated by triple AAV vectors in pig retina reached 40% of those observed with single vectors, and this bodes well for further improving the efficiency of triple AAV vectors in the retina.

  • Standard, transepithelial and iontophoresis corneal cross-linking: clinical analysis of three surgical techniques.

    Publication Date: 28/11/2017 on International ophthalmology
    by Rossi S, Santamaria C, Boccia R, De Rosa L, D'Alterio FM, Simonelli F, De Rosa G
    DOI: 10.1007/s10792-017-0772-3

    To evaluate the clinical results of standard, transepithelial (TE) and iontophoresis (I) corneal cross-linking (CXL), in patients with progressive keratoconus.

  • Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies.

    Publication Date: 20/10/2017 on Genes
    by Di Iorio V, Karali M, Brunetti-Pierri R, Filippelli M, Di Fruscio G, Pizzo M, Mutarelli M, Nigro V, Testa F, Banfi S, Simonelli F
    DOI: 10.3390/genes8100280

    We performed a clinical and genetic characterization of a pediatric cohort of patients with inherited retinal dystrophy (IRD) to identify the most suitable cases for gene therapy. The cohort comprised 43 patients, aged between 2 and 18 years, with severe isolated IRD at the time of presentation. The ophthalmological characterization also included assessment of the photoreceptor layer integrity in the macular region (ellipsoid zone (EZ) band). In parallel, we carried out a targeted, next-generation sequencing (NGS)-based analysis using a panel that covers over 150 genes with either an established or a candidate role in IRD pathogenesis. Based on the ophthalmological assessment, the cohort was composed of 24 Leber congenital amaurosis, 14 early onset retinitis pigmentosa, and 5 achromatopsia patients. We identified causative mutations in 58.1% of the cases. We also found novel genotype-phenotype correlations in patients harboring mutations in the CEP290 and CNGB3 genes. The EZ band was detectable in 40% of the analyzed cases, also in patients with genotypes usually associated with severe clinical manifestations. This study provides the first detailed clinical-genetic assessment of severe IRDs with infantile onset and lays the foundation of a standardized protocol for the selection of patients that are more likely to benefit from gene replacement therapeutic approaches.

  • Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.

    Publication Date: 26/08/2017 on Lancet (London, England)
    by Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM
    DOI: 10.1016/S0140-6736(17)31868-8

    Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness.

  • Prevalence of macular abnormalities assessed by optical coherence tomography in patients with Usher syndrome.

    Publication Date: 13/07/2017 on Ophthalmic genetics
    by Testa F, Melillo P, Rossi S, Marcelli V, de Benedictis A, Colucci R, Gallo B, Brunetti-Pierri R, Donati S, Azzolini C, Marciano E, Simonelli F
    DOI: 10.1080/13816810.2017.1329445

    To investigate the prevalence of macular abnormalities in patients affected by Usher syndrome (USH), by comparing the clinical findings between two types (i.e., USH1 and USH2).

  • Wearable Improved Vision System for Color Vision Deficiency Correction.

    Publication Date: 02/05/2017 on IEEE journal of translational engineering in health and medicine
    by Melillo P, Riccio D, Di Perna L, Sanniti Di Baja G, De Nino M, Rossi S, Testa F, Simonelli F, Frucci M
    DOI: 10.1109/JTEHM.2017.2679746

    Color vision deficiency (CVD) is an extremely frequent vision impairment that compromises the ability to recognize colors. In order to improve color vision in a subject with CVD, we designed and developed a wearable improved vision system based on an augmented reality device. The system was validated in a clinical pilot study on 24 subjects with CVD (18 males and 6 females, aged 37.4 ± 14.2 years). The primary outcome was the improvement in the Ishihara Vision Test score with the correction proposed by our system. The Ishihara test score significantly improved ([Formula: see text]) from 5.8 ± 3.0 without correction to 14.8 ± 5.0 with correction. Almost all patients showed an improvement in color vision, as shown by the increased test scores. Moreover, with our system, 12 subjects (50%) passed the vision color test as normal vision subjects. The development and preliminary validation of the proposed platform confirm that a wearable augmented-reality device could be an effective aid to improve color vision in subjects with CVD.

  • Mutations in the PCYT1A gene are responsible for isolated forms of retinal dystrophy.

    Publication Date: 01/05/2017 on European journal of human genetics : EJHG
    by Testa F, Filippelli M, Brunetti-Pierri R, Di Fruscio G, Di Iorio V, Pizzo M, Torella A, Barillari MR, Nigro V, Brunetti-Pierri N, Simonelli F, Banfi S
    DOI: 10.1038/ejhg.2017.23

    Mutations in the PCYT1A gene have been recently linked to two different phenotypes: one characterized by spondylometaphyseal dysplasia and cone-rod dystrophy (SMD-CRD) and the other by congenital lipodystrophy, severe fatty liver disease, and reduced HDL cholesterol without any retinal or skeletal involvement. Here, we identified, by next generation sequencing, sequence variants affecting function in the PCYT1A gene in three young patients with isolated retinal dystrophy from two different Italian families. A thorough clinical evaluation of the patients, with whole skeleton X-ray, metabolic assessment and liver ultrasound failed to reveal signs of skeletal dysplasia, metabolic and hepatic alterations. This is the first report showing that the PCYT1A gene can be responsible for isolated forms of retinal dystrophy, particularly without any skeletal involvement, thus further expanding the phenotypic spectrum induced by mutations in this gene.

  • Identifying fallers among ophthalmic patients using classification tree methodology.

    Publication Date: 23/03/2017 on PloS one
    by Melillo P, Orrico A, Chirico F, Pecchia L, Rossi S, Testa F, Simonelli F
    DOI: 10.1371/journal.pone.0174083

    To develop and validate a tool aiming to support ophthalmologists in identifying, during routine ophthalmologic visits, patients at higher risk of falling in the following year.

  • Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.

    Publication Date: 01/02/2017 on BMC medical genetics
    by Esposito G, Testa F, Zacchia M, Crispo AA, Di Iorio V, Capolongo G, Rinaldi L, D'Antonio M, Fioretti T, Iadicicco P, Rossi S, Franzè A, Marciano E, Capasso G, Simonelli F, Salvatore F
    DOI: 10.1186/s12881-017-0372-0

    Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS.