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gene therapy eye

Ponson Laura, Gomot Marie, Blanc Romuald, Barthelemy Catherine, Roux Sylvie, Munnich Arnold, Romana Serge, Aguillon-Hernandez Nadia, Malan Valérie, Bonnet-Brilhault Frédérique
Phelan-McDermid syndrome is related to terminal 22q13 deletions of various sizes affecting the SHANK3 gene. In this neurodevelopmental disorder, behavioural symptoms of autism spectrum disorder (ASD) are reported in half of cases. Extensive clinical and neurophysiological characterization is lacking to understand the genotype-phenotype correlation. Eighteen patients (8 males, mean age 12.7 years, SD = 9.2) with known 22q13 deletions were fully explored with determination of deletion size, along with behavioural, language and cognitive standardized assessments...
August 8, 2018: Translational Psychiatry
Arvin B Tam, Lindsay S Roberts, Vivek Chandra, Io Guane Rivera, Daniel K Nomura, Douglass J Forbes, Maho Niwa
The unfolded protein response (UPR) is induced by proteotoxic stress of the endoplasmic reticulum (ER). Here we report that ATF6, a major mammalian UPR sensor, is also activated by specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Single mutations in a previously undefined transmembrane domain motif that we identify in ATF6 incapacitate DHS/DHC activation while still allowing proteotoxic stress activation via the luminal domain. ATF6 thus possesses two activation mechanisms: DHS/DHC activation and proteotoxic stress activation...
August 6, 2018: Developmental Cell
Liujiang Song, Telmo Llanga, Laura M Conatser, Violeta Zaric, Brian C Gilger, Matthew L Hirsch
AAV gene therapy approaches in the posterior eye resulted in the first FDA-approved gene therapy-based drug. However, application of AAV vectorology to the anterior eye has yet to enter even a Phase I trial. Furthermore, the simple and safe subconjunctival injection has been relatively unexplored in regard to AAV vector transduction. To determine the utility of this route for the treatment of various ocular disorders, a survey of gene delivery via natural AAV serotypes was performed and correlated to reported cellular attachment factors...
August 2, 2018: Gene Therapy
Itaru Yamamoto, Yumiko Azuma, Yukie Kushimura, Hideki Yoshida, Ikuko Mizuta, Toshiki Mizuno, Morio Ueyama, Yoshitaka Nagai, Takahiko Tokuda, Masamitsu Yamaguchi
Fused in sarcoma (FUS) was identified as a component of typical inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In FTLD, both nuclear and cytoplasmic inclusions with wild-type FUS exist, while cytoplasmic inclusions with a mutant-form of FUS occur in many ALS cases. These observations imply that FUS plays a role across these two diseases. In this study, we examined the effect of several proteins including molecular chaperons on the aberrant eye morphology phenotype induced by overexpression of wild-type human FUS (hFUS) in Drosophila eye imaginal discs...
July 26, 2018: Scientific Reports
Arnt V Kristen
Transthyretin is a transport protein for thyroxine and retinol-binding protein, which is mainly produced in the liver. Hereditary transthyretin-related amyloidosis (ATTR) is caused by one of more than 120 point mutations in the transthyretin gene and inherited as an autosomal dominant disorder. The mutations cause a reduction in the stability of the tetrameric structure and dissociation into dimers and monomers as the rate-limiting step in amyloid formation is promoted. Clinical symptoms are related to the specific mutation, the age of onset, the ethnic background and environmental factors...
July 23, 2018: Der Internist
Wen-Tao Deng, Saravanan Kolandaivelu, Astra Dinculescu, Jie Li, Ping Zhu, Vince A Chiodo, Visvanathan Ramamurthy, William W Hauswirth
Rod and cone phosphodiesterase 6 (PDE6) are key effector enzymes of the vertebrate phototransduction pathway. Rod PDE6 consists of two catalytic subunits PDE6α and PDE6β and two identical inhibitory PDE6γ subunits, while cone PDE6 is composed of two identical PDE6α' catalytic subunits and two identical cone-specific PDE6γ' inhibitory subunits. Despite their prominent function in regulating cGMP levels and therefore rod and cone light response properties, it is not known how each subunit contributes to the functional differences between rods and cones...
2018: Frontiers in Molecular Neuroscience
Li Fong Seet, Yang Fei Tan, Li Zhen Toh, Stephanie Wl Chu, Ying Shi Lee, Subbu S Venkatraman, Tina T Wong
BACKGROUND: To develop targeted antifibrotic therapy for glaucoma filtration surgery; this study determines the effectiveness of small interfering RNA (siRNA) to reduce in vivo secreted protein acidic and rich in cysteine (SPARC) expression using the mouse model of conjunctival scarring. METHODS: Experimental surgery was performed as described for the mouse model of conjunctival scarring. Scrambled (siScram) or Sparc (siSparc) siRNAs, loaded on layer-by-layer (LbL) nanoparticles, were injected into the conjunctiva immediately after surgery...
July 18, 2018: British Journal of Ophthalmology
Yanghui Xiu, Yihua Yao, Tanchu Yang, Meihua Pan, Hui Yang, Weifang Fang, Feng Gu, Junzhao Zhao, Yihua Zhu
Exploring the genetic basis for idiopathic congenital nystagmus is critical for improving our understanding of its molecular pathogenesis. In the present study, direct sequencing using gene specific primers was performed in order to identify the causative mutations in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. A comprehensive ophthalmological examination, including eye movement recordings, fundus examination, and retinal optical coherence tomography imaging was also conducted, to characterize the disease phenotype...
September 2018: Molecular Medicine Reports
Felix Peter Aplin, Dilawer Singh, Charles C Della Santina, Gene Y Fridman
OBJECTIVE: Prosthetic electrical stimulation delivered to the vestibular nerve could provide therapy for people suffering from bilateral vestibular dysfunction (BVD). Common encoding methods use pulse-frequency modulation (PFM) to stimulate the semicircular canals of the vestibular system. We previously showed that delivery of ionic direct current (iDC) can also modulate the vestibular system. In this study we compare the dynamic range of head velocity encoding from iDC modulation to that of PFM controls...
July 16, 2018: IEEE Transactions on Bio-medical Engineering
Elodie Touchard, Romain Benard, Karine Bigot, Jean-Denis Laffitte, Ronald Buggage, Thierry Bordet, Francine Behar-Cohen
Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secreted therapeutic proteins into the eye, non-viral gene therapy using plasmid electrotransfer in the ciliary muscle has been proposed. In this paper, we report the development steps of pEYS606, a clinical-grade plasmid DNA, devoid of antiobiotic selection gene, encoding a fusion protein consisting of the extracellular domain of the soluble p55 TNF-α receptor linked to the human IgG1 Fc domain (hTNFR-Is/hIgG1 or Protein 6), with high affinity for human TNF-α, for non-viral gene transfer into the ocular ciliary muscle...
July 31, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Seppo Ylä-Herttuala
No abstract text is available yet for this article.
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Wenjuan Zhang, Sun Myoung Kim, Wenwen Wang, Cuiyuan Cai, Yong Feng, Weijia Kong, Xi Lin
Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants...
2018: Frontiers in Molecular Neuroscience
Josune Torrecilla, Ana Del Pozo-Rodríguez, Mónica Vicente-Pascual, María Ángeles Solinís, Alicia Rodríguez-Gascón
Inflammation is the underlying process of several diseases within the eye, specifically in the cornea. Current treatment options for corneal inflammation or keratitis, and related neovascularization, are restricted by limited efficacy, adverse effects, and short duration of action. Gene therapy has shown great potential for the treatment of diseases affecting the ocular surface, and major efforts are being targeted to inflammatory mediators and neovascularization, in order to develop potential treatments for corneal inflammation...
July 4, 2018: Experimental Eye Research
Jason Michael Springer, Selina A Gierer, Hong Jiang, David Kleiner, Natalie Deuitch, Amanda K Ombrello, Peter C Grayson, Ivona Aksentijevich
Objective: Describe the clinical characteristics and histopathology findings in a family with two siblings affected with deficiency of adenosine deaminase 2 (DADA2). Both patients presented in childhood with polyarthritis and developed significant neurological and gastrointestinal features of DADA2 in ear, including variable degrees of immunologic and hematologic manifestations. Methods: Adenosine Deaminase 2 (ADA2; also known as cat eye syndrome chromosome region, candidate 1 gene; CECR1) exon sequencing and serum ADA2 levels were performed to confirm the diagnosis of DADA2...
2018: Frontiers in Immunology
Yusuke Watanabe, Takehito Kobayashi, Itaru Nakamura, Hiroaki Fujita, Midori Shimoinaba, Shinji Fukushima, Yoshitsugu Miyazaki, Tetsuya Matsumoto
We report the first case of invasive ophthalmologic infection by Acrophialophora sp. that was successfully treated using voriconazole (VRCZ). Acrophialophora spp., which has been reported to be an opportunistic pathogen, is rare thermotolerant soil fungus, but its pathogenicity remains unclear. A 77-year-old man had neutropenia and prostate carcinoma, and was receiving hemodialysis. His right eye had been infected for 2 days. His conjunctiva was congested and partially formed an abscess. Liposomal amphotericin B (L-AMB) was administered following systemic itraconazole...
June 29, 2018: Japanese Journal of Infectious Diseases
T N Safonova, G V Zaitseva
The article reviews the results of Russian and foreign studies concerning the search of susceptibility genes for widespread multifactorial diseases: Sjogren's syndrome and rheumatoid arthritis. Studying regularity patterns of genome changes in autoimmune processes with ophthalmic manifestations and their correlation with the severity of dry keratoconjunctivitis will contribute to a better understanding of the etiology and pathogenesis of eye manifestations of the diseases, and will also allow the development of new effective methods of diagnosis and targeted therapy...
2018: Vestnik Oftalmologii
Ioannis S Dimopoulos, Stephanie C Hoang, Alina Radziwon, Natalia M Binczyk, Miguel C Seabra, Robert E MacLaren, Rizwan Somani, Matthew T S Tennant, Ian M MacDonald
PURPOSE: To assess the safety of a recombinant adeno-associated viral vector expressing REP1 (rAAV2.REP1) in choroideremia subjects. METHODS: Design: Phase I clinical trial. PARTICIPANTS: Six adult male subjects, 30-42 years of age, with genetically confirmed choroideremia (CHM) were enrolled. The eye with the worse vision, for all subjects, received a single subfoveal injection of 0.1 mL rAAV2.REP1 containing 1011 genome particles. Subjects were followed up for 2 years thereafter...
June 27, 2018: American Journal of Ophthalmology
Ron Ofri, Edward Averbukh, Raaya Ezra-Elia, Maya Ross, Hen Honig, Alexey Obolensky, Alexander Rosov, William W Hauswirth, Elisha Gootwine, Eyal Banin
Achromatopsia causes severely reduced visual acuity, photoaversion and inability to discern colors due to cone photoreceptor dysfunction. In 2010, we reported on day blindness in sheep caused by a stop codon mutation of the ovine CNGA3 gene, and began gene augmentation therapy trials in this naturally occurring large animal model of CNGA3 achromatopsia. The purpose of this study was to evaluate long-term efficacy and safety results of treatment, findings that hold great relevance for clinical trials in CNGA3 achromatopsia patients that started recently...
June 21, 2018: Human Gene Therapy
Elias Flockerzi, Loay Daas, Ursula Schlötzer-Schrehardt, Annette Zimpfer, Rainer Bohle, Berthold Seitz
PURPOSE: Cystinosis is an autosomal recessive inherited lysosomal storage disease with an incidence of 1:100.000 up to 1:200.000 caused by a gene mutation of a lysosomal transport protein resulting in deposition of cystine in lysosomes in all cells and tissues. In the cornea, crystalline, gold-dust deposition of cystine leads to visual impairment, recurrent erosions, photophobia, epiphora and blepharospasmus. Standard therapy is topical and systemic application of cysteamine which may resolve the accumulated cystine crystals...
June 18, 2018: International Ophthalmology
Mark E Pennesi, Richard G Weleber, Paul Yang, Chris Whitebirch, Beverly Thean, Terence R Flotte, Margaret Humphries, Elvira Chegarnov, Kathleen N Beasley, J Timothy Stout, Jeffrey D Chulay
Previously, results at 2 years after subretinal injection of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in eight adults and four children with retinal degeneration caused by RPE65 mutations were reported. Now, results at 5 years after treatment in 11 of these subjects are reported. Subjects received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye, at either of two dose levels, and were followed for 5 years after treatment. The primary safety outcomes were ocular and non-ocular adverse events...
July 24, 2018: Human Gene Therapy
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