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Clinical Perspectives on Gene Therapy for Retinal and Eye Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Devika S. Joshi, Gaurav M. Karve, Shrikant D. Joshi
In situations like high-risk corneal grafts with poor survival, especially those in which disease recurs, such as full thickness keratoplasty in MPS4, Reis-Bücklers, and other TGFBI corneal dystrophies, gene therapy as a “single shot treatment” is a very good possible treatment option.15
Corneal Disorders
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Darren S. J. Ting, Rashmi Deshmukh, Daniel S. W. Ting, Marcus Ang
Amongst all, keratoconus and FECD are two of the most commonly investigated corneal diseases. This is primarily attributed to the high disease prevalence and the need for corneal transplantation for the severe form of these diseases, which places substantial burden on the limited pool of donor corneas.95 Over the years, GWLS have successfully identified a number of genetic mutations implicated in keratoconus, including COL8A1, CAST, LOX, TCEB1, and TGFBI genes, amongst others.124 GWAS has increasingly been used to identify genetic susceptibility regions in keratoconus and FECD.124,125 For instance, McComish et al.115 recently identified a novel genetic locus in PNPLA2 at chromosome 11 for keratoconus based on over 6 million genetic variants. Several novel genetic loci for FECD, including TCF4, KANK4 rs79742895, LAMC1 rs3768617, and LINC00970/ATP1B1 rs1200114, have also been discovered through GWAS.119 Next-generation sequencing (NGS), which represents the most comprehensive tool in identifying genomic variants,126 has recently been utilized to unravel novel mutations associated with other types of corneal dystrophy.127
Corneal Dystrophy Caused by a Novel Mutation of the TGFBI Gene: A Case Report
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
B. Stix, J. Rüschoff, A. Roessner, C. Röcken
We report on a patient who, at 56-years of age, was found to suffer from amyloid deposits within the cornea probably caused by an unknown mutation in the transforming growth factor-beta-induced (TGFBI) gene on chromosome 5q31. These are thought to cause abnormal folding and precipitation of the encoded protein, keratoepithelin. Our initial investigations have focused on the exons 4, 11, 12, and 14, the exons with the most mutational hotspots.
Pharmacological treatment for transforming growth factor beta induced corneal dystrophies: what is the way forward?
Published in Expert Review of Clinical Pharmacology, 2023
Gabriella Guo Sciriha, Janet Sultana, Joseph Borg
TGFBI expression is controlled directly by the TGF-beta/SMAD signaling pathway [8]. Furthermore, indirect modulation of TGFBI expression also occurs via the JNK signaling cascade [9], the PI3-K/AKT and the cAMP/PKA cascades. Attempts at generating CD animal models which may subsequently be used to test the relevance of potential drugs have been scarce. However, 16 potential drugs that can theoretically reduce the levels of mutant TGFBIp in human corneal cells have been identified in literature [10]. These can be categorized into five groups [10]: compounds targeting TGF-beta/Smad and Akt/GSK-3 signaling cascades (Group a: lithium, tranilast, 2,4-diamino-5-(1-hydroxynaphthalen-2-yl)-5 H-chromeno[2,3-b] pyriine-3-carbonitrile, histone deacetylase (HDAC) inhibitors: vorinostat and givinostat (ITF2357), doxycycline, lobeglitazone, halofuginone, glucosamine, nitric oxide, SB431542 and SP600125); compounds targeting JNK signaling cascade (Group b: SP600125, doxycycline); compounds inhibiting DNA synthesis and function (Group c: MMC); compounds inducing increased elimination of TGFBIp (Group d: 4-PBA, melatonin and Torin1) and compounds binding to mutant TGFBIp (Group e: MO07617, RJF00203, BTB05094, RJF00203 and BTB05094 [11]) (Table 1).
Identifying and categorizing compounds that reduce corneal transforming growth factor beta induced protein levels: a scoping review
Published in Expert Review of Clinical Pharmacology, 2022
Gabriella Guo Sciriha, Janet Sultana, Joseph Borg
CDs are a rare group of conditions and, to date, there is still a lack of research that investigates the prevalence, pathogenesis and possible treatment of these conditions. At present, there is no effective treatment to prevent, halt, or reverse the deposition of mutant TGFBIp. Currently, the only treatment available for the management of TGFBI CD patients consists of medical treatment to relieve discomfort and surgery that includes laser phototherapeutic keratectomy and corneal graft surgery (lamellar keratoplasty or full thickness penetrating keratoplasty). Each surgical technique can be associated with a number of serious complications, including graft rejection in corneal graft surgery. Furthermore, recurrence of the dystrophy within the graft has been reported to be almost universal within 4 years [4]. As a result, patients might have to undergo multiple procedures over a lifetime due to recurrence of the dystrophy. Researchers are now trying to discover more permanent and non-surgical procedures to try and prevent or stop the deposition of corneal material in these dystrophies.
Detailed phenotypic description of stromal corneal dystrophy in a large pedigree carrying the uncommon TGFBI p.Ala546Asp pathogenic variant
Published in Ophthalmic Genetics, 2022
Leire Irusteta, Arturo Ramírez-Miranda, Alejandro Navas-Pérez, Luis Montes-Almanza, José Arteaga, Froylán García-Martínez, Enrique Graue-Hernández, Juan C. Zenteno
Despite significant advances in understanding the genetic basis of corneal dystrophies, the further reason to why identical TGFBI mutations cause morphologically distinct phenotypes remains elusive. Several instances of inter- and intrafamilial clinical variability in TGFBI-linked corneal dystrophies resulting from identical mutations have been described (5,10–14), suggesting the participation of additional genetic factors and/or environmental influences in defining the predominant corneal phenotype. Importantly, in uncommon TGFBI variants, clinical descriptions are limited by the low number of available patients and the described phenotypes are biased by the age of corneal examination. Thus, the study of multigenerational families carrying rare TGFBI mutation provides a unique opportunity for a detailed phenotypic description including aspects such as age of onset, rate of progression, and modification of corneal deposits morphology with age.