Prevention of Nocturnal Elevation of Intraocular Pressure by Gene Transfer of Dominant-Negative RhoA in Rats

Borrás, Teresa; Buie, LaKisha K.; Spiga, Marco; Carabaña, Juan

doi:10.1001/jamaophthalmol.2014.4747

Cited by 30 publications

(21 citation statements)

References 38 publications

(56 reference statements)

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“…Transduction efficiency varies among serotypes of scAAV and host species (Bogner et al, 2015). Expression is slower in the outflow tract than other regions and takes approximately 1 week (Borrás et al, 2015). Gene expression is more persistent with self-complementary vectors and has been reported for at least 3.5 months in rat and 2.3 years in monkey TM (Buie et al, 2010).…”

Section: Established Methods Of Ocular Gene Therapymentioning

confidence: 99%

“…Increased outflow facility after dominant-negative RhoA or exoenzyme C3 (Rho GTPase inhibitor) by an adenoviral vector was observed in a primate anterior segment perfusion model (Liu et al, 2005; Vittitow et al, 2002). Borras et al used a scAAV-mediated RhoA transfer to prevented elevation of IOP for more than 4 weeks in rats (Borrás et al, 2015). Rho-kinase, a key downstream effector of activated RhoA, may present as a more effective therapeutic target since specific inhibition of this gene increased the outflow facility much greater than inhibiting RhoA (80% vs. 32.5%) (Rao et al, 2005; Vittitow et al, 2002).…”

Section: Applicationsmentioning

confidence: 99%

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Gene transfer to the outflow tract

Dang

Loewen

Parikh

et al. 2017

Experimental Eye Research

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Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm's canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15 to 20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adeno-associated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adeno- and herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-β and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm's canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.

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Section: Established Methods Of Ocular Gene Therapymentioning

confidence: 99%

Section: Applicationsmentioning

confidence: 99%

Gene transfer to the outflow tract

Dang

Loewen

Parikh

et al. 2017

Experimental Eye Research

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“…Consistent with the IOP lowering effect of Rho kinase inhibitors, lowering of IOP in rodent eyes has been achieved by inhibition of Rho GTPase activity, either via expression of recombinant C3 exoenzyme which inhibits RhoA through ADP-ribosylation, or expression of dominant negative RhoA in the anterior chamber of rodent eyes (Borras et al, 2015; Liu et al, 2005; Slauson et al, 2015). Similarly, reduction of RhoA activity in the AH outflow pathway using shRNA lowers IOP in rodents (Liu et al, 2012).…”

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 97%

“…In addition to these studies of Rho kinase inhibition, inhibition of Rho GTPase activity in TM cells has been studied using dominant negative forms of RhoA (Borras et al, 2015; Vittitow et al, 2002), direct inhibitors of RhoA including C3 exoenzyme (Liu et al, 2005; Pattabiraman and Rao, 2010; Slauson et al, 2015), and inhibitors of protein isoprenylation, e.g. statins and geranylgeranyl transferase inhibitors-GGTIs (Pervan et al, 2015; Rao et al, 2008; Song et al, 2005; Von Zee et al, 2009).…”

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.

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“…Recently a gene therapy approach was demonstrated to be effective. Thus inhibition of the RHOA pathway in trabecular meshwork by a dominant negatively acting RHOA gene delivered via recombinant viral vector reduced nocturnal elevated IOP in a living rat (Borras et al, 2015a). …”

Section: Cell Biologymentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

125

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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Prevention of Nocturnal Elevation of Intraocular Pressure by Gene Transfer of Dominant-Negative RhoA in Rats

Cited by 30 publications

References 38 publications

Gene transfer to the outflow tract

Gene transfer to the outflow tract

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

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