Prospects for Lentiviral Vector Mediated Prostaglandin F Synthase Gene Delivery in Monkey Eyes<i>In vivo</i>

Lee, Eun Suk; Rasmussen, Carol A.; Filla, Mark S.; Slauson, Sarah R.; Kolb, Aaron W.; Peters, Donna M.; Kaufman, Paul L.; Gabelt, B’Ann T.; Brandt, Curtis R.

doi:10.3109/02713683.2014.884593

Cited by 21 publications

(22 citation statements)

References 57 publications

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“…4A (Barraza et al, 2010)). Using a similar approach in primate model to study prostaglandin pathway gene therapy for future human use, Lee et al transduced cynomolgus monkeys with bovine PGF synthase alone using FIV vectors and observed a significant IOP reduction for 5 months (Lee et al, 2014). …”

Section: Applicationsmentioning

confidence: 99%

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: Applicationsmentioning

confidence: 99%

Gene transfer to the outflow tract

Dang

Loewen

Parikh

et al. 2017

Experimental Eye Research

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“…70 Another gene of the prostaglandin pathway, the prostaglandin F synthase ( PGFS ) gene, also carried in a lentiviral vector, was injected in the intracameral compartment of monkeys and achieved IOP reduction for 5 months. 71 Although the response was weaker than that seen with conventional topical prostaglandin therapy in the monkey eye, 72 the authors discussed a number of potential parameters that could improve the gene therapy efficiency of PGFS under these conditions. 71 …”

Section: Trabecular Meshwork Targeting To Lower Iopmentioning

confidence: 99%

“…71 Although the response was weaker than that seen with conventional topical prostaglandin therapy in the monkey eye, 72 the authors discussed a number of potential parameters that could improve the gene therapy efficiency of PGFS under these conditions. 71 …”

Section: Trabecular Meshwork Targeting To Lower Iopmentioning

confidence: 99%

Post-Vitrectomy Endophthalmitis in Victoria, Australia

Borrás

2017

Asia Pac J Ophthalmol (Phila)

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Treatment of diseases with gene therapy is advancing rapidly. The use of gene therapy has expanded from the original concept of replacing the mutated gene causing the disease to the use of genes to control nonphysiological levels of expression or to modify pathways known to affect the disease. Genes offer numerous advantages over conventional drugs. They have longer duration of action and are more specific. Genes can be delivered to the target site by naked DNA, cells, nonviral, and viral vectors. The enormous progress of the past decade in molecular biology and delivery systems has provided ways for targeting genes to the intended cell/tissue and safe, long-term vectors. The eye is an ideal organ for gene therapy. It is easily accessible and it is an immune-privileged site. Currently, there are clinical trials for diseases affecting practically every tissue of the eye, including those to restore vision in patients with Leber congenital amaurosis. However, the number of eye trials compared with those for systemic diseases is quite low (1.8%). Nevertheless, judging by the vast amount of ongoing preclinical studies, it is expected that such number will increase considerably in the near future. One area of great need for eye gene therapy is glaucoma, where a long-term gene drug would eliminate daily applications and compliance issues. Here, we review the current state of gene therapy for glaucoma and the possibilities for treating the trabecular meshwork to lower intraocular pressure and the retinal ganglion cells to protect them from neurodegeneration.

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“…(67) Experiments injecting viral vectors encoding the cDNA for bovine PGF synthase in monkey eyes showed a significant decrease in IOP for 5 months. (68) Further work is needed to bring this promising technology to the clinic. Issues to be addresses include viral toxicity, regulation of gene expression - turning the gene on/off, immune/inflammatory responses and localization of transfection and/or gene activity.…”

Section: Gene Transfermentioning

confidence: 99%

Exciting directions in glaucoma

Rasmussen

Kaufman

2014

Canadian Journal of Ophthalmology

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Glaucoma is a complex, life-long disease that requires an individualized, multifaceted approach to treatment. Most patients will be started on topical ocular hypotensive eyedrop therapy and over time, multiple classes of drugs will be needed to control their intraocular pressure (IOP). The search for drugs with novel mechanisms of action, to treat those who do not achieve adequate IOP control with, or become refractory to, current therapeutics, is ongoing, as is the search for more efficient, targeted drug delivery methods. Gene transfer and stem cell applications for glaucoma therapeutics are moving forward. Advances in imaging technologies improve our understanding of glaucoma pathophysiology and enable more refined patient evaluation and monitoring, improving patient outcomes.

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Prospects for Lentiviral Vector Mediated Prostaglandin F Synthase Gene Delivery in Monkey EyesIn vivo

Cited by 21 publications

References 57 publications

Gene transfer to the outflow tract

Gene transfer to the outflow tract

Post-Vitrectomy Endophthalmitis in Victoria, Australia

Exciting directions in glaucoma

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