Self-complementary AAV Virus (scAAV) Safe and Long-term Gene Transfer in the Trabecular Meshwork of Living Rats and Monkeys

Buie, LaKisha K.; Rasmussen, Carol A.; C., Porterfield, Eric; Ramgolam, Vinod S.; Choi, Vivian W.; Marković-Pleše, Silva; Samulski, R. Jude; Kaufman, Paul L.; Borrás, Teresa

doi:10.1167/iovs.09-3847

Cited by 88 publications

(88 citation statements)

References 51 publications

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“…By incorporating a second self-complementary DNA strand into these vectors (scAAV), these viruses have been shown to be significantly more efficient in transducing target cells, with the disadvantage of a reduction in the size of their DNA handling capacity [197]. While standard AAV constructs transfect but do not appear to be expressed in cells of the conventional outflow pathway, highly efficient expression has been demonstrated via the use of scAAV [198]. Rapid and widespread transfection of the TM has been demonstrated following intracameral inoculation of GFPexpressing scAAV2 constructs in both rats and nonhuman primates, with expression lasting in rats for greater than 3.5 months and in monkeys for at least 2.35 years.…”

Section: On the Development Of Genetic Therapiesmentioning

confidence: 99%

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

O’Callaghan

Cassidy

Humphries

2017

Expert Opinion on Therapeutic Targets

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Introduction:Ocular hypertension in open-angle glaucoma is caused by a reduced rate of removal of aqueous humour (AH) from the eye, with the majority of AH draining from the anterior chamber through the conventional outflow pathway, comprising the trabecular meshwork (TM) and Schlemm's Canal. Resistance to outflow is generated, in part, by the extracellular matrix (ECM) of the outflow tissues. Current pressure-lowering topical medications largely suppress AH production, or enhance its clearance through the unconventional pathway. However, therapies targeting the ECM of the conventional pathway in order to decrease intraocular pressure have become a recent focus of attention. Areas covered: We discuss the role of ECM of the TM in outflow homeostasis and its relevance as a target for glaucoma therapy, including progress in development of topical eye formulations, together with gene therapy approaches based on inducible, virally-mediated expression of matrix metalloproteinases to enhance aqueous outflow. Expert opinion: There remains a need for improved glaucoma medications that more specifically act upon sites causative to glaucoma pathogenesis. Emerging strategies targeting the ECM of the conventional outflow pathway, or associated components of the cytoskeleton of TM cells, involving new pharmacological formulations or genetically-based therapies, are promising avenues of future glaucoma treatment. ARTICLE HISTORY

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Section: On the Development Of Genetic Therapiesmentioning

confidence: 99%

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

O’Callaghan

Cassidy

Humphries

2017

Expert Opinion on Therapeutic Targets

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“…9 Viral vectors (FIV and scAAV) encoding genes for green fluorescent protein (GFP) show long-term (2 + years) expression in the outflow pathways of nonhuman primate eyes following transcorneal intracameral injection. 15,16 Transcorneal intracameral injection has been the method of choice for transferring transgenes/vectors into the anterior chamber (AC) of the eye. Successful transgene expression has been achieved using this route in rats, cats, and monkeys.…”

Section: Gene Therapy For Decreasing Outflow Resistancementioning

confidence: 99%

“…Successful transgene expression has been achieved using this route in rats, cats, and monkeys. 5,[13][14][15][16]25,26 Disadvantages of the intracameral route for transgene injection are the potential for clinically significant inflammation and possible transgene expression (a concern with high virus titers) in other anterior segment structures, such as the cornea and iris. 16 With most drug delivery methods, for example, topical drops, implants, and others, nontarget tissues are exposed to the active compound.…”

Section: Gene Therapy For Decreasing Outflow Resistancementioning

confidence: 99%

“…3 In recent years, the possibility of decreasing this outflow resistance via gene therapy using TM/SC-targeted transgene delivery systems has generated considerable interest. [4][5][6][7][8][9][10][11][12][13][14][15][16] We hypothesized that a canaloplasty approach might also be used for localized transgene delivery into this region. In this article, we have briefly reviewed canaloplasty surgery and discuss its possible role in transgene delivery into the SC.…”

Section: Introductionmentioning

confidence: 99%

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Application of Canaloplasty in Glaucoma Gene Therapy: Where Are We?

Aktaş

Tian

McDonald

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Schlemm's canal (SC) inner wall is adjacent to the juxtacanalicular trabecular meshwork (TM) over their entire circumference. We seek to transfer reporter and therapeutic genes to these outflow-modulating tissues via canaloplasty surgery in live monkeys. Methods: A standard canaloplasty surgical approach was performed in cynomolgus monkeys using flexible canaloplasty catheters, modified for monkey eyes with a 175-mm outer diameter and an LED-lighted tip. A 6-0 prolene suture was used for the exact localization of SC. Trypan blue was injected during catheter withdrawal to document catheter placement within SC and to determine ease of injecting fluid into SC. Before, during, and after the injection, the position of the catheter and the anatomic details were video-captured with an externally positioned noncontact endoscopic imaging system and 50 mHz ultrasound biomicroscopy (UBM). Results: A 360°catheterization and injection of dye into SC was achieved. Suture, catheter, and trypan blue were imaged with the endoscope camera system and the catheter was also visualized with UBM. Trypan blue was seen in the SC over 5 clock hours after a 1 clock-hour insertion of the catheter. Conclusions: A modified canaloplasty catheter device might be used for gene delivery to the SC/TM area without circumferential catheterization. Further studies comparing different delivery methods of the vector/ transgene into the SC using canaloplasty are needed.

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“…Lentiviral vectors have been used to deliver COX-2, a regulator of prostaglandin formation, to increase uveal scleral outflow of fluid (112). Self-complementary AAV has been shown to provide safe and long-term gene transfer to the trabecular meshwork in living rats and monkeys, making stable expression with minimal risks possible (113). Finally, intravitreal injection of viral constructs carrying neurotrophic factors have also successfully prevented ganglion cell loss in animal models of glaucoma (107), suggesting that viral gene-based therapy may be a viable approach to protect ganglion cells in glaucoma patients.…”

Section: Figurementioning

confidence: 99%

Glaucoma: genes, phenotypes, and new directions for therapy

Fan

Wiggs²

2010

J. Clin. Invest.

128

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Glaucoma, a leading cause of blindness worldwide, is characterized by progressive optic nerve damage, usually associated with intraocular pressure. Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are currently poorly understood and current therapeutic strategies are not curative. This review summarizes the human genetics and genomic approaches that have shed light on the complex inheritance of glaucoma genes and the potential for gene-based and cellular therapies that this research makes possible.

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Self-complementary AAV Virus (scAAV) Safe and Long-term Gene Transfer in the Trabecular Meshwork of Living Rats and Monkeys

Abstract: The scAAV viral vector provides prolonged and safe transduction in the trabecular meshwork of rats and monkeys. The stable expression and safe properties of this vector could facilitate the development of trabecular meshwork drugs for gene therapy for glaucoma.

Cited by 88 publications

References 51 publications

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

Application of Canaloplasty in Glaucoma Gene Therapy: Where Are We?

Glaucoma: genes, phenotypes, and new directions for therapy

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