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Editors Selection IGR 9-1

Medical Treatment: Prostaglandin pathway gene therapy

Comment by Paul Kaufman on:

24688 Prostaglandin Pathway Gene Therapy for Sustained Reduction of Intraocular Pressure, Barraza RA; McLaren JW; Poeschla EM, Molecular Therapy, 2010; 18: 491-501

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PGF2α-analogues delivered as topical eyedrops are mainstays of oculohypotensive therapy for glaucoma. They mimic and amplify the effect of a naturally occurring biosynthesis‐receptor‐ signal transduction‐tissue response pathway that markedly enhances aqueous humor outflow, primarily via the uveoscleral pathway. However, these agents must be self-administered daily by the patient, raising wellknown compliance and ocular surface issues. The concept of gene therapy, whereby cDNAs are delivered to target tissues to provide localized 'one time for all time' optimization and amplification of the system while removing the patient from the delivery 'apparatus' has been attractive for some time.

The important and beautifully done paper by Barraza et al. (1643) brings us closer to this 'holy grail,' giving some insight into the elements and workings of the prostaglandin synthesis and response pathways and also into the potential clinical utility and safety of viral vector mediated gene transfer. Briefly, elements of the prostaglandin biosynthesis and response pathways were introduced, singly and in combination, into the anterior chambers of cats. Elements were a codon-optimized COX-2 (COX-2), PGF synthase (PGFS) and the FP receptor (FPS). Each cat received one or more FIV/GFP/prostaglandin element vectors OD and FIV/GFP OS. The eyes remained quiet, and eyes that received the combinations of COX-2+PGFS+FPR or COX-2+FPR showed the largest, sustained decrease in IOP, lasting for at least five months when the experiment ended. Having PGFS in the construct did not seem to provide additional IOP lowering, indicating that PGFS may not be needed if COX2 and the FP receptor are present in abundance. There was no effect on aqueous production. It cannot be determined which outflow pathway was affected, or to what degree. While transduction was largely seen in the TM, there was detectable expression in the ciliary NPE; no mention was made of expression in the ciliary muscle. COX-2 is absent from the ciliary NPE in POAG and steroid induced human glaucoma eyes, but present in NPE from normal and from angle closure and congenital glaucoma eyes. Whatever the target tissue, the authors posit that enhanced expression of the system components, especially the receptor, by the transduced cDNAs may also enhance responsiveness to topical PGF2α analogues. Interestingly, no major increase in PGF2α was seen in the aqueous humor; levels were below detection threshold for the assay.

The trabecular meshwork and ciliary muscle are attractive targets because they are accessible, the amount of tissue is small and the eye's relative immunoprivileged nature reduces the risk of prohibitive immune responses

The ability to deliver a completely ectopic PG synthesis/response system for the long term that is functionally equivalent to topical drop therapies is a potential step forward in glaucoma therapeutics. Both viral and non-viral vectors have proponents. As noted in the paper, lentiviral vectors are able to integrate permanently in postmitotic cells, which is of particular interest in ophthalmology as many ocular tissues are terminally differentiated. Recent papers from our laboratory report long-term (1 to 2+ years), stable expression of reporter genes in monkeys with quiet eyes using both scAAV and FIV vectors. The former were in collaboration with the Borrás Laboratory at UNC, the latter with the Poeschla lab at Mayo. The TM and CM are attractive targets because they are accessible, the amount of tissue is small and the eye's relative immuno-privileged nature reduces the risk of prohibitive immune responses. The targeted transduction efficiency, quiet eyes and stable, long-term expression are pluses for this gene transfer strategy. The field of gene transfer in ocular therapeutics is continuing to advance, elucidating mechanisms and demonstrating safety and efficacy in carefully planned experiments such as this, and in carefully selected human trials.

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