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Glaucoma Dialogue IGR 12-2

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Comment by Terete Borras on:

26161 Adenoviral gene transfer of active human transforming growth factor-{beta}2 elevates intraocular pressure and reduces outflow facility in rodent eyes, Shepard AR; Millar JC; Pang IH et al., Investigative Ophthalmology and Visual Science, 2010; 51: 2067-2076

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This article by first author Shepard and senior author Clark is of a high quality that has become characteristic for this author team. It elegantly combines a breath of tools and strategies to carefully answer a single question:does TGF-β2 increase IOP by reducing outflow? The answer is a convincing yes. This simple question has surprisingly complex implications. There is increasing evidence that TGF-β plays a key role in the unsolved mystery of why outflow progressively fails in POAG. The fact that expression of bioactive TGF-β2 increased IOP in both rats and mice suggest that we are very close to a realistic POAG animal model that mimics the major risk factors of elevated IOP and decreased outflow.

The authors use cesium gradient purified adenoviral vectors and appropriate controls to deliver TGF-β2 (226/228) that has two point mutations rendering it spontaneously active as it cannot bind to the latency-associated peptide. After tissue culture testing, two to five microliter boluses of normalized vector preps were injected into eyes of rats and mice resulting in near doubling of IOP from 13 to 26 mmHg and a 30% drop of outflow facility within days of verified expression. A limited pathway analysis showed that downstream effector molecules of TGF-β2 are upregulated. Corneal edema shows that transduction is not limited to the TM, but appropriate controls proof proper IOP measurements.

As Shepard et al. state, the next step will be long-term expression and lack of toxicity that remains elusive with adenoviral vectors. This may be best achieved with lentiviral (e.g., FIV, HIV or EIAV) vectors capable of packaging the 2570 base pair long TGF-β2. The authors suggest adeno-associated viral (AAV) vectors but overlook that targeting the TM would require use of recently described selfcomplementary AAV that drastically limit cargo to 2200 base pairs.

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