GenVec abstracts from ARVO; doesn't look earth-shattering. There's a PI trial for AMD that started last November, I believe. Don't know when results are due. Since these proof of concept studies look promising, I would expect the trial results to show some kind of response, but of course, everyone is concerned with gene therapy safety wih adenovectors . . .
>>Abstract Title: Adenoviral Gene Delivery for the Treatment of Ocular Diseases
Presentation Start: Sunday, May 04, 2003, 10:30 AM -12:30 PM
Reviewing Code: 220 retina/RPE: gene transfer/gene therapy - BI
Author Block: D.L. McVey1A, L.L. L. Wei1B, C.Hsu1A, M.Hamilton1B, C.King1B, D.E. Brough1A. AMolecular Virology, BNew Products Research, 1GenVec, Inc., Gaithersburg, MD.
Keywords: 420 gene transfer/gene therapy,417 gene/expression,307 adenovirus
Purpose: Adenoviral vectors expressing PEDF have been shown to be efficacious in preclinical models of age-related macular degeneration and diabetic retinopathy. In these studies an adenoviral vector deleted in the E1, E3, and E4 regions expressing PEDF from a CMV promoter was used. We have demonstrated that expression of PEDF from this vector is transient with peak levels achieved at day one rapidly declining to undetectable levels in 14 days. In the current studies we set out to determine if changing the promoter could increase the persistence of transgene expression from adenovirus vectors delivered intravitreally into the eye.
Methods: In this study, replication-deficient adenovirus vectors were generated that differed only by incorporation of different promoters upstream of a luciferase marker gene. Intravitreal injections were made into mouse eyes in a total volume of 2 ul to deliver a dose of between 1e7 and 1e9 total vector particles. Luciferase levels were monitored on days 1, 14 and 28.
Results/Conclusions: The highest initial level of protein expression was observed when the CMV promoter is driving protein expression. Three different expression profiles were defined in which expression either decreased, remained relatively stable or increased with time. These results indicate that alteration of the promoter contained within an adenovirus vector can result in prolonged expression of a transgene following intravitreal delivery. This may allow for the construction of adenovirus vectors with prolonged expression of anti-angiogenic factors such as PEDF.
Abstract Title: Adenoviral Vector Genome Evaluation after Intravitreal Administration
Presentation Start: Sunday, May 04, 2003, 10:30 AM -12:30 PM
Reviewing Code: 220 retina/RPE: gene transfer/gene therapy - BI
Author Block: D.E. Brough1A, D.L. McVey1A, L.L. Wei1B, C.Hsu1A, C.King1B. AMolecular Virology, BNew Products Research, 1GenVec, Inc., Gaithersburg, MD.
Keywords: 420 gene transfer/gene therapy,417 gene/expression,307 adenovirus
Purpose: Preclinical data has indicated that expression of PEDF from an adenoviral vector has promise as an experimental treatment for ocular neovascular disease. Expression of many genes under the direction of the CMV promoter in an adenoviral vector has been reported to be transient in nature lasting approximately 2 weeks after administration into the vitreous of the eye. The loss of expression could be due to the clearance of vector genomes from the eye or the shut off of expression from the vector genomes. To address these possible mechanisms we measured the presence of vector genomes after intravitreal delivery.
Methods: In this study, replication-deficient adenovirus deleted of E1, E4 and partially of E3 was delivered into the eyes of mice and the amount of vector genome was quantitated using a sensitive and specific quantitative PCR assay. A dose response for the genome in vitro and in vivo showed the sensitivity and reliability of the qPCR assay. Using this assay adenoviral vector genome was quantitated as a function of dose and time post administration.
Results/Conclusions: Our findings indicate that the level of vector genome in the eye at 1-day post administration correlated directly with the amount of vector particles administered. Interestingly, these data showed the amount of vector genomes remained remarkably constant for 28 days post administration while expression dropped rapidly. From these studies the transient nature of expression from adenoviral vectors appears to be due to expression shut off. These data suggest that adenoviral vectors may provide a means to deliver proteins to the eye requiring longer-term expression for the treatment of ocular disease.
Abstract Title: Safety of AdGVPEDF.11D Administered by Subtenon Injection Following Laser Disruption of the Bruch's Membrane in Cynomolgus Monkey Eyes
Presentation Start: Sunday, May 04, 2003, 10:30 AM -12:30 PM
Reviewing Code: 220 retina/RPE: gene transfer/gene therapy - BI
Author Block: A.C. Smith1, H.Rasmussen1, M.Wills2, R.Munger3, M.Tomlinson2, R.Durham1, P.Gelhbach4, L.Wei1. 1GenVec, Inc., Gaithersburg, MD; 2A Division of Charles River Laboratories, Inc., Sierra Biomedical, Sparks, NV; 3Animal Ophthalmology Clinic, Dallas, TX; 4Johns Hopkins, Baltimore, MD.
Keywords: 308 age-related macular degeneration,333 Bruch's membrane,307 adenovirus
Purpose: Antiangiogenic gene therapy has the potential to significantly advance therapy for age-related macular degeneration (AMD). PEDF (pigment epithelium-derived factor) is a potent endogenous inhibitor of ocular angiogenesis. In vivo studies have shown that adenoviral vectored PEDF (AdGVPEDF.11D) administered by subtenon injection, inhibits murine choroidal neovascularization. The safety of AdGVPEDF.11D given by subtenon injection was assessed in cynomolgus monkeys with laser-induced disruption of the Bruch's membrane in both eyes, a model that mimics the ocular condition of AMD.
Methods: After laser treatment, the right eye was given a subtenon injection (150 mL) of vehicle and the left eye was given a single subtenon injection (150 mL) of vehicle or single doses of 1 x108 pu, 1 x109 pu, and 1 x1010 pu of AdGVPEDF.11D. An additional group of animals were given a single subtenon dose of 1 x109 pu once every three weeks for a total of three doses in their left eye. Clinical evaluations, body weight, food consumption, clinical pathology, biomicroscopic and indirect ophthalmoscopic examinations, electroretinography (ERG), and presence of gross and microscopic pathologies were evaluated.
Results: There were no drug-related systemic or ocular toxicities associated with a single subtenon injection of AdGVPEDF.11D at doses of up to 1 x 1010 pu. There were no drug-related ophthalmologic or ERG changes observed in eyes treated with AdGVPEDF.11D. Repeat dosing (x3) of 1 x 109 pu did not result in any evidence of toxicity.
Conclusions: Single doses of up to 1 x 1010 pu or multiple doses of 1 x 109 pu of AdGVPEDF.11D given by subtenon injection were considered safe in a cynomolgus monkey eye with laser disruption of the Bruch's membrane.<<
Cheers, Tuck |
