The Experts below are selected from a list of 2772 Experts worldwide ranked by ideXlab platform
David T W Fei - One of the best experts on this subject based on the ideXlab platform.
-
pharmacokinetics and retinal distribution of ranibizumab a humanized antibody fragment directed against vegf a following Intravitreal Administration in rabbits
Retina-the Journal of Retinal and Vitreous Diseases, 2007Co-Authors: Jacques Gaudreault, David T W Fei, Vanessa Shiu, Joseph C Beyer, Anne M Ryan, Linda Rangell, Lisa A DamicoAbstract:Purpose Ranibizumab (Lucentis) is a humanized antigen-binding fragment designed to inhibit all isoforms and active degradation products of vascular endothelial growth factor A (VEGF-A); it is in clinical development for the treatment of neovascular age-related macular degeneration (AMD). This study evaluated its pharmacokinetics (PK) and retinal distribution in rabbits when administered Intravitreally (ITV). Methods A total of 27 New Zealand white rabbits received a single bilateral ITV injection of ranibizumab 625 muicrog/eye (Group 1, n = 24) or I-labeled ranibizumab 625 microg/eye, 22.5 microCi/eye (Group 2, n = 3). Ranibizumab concentration was determined in the vitreous, aqueous humor, and serum up to 60 days postdose by enzyme-linked immunosorbent assay in Group 1. Group 2 eyes were microautoradiographed on days 1-4. Results Ranibizumab has a terminal half-life of 2.9 days in the ocular compartments. Systemic exposure was low, measuring less than 0.01% of vitreous exposure when comparing AUC0-t values. Microautoradiography analysis demonstrated that ranibizumab penetrated all retinal layers, reaching the choriocapillaris on days 1, 2, and 4. Conclusions This study demonstrates that following ITV injection, ranibizumab has a vitreous half-life of 2.9 days with minimal systemic exposure. Ranibizumab rapidly penetrates through the retina to reach the choroid, supporting its clinical development for neovascular AMD.
-
preclinical pharmacokinetics of ranibizumab rhufabv2 after a single Intravitreal Administration
Investigative Ophthalmology & Visual Science, 2005Co-Authors: Jacques Gaudreault, David T W Fei, Jeriza Rusit, Pamela Suboc, Vanessa ShiuAbstract:PURPOSE Ranibizumab (rhuFab V2; Lucentis, Genentech, South San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all forms of VEGF, thereby blocking vessel permeability and angiogenesis in neovascular age-related macular degeneration. This study evaluated the pharmacokinetic (PK) and serum bioavailability of ranibizumab after a single Intravitreal (ITV) or intravenous (IV) dose in cynomolgus monkeys. METHODS Monkeys received ranibizumab as either a bilateral ITV dose (500 or 2000 microg/eye; n = 6/group) or a single IV dose (1000 or 4000 microg/animal; n = 4/group). After ITV Administration, ranibizumab concentrations were measured in several ocular compartments and in serum for 10 days and, after IV Administration, for 48 hours. Pharmacokinetic parameters were estimated by compartmental and noncompartmental methods. RESULTS Ranibizumab cleared in parallel from all ocular compartments, with a terminal half-life of approximately 3 days. It distributed rapidly to the retina (6-24 hours), and concentrations were approximately one third that in the vitreous. After ITV injection, bioavailability (F) was 50% to 60%. Serum concentrations were very low, reflecting wider distribution and faster clearance when ranibizumab reached the serum. After IV Administration, the terminal half-life was approximately 0.5 day. CONCLUSIONS This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.
-
comparisons of the intraocular tissue distribution pharmacokinetics and safety of 125i labeled full length and fab antibodies in rhesus monkeys following Intravitreal Administration
Toxicologic Pathology, 1999Co-Authors: Joyce Mordenti, Andrew R Cuthbertson, Napoleone Ferrara, Karen Thomsen, Lea T Berleau, Vojtech Licko, Philip C Allen, Celia R Valverde, Gloria Y Meng, David T W FeiAbstract:Access of recombinant proteins to the retina following Intravitreal Administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to co...
-
comparisons of the intraocular tissue distribution pharmacokinetics and safety of 125i labeled full length and fab antibodies in rhesus monkeys following Intravitreal Administration
Toxicologic Pathology, 1999Co-Authors: Joyce Mordenti, Napoleone Ferrara, Karen Thomsen, Lea T Berleau, Vojtech Licko, Philip C Allen, Celia R Valverde, R A Cuthbertson, Y G Meng, David T W FeiAbstract:Access of recombinant proteins to the retina following Intravitreal Administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus Intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter Intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.
Heleen Dewitte - One of the best experts on this subject based on the ideXlab platform.
-
non viral delivery of chemically modified mrna to the retina subretinal versus Intravitreal Administration
Journal of Controlled Release, 2019Co-Authors: Joke Devoldere, Karen Peynshaert, Heleen Dewitte, Christian Vanhove, Lies De Groef, Lieve Moons, Sinem Yilmaz Ozcan, Deniz DalkaraAbstract:mRNA therapeutics have recently experienced a new wave of interest, mainly due to the discovery that chemical modifications to mRNA's molecular structure could drastically reduce its inherent immunogenicity and perceived instability. On this basis, we aimed to explore the potential of chemically stabilized mRNA for ocular applications. More specifically, we investigated the behavior of mRNA-loaded lipid-based carriers in human retinal cells (in vitro), in bovine retinal explants (ex vivo) and in mouse retinas (in vivo). We demonstrate a clear superiority of mRNA over pDNA to induce protein expression in different retinal cell types, which was further enhanced by chemical modification of the mRNA, providing up to ~1800-fold higher reporter gene expression compared to pDNA. Moreover, transgene expression could be detected for at least 20 days after a single Administration of chemically modified mRNA in vitro. We furthermore determined the localization and extent of mRNA expression depending on the Administration route. After subretinal (SR) Administration, mRNA expression was observed in vivo and ex vivo. By contrast, Intravitreal (IVT) Administration resulted in limited expression in vivo. Using ex vivo bovine explants with an intact vitreoretinal (VR) interface we could attribute this to the inner limiting membrane (ILM), which presents a large barrier for non-viral delivery of mRNA, trapping mRNA complexes at the vitreal side. When the vitreous was removed, which compromises the ILM, mRNA expression was apparent and seemed to colocalize with Muller cells or photoreceptors after respectively IVT or SR Administration. Taken together, this study represents a first step towards mRNA-mediated therapy for retinal diseases.
Paul A. Sieving - One of the best experts on this subject based on the ideXlab platform.
-
trans ocular electric current in vivo enhances aav mediated retinal transduction in large animal eye after Intravitreal vector Administration
Translational Vision Science & Technology, 2020Co-Authors: Hongman Song, Yong Zeng, Haohua Qian, Paul A. Sieving, Ronald A. Bush, Henry E. Wiley, Camasamudram Vijayasarathy, Sheik Pran Babu Sardar Pasha, Lisa WeiAbstract:Author(s): Song, Hongman; Zeng, Yong; Sardar Pasha, Sheik Pran Babu; Bush, Ronald A; Vijayasarathy, Camasamudram; Qian, Haohua; Wei, Lisa; Wiley, Henry E; Wu, Zhijian; Sieving, Paul A | Abstract: PurposeElectric micro-current has been shown to enhance penetration and transduction of adeno-associated viral (AAV) vectors in mouse retina after Intravitreal Administration. We termed this: "electric-current vector mobility (ECVM)." The present study considered whether ECVM could augment retinal transduction efficiency of Intravitreal AAV8-CMV-EGFP in normal rabbit and nonhuman primate (NHP) macaque. Potential mechanisms underlying enhanced retinal transduction by ECVM were also studied.MethodsWe applied an electric micro-current across the intact eye of normal rabbit and monkey in vivo for a brief period immediately after Intravitreal injection of AAV8-CMV-EGFP. Retinal GFP expression was evaluated by fundus imaging in vivo. Retinal immunohistochemistry was performed to assess the distribution of retinal cells transduced by the AAV8-EGFP. Basic fibroblast growth factor (bFGF) was analyzed by quantitative RT-polymerase chain reaction (PCR). Muller glial reactivity and inner limiting membrane (ILM) were examined by the glial fibrillary acidic protein (GFAP) and vimentin staining in mouse retina, respectively.ResultsECVM significantly increased the efficiency of AAV reaching and transducing the rabbit retina following Intravitreal injection, with gene expression in inner nuclear layer, ganglion cells, and Muller cells. Similar trend of improvement was observed in the ECVM-treated monkey eye. The electric micro-current upregulated bFGF expression in Muller cells and vimentin showed ILM structural changes in mouse retina.ConclusionsECVM promotes the transduction efficiency of AAV8-CMV-GFP in normal rabbit and monkey retinas following Intravitreal injection.Translational relevanceThis work has potential translational relevance to human ocular gene therapy by increasing retinal expression of therapeutic vectors given by Intravitreal Administration.
-
AAVrh-10 transduces outer retinal cells in rodents and rabbits following Intravitreal Administration.
Gene Therapy, 2019Co-Authors: Yong Zeng, Haohua Qian, Dario Marangoni, Paul A. Sieving, Ronald A. BushAbstract:Recombinant adeno-associated virus (rAAV) has been widely used for gene delivery in animal models and successfully applied in clinical trials for treating inherited retinal disease. Although subretinal delivery of AAVs can effectively transduce photoreceptors and/or retinal pigmental epithelium (RPE), cells most affected by inherited retinal diseases, the procedure is invasive and complicated, and only delivers the gene to a limited retinal area. AAVs can also be delivered Intravitreally to the retina, a much less invasive nonsurgical procedure. However, Intravitreal Administration of non-modified AAV serotypes tends to transduce only ganglion cells and inner nuclear layer cells. To date, most non-modified AAV serotypes that have been identified are incapable of efficiently transducing photoreceptors and/or RPE when delivered Intravitreally. In this study, we investigate the retinal tropism of AAVrh10 vector administered by Intravitreal injection to mouse, rat, and rabbit eyes. Our results demonstrate that AAVrh10 is capable of transducing not only inner retinal cells, but also outer retinal cells in all three species, though the transduction efficiency in rabbit was low. In addition, AAVrh10 preferentially transduced outer retinal cells in mouse models of retinal disease. Therefore, AAVrh10 vector could be a useful candidate to Intravitreally deliver genes to photoreceptor and RPE cells.
-
preclinical safety evaluation of a recombinant aav8 vector for x linked retinoschisis after Intravitreal Administration in rabbits
Human gene therapy. Clinical development, 2014Co-Authors: Dario Marangoni, Yong Zeng, Ronald A. Bush, Henry E. Wiley, Caroline J. Zeiss, Camasamudram Vijayasarathy, Suja Hiriyanna, Lisa L. Wei, Peter Colosi, Paul A. SievingAbstract:X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and one of the most common causes of macular degeneration in young men. Currently, no FDA-approved treatments are available for XLRS and a replacement gene therapy could provide a promising strategy. We have developed a novel gene therapy approach for XLRS, based on the Administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the Intravitreal route. On the basis of our prior study in an Rs1-KO mouse, this construct transduces efficiently all the retinal layers, resulting in an RS1 expression similar to that observed in the wild-type and improving retinal structure and function. In support of a clinical trial, we carried out a study to evaluate the ocular safety of Intravitreal Administration of AAV8-scRS/IRBPhRS into 39 New Zealand White rabbits. Two dose levels of vector, 2e(10) and 2e(11) vector genomes per eye (vg/eye), were tested and ocular inflammation was monitored over a 12-week period by serial ophthalmological and histopathological analysis. A mild ocular inflammatory reaction, consisting mainly of vitreous infiltrates, was observed within 4 weeks from injection, in both 2e(10) and 2e(11) vg/eye groups and was likely driven by the AAV8 capsid. At 12-week follow-up, ophthalmological examination revealed no clinical signs of vitreitis in either of the dose groups. However, while vitreous inflammatory infiltrate was significantly reduced in the 2e(10) vg/eye group at 12 weeks, some rabbits in the higher dose group still showed persistence of inflammatory cells, histologically. In conclusion, Intravitreal Administration of AAV8-scRS/IRBPhRS into the rabbit eye produces a mild and transient intraocular inflammation that resolves, at a 2e(10) vg/eye dose, within 3 months, and does not cause irreversible tissue damages. These data support the initiation of a clinical trial of Intravitreal Administration of AAV8-scRS/IRBPhRS in XLRS patients.
Ronald A. Bush - One of the best experts on this subject based on the ideXlab platform.
-
trans ocular electric current in vivo enhances aav mediated retinal transduction in large animal eye after Intravitreal vector Administration
Translational Vision Science & Technology, 2020Co-Authors: Hongman Song, Yong Zeng, Haohua Qian, Paul A. Sieving, Ronald A. Bush, Henry E. Wiley, Camasamudram Vijayasarathy, Sheik Pran Babu Sardar Pasha, Lisa WeiAbstract:Author(s): Song, Hongman; Zeng, Yong; Sardar Pasha, Sheik Pran Babu; Bush, Ronald A; Vijayasarathy, Camasamudram; Qian, Haohua; Wei, Lisa; Wiley, Henry E; Wu, Zhijian; Sieving, Paul A | Abstract: PurposeElectric micro-current has been shown to enhance penetration and transduction of adeno-associated viral (AAV) vectors in mouse retina after Intravitreal Administration. We termed this: "electric-current vector mobility (ECVM)." The present study considered whether ECVM could augment retinal transduction efficiency of Intravitreal AAV8-CMV-EGFP in normal rabbit and nonhuman primate (NHP) macaque. Potential mechanisms underlying enhanced retinal transduction by ECVM were also studied.MethodsWe applied an electric micro-current across the intact eye of normal rabbit and monkey in vivo for a brief period immediately after Intravitreal injection of AAV8-CMV-EGFP. Retinal GFP expression was evaluated by fundus imaging in vivo. Retinal immunohistochemistry was performed to assess the distribution of retinal cells transduced by the AAV8-EGFP. Basic fibroblast growth factor (bFGF) was analyzed by quantitative RT-polymerase chain reaction (PCR). Muller glial reactivity and inner limiting membrane (ILM) were examined by the glial fibrillary acidic protein (GFAP) and vimentin staining in mouse retina, respectively.ResultsECVM significantly increased the efficiency of AAV reaching and transducing the rabbit retina following Intravitreal injection, with gene expression in inner nuclear layer, ganglion cells, and Muller cells. Similar trend of improvement was observed in the ECVM-treated monkey eye. The electric micro-current upregulated bFGF expression in Muller cells and vimentin showed ILM structural changes in mouse retina.ConclusionsECVM promotes the transduction efficiency of AAV8-CMV-GFP in normal rabbit and monkey retinas following Intravitreal injection.Translational relevanceThis work has potential translational relevance to human ocular gene therapy by increasing retinal expression of therapeutic vectors given by Intravitreal Administration.
-
AAVrh-10 transduces outer retinal cells in rodents and rabbits following Intravitreal Administration.
Gene Therapy, 2019Co-Authors: Yong Zeng, Haohua Qian, Dario Marangoni, Paul A. Sieving, Ronald A. BushAbstract:Recombinant adeno-associated virus (rAAV) has been widely used for gene delivery in animal models and successfully applied in clinical trials for treating inherited retinal disease. Although subretinal delivery of AAVs can effectively transduce photoreceptors and/or retinal pigmental epithelium (RPE), cells most affected by inherited retinal diseases, the procedure is invasive and complicated, and only delivers the gene to a limited retinal area. AAVs can also be delivered Intravitreally to the retina, a much less invasive nonsurgical procedure. However, Intravitreal Administration of non-modified AAV serotypes tends to transduce only ganglion cells and inner nuclear layer cells. To date, most non-modified AAV serotypes that have been identified are incapable of efficiently transducing photoreceptors and/or RPE when delivered Intravitreally. In this study, we investigate the retinal tropism of AAVrh10 vector administered by Intravitreal injection to mouse, rat, and rabbit eyes. Our results demonstrate that AAVrh10 is capable of transducing not only inner retinal cells, but also outer retinal cells in all three species, though the transduction efficiency in rabbit was low. In addition, AAVrh10 preferentially transduced outer retinal cells in mouse models of retinal disease. Therefore, AAVrh10 vector could be a useful candidate to Intravitreally deliver genes to photoreceptor and RPE cells.
-
preclinical safety evaluation of a recombinant aav8 vector for x linked retinoschisis after Intravitreal Administration in rabbits
Human gene therapy. Clinical development, 2014Co-Authors: Dario Marangoni, Yong Zeng, Ronald A. Bush, Henry E. Wiley, Caroline J. Zeiss, Camasamudram Vijayasarathy, Suja Hiriyanna, Lisa L. Wei, Peter Colosi, Paul A. SievingAbstract:X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and one of the most common causes of macular degeneration in young men. Currently, no FDA-approved treatments are available for XLRS and a replacement gene therapy could provide a promising strategy. We have developed a novel gene therapy approach for XLRS, based on the Administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the Intravitreal route. On the basis of our prior study in an Rs1-KO mouse, this construct transduces efficiently all the retinal layers, resulting in an RS1 expression similar to that observed in the wild-type and improving retinal structure and function. In support of a clinical trial, we carried out a study to evaluate the ocular safety of Intravitreal Administration of AAV8-scRS/IRBPhRS into 39 New Zealand White rabbits. Two dose levels of vector, 2e(10) and 2e(11) vector genomes per eye (vg/eye), were tested and ocular inflammation was monitored over a 12-week period by serial ophthalmological and histopathological analysis. A mild ocular inflammatory reaction, consisting mainly of vitreous infiltrates, was observed within 4 weeks from injection, in both 2e(10) and 2e(11) vg/eye groups and was likely driven by the AAV8 capsid. At 12-week follow-up, ophthalmological examination revealed no clinical signs of vitreitis in either of the dose groups. However, while vitreous inflammatory infiltrate was significantly reduced in the 2e(10) vg/eye group at 12 weeks, some rabbits in the higher dose group still showed persistence of inflammatory cells, histologically. In conclusion, Intravitreal Administration of AAV8-scRS/IRBPhRS into the rabbit eye produces a mild and transient intraocular inflammation that resolves, at a 2e(10) vg/eye dose, within 3 months, and does not cause irreversible tissue damages. These data support the initiation of a clinical trial of Intravitreal Administration of AAV8-scRS/IRBPhRS in XLRS patients.
-
Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after Intravitreal Administration in rabbits.
Human Gene Therapy Clinical Development, 2014Co-Authors: Dario Marangoni, Yong Zeng, Ronald A. Bush, Henry E. Wiley, Caroline J. Zeiss, Camasamudram Vijayasarathy, Suja Hiriyanna, Lisa L. Wei, Peter ColosiAbstract:Abstract X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and one of the most common causes of macular degeneration in young men. Currently, no FDA-approved treatments are available for XLRS and a replacement gene therapy could provide a promising strategy. We have developed a novel gene therapy approach for XLRS, based on the Administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the Intravitreal route. On the basis of our prior study in an Rs1-KO mouse, this construct transduces efficiently all the retinal layers, resulting in an RS1 expression similar to that observed in the wild-type and improving retinal structure and function. In support of a clinical trial, we carried out a study to evaluate the ocular safety of Intravitreal Administration of AAV8-scRS/IRBPhRS into 39 New Zealand White rabbits. Two dose levels of vector, 2e10 and 2e11 vector genomes per eye (vg/eye), were test...
Szilard Kiss - One of the best experts on this subject based on the ideXlab platform.
-
analysis of aflibercept expression in nhps following Intravitreal Administration of advm 022 a potential gene therapy for namd
Molecular therapy. Methods & clinical development, 2020Co-Authors: Szilard Kiss, Ruslan Grishanin, Judith S. Greengard, Claire M. Gelfman, Aivan Nguyen, Romeo Rosario, Julio Nieves, Mehdi GasmiAbstract:Several standard-of-care therapies for the treatment of retinal disease, including aflibercept, inhibit vascular endothelial growth factor (VEGFA). The main shortcoming of these therapies is potential undertreatment due to a lack of compliance resulting from the need for repeated injections. Gene therapy may provide sustained levels of anti-VEGFA proteins in the retina following a single injection. In this nonhuman primate study, we explored whether ADVM-022, a recombinant adeno-associated virus (AAV) vector designed to express aflibercept, could induce anti-VEGFA protein levels comparable with those observed following a single-bolus Intravitreal (IVT) injection of the standard-of-care aflibercept recombinant protein. The results demonstrated that intraocular levels of aflibercept measured at 56 days after a single IVT injection of ADVM-022 were equivalent to those in the aflibercept recombinant protein-injected animals measured 21–32 days post-Administration. ADVM-022-injected animals exhibited signs of an initial self-limiting inflammatory response, but overall all doses were well tolerated. ADVM-022 Administration did not result in systemic exposure to aflibercept at any dose evaluated. These results demonstrated that a single IVT injection of ADVM-022 resulted in safe and efficacious aflibercept levels in the therapeutic range, suggesting the potential of a gene therapy approach for long-term treatment of retinal disease with anti-VEGF therapy.
-
Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration.
Molecular Therapy, 2019Co-Authors: Ruslan Grishanin, Brian Vuillemenot, Pallavi Sharma, Annahita Keravala, Judith S. Greengard, Claire M. Gelfman, Mark Blumenkrantz, Matthew Lawrence, Szilard KissAbstract:Inhibition of vascular endothelial growth factor, a key contributor to the choroidal neovascularization associated with wet age-related macular degeneration, is the mode of action of several approved therapies, including aflibercept, which requires frequent Intravitreal injections to provide clinical benefit. Lack of compliance with the dosing schedule may result in recurrence of active wet macular degeneration, leading to irreversible vision impairment. Gene therapy providing sustained anti-vascular endothelial growth factor levels in the retina following a single injection could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, is optimized for Intravitreal delivery and strong protein expression. Here, we report the long-term expression and efficacy of ADVM-022-derived aflibercept in a laser-induced choroidal neovascularization model in non-human primates. Intravitreal Administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels. In addition, ADVM-022 Administration 13 months before lasering prevented the occurrence of clinically relevant choroidal neovascularization lesions, similar to animals that received a bolus of Intravitreal aflibercept (standard of care) at the time of lesioning. These results demonstrate that a single Intravitreal Administration of ADVM-022 may provide a safe and effective long-term treatment option for wet macular degeneration and may ultimately improve patients’ visual outcomes.
-
Persistent Suppression of Ocular Neovascularization with Intravitreal Administration of AAVrh.10 Coding for Bevacizumab
Human Gene Therapy, 2011Co-Authors: Yanxiong Mao, Szilard Kiss, Julie L. Boyer, Neil R. Hackett, Jianping Qiu, Andrew Carbone, Jason G. Mezey, Stephen M. Kaminsky, Donald J. D'amico, Ronald G. CrystalAbstract:Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. Bevacizumab, an anti-VEGF monoclonal antibody, is efficacious for these disorders, but requires monthly Intravitreal Administration, with associated discomfort, cost, and adverse event risk. We hypothesized that a single Intravitreal Administration of adeno-associated virus (AAV) vector expressing bevacizumab would result in persistent eye expression of bevacizumab and suppress VEGF-induced retinal neovascularization. We constructed an AAV rhesus serotype rh.10 vector to deliver bevacizumab (AAVrh.10BevMab) and assessed its ability to suppress neovascularization in transgenic mice overexpressing human VEGF165 in photoreceptors. Intravitreal AAVrh.10BevMab directed long-term bevacizumab expression in the retinal pigmented epithelium. Treated homozygous mice had reduced levels of neovascularization, with 90±4% reduction 168 days following treatment. Thus, a single Administration of AAVrh.10BevMab provides long-term suppression of neovascularization without the costs and risks associated with the multiple Administrations required for the current conventional bevacizumab monoclonal drug delivery.
