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ABSTRACT: Abstract Purpose: We recently demonstrated that direct subretinal (SR) injection of adeno-associated virus (AAV) type 8 (AAV8) into photoreceptor cells and retinal pigment epithelium (RPE) is a highly efficient model of gene delivery. The current study compared transduction efficiency and expression patterns associated with various routes of vector administration. Method: The efficacy of intravitreal (VT), SR and subconjunctival (SC) injections for delivery of AAV8-derived vectors, i.e. those expressing luciferase (Luc) and enhanced green fluorescent protein (GFP) - AAV8/Luc and AAV8/GFP, respectively - were compared in an animal (mouse) model (n = 8 mice/group). Transduction efficiency and expression patterns were examined at post-injection weeks 1 and 2, and months 1, 3, 6 and 12 via in vivo imaging. Results: One year after AAV injection, AAV8/Luc-treated mice exhibited stable and sustained high expression of vector in the VT and SR groups, but not in the SC group (VT:SR:SC = 3,218:2,923:115; 1 × 10(5 )photons/s). Histological analysis showed that GFP expression was observed in the inner retina of VT group mice, and in photoreceptor cells and RPE of SR group mice, whereas no GFP expression was noted in the SC group. Electroretinography (ERG) revealed adverse effects following SR delivery. Conclusions: Results suggest that both SR and VT injections of AAV8 vectors are useful routes for administering ocular gene therapy, and stress the importance of selecting an appropriate administration route, i.e. one that targets specific cells, for treating ocular disorders.
Current eye research 03/2013; · 1.51 Impact Factor
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ABSTRACT: Pterygium and conjunctivochalasis are common diseases in elderly people and are not uncommonly observed together. However, there have been few reports of the simultaneous treatment of pterygium and conjunctivochalasis. We report such a surgical method and describe the results of two cases. Two patients presented with pterygium accompanied by temporal conjunctivochalasis. We decided to perform simultaneous pterygium excision and free conjunctival autograft transfer using the excess conjunctiva from the conjunctivochalasis surgery. The free graft was obtained from the bulbar conjunctiva from the 6 to 8 o'clock position in the conjunctivochalasis. To reduce the temporal conjunctivochalasis, the conjunctiva was extended and sutured to the perilimbal conjunctiva and episclera at the 6 o'clock position using 8-0 polyglactin suture. Tear meniscus break-up induced by pterygium and by conjunctival laxity was reduced, and the patients' symptoms had been significantly reduced by several days postoperatively.
Journal of Nippon Medical School 01/2013; 80(1):74-7.
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ABSTRACT: Screening for anemia has been performed in schools in Japan for over 30 years. The long-term effect of the nuclear power plant disaster on the prevalence of anemia in school age children is unknown. This research was performed to evaluate the prevalence of anemia in school age children and to determine grade-level and gender-related reference hemoglobin (Hb) levels prior to the nuclear disaster. Data for this research were obtained from results of screening for anemia obtained by venous blood sampling in schools in 2002. Mean Hb levels were calculated for each grade level (elementary school grades 1-6 and junior high school years 1-3) and according to gender, and the prevalence of anemia was determined. In our research, Tokyo Health Service Association guidelines were used to determine reference Hb levels for anemia. We demonstrated that Hb levels in boys increased with age during childhood and adolescence (from 13.1 ± 0.7 g/dL in 7 year olds to 14.9 ± 1.1 g/dL in 15 year olds); in girls, Hb levels peaked at menarche (13.7 ± 0.8 g/dL in 12 year olds), decreasing slightly thereafter (13.4 ± 1.1 g/dL in 15 year olds). The prevalence of anemia was 0.26% in elementary school boys, 0.27% in elementary school girls, and 1.21% in junior high school boys. The prevalence of anemia in second- and third-year junior high school girls was lower than that in first-year junior high school girls. Among all junior high school girls, 5.73% had mild anemia. Iron-deficiency anemia is the commonest type of anemia in high school girls, secondary to the relative lack of iron due to menstruation, the growth spurt and exercise. Appropriate dietary therapy and treatment of anemia, together with education about the dietary prevention of anemia, are important to reduce the prevalence of anemia in high school students. When complete blood counts are performed in regions thought to be affected by the Fukushima nuclear power plant disaster, our report can serve as a reference during evaluation of Hb levels.
Journal of Nippon Medical School 01/2012; 79(3):232-5.
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ABSTRACT: Recent studies have examined the effects of intranasal corticosteroids (INSs) in relieving the ocular symptoms of seasonal allergic rhinoconjunctivitis (SAR) and perennial allergic rhinitis. However, because most of these studies were based on subjective assessments by patients, the associated factors and mechanism of action are unknown.
A single-center, randomized, double-blind, parallel-group study was carried out in which patients with SAR were randomly assigned to an INS mometasone furoate nasal spray (MFNS) group or to a placebo group and treated once daily for 4 weeks. Substance P concentrations in tears were measured, ocular and nasal symptoms were recorded by patients in an allergy diary, and findings were recorded by an ophthalmologist.
There was no significant difference between treatment groups in the mean change from baseline of substance P concentration in tears after 4 weeks of treatment, but the mean change tended to increase in the placebo group and tended to decrease in the MFNS group (P = 0.089). All ocular and nasal symptom scores, except eye tearing, were significantly lower in the MFNS group than in the placebo group. Furthermore, substance P concentrations were strongly correlated with ocular and nasal symptom scores.
In patients with SAR, INSs tend to decrease the substance P concentration in tears, which is correlated with the severity of ocular and nasal symptoms.
Journal of Nippon Medical School 01/2012; 79(3):182-9.
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Takenori Kabuto,
Hisatomo Takahashi,
Yoko Goto-Fukuura, Tsutomu Igarashi,
Masakazu Akahori,
Shuhei Kameya,
Takeshi Iwata,
Atsushi Mizota,
Kunihiko Yamaki,
Yozo Miyake,
Hiroshi Takahashi
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ABSTRACT: To determine whether a mutation in the RP1-like protein 1 (RP1L1) gene is present in a Japanese patient with sporadic occult macular dystrophy (OMD) and to examine the characteristics of focal macular electroretinograms (ERGs) of the patient with genetically identified OMD.
An individual with OMD underwent detailed ophthalmic clinical evaluations including focal macular ERGs. Mutation screening of all coding regions and flanking intron sequences of the RP1L1 gene were performed with DNA sequencing analysis in this case with OMD.
A new RP1L1 mutation (c.3596 C>G in exon 4) was identified. The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199. The serine at position 1199 is well conserved among the RP1L1 family in other species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 294 control alleles. The waveform of focal macular ERGs recorded from the patient with OMD had a depolarizing pattern, simulating the ERG waveforms observed after the hyperpolarizing bipolar cell activity is blocked.
We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation. The waveform of focal macular ERGs elicited from the OMD patient with the RP1L1 mutation showed a depolarizing pattern. This characteristic is the same as reported for the focal macular ERGs of OMD.
Molecular vision 01/2012; 18:1031-9. · 2.20 Impact Factor
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ABSTRACT: Primary Sjögren's syndrome (SS) is a rare autoimmune disease, especially in children. Juvenile primary SS with interstitial nephritis is rare in Japan. We report on a 12-year-old girl in whom salivary gland swelling had recurred from the age of 5 years, SS was diagnosed at the age of 10 years, and interstitial nephritis developed at the age of 12 years. The patient presented with a chief complaint of swelling of both parotid glands. The patient had a history of recurrent parotitis from 5 years of age, with episodes recurring 5 to 6 times a year and resolving within 3 days each time. However, at the age of 11 years, the patient had continuous mild swelling of the parotid glands. Examination on admission showed bilateral nontender parotid gland swelling; mild swelling of the lower extremities, xerostomia, and xerophthalmia but no exanthem. Laboratory findings were as follows: serum protein, 10.1 g/dL; immunoglobulin (Ig) G, 3,828 mg/dL; antinuclear antibodies, 1,280-fold; anti-Ro/SS-A antibody, 512-fold; anti-Ro/SS-B antibody, 4-fold; creatinine, 0.45 mg/dL; blood β2-microglobulin, 2.2 mg/L (slightly elevated); and cystatin C, 0.86 mg/L. Urinalysis showed proteinuria and a β2-microglobulin concentration of 11,265 mg/L. Thus, this patient had low molecular weight proteinuria. Schirmer's test showed decreased tear secretion (5 mm), and fluorescein staining showed marked bilateral superficial punctate keratitis. A lip biopsy showed infiltration by small round cells (mild to moderate), interstitial fibrosis, loss of salivary gland parenchyma, and atrophy, with no obvious epimyoepithelial islands, leading to a diagnosis of SS. Light microscopic examination of the renal biopsy specimens showed expansion of mononuclear cell infiltration in the renal interstitium, inflammatory cell infiltration of interstitial areas with edema and mild fibrosis, and tubulitis and mononuclear cell infiltration that included many lymphocytes and plasma cells. There were no pathological findings of glomerulonephritis. Small arteries showed no obvious abnormalities. Immunofluorescent staining showed slight, nonspecific deposition of IgM, but no deposition of IgG, complement 1q, 3, or 4. On the basis of the renal biopsy showing nonspecific chronic interstitial nephritis, renal tubular atrophy, and interstitial enlargement, tubulointerstitial nephritis associated with SS was diagnosed.
Journal of Nippon Medical School 01/2012; 79(4):286-90.
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ABSTRACT: Protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase 1 (POMGnT1) is an enzyme that catalyzes the transfer of N-acetylglucosamine to O-mannose of glycoproteins. Alpha-dystroglycan, a substrate of POMGnT1, is concentrated around the blood vessels, in the outer plexiform layer (OPL), and in the inner limiting membrane (ILM) of the retina. Mutations of the POMGnT1 gene in humans cause muscle-eye-brain (MEB) disease. Several ocular abnormalities including retinal dysplasia, ERG abnormalities, and retinal detachments have been reported in patients with MEB. We have analyzed the eyes of POMGnT1-deficient mice, generated by standard gene targeting technique, to study the retinal abnormalities. Clinical examination of adult mutant mice revealed a high incidence (81% by 12-months-of-age) of retinal detachments. Sheathing of the retinal vessels and the presence of ectopic fibrous tissues around the optic nerve head were also found. Histological examinations showed focal retinal detachment associated with GFAP immunopositivity. The ILM of the mutant mice was disrupted with ectopic cells near the disruptions. The expression of Dp71, a shorter isoform of dystrophin, was severely reduced in the ILM and around retinal blood vessels of POMGnT1-deficient mice. The expression of Dp427, Dp260, Dp140 were also reduced in the OPL of the mutant mice. Electroretinographic (ERG) analyses showed reduced a- and b-wave amplitudes. Examinations of flat mounts revealed abnormal vascular network associated with highly irregular astrocytic processes. In addition, ER-TR7-positive fibrous tissue was found closely associated with reactive astrocytes especially around the optic nerve head. Our results suggest that altered glycosylation of alpha-DG may be responsible for the reactive gliosis and reticular fibrosis in the retina, and the subsequent developments of retinal dysplasia, abnormal ERGs, and retinal detachment in the mutant mice.
Molecular and Cellular Neuroscience 03/2011; 47(2):119-30. · 3.66 Impact Factor
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ABSTRACT: To assess the feasibility of a gene therapeutic approach to treating choroidal neovascularization (CNV), we generated a recombinant adeno-associated viral (AAV) vector (type 8) encoding soluble Flt-1 (AAV-sflt-1), and determined its ability to inhibit angiogenesis. When we treated human umbilical vein endothelial cells (HUVECs) with the supernatant of cells transduced with AAV-sflt-1 or AAV-EGFP (control), we found that tube formation was significantly inhibited by the former but not the latter (area: 25,121 +/- 557 vs. 68,628 +/- 1357 pixels [p < 0.01]; length: 4811 +/- 246 vs. 10,894 +/- 297 pixels [p < 0.01]). CNV was induced in C57BL/6 mice by making four separate choroidal burns around the optic nerve in each eye, using a diode laser. Thereafter, 2 microl (5 x 10(11) vector genomes/ml) of AAV-sflt-1 (n = 11) or control AAV-LacZ (n = 12) was injected into the subretinal space, and 2 weeks later the eyes were removed for flatmount analysis of CNV surface area. Notably, subretinal delivery of AAV-sflt-1 significantly diminished CNV at the laser lesions, as compared with AAV-LacZ (555 +/- 304 vs. 1470 +/- 1000 microm(2); p = 0.007). These results suggest that there was diffusion of the secreted sFlt-1 across the retina and that long-term suppression of CNV is possible through the use of stable rAAV-mediated sflt-1 expression. In vivo gene therapy thus appears to be a feasible approach to the clinical management of CNV in conditions such as age-related macular degeneration.
Human gene therapy 05/2010; 21(5):631-7. · 4.20 Impact Factor
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Journal of Nippon Medical School 04/2010; 77(2):66.
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Japanese Journal of Ophthalmology 11/2009; 53(6):655-7. · 0.92 Impact Factor
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ABSTRACT: Retinal ischemia-reperfusion (I/R) injury by transient elevation of intraocular pressure (IOP) is known to induce neuronal damage through the generation of reactive oxygen species. Study results have indicated that molecular hydrogen (H(2)) is an efficient antioxidant gas that selectively reduces the hydroxyl radical (*OH) and suppresses oxidative stress-induced injury in several organs. This study was conducted to explore the neuroprotective effect of H(2)-loaded eye drops on retinal I/R injury.
Retinal ischemia was induced in rats by raising IOP for 60 minutes. H(2)-loaded eye drops were prepared by dissolving H(2) gas into a saline to saturated level and administered to the ocular surface continuously during the ischemia and/or reperfusion periods. One day after I/R injury, apoptotic cells in the retina were quantified, and oxidative stress was evaluated by markers such as 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine. Seven days after I/R injury, retinal damage was quantified by measuring the thickness of the retina.
When H(2)-loaded eye drops were continuously administered, H(2) concentration in the vitreous body immediately increased and I/R-induced *OH level decreased. The drops reduced the number of retinal apoptotic and oxidative stress marker-positive cells and prevented retinal thinning with an accompanying activation of Müller glia, astrocytes, and microglia. The drops improved the recovery of retinal thickness by >70%.
H(2) has no known toxic effects on the human body. Thus, the results suggest that H(2)-loaded eye drops are a highly useful neuroprotective and antioxidative therapeutic treatment for acute retinal I/R injury.
Investigative ophthalmology & visual science 10/2009; 51(1):487-92. · 3.43 Impact Factor
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ABSTRACT: We studied the contribution made by circulating bone marrow (BM)-derived cells to the newborn and mature retinas of BM-transplanted mice.
Newborn and adult C57BL/6J mice were administered a lethal dose of total-body irradiation, after which pathologic changes to the retinas were periodically assessed. In addition, mice received BM cells from 8-week-old green fluorescent protein (GFP) transgenic mice, and the subsequent differentiation of GFP+ cells was studied.
Within 5 hr after irradiation of newborn mice, retinal cells began to die due to apoptosis. By contrast, irradiation of adult mice elicited no histologic changes in the retina. BM cells generally did not differentiate in adult mice, but numerous GFP+ BM cells were integrated into the retinal tissue of newborn mice, where they expressed various cell type-specific markers. Finally, examination of whole retina mounts showed that GFP+ cells also contributed to retinal vascularization.
Our findings underscore the importance of careful evaluation of the biological effects of irradiation in models making use of BM transplantation.
Current Eye Research 07/2007; 32(6):543-53. · 1.28 Impact Factor
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ABSTRACT: To determine the usefulness of the Pentacam corneal volume assay in the assessment of corneal endothelial damage caused by phacoemulsification and aspiration (PEA).
Prospective, comparative, observational case series.
PEA was performed in 85 eyes by three surgeons under different conditions. Central cell density (CD) was determined using a specular microscope before and one month after surgery. Pentacam was used before and one day, one week, and one month after surgery to determine 3- and 10-mm corneal volumes.
For all surgeons, no significant differences in the 3-mm corneal volumes were noted between the before and one-month after surgery values. However, 10-mm corneal volumes at one month were significantly higher than preoperative levels. No correlation was noted between the increasing rate of the 10-mm corneal volume and decreasing rate of CD.
Pentacam-determined corneal volumes may be useful in assessing PEA-caused corneal damage.
American Journal of Ophthalmology 10/2006; 142(3):525-8. · 4.22 Impact Factor
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ABSTRACT: Metachromatic leukodystrophy (MLD) is an autosomal recessive disease caused by mutations in the gene encoding the lysosomal enzyme arylsulfatase A (ASA). In MLD, accumulation of the substrate, sulfated glycoprotein, in the central and peripheral nervous systems results in progressive motor and mental deterioration. Neural progenitor cells are thought to be useful for cell replacement therapy and for cell-mediated gene therapy in neurodegenerative diseases. In the present study, we examined the feasibility of ex vivo gene therapy for MLD using neural progenitor cells. Neural progenitor cells (neurospheres) were prepared from the striatum of E14 embryo MLD knockout mice or GFP transgenic mice and were transduced with the VSV pseudotyped HIV vector carrying the ASA gene (HIV-ASA). For in vivo study, neurospheres from GFP mice were transduced with HIV-ASA and inoculated into the brain parenchyma of adult MLD mice. HIV vector-transduced progenitor cells retained the potential for differentiation into neurons, astrocytes and oligodendrocytes in vitro. Expression of ASA in neurospheres transduced with HIV-ASA was confirmed by spectrophotometric enzyme assay and Western blotting. In vivo, GFP-positive cells were detectable 1 month after injection. These cells included GFAP- and MAP2-positive cells. Immunohistochemistry using anti-ASA antibody demonstrated localization of ASA in both GFP-positive and -negative cells. Partial clearance of accumulated sulfatide was confirmed in vivo in MLD knockout mice. The present findings suggest that ASA enzyme is released from migrated neurospheres and is able to digest sulfatide in surrounding cells. Our results suggest the potential of genetically engineered neural progenitor cells (neurospheres) for ex vivo therapy in MLD.
Brain Research 07/2006; 1094(1):13-23. · 2.73 Impact Factor
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ABSTRACT: To evaluate the incidence of dry eye in rheumatoid arthritis (RA) patients with or without Sjögren syndrome (SS), and to investigate the correlation between dry eye and RA activity.
Prospective case-control study.
In 72 RA patients, the severity of dry eye was assessed by the Schirmer test, tear break-up time, rose bengal staining, and fluorescein staining. The RA activity was evaluated by the Lansbury index (LI), which is based on the duration of morning stiffness, erythrocyte sedimentation rate (ESR), grip strength, and joint score.
Ten percent of patients met the Japanese criteria for SS. No difference in dry eye tests or LI was observed between SS patients and non-SS patients. Even in the non-SS group, 90% of patients were diagnosed with probable dry eye. In SS patients, positive correlations were observed between LI and Schirmer test (P = .048), ESR and Schirmer test (P = .035), ESR and rose bengal staining (P = .001), and grip strength and rose bengal staining (P = .047). No such correlations were observed in the non-SS patients.
Dry eye is common in RA patients, including those without SS. We found that there was a correlation between LI and Schirmer test in RA patients with SS, but no correlation when the entire group was analyzed. Dry eye always should be taken into consideration regardless of the RA activity, because the severity of dry eye is independent of RA activity.
American Journal of Ophthalmology 12/2005; 140(5):808-13. · 4.22 Impact Factor
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ABSTRACT: We examined the feasibility of the human immunodeficiency virus (HIV) vector-mediated local expression of angiostatin in the treatment of murine collagen-induced arthritis in a mouse model generated by immunization with bovine type II collagen and Freund's complete adjuvant. The HIV vector containing the murine angiostatin expression unit (HIV-angiostatin) was injected into right knee joints after arthritis development; the HIV vector containing the enhanced green fluorescein protein (EGFP) marker gene (HIV-EGFP) was injected into the left joints. Quantitative histological evaluation demonstrated that synovial cell hyperplasia and pannus formation were significantly reduced in the right knee joints as determined by this protocol. Suppression of radiographical changes in the ipsilateral paws was also observed. These results indicate that the HIV vector-mediated expression of angiostatin efficiently inhibits the progression of collagen-induced arthritis. Angiostatic gene therapy may provide a new approach to the effective treatment of rheumatoid arthritis.
Rheumatology International 10/2005; 25(7):522-9. · 1.88 Impact Factor
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ABSTRACT: We examined the feasibility of using adeno-associated virus (AAV)-mediated systemic delivery of endostatin in gene therapy to treat metastasis of pancreatic cancer. We established an animal model of orthotopic metastatic pancreatic cancer in which the pancreatic cancer cell line PGHAM-1 was inoculated into the pancreas of Syrian golden hamsters. Transplanted cells proliferated rapidly and metastasized to the liver. An AAV vector expressing endostatin (5 x 10(10) particles) was injected intramuscularly into the left quadriceps or intravenously into the portal vein. These routes of vector administration were evaluated by comparing various parameters of tumor development. Intramuscular injection of the vector modestly increased the serum endostatin level. The numbers of metastases and the incidence of hemorrhagic ascites were decreased in the treated animals. In contrast, the serum concentration of endostatin was significantly increased after intraportal injection of the vector. The antitumor effects on all parameters (including the size and microvessel density of primary pancreatic tumors, the sizes and number of liver metastases, and the incidence of hemorrhagic ascites) were significant. These results suggest that systemic delivery of endostatin represents a potentially effective treatment for pancreatic cancer and liver metastases. The route of vector administration influences the efficacy of AAV-mediated endostatin expression. Intraportal injection of the AAV vector appears to be more effective as an antiangiogenic gene therapy for pancreatic cancer.
Cancer Research 11/2004; 64(20):7486-90. · 7.86 Impact Factor
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ABSTRACT: To assess the validity of anterior chamber irrigation with an ozonated solution as prophylaxis against endophthalmitis.
Department of Ophthalmology, Nippon Medical School, Tokyo, Japan.
Viability of human corneal endothelium in culture was assessed by the WST-8 assay, lactate dehydrogenase (LDH) release assay, and trypan blue exclusion assay after exposure to a 4 to 40 parts per million (ppm) solution for 10 to 60 seconds. The in vivo effect was observed 1 week after irrigation of a 4 ppm solution in the rabbit anterior chamber by trypan blue exclusion assay. Bactericidal efficacy of the anterior chamber irrigation with the 4 ppm solution was examined by bacterial colony count of the aqueous humor following methicillin-resistant Staphylococcus aureus (MRSA) contaminated intraocular lens implantation in the porcine eye.
The WST-8 assay revealed no significant reduction of viability with 10-second exposure to a 4 ppm solution. Lactate dehydrogenase release and trypan blue exclusion assays similarly demonstrated little damage after 60-second exposure to a 4 ppm solution. In the rabbit cornea 1 week after treatment, damage caused by 30-second exposure to a 4 ppm solution was not significant. The MRSA colony count documented almost complete bactericidal action with 5-second exposure to the 4 ppm solution when no ophthalmic viscosurgical device existed in the anterior chamber.
Limited damage to the corneal endothelium after 10-second exposure and potent bactericidal action with 5-second exposure suggests the validity of anterior chamber irrigation with a 4 ppm ozonated solution as prophylaxis against endophthalmitis.
Journal of Cataract [?] Refractive Surgery 09/2004; 30(8):1773-80. · 2.26 Impact Factor
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ABSTRACT: Ischemic retinal diseases, such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration, are a major cause of blindness worldwide. Angiostatin is an internal peptide fragment of plasminogen that inhibits endothelial proliferation in vitro and tumor growth in vivo. We now demonstrate that HIV vector encoding angiostatin (HIV-angiostatin) can inhibit retinal neovascularization in a mouse model of proliferative retinopathy. Intravitreal injections of HIV-angiostatin led to stable expression of the angiostatin gene in retinal tissue. Retinal neovascularization was histologically quantitated by a masked protocol. Retinal neovascularization in the eye injected with HIV-angiostatin was reduced in 90% (9/10; P=0.025) of animals, compared with the eye injected with phosphate-buffered saline. Reduction of histologically evident neovascular nuclei per 6-microm section averaged 68%, with maximal inhibitory effects of 87%. Neovascularization was not reduced in the eyes injected with HIV vector encoding enhanced green fluorescent protein. This is the first report that HIV-angiostatin can reduce neovascular cell nuclei in a murine proliferative retinopathy model. These data suggest that the anti-angiogenic activity of angiostatin has therapeutic potential for the treatment of retinal neovascularization.
Gene Therapy 03/2003; 10(3):219-26. · 3.71 Impact Factor
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Advances in experimental medicine and biology 02/2002; 506(Pt B):1309-14. · 1.09 Impact Factor
