Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision has been restored by ...subretinal delivery of AAV-RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2.RPE65 in RPE65-mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vectorrelated toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular injections of AAV-2/2.RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2.RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina.
A 16‐year‐old rhesus macaque presented with progressive, ascending quadriparesis following measles vaccination. He was diagnosed with transverse myelitis following MRI, gross necropsy, and ...histopathology. This is the first report of transverse myelitis in a rhesus macaque following measles vaccination.
Age-related macular degeneration (AMD) is a degenerative condition that begins in Bruch’s membrane and progresses to involve the retinal pigment epithelium and ultimately the overlying ...photoreceptors. The only required etiologic factor is age, and AMD is regarded as the leading cause of blindness in individuals older than 65 years. AMD results from variable contributions of age, environment, and genetic predisposition. Many loci are linked to AMD; in the majority of cases, the disease is associated with polymorphisms within these genes, rather than mutations that ablate gene function. The etiologic complexity of AMD is reflected by the paucity of animal models that entirely replicate the human disease. This review compares the salient anatomy of the primate and rodent retina, particularly in the light of AMD pathology. It next discusses prevailing hypotheses explaining how AMD may develop. These include the role of complement activation and macrophage chemotaxis in AMD, molecular mechanisms of choroidal neovascularization, and the roles of oxidative damage and lipid metabolism. Finally, the article gives an overview of spontaneous and induced nonhuman primate models and describes relevant mouse models in the context of each pathogenetic mechanism.
The primary purpose of this study was to evaluate the impact of caspase-3 ablation on photoreceptor degeneration in the rd-1 mouse. Concurrently, the role of caspase-3 in postnatal retinal ...development was evaluated. Caspase-3 is an important effector caspase that mediates many of the terminal proteolytic events of apoptosis. Its activation has been demonstrated in rodent models of photoreceptor degeneration and its ablation results in exencephaly and neonatal death.
Retinal morphometry was performed at the light microscopic level in caspase-3 mutant mice from PN0 through PN23, and in rd-1/caspase-3 double mutant mice at PN14, -16, and -18. This was supplemented by terminal dUTP transferase nick end labeling (TUNEL) and immunohistochemical staining for activated caspase-3, rhodopsin, factor VII-related antigen and proliferating cell nuclear antigen (PCNA).
Caspase-3-deficient animals display marginal microphthalmia, peripapillary retinal dysplasia, delayed regression of vitreal vasculature, and retarded apoptotic kinetics of the inner nuclear layer. Ablation of caspase-3 provided transient photoreceptor protection in rd-1, but TUNEL-positive rod death proceeded, despite the absence of caspase-3 activation.
In vivo, caspase-3 is not critical for rod photoreceptor development, nor does it play a significant role in mediating pathologic rod death. Peripapillary dysplastic lesions suggest that there is delayed fusion of the optic fissure, and inner nuclear layer abnormalities indicate a cell-specific dependency on the mitochondria-caspase axis during development. The temporal nature of apoptotic retardation in the absence of caspase-3 implies the presence of caspase-independent mechanisms of developmental and pathologic cell death.
An adult female beagle (Canis lupus familiaris) used in a model of doxorubicin-induced cardiomyopathy presented with epithelial desquamation on the shoulders and ventrum after receiving the 8th ...weekly intravenous dose of the free form of doxorubicin (20 mg/m2;
total accumulation, 160 mg/m2). The lesions were empirically treated with topical disinfectants and topical and systemic antibiotics. Despite treatment, the lesions progressed and ulcerated. Bacterial culture revealed Staphylococcus aureus, but trichogram, skin scraping,
and fungal culture were negative for microorganisms. Skin biopsies revealed epidermal and apocrine gland hyperplasia, apocrine gland dilation, abnormal maturation of epithelial keratinocytes, and perivascular lymphocytic infiltration. These histopathologic findings resemble those in humans
and canines after chronic administration of doxorubicin-containing pegylated liposomes. Here we report a clinical presentation after chronic administration of the free form of doxorubicin. In dogs, cutaneous toxicity after administration of pegylated liposomal doxorubicin is most often localized
to the footpads, limbs, and axillary and urogenital regions. In the current case, lesions affected the ventrum and trunk but did not involve the footpads or axillary or urogenital regions.
Superficial decidualization of the endometrial stroma is an essential feature of the implantation stage of pregnancy in rhesus macaques and other primates. Decidualization involves proliferation of ...the endometrial stromal cells, with differentiation into morphologically distinct decidual
cells. Previous reports involving nonpregnant rhesus monkeys have described local- ized and widespread endometrial decidualization in response to administration of progesterone and synthetic progestogens. Ectopic decidua or 'deciduosis' describes the condition in which groups of decidual cells
are located outside of the endometrium, most often in the ovaries, uterus and cervix but also in various other organs. In humans, most cases of deciduosis are associated with normal pregnancy, and ectopic decidua can be found in the ovary in nearly all term pregnancies. Here we describe pronounced
endometrial decidualization in 2 rhesus macaques. Both macaques had been treated long-term with medroxyprogesterone acetate for presumed endometriosis, which was confirmed in one of the macaques at postmortem examination. In one animal, florid extrauterine and peritoneal serosal decidualization
was admixed multifocally with carcinomatosis from a primary colonic adenocarcinoma. Cells constituting endometrial and serosal decidualization reactions were immunopositive for the stromal markers CD10, collagen IV, smooth muscle actin, and vimentin and immunonegative for cytokeratin. In contrast,
carcinomatous foci were cytokeratin-positive. To our knowledge, this report describes the first cases of serosal peritoneal decidualization in rhesus macaques. The concurrent presentation of serosal peritoneal decidualization with carcinomatosis is unique.
In the United States, breast cancer is the most common malignancy among women, with an estimated lifetime incidence of approximately 12% in American women. Invasive ductal carcinoma is the most ...common form of breast cancer in women, accounting for approximately 60% of all breast carcinomas.
Prognostic markers are used to assess aggressiveness, invasiveness, and extent of spread of a neoplasm and thus may be correlated with patient survival. Immunohistochemistry is currently widely used for this purpose, with a variety of prognostication markers available. Classic markers for
breast cancer in women include estrogen and progesterone receptor steroid hormone proteins and human epidermal growth factor receptor 2. Many additional markers have been used in diagnosis and prognostication, including p53, p63, and E-cadherin and cell proliferation markers such as Ki67.
Despite an estimated lifetime incidence of approximately 6.1%, naturally occurring mammary neoplasms in nonhuman primates are uncommonly reported, with only sporadic references over the past 75 y. The majority of reported tumors occur in rhesus macaques, although this prevalence has been suggested
to be a consequence of their high frequency of usage in biomedical research. Here we present 2 cases of mammary carcinoma in adult female intact rhesus macaques, with cytology, histopathology, and extensive immunohistochemical analysis. According to current classifications for human breast
tumors, both tumors were classified as invasive ductal carcinoma. The prognostic value of immunohistochemical markers in human breast cancer and in reported cases in nonhuman primates is discussed.
Comparative retinal morphology of the platypus Zeiss, Caroline J.; Schwab, Ivan R.; Murphy, Christopher J. ...
Journal of morphology (1931),
August 2011, Volume:
272, Issue:
8
Journal Article
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.
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