Limited access to appropriate biological materials, especially eye samples from affected donors at different stages of the disease, are an absolute necessity to study mechanisms underlying the macular degenerations. Because it is nearly impossible to obtain these human retinal tissues from patients or from normal controls, animal models play a crucial role for investigating the biological pathway of disease development and for testing therapeutic strategies. Because age-related macular degeneration shares phenotypic similarities with monogenic macular degenerations, manipulation of these genes associated with monogenic macular degenerations to develop transgenic mouse models has been popular. Over the past few years, genetic engineering technologies has allowed the generation of a rapidly growing number of animal models for retinal diseases (Chader, 2002). Animal models have been used to investigate potentially protective therapeutic agents to treat photoreceptor degeneration, stem cell technology, or to test somatic gene therapy strategies (Ali et al., 2000). They are also valuable for studying environmental effects like diet or light on the degeneration process. The animals that have been used to evaluate therapeutic strategies involve rodents, rabbits, pigs, and dogs. However, macula is found only in primates and birds; a monkey model with macular degeneration would be extremely valuable as they not only have a defined macula, but they are also evolutio-narily close to humans.
Macular degeneration in monkeys was first described by Stafford in 1974 (Stafford, Anness, and Fine, 1984). He reported that 6.6% of elderly monkeys showed pigmentary disorders and/or drusen-like spots. El-Mofty and colleagues reported 50% incidence of maculopathy in a rhesus monkey colony at the Caribbean Primate Research Center of the University of Puerto Rico in 1978. The following report from the center indicated that specific maternal lineages had a statistically significant higher prevalence of drusen. Researchers have described a cynomolgus monkey (Macaca fascicularis) colony at the Tsukuba Primate Research Center (Tsukuba city, Japan) with a high incidence of macular degeneration and its pattern of inheritance (Umeda et al., 2005).
Several other naturally occurring animal models have been described for retinal diseases. Rodents, mainly mice, are the most popular animal models as maintenance is less expensive compared to larger animals. However, a low cone:rod ratio and lack of a macula make mice less suitable for studying cone diseases and macular degenerations. Although the pathology in human ARMD is pronounced in the macula area, it is not confined to this central region alone. Abnormal accumulation of drusen and progressive degeneration of the retina, RPE, and underlying choroid characteristics were observed in mouse models generated by candidate gene manipulation or senescence acceleration (Ambati et al., 2003). Choroidal neovascularization also has been described in naturally occurring mouse models. These observations suggest that the lack of a macula in mice may not be a disadvantage when considering the advantages of using the mouse as a model for studying macular degenerations with drusen.
Although monkey models are extremely important for macular degeneration study, there are limitations using nonhuman primates as animal models, such as longer gestation and life span, slow rate of expanding the pedigree, and cost of maintenance. These limitations can be overcome only by utilizing the mouse model parallel to the monkey model. One such model is a mouse line expressing an inactive form of cathepsin D. The impaired enzymatic activity affects phagocytosis of photo-receptor outer segments in the RPE cells, and the mice demonstrate basal laminar and linear deposits.
Animal model of early and late onset macular degeneration monkey
In 1986, a single cynomolgus monkey (Macaca fascicu-laris) with heavy drusen was found in the Tsukuba Primate Research Center. After 19 years of mating experiments, that single pedigree has grown to having 57 affected and 182 unaffected monkeys. Macular changes are observed as early as two years after birth, with basal laminar deposits first appearing in the macular region and progressing toward the peripheral retina throughout the lifetime (see Figure 68.4). In all the cases examined no abnormalities were found in the optic disc, retinal blood vessels, or choroidal vasculatures. The affected monkeys share phenotypic similarities with the early stages of ARMD, such as drusen and accumulation of lipofuscin. The immunohistochemical and proteome analysis of drusen in these monkeys share significant similarity with composition of age-related macular degeneration monkeys and also with previously reported human drusen composition. The meaning of this observation is that early onset monkeys produce the same drusen as ARMD patients at an accelerated rate of 25 times. Thirteen human candidate gene loci have been excluded by linkage and haplotype analysis. Therefore, the gene associated with macular degeneration in these monkeys is likely to be novel and the genes involved in causing drusen phenotype in humans and monkeys could be either the same or belong to the same biological pathway.
Studies involving early-onset and late-onset macular degeneration monkeys present a unique opportunity to study two independent target points in the biological pathway of retinal tissue that lead to degeneration of the macula at different stages of life. The gene associated with monkey macular degeneration is likely to be a novel gene as we have excluded most of the known macular degeneration loci. Cloning of the monkey macular degeneration gene will allow us to study the biological processes causing degeneration of retina. Due to high conservation between human and macaque genomes, genes associated with macular degeneration in monkeys should possibly play a key role in maintaining the normal function of retina in humans and is likely to be associated with macular degeneration in humans. Although some of the monogenic macular degeneration genes are not associated with ARMD, the phenotype observed in monkeys strongly suggests that this gene may play a role in human ARMD, and this cannot be established until validated by screening patients with ARMD. Understanding the mechanism underlying macular degeneration in these monkeys will enhance our understanding of the disease, identify clinical or molecular markers for early detection, and provide critical information needed to develop therapies for these diseases.
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