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Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.

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Fabry Disease: Perspectives from 5 Years of FOS.

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Chapter 6Animal models of lysosomal storage diseases: their development and clinical relevance

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Laboratory of Pathology and Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA, 19104-6051, USA

Progress in understanding how a particular genotype produces the phenotype of an inborn error of metabolism in human patients has been facilitated by the study of animals with mutations in the orthologous genes. These are not just animal 'models', but true orthologues of the human genetic disease, with defects involving the same evolutionarily conserved genes and the same molecular, biochemical and anatomical pathology as in human patients. Such animal orthologues are an important aid to the development of specific gene therapies for these disorders. The initial approach to finding suitable animals was to identify those with a naturally occurring disease. These animals were often domesticated species, because of the individual attention paid to such animals, particularly dogs and cats. In addition, naturally occurring mouse models have been found, and breeding lines established. Within the last several decades, advances in molecular biology and our understanding of murine reproductive physiology have combined to allow the production of knockout mouse models of human genetic disease expressed on various inbred backgrounds. Inbred strains of a small prolific species, such as the mouse, together with larger out-bred animals, discovered because of their disease phenotype, provide a powerful combination with which to elucidate the pathogenesis of human genetic disease and to investigate approaches to therapy. This has been true for inborn errors of metabolism and, in particular, the lysosomal storage diseases.


Isolation of the genes involved in genetic disorders has paved the way to understanding the mechanisms underlying the molecular derangements associated with inherited diseases. There are encouraging new prospects for treating genetic diseases, including stem cell therapy and gene therapy. However, to understand fully and to treat human genetic diseases, authentic (gene-orthologous) animal models are required in studies that, for ethical and practical reasons, are not possible in humans. Mouse gene knockout technology has provided a valuable source of such models, but additional animal models are needed for studies that require larger and longer-lived species with clinical signs and underlying lesions more closely resembling those in humans.

As in humans, most of the lysosomal storage diseases (LSDs) known to occur in dogs and cats are inherited as autosomal recessive traits. Among humans, recessively inherited genetic diseases tend to aggregate in particular ethnic groups where consanguineous unions are likely to be more common. Similarly, many recessively inherited diseases in dogs and cats tend to aggregate within particular breeds [1]. This follows from the requirement of the American Kennel Club (concerned with canine pedigrees), as well as pure-bred dog and cat registries, that, to be registered as a member of a particular breed, an animal must have parents that are both previously registered members of the same breed. Consanguineous matings are further promoted by the tendency for breeders to concentrate the genes from a sire famous for winning at shows by instituting matings between his descendants. Occurring as they do under the scrutiny of concerned breeders and their veterinarians, genetic diseases in dogs and cats, particularly those associated with specific breeds, are often well characterized.

The need for animal models

While much progress has been made in defining the molecular basis of genetic diseases in man, there are large gaps in our understanding of the complex chain of events between the underlying genetic defect and the phenotypic abnormalities at various levels – from cells, tissues and organs to the whole organism. As most of the studies necessary to unravel the pathogenic mechanisms involved cannot be performed in humans, animals with the same genetic disorders are an important source of knowledge. For example, while we know the genes and many of the mutations underlying the mucopolysaccharidoses (MPS), which constitute a particular class of LSD, and while the clinical and pathological features of the articular cartilage lesions in these diseases have been described, how substrate storage results in the cartilage lesions is only now beginning to be described and understood from investigations in cat, dog, and rat models of MPS (Figures 1 and 2) [2, 3].

Figure 1. The profile of a Siamese cat with mucopolysaccharidosis VI.

Figure 1

The profile of a Siamese cat with mucopolysaccharidosis VI. Instead of the elongated face of a normal Siamese cat, affected cats have a shortened midface with a depressed nasal bridge, small ears and corneal clouding.

Figure 2. Erosions (arrows) of the articular cartilage of the distal femur of a cat with mucopolysaccharidosis VI.

Figure 2

Erosions (arrows) of the articular cartilage of the distal femur of a cat with mucopolysaccharidosis VI.

For many lethal or debilitating genetic disorders in man, there are still no satisfactory means of treatment. One of the most exciting prospects for the use of animals with orthologous genetic diseases lies in testing new approaches to therapy. The monogenic inborn errors of metabolism are particularly attractive targets for gene and stem cell therapies because (i) they constitute a significant proportion of genetic diseases and (ii) they are usually autosomal recessive disorders involving the deficiency of a single specific protein gene product. Although simple in concept, examples of patients with inherited metabolic diseases being treated effectively using somatic cell gene therapy are limited [4], and not without complications, including insertional mutagenesis [5]. Currently, the major difficulties are obtaining adequate levels of gene product in the specific cell types in which they are needed (e.g. in the cells of the CNS), maintaining expression over long periods of time in vivo, and regulating the levels of gene expression.

The research necessary to improve this situation requires animal models that are true homologues of the human disease, with the same molecular, pathological and clinical phenotype as the human disease. Because the treatment of many different human disorders will eventually be attempted and the details of the approach will be specific to each genetic disease, many different animal models will be required.

Gene knockout technology

Gene knockout technology has been a powerful experimental approach that has contributed in a major way to the understanding of gene function in health and disease, and can be used in cases in which the gene of interest has been cloned. It is not always successful, however, in producing a model that accurately reproduces the human disease phenotype. Because large animal models are discovered through their clinical phenotype, they are more suitable than some knockout or point mutation mouse models that may have lesions but are lethal in utero or lack the full range of clinical disease, as has been the case in mice with Tay–Sachs disease, Fabry disease, cystinosis and Gaucher disease [610]. In addition, in some knockout models, such as those with type II or type III Gaucher disease, animals die within a few days of birth, limiting their value for gene therapy research [10, 11]. Mice and other small laboratory animals will, however, continue to be a valuable source of disease models and have the advantages of being available in well-characterized inbred strains. In addition, it is easy to produce large numbers of affected as well as unaffected control animals with the same genetic background. For initial studies, naturally occurring and knockout mice with LSDs have proven extremely valuable.

Use of larger animal models

Clinical veterinary medicine provides a vast and sophisticated screening mechanism in which animals are examined individually and in detail by using diagnostic methods that have an accuracy and sensitivity approaching those used in humans. Furthermore, the naturally occurring disease models in dogs and cats exist in various genetic isolates (breeds) maintained by members of the public. Once identified, these models can be established in special research colonies, frequently associated with veterinary schools. Breeders have been eager to cooperate in these endeavours because the scientific knowledge gained aids in the understanding and control of the animal diseases as well as contributing to human health [12].

Larger species, such as the dog and cat, have the advantages of a heterogeneous genetic background more similar to humans, and a size and longevity more suitable for surgical manipulations, clinical evaluations, and assessment of the long-term consequences of therapy over many years. These advantages, along with the accumulated background of physiological and clinical veterinary knowledge in these species, make them extremely useful. Of course, not all genetic diseases have been found in large animals, and knockout mice have been essential to fill the gap. Nevertheless, domesticated animals have been a rich source of models for LSDs, perhaps due to the progressive nature and striking clinical signs of disease in these species. Some LSDs were recognized in veterinary medicine before the diseases were understood at the level of the specific enzymes involved. Because of the distinctive central and peripheral nervous system lesions, the first of these diseases to be described was globoid cell leukodystrophy in Cairn and West Highland white terriers in 1963 (Figures 3 and 4) [13]. These two breeds of dogs are now known to have the same mutation in the gene coding for galactosylceramidase [14]. This mutation apparently originated in the 19th century from an ancestor common to these two breeds, which diverged around the beginning of the 20th century. The first LSD in animals that was identified by its deficient enzyme (β-galactosidase) activity was GM1-gangliosidosis in a Siamese cat, in 1971 [15]. Since then, naturally occurring LSDs have been recognized in cats, cattle, dogs, guinea pigs, goats, mice, pigs, rats, sheep, quail, emus and horses [16, 17] (Table 1). Breeding colonies have been established and exist for a large number of LSDs in various species [80, 81].

Figure 3. A West Highland white terrier with globoid cell leukodystropy (Krabbe disease).

Figure 3

A West Highland white terrier with globoid cell leukodystropy (Krabbe disease). The dog has early signs of posterior limb paresis.

Figure 4. Histological appearance of the cerebral cortex of (a) a normal dog and (b) a dog with globoid cell leukodystrophy.

Figure 4

Histological appearance of the cerebral cortex of (a) a normal dog and (b) a dog with globoid cell leukodystrophy. The sections were treated with luxol blue, which stains normal myelin blue, as can be seen in (a) [arrows]. The white matter in the affected (more...)

Table 1. Naturally occurring mucopolysaccharidoses (MPS) and related diseases in animals.

Table 1

Naturally occurring mucopolysaccharidoses (MPS) and related diseases in animals.

These examples illustrate that it is important to continue to find and utilize genetic disease models that arise spontaneously in out-bred animal populations, in addition to using knockout mouse models. In the Section of Medical Genetics at the University of Pennsylvania's School of Veterinary Medicine, dogs and cats with clinical signs suggestive of an inherited metabolic disease are routinely screened for the presence of abnormal metabolites in urine and blood, using methods similar to those used in paediatric hospitals. Urine screening has proven to be the most productive method, as the concentration of metabolites from many inborn errors of metabolism are highest in the urine. Defects in renal transport are also detected by these tests. Abnormalities detected by screening tests are further investigated by more definitive tests to determine the identity of abnormal metabolites, as indicated in Figure 5. If a disorder with tissue storage is suspected and urine and blood tests fail to reveal any abnormality, tissue biopsy material and other body fluids are examined. In addition, examinations of biopsy and post-mortem specimens from animals with congenital or genetic diseases are useful in identifying other inherited diseases with abnormalities of tissue and cell metabolism. From understanding the metabolic pathways, the genes involved in particularly promising animal models can be cloned from normal animals when the defective protein is known, providing the species-specific complementary DNA (cDNA) needed for therapy. Approaches for cloning include screening cDNA libraries and reverse transcriptase–polymerase chain reaction, taking advantage of the recently completed 7.6 × canine genome sequence (where 7.6 times as many nucleotides of dog genome sequence were generated in the dog genome project) and an emerging feline genome sequence approved for 2×, which is currently more than half completed.

Figure 5. The scheme used to evaluate urine from animals with clinical signs and history consistent with a genetic metabolic disease.

Figure 5

The scheme used to evaluate urine from animals with clinical signs and history consistent with a genetic metabolic disease. The initial tests are relatively quick and inexpensive and are used to screen for abnormal metabolites present in urine; they can (more...)

Clinical relevance to therapy

The basic approach to treating LSDs relies on the capacity of cells to take up exogenous normal enzyme and deliver it to the lysosome, usually by a mannose-6-phosphate receptor-mediated process [82]. Fortunately, the amount of enzyme needed in the lysosome for phenotypic correction of an individual cell is only a small percentage of normal. The three approaches to providing normal enzyme to a patient's cells are enzyme replacement therapy (ERT), bone marrow transplantation (BMT) and gene therapy. In general, the most difficult target tissue in the LSDs is the CNS. Approximately 60% of LSDs have a CNS component, for which systemic therapy is limited by the blood–brain barrier. Successful treatment of the neuronopathic LSDs will require direct therapy to, or systemic therapy that targets, the CNS. Animal models have been used extensively to evaluate these approaches to therapy.


The efficacy of the parenteral injection of purified recombinant enzyme has been tested in various animal models of LSDs, including MPS VII mice, MPS I dogs and cats, MPS VI cats, and glycogen storage disease in Japanese quail [80, 81]. In knockout mice, enzyme derived from rabbit milk or from Chinese hamster ovary cells has been used, including experiments in Fabry mice [83] (see below). Today, ERT is the standard therapy for non-neuronopathic Gaucher disease and is available or under evaluation for the treatment of Fabry disease, Pompe disease, MPS I, MPS II and MPS VI.


Heterologous BMT as therapy for LSDs has been performed for decades (reviewed in [8490]. This approach provides both normal bone marrow and bone-marrow-derived cells, which are available to release enzyme continuously for uptake by other cells. In addition, monocyte-derived cells can cross the blood–brain barrier, becoming microglia and secreting enzyme that can be available to neurones. BMT has been carried out in MPS VII mice, mannosidosis cats, GM2-gangliosidosis mice, MPS VI cats, and the MPS VII dog, among others [87]. A combination of neonatal ERT followed by BMT at 5 weeks of age in MPS VII mice has been shown to have long-term positive effects [91].

Gene therapy

The most striking clinical results of gene therapy involving an LSD have been those seen in a series of neonatal gene transfer studies conducted using viral vectors in the murine and canine models of MPS VII [9296]. Even for an LSD, MPS VII is a very rare condition, affecting fewer than 1/250 000 live births. In spite of the rarity of MPS VII, these models have become a paradigm for LSDs in general because of the ability to detect the normal enzyme (β-glucuronidase) activity directly by using a histochemical technique.

The α-galactosidase A knockout mouse

No large animal model for Fabry disease has been discovered, although a knockout mouse model has been developed [7]. The model displays a complete lack of α-galactosidase A activity, which in humans leads to impaired catabolism of α-galactosyl-terminal lipid (i.e. globotriaosylceramide). In this X-linked disease, humans develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular and renal dysfunction, and early death. However, knockout Fabry mice appear clinically normal, with normal blood and urine analyses and a normal adult lifespan [7, 97]. The limitation imposed by a lack of clinical signs has not, however, prevented the use of these mice in therapy trials, as they do have lesions that can be evaluated for improvement. α-d-Galactosyl residues have been shown to accumulate progressively in the kidneys of Fabry mice until they are 20 weeks of age, and lipid analysis has shown a marked accumulation of ceramidetrihexoside in the liver and kidneys. However, there were no obvious histological lesions visible under light microscopy in haematoxylin–eosin-stained sections of the kidneys, liver, heart, spleen, lungs and brain. Typical lamellar inclusions have frequently been observed by electron microscopy in the lysosomes of Kupffer cells and, to a lesser degree, in hepatocytes from affected mice. In the brain, inclusions in the lysosomes were identified in vascular smooth muscle cells but not in neuronal or glial cells. In the kidney, compared with wild-type mice, there are increased numbers of lamellar bodies within proximal and distal tubular cells and, to a lesser extent, within glomerular epithelial cells and peri-tubular capillary endothelial cells.

Preclinical studies of ERT for Fabry disease have been performed in the knockout mouse model [83]. The pharmacokinetics and biodistribution of administered α-galactosidase A were evaluated. In spite of the lack of clinical signs, the reduction of substrate in various tissues and plasma was found to be dose dependent, and re-accumulation rates were determined for the liver, myocardium and spleen, providing an in vivo rationale for ERT in patients with Fabry disease [83].

Various gene therapy studies have been performed in the knockout Fabry mouse, including: in vitro transduction of bone marrow cells with a retroviral vector and transplantation into radiation-conditioned knockout mice [98, 99]; the intravenous or intramuscular injection of an adeno-associated virus vector [100103]; and the pulmonary instillation [104] or intravenous injection of an adenovirus vector [105, 106]. Increased activity of α-galactosidase A was documented, with substrate reduction in various tissues, which was dependent upon the vector and mode of administration.


Domestic animals with spontaneous genetic diseases can be of great importance in understanding the pathogenesis of the condition and the development of therapy. Veterinary medicine provides an increasingly high degree of medical scrutiny of animals, particularly the dog and cat, and new orthologues of human genetic diseases are being recognized with increasing frequency. These models provide an opportunity to monitor therapeutic efficacy and the possible development of untoward side effects in out-bred, long-lived animals that can be monitored individually using the same methods that are applicable to humans. Finding spontaneous mouse models, as well as producing knockout mice with a disruption of the gene of interest, allows the evaluation of disease and therapy in a relatively large number of animals with a uniform genetic background. The ideal is to have a mouse model and a dog or cat model, together with an authentic primate model. This has so far been achieved only for globoid cell leukodystrophy (Krabbe disease), with the twitcher mouse [107], the dog [14] and the rhesus monkey [108] providing spontaneous models of the human disease.


The discovery and characterization of large animal models of human genetic disease have been supported by grants from the National Institutes of Health, currently P40-RR02512, DK25659 and DK54481.


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