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Vet. Pathol. 16: 635-649 (1979)
The Gangliosidoses: Comparative Features and Research
Applications
H.J. BAKER,G. D. REYNOLDS,
S. U. WALKLEY,
N. R. Cox and G. H. BAKER
Department of Comparative Medicine, Schools of Medicine and Dentistry, University of
Alabama in Birmingham, Birmingham, Ala.
Abstract. Ganglioside storage diseases are inherited defects of lysosomal hydrolases that
result in intralysosomal accumulation of gangliosides and other complex metabolites. Gangliosidoses occur in man, cats, cattle, dogs and swine. In all species, these diseases are
characterized clinically by relentlessly progressive neurological deterioration. Lysosomal hypertrophy with characteristic ultrastructural inclusions occur in neurons, endothelial and other
cells. Definitive diagnosis requires biochemical identification of the storage product and
enzyme deficiency. Gangliosidoses in animals are important models of human lysosomal
diseases and may be a significant complication in the maintenance of certain purebred stocks
of domestic animals.
According to current concepts, the lysosomal system is the principal site of
intracellular digestion and consists of membrane-bound cytoplasmic organelles containing more than 40 acid hydrolases capable of degrading most biologically important macromolecules. Mutations that cause reduced hydrolytic activity of lysosomal
hydrolases result in diseases characterized by incomplete catabolism and concomitant
accumulation (“storage”) of undergraded substrate within lysosomes [7, 9, 181.
The gangliosidoses are lysosomal diseases resulting from incomplete catabolism
and intralysosomal accumulation of gangliosides and related complex glycolipids
and glycoproteins. These diseases have been recognized in five mammalian species
including man, cats, cattle, dogs and swine (31. Regardless of species affected, the
gangliosidoses are characterized by 1) progressive nervous system deterioration that
usually begins early in life and ultimately leads to premature death; 2) autosomal
recessive inheritance; 3) lysosomal hypertrophy in neurons, hepatocytes, macrophages
and other cells resulting from deposition of glycoproteins or glycolipids; and 4)
absence or marked reduction in activity of specific lysosomal enzymes required for
hydrolysis of accumulated compounds.
Most lysosomal storage diseases, including the gangliosidoses, are untreatable.
Furthermore, the pathogenesis of cell injury and death resulting from lysosomal
hypertrophy remains obscure. Therefore, animal models of these diseases are of
critical importance for progress in basic and applied research. Also, it is becoming
635
Baker et a1
636
Table 1. Major clinicopathological features of human gangliosidoses
GM2 gangliosidoses
Type I
(TaySachs')
Age of onset of symptoms
Age at death
Mental/motor retardation
Facial appearance
Edema
X-ray changes, long bones
X-ray changes, vertebrae
Vacuolated lymphocytes
Foam cells in marrow
Hepa tomegaly
Splenomegaly
Cherry-red spot
Startle response to sound
Macrocephaly
Macroglossia
Seizures
Blindness
Neuronal lipidosis
Visceral histocytosis
Glomerular epithelial
ballooning
Mucopolysakhariduria
Type I1
(Sandhoff's
disease)
3-6
3-6
months
months
2-5
2-5
months
months
GM I gangliosidoses
Type 111
(juvenile)
Birth
6-20 months
5- I5 years
1 /2-2
years
3-10 months
Coarse
Normal
-
Mild
Mild
+'
+
+
Doll-like
Normal
-
-
-
90%
+
+
+
Early
+
-
-
+
+
+
-
gliosidosis)
Type I1
(juvenile)
2-6 years
Doll-like
-
Type I
(generalized gan-
-
-
-
+
-
+
+
+
+
+
+
50%
+
Rarely
+
+
-
+
+
-
-
+
-
Mild
-
-
+
+
+
+
+
Late
+
+
+
-
-
*
f
+
Early
+
-
+
Late
+
+
Early
~
+ = present; - = absent.
increasingly apparent that gangliosidoses are not uncommon in purebred animals
and may constitute a significant complication in the maintenance of some purebred
stocks.
Comparative Features
Following the first clinical description of a human gangliosidosis (Tay-Sachs
disease) in 1881, more than 86 years elapsed before a reasonably complete understanding of the basic biochemical defect in these diseases emerged and additional
clinical forms of gangliosidoses were recognized. Presently, five clinically distinct
human gangliosidoses are well documented [27, 38, 441; the principal differences are
outlined in table I.
The first documented ganglioside storage disease of domestic animals was a case
of GM2 gangliosidoses in German Shorthair Pointer dogs in 1967 [21]. The specific
Gangliosidoses
637
Table 11. Ganglioside storage diseases in man and animals
GMI gangliosidoses
GM2 gangliosidoses
Human disease
Animal analog’
Generalized gangliosidosis,
type 1, Norman-landing
disease
Juvenile GMI gangliosidosis, type 2, Derry’s disease
Bovine GMI gangliosidosis
Friesian cattle
Feline GMI gangliosidosis
Siamese, Korat and
mixed
Canine GMI gangliosidosis
Canine GM:, gangliosidosis
Beagle/mixed breed
dogs
German Shorthaired
Pointer dogs
Porcine GM2 gangliosidosis
Yorkshire swine
Feline GM2 gangliosidosis
Mixed breed cats
GM2 gangliosidosis type 1,
Tay-Sachs disease
GM2 gangliosidosis type 2,
Sandhoff’s disease
Juvenile GM2 gangliosidosis, type 3, BernheimerSeitelberger disease
Breed
’ Arrangement in table does not imply analogy between animal disease and clinical subtype
of human disease.
enzyme defect, however, remains undefined. Since 1971, additional cases of gangliosidoses with complete biochemical confirmation have been reported in cats [ 1, 2, 4,
5, 171, cattle [ll, 121, dogs [16, 24, 331 and swine [28, 341 (table 11).
Clinical characteristics
Although some differences exist in age of onset, severity of signs and rapidity of
progression, clinical characteristics are remarkably similar in all species, including
man.
Relentlessly progressive neurological dysfunction is the sine qua non of these
diseases. Discrete head or limb tremors and dysmetria constitute the earliest signs in
animals and first become apparent when the animal is 3 months old or older.
Locomotor deficits progress in intensity over succeeding months and terminate in
quadraplegia, somnolence, blindness and epileptiform seizures. The progressive
nature of neurological signs is useful for differentiating the gangliosidoses from other
neurological disorders of early onset, such as feline cerebellar hypoplasia. The age of
onset of neurological signs in children varies considerably with clinical variants and
a few cases are reported in adults with relatively mild neurological deficits [40].
Children with some forms of gangliosidoses have a distinctive retinal lesion, the
“cherry red spot,” resulting from lipid filled retinal cells that form a pale ring around
the red macula [38]. In animals, retinal lesions have been seen only in swine with
GM2gangliosidosis in which punctiform retinal lesions are a consistent, characteristic
clinical sign 1281.
Corneal clouding has been seen in feline GMI and GM2 gangliosidoses. This
638
Baker era/
apparently results from lysosomal storage of proteoglycans in corneal endothelial
cells and fibroblasts [5, 251.
Clinically apparent hepatosplenomegaly and skeletal abnormalities, which are
prominent features of some human gangliosidoses, have not been seen in other
species.
Genetics
All of the gangliosidoses for which adequate data are available seem to be inherited
as autosomal recessive traits. Heterozygotes for these traits are phenotypically normal,
but have about half-normal activity of the pivotal lysosomal hydrolase. This unique
feature has been used to survey high risk human populations and can be an effective
tool for eliminating carrier animals in domestic animal breeding programs or for
selective breeding in research colonies. Consanguinity is a consistent feature of the
expression of these diseases in domestic animals.
Biochemistry
The putative catabolic pathway of gangliosides is shown in figure I . The gangliosidoses are classified into two major biochemical subgroups, GMI or GM2 gangliosidoses, based on the nature of the storage product. GM, gangliosidosis results from a
block in the hydrolysis of the terminal galactose moiety normally achieved by one or
more isozymes of acid optimal B-galactosidases. Similarly, GM2 gangliodosis results
from the failure of B-hexosaminidases to cleave hexosamine terminals. Clinical
subtypes of human GM2 gangliosidoses correlate with partial or complete defects of
hexosamine isozymes. Of the animal analogs of GM2 gangliosidoses, only the feline
disease is known to be an exact biochemical replica of human infantile GM2
gangliosidosis (Type I1 or Sandhoff's disease) in which both isozymes are inactive
[51.
Total ganglioside content of cortical brain tissue in diseased animals is high,
reaching levels two to three times normal. Because GM2 ganglioside is normally a
minor component of the total ganglioside pool (less than l%), in GM2 gangliosidosis
the relative increases in this compound is particularly high. Asialo derivatives (sialic
acid free) of the gangliosides also accumulate in brain and liver of most species. High
concentrations of other neutral glycosphingolipids are found in some gangliosidoses.
Visceral storage of glycolipids and glycoproteins is characteristic of human, feline
and canine GMI gangliosidoses, but not bovine GM 1 gangliosidosis [20]. Hepatocellular lysosomal hypertrophy also is found in Sandhoff's disease of man and the feline
counterpart [ 6 ] , but not canine or porcine GM2 gangliosidosis. The hepatocellular
storage product in GMI gangliosidosis is a large molecular weight glycopeptide with
nonreducing galactose in p-D linkage [ 191. These compounds are highly water soluble
and are usually leached from tissue fixed with usual aqueous fixatives. In both GMI
and GM2gangliosidoses hepatocellular storage includes asialo gangliosides and other
glycolipids. Macrophages and endothelial cells often accumulate storage products.
639
Gangliosidoses
gal-NAcgal-gal-glc-cer
GM 1 Ganglioside
GM2 Ganglioside
hexororninidase
gal-glc-cer
GM3 Ganglioside
Neurarninidose
gal-glc-cer
LactosyI ce ramide
glc-cer
Glucosyl ceramide
'
t
Ceramide
Fig. 1: Sequential catabolic pathway of gangliosides. Lysosomal hydrolase (in box) required
for degradation of each compound.
cer
Morphology
Except for muscle atrophy associated with prolonged neurological- disease, gross
lesions are absent in animals other than man. Slight macroencephaly and hydrocephalus are associated with some human gangliosidoses but are not found in
animals. In the terminal stages of disease the brain may be moderately firm in all
species.
Lesions in nervous tissue are remarkably consistent, regardless of species affected
or biochemical subtype. Lysosomal hypertrophy caused by accumulation of gangliosides is apparent in most neurons even before birth. When clinical signs are advanced,
routine histological examination of brain, spinal cord or peripheral ganglia reveals
widespread neuronal degeneration characterized by varying degrees of swelling,
cytoplasmic vacuolation, loss of Nissl substance, margination of nuclei or loss of
neurons (fig. 2).
In frozen sections the cytoplasm of affected neurons and glial cells stain intensely
with periodic acid-Schiff (PAS) and faintly with stains for neutral fats. Epoxy
embedded thick sections (0.5 micrometer) stained with toluidine blue and examined
under the light microscope have dense blue, oval to round inclusions that fill the
cytoplasm of neurons and glial cells (fig. 3). Ultrastructurally, these inclusions are
spherical bodies about 1 micrometer in diameter consisting of multiple concentric
Fig. 2 Purkinje cells from the cerebellum of a cat with GMI gangliosidosis. HE.
Fig. 3 Cortical neurons of cat with GM I gangliosidosis. Hypertrophied lysosomes. Epoxy
embedded. Toluidine blue.
Fig. 4 Transmission electron micrograph of membranous inclusion bodies in lysosomes of
neuron. Glutaraldehyde and OsO,, lead citrate.
9
Fig. 5 Liver from cat with G M , gangliosidosis. Large unstained vacuoles in cytoplasm of
most hepatocytes. HE.
640
Gangliosidoses
64 1
lamellae with an interlamellar periodicity of 500 to 600 nanometers (fig. 4). The fine
structure of these inclusions is identical to that of the membranous cytoplasmic
bodies typically found in human gangliosidoses. Gliosis and demyelination are
significant only in the terminal stages of disease.
Recent studies with the rapid Golgi technique have shown bizarre morphological
abnormalities, known as meganeurites, in cats [29] with GMI gangliosidosis and
children [32] with gangliosidoses and Hurler's syndrome. These meganeurites, between the perikaryon and axon, appear to give rise to neurites and dendritic spines.
Some of these projections form synapses with presynaptic fibers of unknown origin.
Hepatocellular lesions are characteristically found in human [44],feline [3] and
canine [33] GMI gangliosidoses, as well as human [38] (Sandhoff s disease) and feline
[5] GMPgangliosidosis. Lesions in liver prepared by routine histological procedures
consist of diffuse vacuolation representing distended lysosomes from which watersoluble glycopeptidesleached during fixation (fig. 5,6). After glutaraldehyde-osmium
fixation, these vesicles can be shown to contain colloidal-iron-positive material,
presumed to be a proteoglycan with nonreducing terminal galactose residues (fig. 7).
Ultrastructural examination shows lysosomes of hepatocytes and Kupffer cells distended with material that has granular or lamellar structure [6].
Endothelial cells and perivascular macrophages in many organs are vacuolated.
Cytoplasmic vacuolation and lysosomal inclusions also have been found in pancreatic
acinar cells, renal tubular epithelium, myocardial cells, corneal stroma and cultured
fibroblasts [6]. Testes of pubescent cats homozygous recessive for GM I gangliosidosis
show a normal complement of spermatogonia, but are virtually devoid of mature
spermatozoa.
Laboratory diagnosis
The appearance in recent years of numerous reports of gangliosidoses in a variety
of species indicates the potential importance of these diseases as complications in the
maintenance of purebred domestic animal stocks. Current diagnostic technology is
sufficiently advanced to permit the detection and elimination of heterozygous carriers
from purebred stocks. Furthermore, the value of these disorders as models for
research on human lysosomal diseases has been documented [3] and further development of mutant stocks for research is needed. For these reasons, it is imperative
that cases of gangliosidoses be fully investigated and documented.
Veterinary clinicians should consider the gangliosidoses in the differential diagnosis
of animals with progressive generalized locomotor disease that first appears soon
after weaning. In addition to routine data, the clinical record should include thorough
documentation of the pedigree, with special reference to occurrences of previous
cases in the family, and complete description of neurological signs, including age of
onset and rate of progression. A motion picture record of neurological signs is
valuable.
Accurate laboratory confirmation of suspect cases can be done by morphological
and biochemical methods. Sample collection at necropsy should include preservation
642
Baker er al
Fig.6 Epoxy embedded thick section of liver from cat with GM, gangliosidosis. Single
large vesicle and multiple small vesicles in cytoplasm of hepatocytes and Kupffer cells.
Toluidine blue.
Fig. 7: Thick section of liver of cat with GMIgangliosidosis.Colloidal-iron-positivematerial
in vacuoles of hepatocytes and Kupffer cells. Glutaraldehyde-osmium,colloidal-iron.
of generous portions of brain, liver and kidney in air tight containers at -4" C or
colder; processing representative parts of brain, spinal cord and visceral organs for
routine light and electron microscopy and frozen sectioning; and aseptic excision of
skin for fibroblast culture.
Tentative diagnoses may be based on the observation of typical lesions in neurons,
hepatocytes and macrophages [2, 6, 131. Glycolipid storage in neurons and glia
should be confirmed by histochemistry. Demonstration of multilamellar inclusions
by electron microscopy completes the morphological assessment.
Final diagnosis must be based upon biochemical demonstration of accumulated
ganglioside storage product or deficiency of the corresponding lysosomal hydrolase,
or both. Assistance in biochemical evaluation of tissues from suspected cases should
be sought from laboratories specializing in diagnosis of sphingolipid storage diseases
or scientists studying these diseases [22].
Quantitative determination of gangliosides in brain is done by differential solvent
extraction [ 141, thin-layer chromatography [411, and quantification of the sialic acid
Gangliosidoses
643
Table 111. Enzyme specific activities in cultured fibroblasts
Mean P-galactosidase Mean P-hexosaminidase
specific activity (Na- specific activity (Nanonomoles cleaved/mg
moles cleaved/mg proprotein/hr f SD2 (n)3)
tein/hr k SD2 (n)3)
Genotype'
Normal (dominant) (8)
GMI heterozygote (3)
GMI homozygous recessive (10)
GM2 heterozygote (2)
GM2 homozygous recessive (6)
138 f 6 (20)
79 f 6 (12)
4 f 3 (20)
138 f 5 (12)
166 & 20 (20)
3 182 f 282 (20)
3189 & 373 (12)
3482 f 371 (20)
1724 f 93 (12)
101 12 (20)
*
' Number in parenthesis = number of cell lines derived from different animals.
' One standard deviation.
'Number in parenthesis = number of samples.
content of separated gangliosides [43]. Ganglioside analysis is done best on fresh or
frozen brain, but patterns of diagnostic value can be assessed in fixed brain tissue
preserved in aqueous buffered formalin for less than a year [41].
Definitive biochemical confirmation of suspected gangliosidoses can be made by
assay of tissue for GM ganglioside @-galactosidaseand @-hexosaminidases.Routine
diagnostic assay of enzyme activity uses chromogenic or fluorogenic synthetic substrates. Practical methods for assay of GM1 ganglioside @-galactosidaseand @hexosaminidases have been described [39, 421. Homozygous recessive individuals
have a profound deficiency (usually greater than 90% reduction) in the activity of the
pivotal enzyme in most tissues. Antemortem diagnosis can be made by enzyme assay
of whole skin, cultured skin fibroblasts, purified leukocytes, and in some species,
serum [ 10,281. Postmortem diagnosis is made most reliably by enzyme assay of brain
(cortex) and liver. Enzyme activity is retained for months in tissues stored at -4" C.
Biochemical diagnosis of recessive genotype can be made in utero by amniocentesis
and before onset of clinical signs in the neonate. Assay of enzyme activity in tail tips
removed aseptically during the first few days of life has been a useful procedure in
the management of feline GM1 and GM2 gangliosidosis colonies for research.
Tissue of heterozygotes contain about 50%of normal enzyme activity but individual
variation requires that prediction of heterozygous genotype by enzymology must be
based upon highly standardized methods of sample collection and assay. While it is
possible to use whole skin homogenate or leukocytes isolated from peripheral blood,
experience with the feline gangliosidoses indicates that cultured fibroblasts provide
the most reliable sample. Data in table I11 illustrate enzyme values of cultured
fibroblasts from cats of dominant, heterozygous and recessive genotypes from feline
GM1 and GM2 gangliosidoses colonies.
Research Applications
Early research on the lysosomal storage diseases was limited to clinicopathological
observations of individual human patients. In recent years, biochemical and morphological study of autopsy material has been augmented by use of cultured
644
Baker el a1
fibroblasts, brain biopsies and tissues from therapeutically aborted homozygous
recessive fetuses. While this approach has provided valuable insight, it suffers from
serious restrictions on the application of complex research procedures to human
subjects. The recent initiative by the National Institutes of Health emphasizing
research on rare human genetic diseases intensifies the need to develop model systems
that circumvent the limitations imposed on the use of human patients.
Investigators in this field have appealed consistently for development and use of
cell culture systems and animal models. Useful models must be well defined, easily
manipulated, relevant to analogous human disease processes, and readiIy available.
Special advantage is gained from models that provide parallel in vitro and in vivo
systems. In some instances it has been possible to simulate the metabolic or pathological consequences, or both, of inherited diseases by perturbing normal cultured
cells or animals [23, 371. Induction of simulated lysosomal disease has been accomplished by lysosomal loading with the substrate of interest or chemical block of the
pivotal enzyme system. While such systems can be useful, they rarely approach the
value of spontaneous animal disease analogs. Regretably, relatively few animal
analogs of human lysosomal diseases have been identified and thoroughly characterized. About I 1 diseases affecting one or more species have been reported that are
thought to be analogous to lysosomal storage diseases of man [3]. All of these diseases
are associated with degenerative disorders of the nervous system and nine have been
noted in domestic cats. The complete metabolic defects operating in these animal
analogs have been elucidated only for the gangliosidoses, canine globoid cell leukodystrophy, bovine mannosidosis and feline mucopolysaccharidosis.
Animal analogs of the gangliosidoses fulfill many of the requirements for useful
research model systems. Cats with GM1 and GM2 gangliosidoses, swine with GM2
gangliosidosis and dogs with GM1 gangliosidosis are being maintained in laboratory
colonies for use in biomedical research. Those herds of cattle that have produced
calves with GM gangliosidosis apparently continue to be maintained in Ireland;
presumably it may be possible to procure heterozygous breeding stock from these
sources. Breeding stock of German Shorthaired Pointers with canine GM2 gangliosidosis, however, has not been maintained for research use.
Use of farm animals in research presents substantial difficulties in maintenance of
such species, particularly in breeding colonies. This is an especially important
limitation in the bovine disease because of the low fecundity and large body size of
this species. Swine present fewer problems because of their high reproductive capacity
and the opportunity to transfer the mutant GM2 gangliosidosis gene to miniature
breeds.
There is much to recommend feline gangliosidoses as models for research: 1)
availability of established research colonies; 2) extensive characterization of the feline
diseases; 3) remarkably close and specific analogy with diseases in children; 4) high
reproductive capacity of cats; 5 ) ease of laboratory maintenance and handling of
cats; 6) body size which facilitates clinical observations, surgical manipulations,
testing and treatment procedures, and availability of reasonable volumes of tissues
Gangliosidoses
645
and body fluids; 7) unrivaled position of cats as the favorite species for neurological
research and the vast repository of data on the feline nervous system; and 8)
availability of well characterized companion cell culture systems.
Animal models of the gangliosidoses are particularly valuable for research aimed
at defining the pathogenesis of neuronal dysfunction caused by lysosomal disease
and for evaluating promising therapeutic methods.
Despite advances in understanding the biochemical lesions of lysosomal storage
diseases, surprisingly little is known about the relationships between disrupted
catabolism of complex metabolites, lysosomal hypertrophy and cell injury or death.
Because neurological disease is such a prominent and important part of most
lysosomal diseases it is important to understand the specific effect of lysosomal
hypertrophy on neuronal dysfunction and death. Demyelination secondary to functional disturbances of Schwann cells has been proposed as a primary factor [ 181, but
the complex neurological manifestations and lack of marked demyelination until late
in the disease process makes this explanation insufficient.
The gangliosidoses are known to be associated with changes in the shape and size
of certain neurons. In studying cortical biopsies from children with Tay-Sachs disease
(infantile GM2 gangliosidosis), juvenile GM2 gangliosidosis and Hurler’s disease
(mucopolysaccharidosis,type I), large neuronal processes (meganeurites) were found
between the perikaryon and axon of cortical pyramidal neurons (321. In some neurons
the volume of meganeurites exceeded that of the associated soma. Recently, meganeurites comparable to those seen in children have been seen in many areas of brain
from cats with GM, gangliosidosis (fig. 8) [30, 3 11.
The discovery of abnormal neuronal morphology in gangliosidoses forms the basis
for advancing a hypothesis to explain neuronal dysfunction caused by lysosomal
hypertrophy [32]. This hypothesis is based on the generally accepted view that the
geometric features of multipolar neurons are important in determining the integrative
electrophysiological effects of spatially distributed synaptic inputs. Thus the output
of neurons conceivably can be altered by abnormal cell morphology such as generalized increases in cell size, or by regional expansions such as meganeurites. Furthermore, if aberrant synaptic inputs associated with meganeurites are functional,
the integrative function of affected neurons could be altered profoundly. The
formation of neurites in mature neurons engorged with ganglioside also suggests the
role of these compounds in neurite induction during normal neuronal differentiation.
Continued study of the pathogenesis of the animal gangliosidoses thus provides an
unprecedented opportunity to advance understanding of several important aspects of
neuronal function in health and disease.
In the past, treatment of individuals with most inherited metabolic diseases has
been palliative only. In search of alternative methods for treating inborn errors of
metabolism, dietary control of substrates and substrate precursors has been suggested
as a method to prevent the pathological accumulation of toxic substrate. Dietary
therapy has been successful in preventing clinical disease in at least 20 other disorders
of amino acid metabolism [45]. While this approach has been extremely effective in
646
Baker era/
'
25rm
'
Fig. 8 Camera lucida drawings of entorhinal cortex pyramidal cells from cat with GMI
gangliosidosis. Soma (S)and meganeurite (M).
From Purpura and Baker, Brain Research 143
13-26, 1977, with permission of Elsevier, North Holland Biomedical Press.
those disorders where restriction of the offending metabolite is feasible, most lysosoma1 storage diseases do not lend themselves to dietary treatment. Diseases such as
the gangliosidoses involve faulty degradation of complex molecules which are
necessary for life and cannot be controlled by dietary restriction.
The thrust of current research is directed toward the development of corrective
therapy for these enzymatic deficiencies. An ideal cure for inherited disorders would
be substitution of normal DNA coding for synthesis of the defective gene product.
Current concepts and the potential for gene therapy recently have been reviewed
[ 15). While promising therapeutically, progress in gene therapy will be slow because
of technological and ethical restrictions.
The theoretical possibility of correcting lysosomal diseases by enzyme replacement
was recognized soon after the pathogenetic basis for these diseases was first advanced
[26]. The rationale for this approach is based on the assumption that endocytosed
replacement enzymes would be brought into direct contact with diseased lysosomes
and function in degradation of accumulated substrate. Attempts at in vivo enzyme
replacement for lysosomal storage disease have been reviewed [8, 361. Although the
progress in enzyme replacement therapy has been significant, the optimistic goal of
effective therapy for human lysosomal storage disease has not been realized. Major
Gangliosidoses
647
obstacles that must be overcome if enzyme replacement is to be effective include: 1)
availability of stable enzymes with high specific activities for natural substrates; 2)
protection of replacement enzyme from bioinactivation and immunological reactivity;
3) perfection of methods to deliver replacement enzyme to target pathologic sites;
and 4) development of well defined, representative mammalian model systems to test
therapeutic methods.
In vitro and in vivo systems of the feline gangliosidoses are being used effectively
in addressing fundamental aspects of enzyme replacement therapy, such as biological
carriers of replacement enzyme; organ, cell and intracellular targeting; enzyme-cell
interactions; reversibility of lysosomal hypertrophy; and penetration of endothelial
barriers.
Lysosomal hypertrophy and retarded catabolism of glycoproteins have been seen
in fibroblasts cultured from cats with feline gangliosidoses. Incorporation of ( 14C)galactose into the glycopeptides stored in lysosomes of feline GM1 gangliosidosis
provides a predictable and sensitive system to evaluate quantitatively the effects of
enzyme replacement therapy. With this system it has been demonstrated that
exposure of mutant fibroblasts to liposomes carrying hydrolytically active /I-galactosidase resulted in clearance of more than 80% ''C-glycopeptide and an increase of
/3-galactosidase activity to 70% normal within 240 hours 1351.
Research on therapy for lysosomal storage diseases is at the threshold of development and many questions remain. It is clear, however, that the animal gangliosidoses
will provide the necessary models for exploration of this fundamental and exciting
research.
Acknowledgements
This work was supported by a grant from the National Institute of Neurological and
Communicative Disorders and Stroke, NS 10967.
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J.R.; MCKHANN,
G.M.; FARRELL,
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H.J.; MOLE,J.A.; LINDSEY,
J.R.; CREEL,R.M.: Animal models of human ganglioside
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10 DONNELLY,
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1 I DONNELLY,
W.J.C.; SHEAHAN,
B.J.; KELLY,M.: Beta-galactosidase in GMI gangliosidosis
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