Biomedical Engineering Reference
In-Depth Information
gain-of-function disease models include Alzheimer's
disease, which was modelled by overexpression of the
amyloid precursor protein (Quon
et al.
1991), and
the triplet-repeat disorder spinocerebellar ataxia
type 1 (Burright
et al.
1995). Simple transgene addi-
tion can also be used to model diseases caused by
dominant negative alleles, as recently shown for
the premature ageing disease, Werner's syndrome
(Wang
et al.
2000).
Recessively inherited diseases are generally caused
by loss of function, and these can be modelled by
gene knockout. The earliest report of this strategy
was a mouse model for hypoxanthine-guanine
phosphoribosyltransferase (HPRT) deficiency, gen-
erated by disrupting the gene for HRPT (Kuehn
et al.
1987). A large number of genes have been modelled
in this way, including those for cystic fibrosis (Dorin
et al.
1992, Snouwaert
et al.
1992), fragile-X syn-
drome (Dutch-Belgian Fragile X Consortium, 1994),
β
symptoms (Blouin
et al.
2000). Similarly, crossing
transgenic mice overexpressing the anti-apoptotic
protein Bcl-2 to rds mutants, which show inherited
slow retinal degeneration, resulted in hybrid off-
spring in which retinal degeneration was strikingly
reduced. This indicates that Bcl-2 could possibly
be used in gene therapy to treat the equivalent
human retinal-degeneration syndrome (Nir
et al.
2000).
The most complex diseases involve many genes,
and transgenic models would be difficult to create.
However, it is often the case that such diseases can
be reduced to a small number of 'major genes' with
severe effects and a larger number of minor genes.
Thus, it has been possible to create mouse models of
Down's syndrome, which in humans is generally
caused by the presence of three copies of chromo-
some 21. Trisomy for the equivalent mouse chro-
mosome 16 is a poor model because the two
chromosomes do not contain all the same genes.
However, a critical region for Down's syndrome has
been identified by studying Down's patients with
partial deletions of chromosome 21. The generation
of yeast artificial chromosome (YAC) transgenic
mice carrying this essential region provides a useful
model of the disorder (Smith
et al.
1997) and has
identified increased dosage of the
Dyrk1a
(
minibrain
)
gene as an important component of the learning
defects accompanying the disease. Animal models of
Down's syndrome have been reviewed (Kola &
Hertzog 1998, Reeves
et al.
2001).
-thalassaemia (Skow
et al.
1983, Ciavattia
et al.
1995) and mitochondrial cardiomyopathy (Li
et al.
2000). Gene targeting has been widely used to
model human cancers caused by the inactivation
of tumour suppressor genes, such as
TP53
and
RB1
(reviewed by Ghebranious & Donehower 1998,
Macleod & Jacks 1999).
While the studies above provide models of single-
gene defects in humans, attention is now shifting
towards the modelling of more complex diseases,
which involve multiple genes. This is a challenging
area of research but there have been some encour-
aging early successes. In many cases, the crossing of
different modified mouse lines has led to interesting
discoveries. For example,
undulated
mutant mice lack
the gene encoding the transcription factor Pax-1,
and
Patch
mutant mice are heterozygous for a null
allele of the platelet-derived growth-factor gene.
Hybrid offspring from a mating between these two
strains were shown to model the human birth defect
spina bifida occulta (Helwig
et al.
1995). In other
cases, such crosses have pointed the way to possible
novel therapies. For example, transgenic mice over-
expressing human
Gene transfer to humans - gene therapy
The scope of gene therapy
Gene therapy is any procedure used to treat disease
by modifying the genetic information in the cells of
the patient. In essence, gene therapy is the antithesis
of the disease modelling discussed above. Whereas
disease modelling takes a healthy animal and uses
gene-manipulation techniques to induce a specific
disease, gene therapy takes a diseased animal (or
human) and uses gene-manipulation techniques
in an attempt to correct the disorder and return
the individual to good health. Gene transfer can be
carried out in cultured cells, which are then reintro-
duced into the patient, or DNA can be transferred
to the patient
in vivo
, directly or using viral vectors.
α
-globin and a mutant form of
the human
-globin gene that promotes polymeriza-
tion provide good models of sickle-cell anaemia
(Trudel
et al.
1991). However, when these mice are
crossed to those ectopically expressing human fetal
haemoglobin in adulthood, the resulting transgenic
hybrids show a remarkable reduction in disease
β
