Biomedical Engineering Reference
In-Depth Information
Huntington's Disease and Stem Cell Therapy
It is a progressive, fatal autosomal dominant neurodegenerative disorder caused by
increased CAG repeats in the Huntington gene. Clinically it is characterized by
chorea and progressive dementia-deterioration in cognitive and neuropsychiatric
functions [ 59- 76 ]. The main pathology is the loss of medium spiny projection neu-
rons in the striatum, due to mutation in the huntingtin gene. Cell therapy in
Huntington's disease aims at restoring brain function by replacing these neurons
[ 64, 75, 76 ]. There is another aspect to this disease which is an inherited neurode-
generative disorder that affects roughly 30,000 Americans, incurable and fatal. But
a new discovery about how cells repair their DNA points to a possible way to stop
or slow the onset of the disease gives the hope that the cure might be found. Unlike
most inherited diseases, Huntington's disease symptoms usually do not appear until
middle age, leading scientists to wonder what triggers the disease onset, and whether
it can be halted—or at least slowed down.
People with the disease have a version of a gene called huntingtin that carries an
extra segment with a particular sequence of repeated subunits. If the segment is too
large, the gene produces a faulty protein that has a destructive effect in the brain.
Huntington's disease is a progressive disease, but nobody knows exactly why.
Research work supports the idea that the disease progresses when the extra segment
expands over time in non-dividing cells such as nerve cells. McMurray's study
shows that the inserted segment grows when cells try to remove oxidative lesions,
which are caused by by-products of the oxygen we breathe [ 62 ] . DNA repair
enzymes initially keep oxidative lesions in check, but over time, increasing numbers
of lesions overwhelm the repair systems.
Oxidative lesions also accumulate in people who do not have Huntington's
disease, but because their huntingtin gene lacks the extra segment it is not prone to
expansion. While scientists have long suspected that oxidative lesions play a role
in Huntington's disease, the specific role of the lesions has remained elusive until
now. Nobody has connected the dots before. To show that the extra segment
enlarges with age, the researchers engineered mice to carry a version of the human
huntingtin gene with an inserted segment—one large enough to cause Huntington's
disease in humans [ 62 ]. After a few months—when the mice had aged—the scien-
tists analyzed the gene and found that the segment had expanded. They also
observed an increase in oxidative lesions in the mouse DNA [ 62 ] . To see if the
oxidative lesions played a role in expansion of the extra DNA segment, the
researchers next deleted 8-oxoguanine glycosylase (OGG1), a key enzyme in oxi-
dative lesion repair. Without OGG1, the bulk of the DNA's oxidative lesions
remained untouched, and the inserted segment did not grow at all, or it grew far
less than in mice carrying a working version of OGG1. These findings show that
while doing its part in removing oxidative lesions, OGG1 triggers a far more dam-
aging effect—the DNA expansion associated with Huntington's disease. The study
suggests that OGG1 might offer a target for the development of new Huntington's
disease treatments. McMurray's team is already pursuing this path and is screening
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