Huntington's Disease
from Bench to Bedside
Huntington's disease (HD) is an autosomal dominant inherited
disorder that affects approximately four to ten out of
each 100,000 members of the population. It begins insidiously
in midlife with personality changes and involuntary jerk-like
movements of the limbs, chorea. The illness results in
inevitable death after about fifteen years of illness.
The mutation in the HD gene that causes the illness is
an unstable, expanded trinucleotide (CAG) repeat in the
N-terminal region of the open reading frame.
In the last five years, numerous studies have been carried
out examining the potential mechanisms whereby the gene
may cause the pathology. It is now possible to examine
these mechanisms in cell- based assays and whole animals
(including drosophila and c. elegans). Dr. Young and her
laboratory devised a set of strategies to look for compounds
that delay the onset and slow the progression of the disease.
They chose to use assays that examine the most fundamental
aspects ot protein mishandling. She has also set up a
laboratory for high throughput screening of compound libraries
to assess methods to improve function in cell-based assays
and animal models.
To date, they have found one compound, C2-8, that reduces
inclusion formation and aggregation and slightly improves
survival in HD transgenic mice. They have also found compounds
that increase aggregation but improve survival in cell-based
assays. The results suggest that aggregation per se is
not toxic, but that other mechanisms involved in the aggregation
events may be important. In summary, drug discovery in
academia is possible and will hopefully interface with
biotechnology and pharmacological goals.
