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Genetic
Defects: Since 1984, the primary approach we have pursued to
understanding the cause of ALS has been to analyze genetic forms
of the disease. The underlying premise is that a detailed understanding
of inherited forms of ALS will provide insight into all forms
of ALS. This is critical to our philosophy, as most ALS cases
are not inherited. Our studies to date suggest that this premise
is valid. For example, the observation that mutations in the
SOD1 gene cause ALS suggested that there might be free radical
injury in the disease. With associates, we have subsequently
found that such injury is as abundant in familial as non-inherited
(sporadic) ALS.
As mentioned above, we were fortunate to play a role in the
discovery of SOD1 mutations in ALS. We are now actively pursuing
other gene defects that can cause ALS. We have identified new
chromosomal addresses for such ALS gene defects. Studies are
underway to identify the critical genes within those addresses.
Risk Factors: In parallel with these investigations,
we embarked two years ago on another tack to understand non-inherited
ALS. We are now using the methods of genetics to identify risk
factors for ALS in sporadic ALS patients. Such risk factors
have recently been shown powerfully to influence the onset of
Alzheimer's disease. We believe that insights into such risk
factors in ALS will both help elucidate the cause of the illness
and assist in the design of new therapies.
Gene Expression: A third arm of the basic program is
to identify patterns of molecular events that accompany the
motor nerve death process in ALS. Such patterns can be recognized
by studying genes that are either activated (turned on) or inactivated
(turned off) as the the disease evolves. The identities of these
patterns of genes should provide clues as to events that cause
the disease and, at the same time, delineate possible targets
for treatment.
Biomarkers: A fourth project is to define biochemical
markers of the motor nerve death process that can be detected
in tissues and fluids (spinal fluid, blood) of ALS patients.
Such markers are important because they identify possible causes
of the disease and because they can be used as markers for progression
of the illness. The latter is helpful in monitoring for subtle
beneficial effects of drugs, for example.
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