Tip:
Highlight text to annotate it
X
2012 ALSRP Investigator Vignette
Title: AAV-Mediated Inclusion Formation as a Novel Gene Therapy Strategy for ALS
Investigator: Ole Isacson, MD, PhD; McLean Hospital
ALS is a progressive neurodegenerative disease, and when a patient has the signs of ALS or
Lou Gehrig's disease as it sometimes is called, up to 50% of those so-called motor
neurons have died. So it's already quite late in the disease process.
So, the research goal for my DoD grant is to try to find ways of treating disease very
early or even preventing it.
The most linear way of thinking about neurodegenerative diseases or all disease for that matter is
to look for one thing that causes the disease. For example, in ALS there is a gene called
SOD, superoxide dismutase that has a genetic defect. But what usually happens is that single
mechanism is not the only reason a cell dies, because that gene is expressed in every cell
in the body. But ALS or neurological diseases are not skin diseases or liver diseases for
that matter.
So we took a different approach, which was to look at how each cell deals with the mutation
of the protein and tried to discover why certain cell types are affected by disease.
And the way that developed was, we had a rat model of ALS called an SOD-mutant rat, which
is the same gene that mutates in familial ALS and when the rat started to show symptoms
of disease we sacrificed them and studied their nervous system. And just like in ALS,
we found that 50% of the nerve cell had died in the spinal cord, but we also found that
the motor neurons that control the eye muscles or also the facial muscles were relatively
spared or protected.
We then used a laser capture technology in which you shine a laser on each one of these
nerve cells, maybe 1,000 are contained in each of these regions—and you can then collect
their characteristic expression for each cell. And that meant that we could study each motor
neuron that's affected in ALS and actually dividing them up in populations, and so we
could isolate the nerve cells that were most vulnerable and the ones that were most resistant
and then compare their genomic profile, we call them genetic profiles.
What you see here in the red and blue are each little dots there are different genes
and their level is high or low depending on their color. So in the protected regions like
your eye muscle control you see there's an up-regulation in red or compared to others
that are more vulnerable in blue.
And so by analyzing these patterns of genes, we came up with genes that seemed to correspond
to very healthy or strong neurons even in the face of this disease process. And one
of the genes that stood out—we knew was a trophic factor, an insulin growth factor
two- was overexpressed, so about two- to threefold in neurons that were protected versus those
that were more vulnerable.
So we took this protein actually and poured it onto these motor neurons you see here in—in
red and green. And indeed when we stressed the neurons with a toxin that simulates ALS
all of the neurons were protected in the dish versus about a 50% loss, which is what you
see in the disease as well,
We then developed a plan for how to induce or make more of an expression of such proteins
in these neurons. And the DoD program that was funded basically allowed us to take already
approved drugs, they're called FDA-approved drugs, they're called a library sometimes,
and test them on nerve cells and see which one of these already nontoxic drugs could
induce these protective proteins.
One of the most important parts of our research program on ALS is to do a high-throughput
screening. And what we did was to build a cell that had a fluorescent color marker that
showed us when the IGF-II neuroprotective protein was turned on.
And that we did in collaboration with the lab of drug development which is a Harvard-based
laboratory that helps with drug discovery. So in that work we're now studying new chemical
compounds that could drive this protective protein in cells and some of which could become
new drugs in the future.
At the same time though we're using already established drugs which brings down the discovery
time by about 90% and the cost also by 80 to 90% because most drugs fail in clinical
development because they're toxic, not to the cells that you try to treat, but usually
to other cells and organ systems in the body.
So our program now has identified a molecule, a drug already on the market for various other
indications that drive the expression of this IGF-II. And we're now going to test that
drug on rat models of ALS and see whether it can prevent or delay the disease in those
animal models. So this new idea, which is called repurposing of drugs, is something
that we really have followed in this DoD program and we think it's very promising.
�