ALS Alert Newsletter | March 2010

Piera Pasinelli

Stepping Back to Look: From the Recent Berlin Symposium

A drug to keep an eye on, a new ALS path that steps into the ring, cultures that’ll revolutionize research—now we really roll up our sleeves, says our scientific director

The few months have flown since the International Symposium on ALS/MND in Berlin. In December, this largest annual meeting brought together a record 900 delegates from academic medical centers, biotech and pharma companies, and smaller private laboratories.

Packard Center scientists attended, stepping between the clinical and scientific sessions held in parallel—all hoping for a spark of information to fan into therapy.

But for Packard Scientific Director, Piera Pasinelli, the meeting has since become a call to action. Far from offering the odd “sparks,” she says, “this year’s symposium was exceptionally good for the quality of the science, the large number of new, potential collaborators and the novel directions the advances are taking. And we need to capitalize on that.”

What stands out in her mind, after these two months, is what the two newest ALS genes are beginning to reveal, how several barely-studied disease pathways could be major players, and how having human ALS cell cultures has the potential to lift research to places scientists could only hope to go.

Here are a few of Piera’s Picks:

A Pathway Gains Strength

Jean-Pierre Julien

Julien’s studies with the molecules center on the mutant SOD1 gene that can trigger ALS. When the mutant SOD1 gene is active, the protein it codes for binds to chromogranins. Then, joined, both molecules are ushered out of cells. It’s from that outside position, Julien has shown, that mutant SOD1 protein can induce motor neuron death.

“Building on his research,” says Pasinelli, “Julien asks having a mutation in one type of chromogranin could also make people susceptible to ALS. And his new work shows it apparently can.”

In the new study, Julien’s team analyzed the makeup of the chromogranin B gene from more than 600 patients and controls. His finding: Having a mutant chromogranin gene significantly increases the risk of having ALS. Mutant chromogranin also appears to promote earlier onset of the disease.

“What we find especially interesting,” says Pasinelli, “is that, in increasing our understanding of the biological path of one familial form of ALS, Jean-Pierre has also identified a suspect gene—for chromogranins—whose abnormal behavior may be relevant to ALS in general.

“For us, this is a call to action: we now have a probable susceptibility gene and a clear mechanism to investigate further. And Jean-Pierre’s research validates the Packard approach to build good animal models of ALS and develop other scientific tools. In letting us understand the disease process, they will also help us uncover new research areas to explore.”

Julien, a long-time Packard investigator, is at Laval University in Quebec.

New Tools/New CapabilitieS

Scientists’ wish lists have always included living ALS cultures—human brain and spinal cord cells with the actual disease—to screen therapies and understand the biology. But sampling patients’ nervous systems for cells to culture is, obviously, not possible. Work by P²ALS collaborator Chris Henderson, however, opens doors to technology that gets around that problem.

At the Berlin meeting, Henderson reported success in creating iPS cells (induced pluripotent stem cells) from ALS patients’ skin. The iPS cells are maintainable as lab cultures; they also can be biochemically prompted to morph into spinal motor neurons.

Henderson’s earlier work using healthy human embryonic stem (ES) cells shows that techniques exist to grow many subtypes of motor neurons as well as the astrocytes that help sustain ALS. He expects that patient-derived iPS cells—which resemble ES cells—will let researchers do the same. But the important difference is that these are cells from actual patients.

The next step, he says, is to use iPS cells to recreate the ALS disease process in his lab.

Pasinelli comments: “Because Chris Henderson is part of the new collaboration of Packard and Project A.L.S. scientists, we feel sure that this arrangement will exponentially accelerate the work it will take to make the iPS cells he studies useful for screening therapies.”

Henderson is a researcher with P²ALS, the new joint enterprise between the Packard Center and Project A.L.S., which helps support his work. His research is additionally supported by MDA Wings Over Wall Street, also a major Packard donor. Henderson is at Columbia University in New York

More on the Two New Genes

Pasinelli singles out work by Manuela Neumann that strengthens the growing case for errors in RNA metabolism as a key disease process.

Meanwhile, Eric Pioro has traced the motor neuron problems of the “wobbler” mouse to TDP-43-caused abnormal RNA metabolism. That adds to the theory.

Neumann is with the Institute of Neuropathology in Zurich, Switzerland.
Pioro is a former Packard Center investigator based at the Cleveland Clinic.