In Five Short Years

THERAPEUTICS

In an NIH partnership, we screened more than a thousand drugs, then, in three years, moved the top one, ceftriaxone, into animal and clinical trials—record time for a potential therapy. Our scientists also participated in the discovery of other ALS candidate treatments, including minocycline, IGF-1, VEGF and talampanel, now in the midst of or about to begin national clinical trials. Celebrex, tried because of cell targets uncovered by Packard scientists, also completed animal and human studies in less than three years. More drugs and new approaches are in the pipeline. The steps continue.

PATHOGENESIS
How does ALS occur?

Having no clear idea how a deplorable disease begins and spreads in the body means you need to probe far and wide. That’s just what we’ve done. Prior to the Center’s opening, its core scientists were the first to spot a basic molecular flaw in ALS—the inability of nerve endings to clear the molecule glutamate efficiently. This discovery ultimately led to the current ceftriaxone trials.

Other molecular-level work centers on the flawed SOD1 protein seen in patients’ nervous systems. We’ve shown ties between its amount and the severity of symptoms, explained how the abnormal molecule might have formed and how it may harm cells. Packard work has advanced ideas that ALS may be a disease of protein chemistry gone wrong.

The SOD1 research has nudged Packard Center work to the next level—cell structure. We’ve shown that flawed SOD1 protein clogs the cell’s energy-producing mitochondria only in the brain and spinal cord. That alters cell chemistry and unleashes havoc. The work has at last offered a plausible reason why ALS targets the central nervous system.

Several of our studies show that ALS strikes motor neurons earlier than suspected. Damage appears first, apparently, at the myoneural junction. Knowing that lets us zero in on what might go wrong between nerve and muscle and on what could be blocked to stop or lessen the downhill progress. Packard Center scientists, for example, are showing that key protective molecules aren’t properly transported from muscle to a motor neuron’s interior.

On the cell level, we’ve found that motor neurons’ neighbors, the astrocytes and microglia, are real players in ALS’s downhill story.

MODELS
How do you best explain what’s happening? Test new treatments?

Without animal models, we feel, there’s no progress against ALS. The premier model—the mutant SOD1 mouse—was developed a decade ago, in part by future Center scientists. It’s been in constant use and refined here. For example, the SOD1 rat that we co-developed models rapidly progressing disease and makes testing stem cell therapies easier. Our Sindbis virus mouse model mimics some of ALS’s worst damage and is quicker and cheaper to produce. A unique “chimeric” mouse—with some cells carrying mutant SOD1 and some not—is helping to reveal the role of each nervous system cell in ALS. And that keeps our search for a cure properly focused. Our major discovery that ALS probably doesn’t start in motor neurons came from chimeric mice. And our newest model, the dynactin mouse, is telling us how cell “circulatory” problems hasten ALS while it lets us test therapies to fix them.

RESCUE and REPAIR
How do you help nerves
that are dying?

In five years of research, we’ve clocked how long nerve cells stay salvageable. We’ve shown that natural cell agents such as pleiotrophin and VEGF can help protect neurons; we’re exploring them as potential therapies. Our basic studies give clues on how to guide repaired or new nerve cells to the right muscle contacts. And because ALS alters synapses, some Packard scientists are learning how the body creates and recycles them—a step toward synapse protection. Most exciting is our find of a master gene for natural protection in cells and how it extends life in ALS animal models.