ALS Alert Newsletter | June

Q & A with Jeff Rothstein

Packard director Jeff Rothstein discusses the current state of ALS research and Packard’s role.

Jeff Rothstein, founder and director of the Robert Packard Center for ALS Research at Johns Hopkins

1. Talk a little about where the Packard Center has come since its inception

Packard is a consortium designed to take observations from patients and new genes discovered by others and really investigate that by building models of the disease and then using these to understand why ALS occurs in the first place, what damage it's doing to the body at the cellular level, and to find ways of stopping disease. Scientists have used this information to investigate biomarkers to detect disease earlier and to tell if drugs are working in ALS patients.

The Packard Center has grown to encompass a worldwide network of pre-clinical and clinical scientists in the past twelve years. These researchers have built new animal models of ALS and have come up with new drugs for ALS clinical trials. These animal models help build the tools to determine what elements of the nervous system are affected by the disease and identify potential subtypes of ALS patients. At the other end of that, Packard researchers have helped develop the clinical trials network so we can take these insights back to patients.

2. Twelve years later, what do you consider the Center’s great accomplishments?

Packard is a multiplier of research. When a single ALS researcher builds a tool, he or she can use that tool. If it's a valuable model, however, thousands of other scientists will use those tools as well. We may start focal and small, but we're being very strategic about that by building the tools that everyone must have to understand ALS. Those are some of the most valuable things we can do.

Around the world, other scientists and drug companies use the tools that we build to help find answers to ALS. Discovering a new pathway leading the way for others to build on that is really important. No single person will find the answer to ALS--the disease is far too complex. You need teams to work it out. So if you can build something various teams can use, you can be more successful at actually finding an answer.

3. Where would you like to see the Center go over the next decade?

No one can predict science. It's impossible. A year ago, we would never have known that the discovery of the most important gene in ALS would be published in November. We never could have predicted that. Now scientists must rapidly jump on that observation and develop new tools that others can use to understand the disease. Packard needs to build a solid foundation in research so that we can nimbly follow the clues as they are discovered and published. The better the tools that we use, and the more efficient we are at moving those into patients, the better our patients will be.

As of today, that means we need to better understand the subtypes of patients and realize that all patients aren't the same. We've discovered some of the tools that might help identify these subtypes. Like in cancer, not all drugs will work on all patients. We need to figure out the right subsets for the right medications as they're developed. That will be coming with imaging and biomarker approaches.

4. Talk a little about what is going on in the state of ALS research

The field is the most active ever since I started in ALS research. Multiple genes have been discovered in the past few years, and the most important one is probably C9ORF72, which accounts for almost half of familial ALS and ten percent of sporadic disease.

The other important thing that is going on is the recognition that non-neuronal cells like glial cells participate in the disease process. Understanding this has given us new targets for drug discovery and for imaging approaches to ALS. Probably the biggest story in the next year will be about research on a type of cell that we never envisioned would be part of ALS called an oligodendroglia. This is important not just because it gives us a better understanding of disease, but because other pharmaceutical companies have been developing drugs targeting the same cell in a disease completely unrelated to ALS. But the tools and drugs they've developed might turn out to be useful for us as well.

5. How has the discovery of the c9 gene changed the face of ALS research? What impact will it have?

There's been nothing like that in any other neurodegenerative disease. We have a mutation that is found in a large percentage of what were thought to be sporadic cases. That's a key element to the vast majority of ALS patients. The change to research is coming, although we haven't seen the results of it yet because it takes time to go from two publications to all of the necessary follow-up studies.

Within a day, Packard was building a team of researchers to tackle this new gene. Understanding this gene will be difficult due to the complex nature of this defect. The defect in the gene looks a lot like a mutation in an unrelated disease known as myotonic dystrophy. So we might be able to take advantage of progress made in that field, especially the use of gene inactivation approaches and therapeutics. This is also the first case where stem cells will prove to be exceptionally useful tools for drug discovery.

6. What are the next steps with this gene discovery?

First, we need to start building models around the C9ORF72 gene so that we can understand how a defect in this gene causes damage to the nervous system. We also need to start building all of the stem cell lines, so we have not just mice that get the disease, but also human cells. As we've done in the past, we need to build up that foundation of tools. These tools are the first step towards understanding the disease. We can use these at Packard and loan them to other people to figure out why C9ORF72 is so toxic.

We also want to find ways to identify patients with this mutation early on in their illness and follow them. And, of course, we want to design therapies, and that is one of the first things we began working on: targeting therapies specifically to C9ORF72.

7. Our byline is the “The Hope is in the Science”, as a clinician and a researcher, what would you tell a patient if they asked you what hope they have?

There are more tools and clinical trials today in ALS than there has ever been before. Those are the steps that take us closer to a therapy, and therapies are what all patients want. I believe that the foundation-building tools that Packard has built, and the collaborating, sharing nature of the Center ensures that the science will move faster and get out to the public more quickly. The vast majority of ALS clinical trials are built upon Packard research. This speaks to the impact the Packard Center has in moving therapies towards patients.