How To Spend All That Ice-Bucket Money? Multiple ALS Research Leads Heat Up

I sighed this week when I heard, "Hey, Mom, do we have a clean bucket and some ice?"

Yes, the viral ALS ice-bucket challenge that has swept the country had reached our household as well. And though my daughter averred that she would never have heard about ALS otherwise, it pushed some of my cynic buttons. (My favorite response so far had come from an acidly hilarious Facebook friend who advised celebrities: "Just write a check to support ALS research. If you still need a gimmick and social media attention, set your hair on fire instead.")

For me, the trouble was that I had looked into ALS research a few years ago and it had struck me then as extraordinarily frustrating. It was the field that first taught me that it's all too common for a potential treatment to look good in initial testing and then fail to pan out when tried in a bigger clinical trial. That happened with ALS over and over again. And meanwhile, patients faced inexorable neurological degeneration and far too early deaths. (One of my most admired colleagues, Dudley Clendinen, died of ALS in 2012 after eloquently chronicling his time with it.)

But then I thought: Let's be positive. Whatever the narcissistic elements of the ice-bucket dousings, the challenge is raising millions of dollars — more than $50 million as of Friday, from more than a million new donors, according to the ALS Association. And maybe ALS research has changed?

Indeed it has, say scientists working in the field. Not that it looks like there's a cure around the corner, but there has been major progress of late, they say, and we can expect more to come.

"In about the last seven years, the genetics of ALS has just exploded the field, and just come up with so many new ideas for how we can tackle the disease," said Avi Rodal, an ALS researcher at Brandeis University whose work is funded by the Blazeman Foundation for ALS.

Dr. Lucie Bruijn, chief scientist of the ALS Association that is reaping the ice-bucket windfall, also describes a field that is forging ahead in multiple directions. "The understanding of the disease, the research that has gone into it, has grown exponentially," she says. "So we're much closer to understanding the complexity of the disease and how to approach it in a very different way from before, when many of the trials were challenging partly because we didn't understand the disease as closely."

The Association, she says, is focusing on six main areas, and the ice-bucket money will likely be divided among them: "We want to invest in many areas," she says, "to be sure not to dilute it too much but to be very strategic that we don’t put all our eggs in one basket."

Those areas, in brief and lightly edited, as she described them:

1. Genetics:
About five to 10 percent of ALS runs through families, but 90 percent is sporadic. However, we’ve found that many of the genes we identify in familial disease are potential risk factors, and certainly also seem to be involved in the sporadic form. So there’s an underlying genetics in all ALS, but sometimes it’s more dominant than others.

Through our funding, we’ve been able to build large consortia. In fact, a couple of years ago there was a very exciting finding — a quite tricky gene, one that we couldn’t find so easily, so we invested heavily into it — it affects about 40 percent of familial ALS. Also, in some cases of ALS, there’s a kind of dementia called frontotemporal dementia, and this gene finding affects both ALS and frontotemporal dementia. So there’s an interesting link we’re trying to understand, with different biologies with the same gene, and that really made the field explode.

The gene has a complicated name — C9orf72 — because it produces a protein that we don't know anything about, and the name is just a location number — it's located on chromosome 9, Open Reading Frame 72 — until we understand more about what the gene does.
So it's a mystery gene?
It is, and even more fascinating is that it’s the first for ALS we’ve found where it’s not a point mutation — it’s not one change on the reading code that causes an abnormal protein — it’s actually an expansion that is inserted into this region of the gene. And it’s a repeat, it’s called a hexanucleotide repeat — six things repeating over and over again a thousand times when it should be only 20. So it’s similar to Huntington's disease and others like it. And experts in those fields are now using their knowledge and bringing it to the ALS field.

2. Biomarkers:
Biomarkers are very important because they are signatures of the disease, they tell us if the disease is changing or give us clues for diagnosis.

What had been really challenging in the clinical trials that you mentioned that had failed is that often we don’t know why they have failed. Partly, we think maybe ALS is a spectrum of diseases — that some might react to the treatment approach differently than others. And we’ve started to see if we can group and discern patients in different categories, some that might have a particular profile in their blood or the fluid around their brain that tells us, for example, that they might have more of an inflammatory profile and they might respond better to drugs if we treat along that pathway.

So it's a fascinating area, and it really requires significant investment because all these efforts require large studies, large collaborations. It’s been done very successfully in Alzheimer's disease, so we are borrowing expertise to see how we could do something like that.

3.Stem cells (not the embryonic kind) :
Early studies trying to understand whether stem cell technologies would be of value in ALS were done using embryonic stem cells, but we have really been so lucky with technological advances. Now you can get skin cells from someone with the disease, or someone who doesn’t have ALS, and you can reprogram them to make them be immature cells that can develop into motor neurons and the surrounding astrocytes.

We are starting to try to develop these model systems in a dish, using these cells from people who live with the disease, and then testing drugs that might change what that looks like. So if the cells are looking different from those that comes from someone who doesn't have the disease, what are those differences and how can you correct them using drugs? That’s really going to spearhead a new direction.

Stem cells can also play a role as potential therapy, but it’s very complicated in ALS. We are very excited that there are FDA-approved trials testing the idea, but ALS is unlike Alzheimer's disease — it does’t happen just in one region, it’s a complex architecture where the nerve cells connect to the muscles, and it’s really quite widespread. So where you have to put the cells is often the big challenge. In the approved stem cell trial, they are injecting them straight into the spinal cord. But it’s extremely difficult. Still, stem cells are also invaluable for their use as model systems.

4. In the clinic:
We're trying to move things forward in clinical management, in day-to-day care of people living with the disease. One example is a trial we're funding of a compound that has been approved for people who have changing emotions in ALS — laughing and crying that's exaggerated. This compound, which we are now testing in a trial, has already been approved for that, but one of our clinicians and some anecdotal information seem to indicate that it improves swallowing. It’s not proven yet, but this is the kind of thing that we can provide funding for, to test that idea. So we seed small clinical trials — though trials can be anywhere up from $25 million plus, just for perspective. So these are not small investments.

5. Understanding disease mechanism:
A yeast model has helped us understand more risk factors for ALS; flies, worms, zebrafish, yeast, mice — all are models that can be used, and we invest in that.

What have you come to understand in recent years about the disease?

We were very fixated on the motor neuron being the main thing that goes wrong — but actually, we’ve learned so much more now: the surrounding cells, the astrocytes, which are important in regulating glutamate, are very important, as are the cells that are the inflammatory cells of the brain, the microglia.

Now we know that these support cells are critical to the process, we’ve actually started to look for ways to intervene, and one idea is to replace the dying astrocytes — that's a stem-cell transplant idea that's moving forward. The other is looking at inflammation and seeing if we can find drug targets.

6. Drug development: 
We can bring together all the right players — academia and industry. So we give out contracts — academia-industry contracts — where we mostly fund the academic partner, but the industry partner gives resources in kind and the expertise to really help bring the idea from the laboratory through the process of drug discovery into a treatment.

One great example of that, which is thrilling, is the use of antisense technology — which has now been used for all kinds of other diseases — for ALS. Simplistically, what happens with this technology is that it lets you down-regulate or suppress the production of something you don't want to have. It was first tried on SOD1 [the first ALS gene found] but an attempt is moving forward very, very fast to try the same thing with the new gene, C9orf72. We don't know yet whether it's going to be effective in humans but it's certainly safe.

Readers, thoughts? Does knowing more about how the money may be spent change your view of the ice-bucket challenge in any way?