From Lab to Clinic (and Sometimes Back Again)

Progress in ALS research requires a free flow of information between MDA-supported laboratory investigators and leaders in the drug-development industry

by Margaret Wahl on April 21, 2015 - 9:17am

Quest Spring 2015

ALS, also known as amyotrophic lateral sclerosis and Lou Gehrig’s disease, is among the most feared diseases facing people in the U.S. and worldwide. In ALS, the motor neurons — the nerve cells of the brain and spinal cord that control muscle action — mysteriously deteriorate, often within just a few years, leaving behind orphaned muscle fibers. Without signals from motor neurons, voluntary muscles can’t work properly, and the person with ALS experiences increasing weakness and ultimately paralysis.

Despite decades of research, there are only a few marginally effective treatments. But today, there is hope on the horizon, as academic laboratory research and industrial drug development are working hand in hand more than ever before to better understand ALS and uncover treatments and cures.

Many of the questions asked and answered by MDA-supported laboratory researchers have resulted in clinical trials of new drugs. In addition, many drug developers needing a competitive edge have turned to MDA-supported basic research to optimize their compounds and improve their strategies.

Stan Appel, M.D.

Affiliations: Houston Methodist Neurological Institute

Strategy: Tipping the balance toward protective immune cells

Related drug development: Regulatory T cells, interleukin 2, NP001

One factor that appears to contribute to ALS is harmful behavior of the immune system. However, the disease doesn’t seem to respond to treatments used to suppress an unwanted immune response in other disorders.

“I’m a big fan of targeting immune cells to treat ALS,” says Stan Appel, a longtime MDA research grantee who also directs the MDA/ALS Center at Houston Methodist Neurological Institute. “Until recently, most of my colleagues said any immune system attack on nerve cells in ALS was the consequence of some other injury, not the cause of it, and few believed targeting it was a good strategy for ALS. That’s changing now.”

Back in the 1980s, researchers documented an increase in thyroid disease in people with ALS. Thyroid disorders in adults are usually caused by an overactive or misguided immune system. Based on that finding and evidence of an immune response in the spinal cords of deceased people with ALS, Appel proposed a trial of cyclosporine, a powerful immunosuppressant drug. But the results, published in 1988, were disappointing, showing no difference in the rate of disease progression in patients treated with the drug and those treated with a placebo.

Appel believes the main reason that cyclosporine didn’t help is that the complexity of the immune system wasn’t well understood at the time. Scientists now recognize that the immune system has many kinds of cells, some of which are “attackers,” fueling the fire of an immune response to a perceived threat, while others are “dampeners” that keep the fire from getting out of hand and destroying the tissue it’s trying to save. “Immunotherapy that suppresses both the dampeners and the attackers is not beneficial in ALS,” Appel says.

Distress signals

Research led by Appel suggests that in ALS there is an initial injury to muscle-controlling nerve cells called motor neurons, probably resulting from a combination of genetic and environmental factors. But, according to Appel, “Degeneration of cells in the nervous system will not develop until there are signals sent out from injured motor neurons to surrounding immune cells.”

Appel doesn’t think the immune system starts the ALS disease process. But he believes it plays both a beneficial and a harmful role as it progresses, and that both actions provide opportunities for treatment.

During the early stages of ALS, Appel’s research suggests that immune system dampeners called regulatory T cells (“Tregs”), along with certain cells in the brain and spinal cord, as well as cells that decrease inflammation and encourage tissue repair in the bloodstream can at least partially protect nerve cells from the firestorm of the immune response against the initial injury.

But as ALS continues, immune system attackers known as effector T cells, along with other cells in the brain, spinal cord and bloodstream, predominate — overwhelming the protective efforts of the dampeners and killing nerve cells.

Boosting dampener cells and suppressing attacker cells have potential in treating ALS, Appel believes. “The important thing is to end up with more ‘good guys’ than ‘bad guys’ at every stage of the disease,” he says.

Tipping the balance

Based in part on Appel’s research, a U.S.-based clinical trial to infuse dampener cells into people with ALS is being developed. And in France, investigators are conducting a trial to see if the interleukin 2 protein can increase levels of these cells.

Additionally, the experimental compound called NP001, in development by Neuraltus Pharmaceuticals, targets attacker cells in the bloodstream, aiming to switch their activity from attack mode to the beneficial, protective mode. A phase 2 trial in some 136 people with ALS showed positive trends in slowing disease progression.

Appel says he’s “hopeful that compounds that can enhance protective immunity and suppress harmful immunity will benefit people with ALS.”

James Shorter, Ph.D.

Affiliations: University of Pennsylvania, Philadelphia

Strategy: Developing protein “disaggregases” that can prevent protein misfolding and clumping and retrieve functional proteins from clumps

Related drug development: CytRx’s arimoclomol

In the early 2000s, James Shorter was a postdoctoral fellow at the Massachusetts Institute of Technology working in the laboratory of biologist Susan Lindquist. The Lindquist lab was (and is) pursuing questions about protein misfolding — a contributing factor that causes ALS. Protein misfolding occurs when cellular proteins do not correctly fold into specific and intricate shapes to carry out their functions. Since 2013, Shorter has been an MDA grantee tackling protein misfolding in ALS — with the goal of preventing and reversing this phenomenon.

Sometimes the folding mistake is the result of a mutation in a gene, but sometimes it happens without any clear reason. Misfolded proteins tend to clump together, sometimes trapping other proteins with them, and they can cause other kinds of harm in cells. In ALS, they may be a major cause of the death of nerve cells that control muscles (motor neurons).

Mutations in genes known as SOD1, TDP43 and FUS can cause ALS, and it appears they do that by triggering the proteins made from these genes to take on abnormal and toxic shapes. However, TDP43 and FUS proteins and possibly SOD1 are prone to misfolding even when there’s no genetic mutation.

“Ninety-five percent or so of ALS patients have TDP43 aggregates [clumps],” Shorter says, explaining that the overwhelming majority do not have anything wrong with their TDP43 genes. For some reason, “TDP43 is getting into difficulty.” Shorter wants to reshape toxic TDP43 and other
proteins that cause trouble in ALS.

Withstanding a harsh environment

Scientists now understand that cells respond to adverse conditions, such as high temperatures, by producing stress proteins. The job of many of these stress proteins is to try to get other proteins in the cell to behave properly despite their uncomfortable environment — and if they don’t, to disable or destroy them. Because heat was the stress most often imposed in the lab, these critical compounds are often called “heat shock” proteins.

Many heat shock proteins (HSPs) act as “chaperones” for misbehaving proteins, grabbing them and holding them until they fold into the right shape and preventing them from forming clumps with other proteins. But a few, including one called HSP104, which particularly interests Shorter, can do that and more.

“Chaperones help proteins fold and stop aggregation,” Shorter says. “But HSP104 actually reverses aggregation and can recover properly folded proteins from misfolded aggregates. We call it a protein ‘disaggregase,’ and it’s the most powerful one we know about.” Shorter’s team is working to optimize the biochemistry of HSP104 and develop it into a potential ALS treatment.

Meanwhile, the experimental drug arimoclomol, which causes production of HSPs, is being developed by the Los Angeles biopharmaceutical company CytRx. It’s currently in a phase 2–3 clinical trial in people with ALS due to SOD1 gene mutations. (The study is ongoing but closed to new participants.)

“It’s an interesting strategy and looks quite promising in model systems,” Shorter adds. Those include mice with a mutation in the SOD1 gene that causes an ALS-like disease.” Shorter says he isn’t directly involved with CytRx but that research conducted in his and other labs provided a foundation for the company’s development of arimoclomol — and he’s eager to see what the results of the clinical trial will be.

Asked if he thinks HSP104 has greater potential to prevent and break up protein clumps than other compounds now in development, Shorter says, “I’m biased, of course. But I would say, yes, without a doubt.”

MDA-supported laboratory researchers worldwide are advancing the ALS drug development pipeline and continue to do so. Here are three standouts:

MDA grantee: Daniel Offen, Ph.D., Tel Aviv University, Israel

Basic Science Project: 2010–2013: Laboratory experiments  to deliver nerve-nourishing proteins (“neurotrophic factors”) to the brain and spinal cord using cells that secrete them

Related Drug Development: BrainStorm Cell Therapeutics began testing this approach using its NurOwn cells in people with ALS in 2010 and continues to develop and refine its strategies.

MDA grantee: Li Niu, Ph.D., State University of New York at Albany

Basic Science Project: 2013–2016: Studying how over-activity of a protein called the AMPA receptor may contribute to ALS and how inhibiting it may provide benefit

Related Drug Development: Teva Pharmaceuticals began testing talampanel, an AMPA receptor blocker, in people with ALS, in 2008; the strategy may be refined and improved by new research from Niu and others.

Margaret Wahl is a former MDA medical and science editor.

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