Until recently, most scientific knowledge about amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, came from mouse studies. But new research is taking this incurable neurodegenerative condition to the dish, tapping induced pluripotent stem cells (iPS cells)—made from ALS patients’ skin cells—to create motor neurons. These motor neurons are being used not just to model how ALS works at the cellular level but also to screen potential drugs.
This work, taking place at the Harvard Stem Cell Institute (HSCI) in collaboration with Boston Children’s Hospital and Massachusetts General Hospital (MGH), has now paved the way for a clinical trial of a drug that might never otherwise have been thought of.
In ALS, the motor neurons that connect the spinal cord to the muscles of the body progressively die off, causing weakness, limb paralysis and ultimately respiratory failure. In a study published in Cell Stem Cell in April 2013, researchers at the HSCI and Boston Children’s, led by Lee Rubin, PhD, of HSCI, created motor neurons from patients’ iPS cells and used them to test a series of small-molecule compounds.
One compound, kenpaullone, outperformed two drugs that had failed in phase III clinical trials (olesoxime and dexpramipexole). It extended the life of motor neurons by weeks and maintained normal neuronal processes, synapses and electrophysiologic characteristics. Among other useful properties, it lowered levels of mutant SOD1 protein (which causes some familial forms of ALS) and inhibited two enzymes—GSK-3 and HGK—that trigger reactions causing motor neurons to die.
The rub is that kenpaullone would need substantial tweaking to make it useful as a drug. But a pair of new papers, published online April 3 by Cell Stem Cell and Cell Reports, dived further into the workings of ALS motor neurons and emerged with a new candidate drug—one that’s already FDA-approved.
Breaking a vicious cycle
Clifford Woolf, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s, along with Brian Wainger, MD, PhD, of Boston Children’s and MGH, and Kevin Eggan, PhD and Evangelos Kiskinis, PhD, at HSCI, together showed that motor neurons bearing ALS mutations are hyperexcitable, firing more than normal. They further showed that this excess excitability caused the neurons to make more errors in protein folding—which in turn made them more excitable. This vicious cycle put a strain on the cells that often proved fatal.
The researchers suspected that there was something wrong with the motor neurons’ potassium channels, making the cells more excitable. This hunch—tested by measuring electrical currents in motor neurons bearing SOD1 and two other kinds of ALS mutations—proved correct.
“The convergence on a single mechanism offered a very attractive place to intervene therapeutically,” Woolf, who is also co-leader of HSCI’s Nervous System Diseases Program, told the Harvard Gazette.
As it happens, the FDA had recently approved ezogabine (known internationally as retigabine) as an anticonvulsant. The drug facilitates the opening of specific potassium channels, allowing more potassium to exit the neuron and reducing its tendency to fire. “As a neurologist, I was always interested in it because it had an unusual mechanism of action for an anti-epileptic,” says Wainger.
Tested in the dish, ezogabine (Potiga) normalized the motor neurons’ hyperexcitability and improved the cells’ survival.
So could ezogabine help improve motor function in patients with ALS? That question will take some time to answer. Initial clinical work at MGH by Wainger and neurologist Merit Cudkowicz, MD, will investigate whether the drug is safe in ALS patients. At the same time, the drug will be tested in iPS-derived motor neurons from each patient to cross-check the findings.
“For the first time, there will be a clinical trial in a dish alongside a real clinical trial,” Woolf says. “There is no mouse work—we’re going straight to human trial.”
The trial is still in the design phase and has not been formally announced. “This trial will be first and foremost about the safety of this drug in ALS patients,” says Wainger. “Using human stem-cell-derived neurons may set a paradigm for more direct translation of therapeutics to the clinic.”