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Will gene therapy bring us closer to an ALS cure?

French neurologist Jean-Martin Charcot identified amyotrophic lateral sclerosis (ALS) 150 years ago — but scientists are still searching for the cause of the incurable neurological disease and how to halt its fatal progress.

What we know is that as ALS advances, nerve cells responsible for controlling voluntary muscle movement progressively die, meaning muscles stop moving because they no longer receive signals from the brain.

“One of the huge things that we’re interested in is why do these motor neurons die?” said Stephen Kolb, MD, PhD, physician-scientist and neurologist at The Ohio State University Wexner Medical Center.

The answer to that basic question about ALS — also known as Lou Gehrig’s disease — is beginning to come into focus.

“What is emerging is that genetics is much more important in ALS than we thought, even in people who don’t have a family history of the disease,” said Kolb, director of Ohio State’s ALS/Motor Neuron Disease Multidisciplinary Clinic and Translational Research Program.

The challenges of studying ALS

As they probe the role genes play in the development and progression of ALS, researchers on Kolb’s team at Ohio State — together with others in the scientific community — are making significant progress on modeling motor neurons in a laboratory.

“It’s only been in the past five years that we’ve been able to actually do that modeling,” Kolb said. “The reason that this is accelerating is because of the technology used to understand what’s in your DNA.”

ALS was first linked to genetic mutation in 1993, but until recently, modeling motor neuron cells in a laboratory has been a challenge to researchers.

“With cancer, you can take a tumor from someone’s body, bring it back to the lab and study it,” Kolb said. “You can take a tumor sometimes and put it in a mouse, and that mouse will get cancer. Cancer is very robust and not going to die. If you can kill it in the lab, that’s actually the beginning of a treatment trial.

“But with neurodegenerative diseases like ALS, the opposite is happening. The cells are already dead. We can’t scoop out the spinal cord and bring it to the lab to understand what’s going on. Also, we want to see things before they happen. We need to model the disease in order to study it. This comes down to technology.”

Technological advances are leading to research breakthroughs in the study of neurological disorders.

“The ability to safely alter gene expression in motor neurons is actually happening now,” Kolb said. “We are doing that in babies who have another motor neuron disease, spinal muscular atrophy. That work, which our Ohio State program has been part of, is just paving the way for what we hope to do in ALS.”

Dr. Stephen Kolb, pictured here, is working to learn what role genetics play in ALS.
"Genetics is much more important in ALS than we thought," says Dr. Stephen Kolb (pictured), "even in people who don’t have a family history of the disease."

A hopeful future for ALS treatment

Ohio State researchers, in partnership with Nationwide Children’s Hospital in Columbus, are now taking an ALS patient’s skin cells and turning them into motor neurons and other relevant cell types to better understand each individual's ALS in the lab. This is allowing for study of the underlying cause of ALS in individuals and may result in personalized treatments.

“We don’t know if this is going to work clinically, but this is the first thing that allows us to say, hey, maybe there’s something going on here,” Kolb said.

The cutting-edge research earned Ohio State selection to Answer ALS, the largest comprehensive research project seeking a cure for ALS. Wexner Medical Center is one of eight clinical sites and laboratories working together to create a database of information collected from 1,000 volunteer ALS patients.

Kolb hopes to build on current research by bringing gene therapy clinical trials for ALS — in which gene expression in motor neurons is altered — to Ohio State. That could lead to treatment options for patients, with the possibility of developing therapies on a case-by-case basis.

“There is now true hope to the fact that in the next five to 10 to 20 years, we’re definitely going to have ways to modulate the disease and maybe prevent it from progressing over time,” Kolb said.