In the beginning, not even Hynek Wichterle's postdoc thought his idea to slow the progression of ALS had a chance.
"When Hynek proposed this, I thought it would never work and was maybe a little bit of a waste of my time," says Emily Lowry, now co-director with Wichterle of the Project ALS Therapeutics Core at Columbia University's Vagelos College of Physicians and Surgeons.
The idea itself was simple. Because aging is often the trigger for many neurodegenerative diseases-including ALS-Wichterle reasoned that restoring vulnerable neurons to a more youthful state could make the neurons more resilient to the disease's assault and slow disease progression.
Though Lowry was initially skeptical, she took charge of the project. Funding from Project ALS helped get the research off the ground, and Lowry's initial results not only quashed her own doubts but started to convince other skeptics and garner funding from the NIH.
Lowry and Wichterle's latest findings now clearly demonstrate that rejuvenation therapy has real potential. In their study, conducted with ALS mice, a revitalizing gene therapy created by the researchers returned the animals' neurons to a more youthful state, made the neurons more resilient to damage caused by ALS, and delayed the onset of ALS symptoms.
"It's the first time that motor neurons have been rejuvenated in any kind of capacity," says Wichterle, co-director of Columbia's Motor Neuron Center and professor of pathology and cell biology. "The results provide compelling proof that we can revert adult neurons to a more immature state without compromising their normal function."
Though challenges remain in developing a rejuvenating therapy for human patients, Lowry says, "our hope is that this work will open the door to future therapies for age-related neurodegenerative diseases."
Youthful resilience
ALS, like many neurodegenerative diseases, typically strikes adults after they pass middle age, with most cases diagnosed between the ages of 55 and 75. The disease targets motor neurons in the spinal cord that control most muscles in the body. As motor neurons die, patients progressively lose their ability to move their arms and legs, speak, and breathe without mechanical assistance.
"We know that even in people who are born with mutations that almost always cause ALS, the motor neurons do not degenerate for several decades," Wichterle says. "It's the most direct evidence that the young motor neuron is much more resilient in the face of the disease."
Other studies have successfully rejuvenated various types of cells from other tissues with a cocktail of four proteins called Yamanaka reprogramming factors. The factors are often used to convert fully mature cells into pluripotent stem cells that resemble an embryo's earliest cells. But this type of rejuvenation therapy has potential drawbacks. If rejuvenated too much, neurons could become too young to perform the essential tasks of mature, adult cells.
"If that happened with motor neurons, it could cause paralysis," Lowry says.
A different approach to cell rejuvenation
The trick, Wichterle and Lowry found, is to rejuvenate with factors the neurons use normally in their development.
"We thought, what if we just went back in time in a motor neuron's normal development to make the neurons just a little bit younger," Lowry says. "We wanted motor neurons that were more like teenagers than embryos."
Wichterle and Lowry looked more closely at how motor neurons develop and found that when motor neurons are first born, two transcription factors are turned on that help choreograph the activity of dozens and dozens of genes as the neurons continue to develop.
The researchers found that reactivating these two factors-ISL1 and LHX3-in mature neurons could restore some of this youthful program, which was sufficient to quell ALS symptoms in adult mice without affecting normal motor neurons.
Translating to patients
The strategy that Wichterle and Lowry devised to turn on the two factors in the mice uses a virus to deliver genes to the animals' motor neurons. The viral system, developed in the Wichterle lab by postdoctoral researcher Tulsi Patel, now an assistant professor at Rutgers University, was essential in allowing the researchers to deliver genes specifically to the motor neurons vulnerable to ALS.
A similar strategy for people is possible but faces significant hurdles.
Instead, Wichterle and Lowry are putting much of their effort into understanding how the two factors rejuvenate mature neurons and restore resiliency.
"The two factors control about 200 other genes in the motor neurons, but it's possible that just one or two of those genes are sufficient and could be targeted with a drug," Lowry says. "We're looking through all the possibilities right now."
The researchers also hope that they'll uncover a mechanism that can work in other types of cells affected during other age-related neurodegenerative diseases such as Parkinson's and Alzheimer's that are characterized by toxic aggregates.
As Lowry says: "Everyone is looking for the fountain of youth."
