New Directions in Research, Care Focus of Les Turner ALS Symposium

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by Marta Figueiredo PhD |

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Recent findings and ongoing efforts to more fully understand the underlying molecular mechanisms of amyotrophic lateral sclerosis (ALS), and to identify new and better ways of helping patients were discussed at the 11th Annual Les Turner Symposium on ALS.

The daylong event, held virtually Nov. 1, was sponsored by the Les Turner ALS Center at Northwestern University Feinberg School of Medicine, which fosters ALS research, patient care, and educational opportunities for scientists.

“We ensure that each person living with the disease receives the best quality care and access to promising therapies. As the longest-serving independent ALS group in the country, our approach has not changed,” Andrea Pauls Backman, CEO of the Les Turner ALS Foundation, which established the Les Turner ALS Center, said in a university press release.

The program included five oral presentations, followed by a Q&A session in which presenters and other ALS experts answered questions from the more than 400 people live-streaming the event, including ALS patients, family members, and caretakers.

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In his keynote presentation, Robert H. Brown Jr., MD, PhD, the director of University of Massachusetts Medical School’s neurotherapeutics program, emphasized the emergence of a new direction in ALS treatment. Research efforts are increasingly focused on targeting molecular pathways related to the more than 50 ALS-associated genes identified over the past 30 years, Brown said.

“I’m always optimistic,” Brown added. “But I’m particularly optimistic now that some combination of the new biological therapies and the small-molecule therapies are eventually going to substantially slow this disease, and that the day will come when ALS behaves more like post-polio syndrome and becomes a chronic non-lethal disease.”

Post-polio syndrome is a slowly progressive neuromuscular disorder that develops in some people decades after they have had poliomyelitis.

Colin Franz, MD, PhD, an assistant professor of neurology and of physical medicine and rehabilitation, talked about how understanding the implications of lower motor neuron degeneration after a spinal cord injury and surgical rehabilitation can help advance ALS research and care.

ALS is characterized by the death of both upper motor neurons, those that send messages from the brain to the spinal cord, and lower motor neurons, which send signals from the spinal cord to muscles.

“Trauma is definitely not a genetic disease,” but genetic factors “can influence outcomes,” Franz said. “I think we can learn from ALS and vice versa in terms of how motor neuron health is important for both diseases.”

Michael E. Ward, MD, PhD, co-director for the National Institutes of Health’s iPCS Neurodegenerative Research Initiative, described his team’s recent discovery of a potential therapeutic target in ALS: a cryptic exon in the UNC13A gene.

UNC13A, whose mutations have been previously associated with ALS, provides the instructions to produce a protein of the same name that is involved in nerve cell communication.

Exons are the sections of a gene containing the information necessary to build proteins. Cryptic exons are smaller sections that are normally excluded from messenger RNA (mRNA), the intermediate molecule derived from DNA that guides protein production.

Ward and his team found that, similar to what was previously reported for the STMN2 gene, impaired function of TDP43 promotes the inclusion of this cryptic exon in UNC13A’s mRNA, leading to an early stop in protein production and the generation of a shorter, non-working molecule.

TDP43, a protein that regulates gene activity by binding to DNA and RNA, is typically misplaced, and therefore dysfunctional, in cells of ALS patients, forming toxic clumps that drive neuronal damage.

“Targeting this cryptic exon may be a promising new therapeutic strategy for ALS, potentially improving symptoms in patients with ALS by improving [nerve cell communication] despite TDP-43 loss,” said Ward, who is also a principal investigator at the National Institute of Neurological Disorders and Stroke.

Notably, a separate team of researchers reached the same conclusion; neither study has yet been published.

The therapeutic potential of the NU-9 compound in upper motor neuron diseases was discussed by Richard Silverman, PhD, a professor of pharmacology at Northwestern.

In a previous study, Silverman and colleagues showed that treatment with NU-9 restored the health of diseased upper motor neurons and improved motor function in mouse models of ALS with TDP43 and SOD1 disease-causing mutations. SOD1 is another protein that forms clumps in ALS patients and contributes to neurodegeneration.

“Since the upper motor neurons in mice and in humans are functionally and structurally really similar, it seems that if you can have a positive effect on upper motor neurons in mice, that should translate to humans,” Silverman said.

“We’re hoping this can be a paradigm shift in how you look for molecules to treat upper motor neuron disease resulting from SOD1 and TDP-43 [toxicity],” Silverman added.

The importance of expanded access, or “compassionate use,” programs and patient decision-making tools were among the topics discussed during the Q&A session.

Expanded access programs (EAPs) are meant to make specific investigational therapies — those whose benefits are considered to outweigh their potential risks — available outside the clinical trial setting to people whose serious or life-threatening conditions have few or no adequate treatments.

“We would like to see the day where every single ALS patient will be eligible for one kind of therapy, whatever it is, but it has to be done the right way,” said Senda Ajroud-Driss, MD, an associate professor of neurology at Northwestern and the director of the Lois Insolia ALS Clinic at the Les Turner ALS Center.

Lisa Wolfe, MD, a Northwestern professor of medicine and neurology, noted that with growing research focused on personalized genetic therapies, such as those targeting specific disease-causing mutations, pharmaceutical companies should plan early to set up EAPs.

Such efforts could help to make EAPs standard practice and eventually part of a larger clinical trial program.

“When the trial contracts are being signed, the obligation of the company for expanded access and extended access has to be signed in the beginning because those costs should not be thought about after,” Wolfe said.

“They should be thought about before and we need to be the advocates to do it up front,” she added.

A preview of Les Turner ALS Foundation’s soon-to-be-released My ALS Decision Tool was provided by Lauren Webb, director of the foundation’s support services and education.

The interactive and online patient tool, the first of its kind in the U.S., is designed to help people with ALS and their caregivers make informed decisions early about potential care needs, such as breathing and nutritional support.

“The decision-making tool is a way to have people with ALS and their caregivers think through what their values are and what kinds of questions they want to ask their physicians,” Webb said.