Emerging therapeutics may improve outcomes in pediatric patients with rare disorders

SEATTLE — Clinicians should consider disease-modifying therapeutics when treating patients with rare pediatric disorders, according to an expert at the 2022 American Academy of Neurology annual meeting.

“I want people to think about the rationale behind genetic-based therapies,” Lisa Emrick, MD, assistant professor of neurology and developmental neuroscience at Baylor College of Medicine, told attendees. “But I also want everyone ... to think about ways that, even in your clinic, you can help these patients with varied genetic disorders.”

Emrick based the importance of research, development and utilization of emerging therapeutics on the fact that there are more than 23 million rare disorders that affect children, and more than 90% do not have therapies. In addition, much of what researchers and clinicians learn from adult conditions is based on rare conditions observed in children.

Among disease-modifying strategies already in development are small molecule therapies, enzyme replacement and gene-replacement therapies with adeno-associated vectors (AAV), along with gene editing and splicing.

“First, we have to know the gene, then the pathway, and then obviously the next gene sequence,” Emrick said. “We’ve learned quite a bit about the new genes and the pathways involved, and we’re learning that multiple pathways can be involved within the cell.”

How a variant affects a particular gene, and whether there is gain or loss of function, are also considerations in cases involving epilepsy-related channels, she added.

Citing a recent study by Flotte and colleagues in which AAV gene therapy was used in two patients with infantile Tay Sachs Disease, Emrick explained that the first patient became seizure-free at age 5 years, while the second patient demonstrated disease stabilization by 3 months but disease progression 6 months after treatment.

“It shows you that there is proof-of-concept as something to go on for this approach, for the AAV vector and for future use,” Emrick noted.

It is likely in the future that multi-modal approaches to disease modification and treatment will be necessary to overcome obstacles and address difficulties in enzyme-replacement therapy because of the blood-brain barrier.

“For many of these conditions, there’s not just one way to handle things,” Emrick said. “We have to do multiple pathways, thinking about the genes and the metabolic underlying systems.

“We need the numbers; we need to improve diagnosis. ... I think it’s important for us to share our positive and negative results as well.”