Though extremely uncommon, there are individuals diagnosed with amyotrophic lateral sclerosis (ALS) who manage to recover partially or completely from this deadly neurodegenerative disorder. Gaining deeper insights into this puzzling occurrence, noted in medical research for over six decades, might lead to innovative treatment strategies. In pursuit of this, researchers initiated a study focusing on ALS recovery patients and discovered specific genetic traits that seem to offer protection against the usual damage the disease inflicts on motor neurons.
Though extremely uncommon, there are individuals diagnosed with amyotrophic lateral sclerosis (ALS) who manage to recover partially or completely from this deadly neurodegenerative disorder.
Gaining deeper insights into this puzzling occurrence, noted in medical research for over six decades, might lead to innovative treatment strategies. In pursuit of this, researchers at Duke Health and St. Jude’s Research Hospital began a study involving patients who have recovered from ALS and identified certain genetic aspects that seem to defend against the disease’s typical harm to motor neurons.
The outcomes of the research have been published in the journal Neurology, which is managed by the American Academy of Neurology.
“With other neurological disorders, there are already effective therapies available,” remarked Richard Bedlack, M.D., Ph.D., the Stewart, Hughes, and Wendt Professor in the Department of Neurology at Duke University School of Medicine. “However, we still lack robust options for these patients, and there is an urgent need to find solutions. This study serves as a foundation for delving into the biological reversals linked with ALS and exploring how we may harness those effects for therapeutic benefit.”
Bedlack and his team, including co-lead author Jesse Crayle, M.D., now at Washington University in St. Louis, carried out a genome-wide association study involving 22 participants who had been diagnosed with ALS and subsequently recovered, comparing them to similar patients whose condition worsened. Researchers at St. Jude Children’s Research Hospital conducted the genetic analysis.
“Our comprehensive genome sequencing process utilized a multiomics approach to integrate newly accessible gene expression and epigenetic data, maximizing not only this unique dataset but also the CReATe and TargetALS patient databases,” explained co-lead author Evadnie Rampersaud, Ph.D., from St. Jude Children’s Research Hospital Center for Applied Bioinformatics. She noted that the successful identification was enabled through thorough characterization of the patient samples.
The team pinpointed a common genetic variation known as a single nucleotide polymorphism (SNP). This SNP lowers levels of a protein that inhibits the IGF-1 signaling pathway. Participants with this particular change in their DNA were 12 times more likely to have achieved recovery compared to those without it.
IGF-1, a growth factor, has been a significant focus in ALS studies due to its protective role for motor neurons. Patients with rapid disease progression often exhibit lower levels of IGF-1 protein; however, clinical trials aimed at elevating IGF-1 levels have not yielded encouraging results.
The current discovery offers a potential avenue to target IGF-1 more effectively.
“This suggests that the IGF-1 pathway warrants further investigation as a possible target for future ALS treatments,” Crayle commented. “While simply providing IGF-1 might not be effective, our findings indicate an alternative approach by decreasing the levels of this inhibiting protein. It’s also feasible that previous studies with IGF-1 were not sufficiently dosed or required a different dosing regimen.”
Bedlack stated that the research team is now assessing whether there is a relationship between the inhibitory protein and disease progression in a larger cohort of patients. The results of this analysis could lead to a clinical trial focused on this protein.
Alongside Bedlack and Crayle, the authors of the study include Jason Myers, Joanne Wuu, J. Paul Taylor, Gang Wu, and Michael Benatar.
The study was funded by the Duke ALS Patient Gift Fund, ALSAC – the fundraising and awareness organization of St. Jude Children’s Research Hospital; the ALS Association (grants 17-LGCA-331 and 16-TACL-242); the CReATe Consortium (U54NS092091), part of the NIH Rare Diseases Clinical Research Network (RDCRN); and the National Cancer Institute (P30 CA021765).
