Between Bench and Bedside
Bringing Scientific & Clinical Expertise Together to Tackle ALS
April 14, 2023
ALS (or Amyotrophic Lateral Sclerosis) became a household name in 2014 when the Ice Bucket Challenge took the internet by storm almost a decade ago, making a massive impact in raising awareness of and accelerating the fight against the disease. In this devastating disorder, motor neurons – cells in the central and peripheral nervous system that transmit signals to make muscles work – degenerate, leading to muscle weakness and wasting that gets worse over time. Despite significant increases in research funding and efforts, effective treatments for ALS are still lacking. Most people die between 2-5 years of disease onset.
Around 5-10% of ALS patients have a family history of the disease, suggesting a strong genetic component. These cases are referred to as "fALS". The remaining 90-95% present with sporadic ALS, or "sALS". With the advent of precision medicine, the interest in gene testing for ALS has been increasing. It is common practice to offer this gene testing for fALS, with several variants for this subtype – for example in C9orf72, SOD1, FUS and TARDBP genes – already well established. However, far less is known about the genetic landscape ofsALS. A better insight into this is key to interpreting variants in diagnostic settings, counselling patients and their families, and for use in clinical drug trials.
This is where Philip Van Damme comes in. A neurologist at UZ Leuven, professor at KU Leuven, and researcher at the VIB-KU Leuven Center for Brain & Disease Research, Van Damme has spent the past eighteen years dedicating himself to ALS research and clinical practice. His multi-award-winning science spanning over 200 peer-reviewed articles focuses on genetic, biomarker and neuroimaging studies and clinical trials with new treatments for ALS, as well as genetic modifiers of ALS and on disease pathways in pluripotent stem cell models derived from ALS patients (watch this bite-sized video explainer for an example of such a project that he was involved with, published earlier this year!).
"When I first started my career, there was only one gene known to cause the disease," Philip explained in an interview with patient organization ALS Liga Belgium last year. "Since then, we've come to know of about twenty genes involved in ALS." In light of the lack of knowledge on genes involved in sALS specifically, Van Damme and colleagues decided to conduct research to characterize these sALS genes. The results of this research were published in Brain this week.
In this research, Van Damme and several other collaborators studied genetic variation in 90 ALS-associated genes, using data from a total of 9600 samples of ALS cases and matched controls from Project MinE. As a result, they were able to provide a comprehensive genetic profile – in the form of an inventory of pathogenic and likely pathogenic genetic variation –of a large cohort of sporadic ALS patients.
How do these findings translate from research to the clinic, or from bench to bedside? "An overview of the genetic findings in ALS patients is a first step to get better understanding of the genetic architecture of ALS," Philip reveals. "Especially in the era of next generation sequencing and with the advent of gene-specific therapies, genetic screening is offered to an increasing number of patients. Therefore, a comprehensive genetic characterization of sALS patients is a valuable resource for informed genetic counselling of these patientsIn addition, we can also start looking at combinations of genetic risk factors, which will ultimately lead to genetic risk scores. Understanding the cause of the disease is an essential first step in understanding the disease mechanisms."
Read the research article to find out more: Genetic variability in sporadic amyotrophic lateral sclerosis - PubMed (nih.gov)
About the VIB-KU Leuven Center for Brain & Disease Research
Scientists at the VIB-KU Leuven Center for Brain & Disease study how brain cells are organized and how they communicate with each other. These mechanisms reveal and provide insights into what goes wrong in brain diseases such as Alzheimer's, Parkinson's, ALS, and dystonia. This basic work should ultimately lead to new drugs for use against these currently incurable diseases.