Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s Disease, is neurodegenerative disease with an estimated prevalence in the United States of 30,000 people and an average age of onset in the middle to late 50’s. As the population ages, the number of new cases per year could double. Luckily, it is an area of active research and innovative clinical trials. Researchers at MIND and the Sean M. Healey & AMG Center for ALS at Mass General, and major initiatives such as the HEALEY ALS Platform Trial, are at the forefront of a wave of new breakthroughs that are propelling the field toward novel therapeutics.
ALS causes degeneration of motor neurons in the motor cortex of the brain (“upper motor neurons”) and those in the brainstem and spinal cord (“lower motor neurons”). ALS symptoms generally manifest first as muscle weakness, with or without thinning and twitching of muscles, spasticity, fatigue or weight loss. Symptoms may begin in the legs, arms, or tongue, or rarely with muscles of respiration. The symptoms then spread.
There are both familial and sporadic cases of ALS. We now know the genetic basis of the majority of familial ALS. The most common mutation, causing up to 40% of familial ALS, occurs in a gene called C9ORF72. This same mutation can also cause frontotemporal dementia (FTD), another neurodegenerative diseaseThe second most common ALS causative gene mutation is in the SOD1 gene. More than 20 other genes also have been associated with familial ALS, though less commonly. Almost all ALS-causative gene mutations are inherited in an autosomal dominant pattern, which means that inheriting a single mutated gene should cause the disease and no generations are “skipped.”
There are now therapies in clinical trials that specifically target both C9ORF72 and SOD1 mutations, as well as other mutations causing familial ALS. In trials, we are even beginning to be able to target genes that may impact sporadic ALS.
There are currently three approved treatments for ALS, all of which affect symptoms or modestly slow progression. Riluzole, approved for use in 1995, slows the progression of ALS by approximately 10% by decreasing the toxic effects of nerve over-excitation. Riluzole is available in at least two oral formulations. Edaravone, a free radical scavenger, slows ALS progression and was approved by the FDA in 2017. Dextromethorphine/quinidine reduces symptoms of incongruous laughing or crying, called pseudobulbar affect (PBA). We also helped demonstrate that it can increase speech intelligibility in some people with ALS.
Our ALS Research
To overcome ALS, we must understand it as fully as possible. Our basic researchers are focused on discovering the causes of ALS. They are using cutting edge approaches in induced pluripotent stem cells, gene discovery, manipulation and targeting, RNA and protein biology and electrophysiology to shed light on the mechanisms of ALS. And with each new discovery comes a new opportunity for ALS therapies. Our clinical ALS researchers are storing blood and spinal fluid from people with ALS, studying new tools to hasten diagnosis and track the disease more accurately, and developing more efficient trial mechanisms to test more ALS therapies faster.
Over the past decades, new research tools, new insights, and new scientists have brought major advances in our understanding of ALS. These discoveries have opened the door to promising new therapeutic approaches that are currently tested in clinical trials. ALS labs at MIND work function as part of the Healey Center for ALS, and have been at the center of that progress with projects like the HEALEY ALS Platform Trial, which is testing multiple new treatments, including AMX0035 from Amylyx Pharmaceuticals. The MIND ALS labs also coordinate closely with the Neurological Clinical Research Institute (NCRI), which provides clinical trial services for the Healey Center and other research groups. The collaboration between all these research teams, exemplified by the monthly Translational ALS meetings, affords our researchers the opportunity to move from fundamental breakthroughs to human research in ALS more rapidly than ever before.