Our project addresses one of the biggest challenges for therapeutic discovery in ALS: the lack of clarity regarding the underlying causes of the disease.
Discovering subtypes of ALS : Aneesh Donde, PhD
When the root cause of ALS is known, there are now paths to therapy, as has been shown by the recent development of tofersen for people whose disease results from the SOD1 gene. We seek to bring the same clarity of the root causes – and the same hope for treatment – to the vast majority of the people living with ALS who do not carry a known disease-causing gene. Increasing evidence suggests that there are multiple subtypes of sporadic ALS associated with underlying molecular heterogeneity. The roughly 20 different genes that are strongly associated with ALS have many different molecular functions. For example, SOD1–ALS displays substantial changes in mitochondrial function, oxidative stress and the unfolded protein response. By contrast, C9ORF72 – ALS, which is the most common known genetic form, has less of an effect on these pathways and more of an effect on nuclear-cytoplasmic transport and RNA processing.
We hypothesize that cell lines from people with ALS arising from distinct root causes will respond differently to experimental conditions. For example, C9ORF72 lines might be more sensitive to inhibition of nuclear-cytoplasmic transport, whereas SOD1 lines might be more sensitive to inhibitors of mitochondrial function. Other forms of ALS may be particularly sensitive to still other cellular stresses. Grouping ALS cases together based on their common responses to stresses will define types of ALS that need to be treated separately in drug screens and ultimately in clinical trials.
Strategy
We are developing a robust platform that can identify disrupted cellular processes in different types of ALS. Our work builds on the pioneering Answer ALS study of more than 1,000 people with ALS and those without the disease. Cell lines were derived from the volunteers that can be grown into neurons in the lab, creating a “living biopsy” for each patient. Our platform analyzes these cells under diverse conditions and then uses Artificial Intelligence to find similar types of ALS and to identify potential molecular mechanisms.
Aneesh Donde, PhD is a postdoctoral researcher in the lab of Ernest Fraenkel at the Massachusetts Institute of Technology. He uses stem cell-derived motor neuron cell culture models to study the mechanisms of ALS and other neurodegenerative diseases. He is the recipient of the MIT-GSK Gertrude B. Elion Postdoctoral Fellowship for Drug Discovery and Disease and received his training in neuroscience from Johns Hopkins University.
