Exploring New Therapeutic Targets for Neurodegenerative Diseases: Robert G. Kalb, MD

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"Over the years, I’ve changed my perspective. I’m interested in the basic science mechanisms, but I’m mostly interested in [whether we] can turn this into a therapeutic? I’ve purposely focused on targets that I think can be engaged by, for instance, antisense oligonucleotides."

The Kalb Neuronal Biology Laboratory at Northwestern University Feinberg School of Medicine, led by research scientist Robert G. Kalb, MD, investigates cellular responses to stress and the activity-dependent development of neural circuits. In the lab, Kalb and researchers use genetically manipulated mice, primary neuron cultures, induced pluripotent stem cell–derived neurons, and C. elegans, applying cell and molecular biology approaches to study mechanisms regulating neuronal survival and circuit formation.

Kalb’s lab specifically focusses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which are linked to mutations in proteins including SOD1, TDP-43, and C9ORF72. These gene mutations can cause the accumulation of misfolded, sometimes ubiquitinated proteins, disrupting cellular protein homeostasis and harming neurons. Through genetic screens, researchers in the lab have identified suppressors of this toxicity and are investigating their mechanisms of action.

In a recent interview with NeurologyLive^®, Kalb, a professor in the Department of Neurology and the director of the Les Turner ALS Center at Northwestern Medicine, spoke about his lab’s multifaceted approach to identifying genetic therapeutic targets for neurodegenerative diseases, such as ALS and FTD. During the conversation, he explained further how the lab studies genes that influence disease mechanisms through the use of preclinical models. He emphasized a translational approach, focusing on targets modifiable by antisense oligonucleotides or small molecules and highlighting promising preclinical results for select genes.