Evangelos Kiskinis, assistant professor in the department of neurology & physiology at Feinberg School of Medicine, Northwestern School of Medicine in Chicago, was awarded an MDA research grant totaling $300,000 over three years to decipher the degree of mechanistic overlap in different forms of amyotrophic lateral sclerosis (ALS). Using cutting-edge technology, Kiskinis will activate ALS patient motor neurons in culture by shining a light on them to cause them to fire. Motor neurons from people with different forms of the disease will be examined to determine if their firing patterns are similar or divergent. Results from this work may yield insight into whether certain drugs will be broadly relevant to all ALS patients or, instead, work better for specific subgroups of patients.
Please describe your current research.
We have successfully been using stem cells generated from the skin of ALS patients to make patient-specific human motor neurons and study their disease in the lab. This novel technology has essentially given us access inside the brain and spinal cord of patients. We have shown that motor neurons with mutations in the SOD1 gene exhibit mitochondrial dysfunction and electrical excitability defects. We have also shown that by using small molecules that target these pathways, we can extend the survival of patient motor neurons.
In this study we will extend this approach and generate motor neurons from patients with a wide range of different genetic ALS types. By studying these different motor neurons and comparing how similar they are in terms of the disease mechanisms we can understand how similar or different ALS patients might be. This will be invaluable in our efforts to: a) design drugs that will target specific patients; b) identify therapeutics that might be broadly relevant to all ALS patients.
In the second part of our proposal we will determine whether the irregular manner in which ALS motor neurons fire electrical signals might contribute to their death. This is an important question as work done in our cellular system as well as in human patients has shown that this is a consistent problem that may significantly contribute to the disease. If we understand why it happens and how motor neurons deal with it we might discover ways of stopping it.
What inspired you to study ALS?
ALS is a devastating and currently untreatable neurodegenerative disease. I have been involved in ALS research for the past eight years and I got interested in it because it is a complex and biologically intriguing disease. I felt that the approaches and the technologies that we apply in my lab including using patient stem cells would allow us to address mechanistic questions in a novel way that could have a significant impact in the fight for a cure.
What is your area of focus within the ALS field and why is it important?
The main focus of my lab is to elucidate the molecular pathways that lead to the degeneration of the spinal motor neurons — we are particularly interested in addressing whether there are common such mechanisms amongst the different genetic and sporadic ALS subtypes.
Deciphering the degree of mechanistic overlap in ALS cases will help us identify therapeutics that might be broadly relevant to all ALS patients, or others that are specific to certain cases.
Why is it important that MDA continue to fund research in ALS?
Although ALS research has certainly received a boost with the recent Ice Bucket Challenge, it is still an orphan disease. It is particularly hard for young researchers like myself to sustain a sufficient level of funding to study a disease that impacts a relatively small number of patients.
What do you feel people impacted by ALS can have the most hope about with respect to research right now?
There has never been a more exciting and stimulating time in ALS research than right now — major recent discoveries have fueled the interest for ALS. There are a lot of really smart and capable people working very hard to figure out a cure for this terrible disease right now. That is certainly hopeful.
Does your work have any potential implications for other disease fields?
Certainly — if we can figure out how dysfunctional electrophysiological patterns contribute to the pathology of ALS, this would have implications for a range of other neurological diseases.