Henry Schiffman

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a severe disorder affecting many organs that is caused by a mutation in an individual’s mitochondrial DNA. Neurons, which require high amounts of energy and thus functioning mitochondria, are especially vulnerable to this dysfunction, leading to neurological deficits such as seizures and stroke-like episodes. Current treatments for MELAS are largely symptomatic and fail to address the root cause of disease. Because of the frequent occurence of seizures, it is no surprise that one of the most commonly prescribed class of drugs is anti-epileptic drugs (AEDs). Many AEDs have mitochondrial toxic effects, exacerbating cellular stress and potentially precipitating a health emergency. 

Despite increased attention to patient-specific models, accurate, human-specific systems that replicate the complexity of 3D neuronal organization are needed to better understand how the mutation influences neuronal function. Separately, from a clinical perspective, it is incumbent upon researchers to categorize the safe and harmful AED therapies. It remains unclear which AEDs are safe and beneficial for MELAS-associated seizures. In particular, there is no consensus on how the MELAS mutation at varying ratios of “good” DNA to “bad” DNA affects the cellular response to these interventions. Accordingly, my project aims to determine how different AEDs influence neuronal and mitochondrial health in MELAS neurons. 

I will develop three-dimensional cortical brain organoids from patient-derived stem-cells with known mutation loads of the mutation. After differentiating these organoids and culturing them, I will treat them with the AEDs of interest. Mitochondrial function and transcriptional changes will be measured via oxygen consumption assays and through scRNA-seq, respectively. Neuronal health will be assessed by imaging and electrophysiological recordings (which allows us to see neuronal communication patterns).