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Abstract
Neurological diseases account for the leading cause of disability and second leading cause of death, worldwide; however, treatments remain severely limited. Despite
preclinical success, very few have been successfully translated for clinical use. Here, we
discuss strategies to overcome this in two major categories: improved therapeutics and
improved preclinical disease models.
Perhaps an obvious – if not simple – approach is to develop improved therapeutics
that more effectively treat neurological disorders. Recently, extracellular vesicles (EVs),
nanoscale particles secreted by cells containing proteins and genetic material, have been
recognized for their role in intercellular communication. As many benefits of cell therapies
appear to be due to paracrine factors and signaling – known as the “bystander effect” –
EVs appear to recapitulate some, if not most, of these effects, without associated drawbacks
(e.g., tumorigenicity, ability to cross the blood-brain barrier). Here, we examine the
therapeutic potential of neural stem cell-derived EVs to treat traumatic brain injury,
demonstrating improved structural protection and functional recovery 4 weeks post-injury.Additionally, more physiologically relevant disease models and assays are needed
to study neurological disorders and evaluate novel therapeutics. Electrophysiology is a key
endpoint to assess neural health in vitro, and improved technologies (i.e., microelectrode
arrays; MEAs) allow for higher throughput and detailed network analysis. While these are
useful tools, data analysis can be complicated and hinder efficacy. We developed a novel
index to improve interpretation of MEA and electrophysiological data by condensing high
dimensional data into a single score, allowing culture health and effects of potential
therapeutics to be assessed more effectively, significantly improving the applicability of
MEAs to evaluate disease phenotypes and treatments.
Finally, we discuss implementation of electrophysiology in brain organoids to
bridge the gap between traditional in vitro and in vivo models. While organoids have
provided considerable insight into neural development and pathologies, functional analysis
is needed to reach their full modeling potential. We highlight and propose the application
of novel electrophysiological methods to study brain organoids and their improvements
over current methods.
Together, these studies support several strategies to improve therapeutic
development for neurological disorders, including both improved treatments and more
effective modeling approaches and evaluation.