The Miller Lab seeks to understand the mechanisms underlying neurodegeneration in ALS and to develop new, innovative therapies for ALS and other neurodegenerative diseases, such as Alzheimer’s disease.
Antisense oligonucleotides for ALS
A main focus of the Miller Lab has been the development of RNA-targeted therapeutics for ALS using antisense oligonucleotides. Recent work (Mccampbell et al. 2018) shows impressive extension of survival in SOD1 ALS animal models and reversal of some components of muscle function. We continue to expand the number of targets for therapeutics and welcome new ideas.
MicroRNAs as drivers and biomarkers of disease
miRNA are small RNA that regulate other RNA. As some of the master regulators of multiple RNAs, we consider miRNA both an interesting way to understand disease pathogenesis as well as a way to develop novel targets for therapy. We identified motor neuron specific miRNA (Hoye et al. 2017) and found that one of these miRNA. miR-218, is release from motor neurons and taken up by astrocytes causing damage to astrocytes and likely further damage to motor neurons (Hoye et al. 2018). We are studying how miRNA are taken up by cells, how other motor neuron specific miRNA participate in disease pathogenesis and how to best to inhibit this class of RNA.
Understanding mutant SOD1 protein kinetics
Understanding protein turn over is likely to inform both on the biology of misfolded proteins and as a readout for RNA-targeted therapeutics. Using C-13 leucine labeling, we have established a method to measure SOD1 protein kinetics in humans and animal models and have shown that this is may be an excellent way to track the effect of antisense oligonucleotides (Crisp et al. 2015 jci, Self et al. actn 2018). The most interesting work on SOD1 protein kinetics is yet to come examining the protein in people with ALS. We are studying other disease-related protein turn over and developing new methods to do so.