Goals: To understand the mechanisms underlying neurodegeneration and to develop novel therapies for neurodegenerative diseases.
Background: ALS, amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is a devastating, adult onset, neurodegenerative disease that leads to dysfunction and loss of neurons in the motor pathways of the brain and spinal cord. There are no adequate therapies.

1. Is it safe to specifically target and down regulate SOD1 mRNA in humans with ALS?

The ability to target and “turn off” genes using oligonucleotide based strategies (RNAi and antisense oligonucleotides) has been a huge step forward in understanding a wide variety of biological processes. These tools also offer a great opportunity to develop gene targeted therapies for the central nervous system. By down regulating SOD1 (superoxide dismutase 1) with antisense oligonucleotides delivered to the cerebral spinal fluid (that bathes the brain and spinal cord), we prolonged survival in an animal model of ALS. This novel therapy for inherited ALS is currently being tested in an ongoing human Phase I (safety) trial.

2. Which miRNAs are changed in ALS, what do they do, and how does inhibiting miRNA function affect disease course and pathology?

microRNAs (miRNAs) are short, non-coding RNAs that regulate mRNA expression. Dysregulation of miRNA expression has been implicated in a number of neurodegenerative diseases. Recent work from our lab demonstrates that miR-155 is significantly enriched in the spinal cords of ALS model mice and human ALS autopsies. Inhibiting miR-155 using antisense oligonucleotides extended survival in ALS mice by 38%. miR-155 inhibitors are being developed for human clinical trials. One of the greatest limitations to understanding the roles of miRNAs in neurodegeneration is the lack of in vivo miRNA expression data. We have begun to define cell-type specific miRNA expression in the central nervous system. Upon completion of this work, we will be able to study the dysregulation of miRNAs in their native cellular context. Cell-type specific miRNA expression data will inform miRNA mechanism as well as therapeutic development for modulating miRNA expression in disease.

3. Why do some misfolded proteins cause damage to specific parts of the nervous system in ALS?

In many neurodegenerative diseases, including ALS, mutant (usually misfolded) proteins selectively damage the brain and spinal cord, despite ubiquitous expression in all tissues of the body. An attractive hypothesis to explain this phenomenon is that mutant protein turnover, the combined synthesis and degradation of a protein, is less efficient in the central nervous system compared to other tissue types. To address this hypothesis, we are using a variety of biochemical techniques in cell culture, mouse models, and humans to understand how protein turnover of mutant superoxide dismutase 1 (SOD1) influences motor neuron-specific degeneration in ALS.