Goals: To understand the mechanisms underlying neurodegeneration and to develop novel therapies for neurodegenerative diseases.
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 disumutase 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.) Will modulating Tau improve behavioral phenotype and what is the role of different tau isoforms?
Tau is a microtubule binding protein involved in Alzheimer’s disease and other dementias. We have started an antisense oligonucleotide strategy to decrease levels of tau or change tau splicing as a way to determine the biological importance of different tau isoforms and as a therapy for Alzheimer's disease and Frontotemporal Dementia.
3.) Which miRNAs are changed in ALS, what do they do, and how does inhibiting miRNA function affect disease course and pathology?
MicroRNAs are small, non-coding RNAs that control the regulation of typically 200-300 genes. We have defined miRNA changes in ALS model animals and in human ALS tissues and are now dissecting out what the miRNAs are doing and whether they are important for ALS. We have also begun to develop antisense oligo inhibitors of miRNAs.
4.) How does mitochondrial dysfunction cause ALS?
Mitochondrial dysfunction has been implicated in many neurodegenerative diseases, including ALS. We are using a variety of techniques including biochemical and functional analysis of isolated mitochondria, solution mass spectrometry, and mouse models of disease. Our recent data suggest that mitochondrial protein import pathways are damaged out of proportion to other parts of the mitochondria in ALS mouse models.
5.) Why do some misfolded proteins cause damage to specific parts of the nervous system?
One of the most interesting aspects of neurodegenerative disease is the specific damage that mutant (usually misfolded) proteins cause to the brain and spinal cord despite widespread expression of the proteins. We are using a variety of biochemical techniques to understand this disease specificity.
- Determining cell type specific miRNAs
- Antisense oligo approaches to modulating/understanding new ALS genes (TDP-43 and C9ORF72)
- miRNAs as disease biomarkers
- Basic studies of different tau isoforms
- Studies of SOD1 synthesis and degradation in animal models and in humans
Contact Miller Lab
Timothy Miller, MD, PhD
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