Research Abstract:
We are focused on 1.) gene downregulation strategies (RNAi and antisense oligonucleotides) to understand disease pathogenesis and provide novel therapies for neurodegenerative diseases, in particular amyotrophic lateral sclerosis (ALS) 2.) how dysfunction of mitochondria causes loss of motor neurons.
ALS, also known as Lou Gehrig’s diseases, is an adult onset, neurodegenerative disease that leads to dysfunction and loss of neurons in the motor pathways of the brain and spinal cord. This results in stiffness, severe weakness, muscle atrophy, inability to speak/swallow, and eventually death from respiratory failure 3-5 years after diagnosis. One known genetic cause for a proportion of ALS patients is mutation within the SOD1 (superoxide dismutase 1) gene. However, how mutant SOD1 kills motor neurons remains unclear.
The ability to target and “turn off” genes using oligonucleotides 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 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 likely to go into humans in Spring of 2008. We are now developing antisense oligonucleotide and RNAi strategies to dissect out which other genes (and micro RNAs) are critical for survival of motor neurons. We anticipate these will also be translated into human therapies.
Mitochondrial dysfunction has been implicated in many neurodegenerative diseases, including ALS. Mitochondria demonstrate morphological changes in ALS patients and early in the course of the disease in SOD1 ALS mice, suggesting that mitochondrial pathology may be one of the initiating events in neuronal dysfunction. In addition, mutant SOD1 associates with the mitochondrial fraction from spinal cord (affected tissue), but not from liver (unaffected tissue) in SOD1 mice and rats. In order to understand how mutant SOD1 associates with mitochondria and what are the functional consequences of this association, we are using a variety of techniques including biochemical and functional analysis of isolated mitochondria, solution mass spectrometry, and mouse models of disease.
Selected Publications:
Miller TM, Kim SH, Yamanaka K, Hester M, Umapathi P, Arnson H, Rizo L, Mendell JR, Gage FH, Cleveland DW, Kaspar BK. Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2006 103:19546-19551.
Miller TM, Smith RA, Cleveland DW. Amyotrophic lateral sclerosis and gene therapy. Nat Clin Pract Neurol 2006 2:462-463.
Smith RA*, Miller TM*, Yamanaka K, Monia BP, Condon TP, Hung G, Lobsiger CS, Ward CM, McAlonis-Downes M, Wei H, Wancewicz EV, Bennett CF, Cleveland DW. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest 2006 116:2290-2296. (* Co-first authors)
Miller TM, Kaspar BK, Kops GJ, Yamanaka K, Christian LJ, Gage FH, Cleveland DW. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann Neurol 2005 57:773-776.
Miller TM, Cleveland DW. Has gene therapy for ALS arrived? Nat Med 2003 9:1256-1257.
Last Updated: 11/12/2007 |