Huntington's disease (HD) is the most prevalent autosomal dominant, trinucleotide repeat neurodegenerative disease. The huntingtin gene encodes a protein of 350 kD;the disease causing mutation is an expansion of an amino-terminal polyglutamine repeat of more than 36 successive glutamines. Our broad research goal is to understand the molecular basis of HD pathogenesis to target therapy. Because HD is an inherited disease, we expected that the mutant allele will differ from wild-type by at least a single nucleotide polymorphism, thereby offering a target for gene silencing by RNAi. Thus demonstrated, our core idea is that RNA silencing is useful to selectively reduce mutant huntingtin expression and slow or block neuronal dysfunction and death in HD. We hypothesize that selective knockdown of mutant huntingtin restores normal neuronal function, but excessive silencing impairs neuronal function by interfering with essential signaling events.
Aim 1 examines in vivo in mice whether allele specific silencing can delay or prevent HD neuropathy and abnormal behaviors.
Aim 2 investigates in post-mortem HD brain post- transcriptional regulation of huntingtin mRNA, to find molecular processes that favor synthesis of mutant huntingtin mRNA. We will use a new strategy to quantify each huntingtin allelic mRNA, based on SNP heterozygosities of the alleles. Knowledge from aims 1 and 2 is essential in applying mRNA silencing to HD patients.
Aim 3 studies cellular mechanisms by which RNAi restores essential neuronal signaling activity in HD cells and the threshold for wild type huntingtin to main normal neuronal integrity.
Aim 3 combines allelic RNAi and neuronal signaling of the cysteine transporter that regulates glutathione clearance of reactive oxygen species.
Aim 4 examines the safety of administration of allele specific siRNA, by evaluating innate immunity and inflammatory responses. This proposal satisfies NINDS goals in translational science: translation of gene silencing therapeutics, early-state therapy development, and identifying mechanisms that underlie nervous system function. Innovations include targeting mRNA alleles for RNAi, use of HD mouse models that express only human huntingtin genes, quantitative measurement of huntingtin allelic mRNA based on SNP heterozygosities, deep sequencing analysis to identify 3 UTR huntingtin mRNA regulation, and zinc finger nuclease strategy to eliminate huntingtin alleles at the genomic level. This proposal applies fundamental biology to understand pathogenesis of HD and translate this knowledge into better therapies.

Public Health Relevance

Patients with Huntington's disease (HD) develop cognitive deficits, depression and movement abnormalities. Brain cells die early. We will examine how gene silencing can reduce production of the mutant huntingtin protein that causes HD, thereby preventing dysfunction and death in neurons in animal models of HD and in HD neurons in culture. We will study safety, in brain, of the molecules that initiate gene silencing. This proposal addresses treatment of HD through study of basic mechanisms of silencing the gene that causes the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Träger, Ulrike; Andre, Ralph; Lahiri, Nayana et al. (2014) HTT-lowering reverses Huntington's disease immune dysfunction caused by NF?B pathway dysregulation. Brain 137:819-33
Zhu, Lihua J; Holmes, Benjamin R; Aronin, Neil et al. (2014) CRISPRseek: a bioconductor package to identify target-specific guide RNAs for CRISPR-Cas9 genome-editing systems. PLoS One 9:e108424
Evans, Melanie S; Chaurette, Joanna P; Adams Jr, Spencer T et al. (2014) A synthetic luciferin improves bioluminescence imaging in live mice. Nat Methods 11:393-5
van der Bom, Imramsjah M J; Moser, Richard P; Gao, Guanping et al. (2013) Frameless multimodal image guidance of localized convection-enhanced delivery of therapeutics in the brain. J Neurointerv Surg 5:69-72
Sapp, Ellen; Valencia, Antonio; Li, Xueyi et al. (2012) Native mutant huntingtin in human brain: evidence for prevalence of full-length monomer. J Biol Chem 287:13487-99
Li, Xueyi; Valencia, Antonio; Sapp, Ellen et al. (2010) Aberrant Rab11-dependent trafficking of the neuronal glutamate transporter EAAC1 causes oxidative stress and cell death in Huntington's disease. J Neurosci 30:4552-61
Valencia, Antonio; Reeves, Patrick B; Sapp, Ellen et al. (2010) Mutant huntingtin and glycogen synthase kinase 3-beta accumulate in neuronal lipid rafts of a presymptomatic knock-in mouse model of Huntington's disease. J Neurosci Res 88:179-90
Li, Xueyi; Standley, Clive; Sapp, Ellen et al. (2009) Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity. Mol Cell Biol 29:6106-16
Li, Xueyi; Sapp, Ellen; Chase, Kathryn et al. (2009) Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease. Neurobiol Dis 36:374-83
Pfister, Edith L; Kennington, Lori; Straubhaar, Juerg et al. (2009) Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. Curr Biol 19:774-8

Showing the most recent 10 out of 28 publications