Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown function, huntingtin (htt). There is no known treatment for HD. Although the exact cause of neuronal death in HD remains unknown, it has been postulated that the abnormal aggregation of the mutant huntingtin protein may cause toxic effects in neurons, leading to pathogenic mechanisms of oxidative stress, mitochondrial dysfunction, apoptosis, energy metabolism defects, and subsequent excitotoxicity. We have identified a number of drug compounds that separately target these mechanisms and have shown that they significantly ameliorate the phenotype of HD transgenic mice. These compounds or their analogs are available for human use and represent the immediate pipeline of candidate neuroprotective agents for clinical trials in HD. We have shown that these drugs have great potential for combined use to maximize neuroprotection. Much as treatment for cancer and AIDS has evolved, the most effective neuroprotection for HD will likely come from a cocktail of medications. Such combination therapies in HD mouse models would provide critical pre-clinical data to pilot combined therapies in humans. We propose a logical series of combination therapeutic trials in both HD transgenic mice and HD knock-in mice with proven drug compound regimens, using phenotype analysis, histopathology, toxicology, biochemistry, and pharmacokinetics as outcome measures. We will begin with two-drug trails using creatine and coenzyme Q10. These compounds are under trial in HD patients and will serve as a foundation to build further two-drug combinations. We will continue to add compounds to both creatine and coenzyme Q10 that we have already shown to be efficacious in transgenic HD mice. Because planning is underway for cysteamine to enter early phase clinical testing, a high priority will be to combine it with creatine and coenzyme Q10. Once the best combinations with creatine and coenzyme Q10 are determined, we will select additional compound pairs based on their potential for the greatest efficacy and least toxicity in humans (ie. inhibitors of htt aggregation, histone deacetylase inhibition, and transcription dysregulation). To model medication trials in presymptomatic individuals, as well as symptomatic individuals, we will perform studies in R6/2 mice initiating treatment upon weaning and repeated with treatment initiated once symptoms are present (6 weeks, analogous to early stages of human HD). We will confirm the most efficacious single and combination drug strategies identified in the transgenic HD mice within the full-length HD knock-in mice. By modeling combination therapeutic trials in both transgenic and knock-in HD mice we expect to emerge knowing which combinations have the most promise for prospective clinical drug-trials in HD patients and will initiate treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS045806-05
Application #
7342108
Study Section
Special Emphasis Panel (ZNS1-SRB-E (01))
Program Officer
Sutherland, Margaret L
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
5
Fiscal Year
2008
Total Cost
$594,653
Indirect Cost
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Tourette, Cendrine; Farina, Francesca; Vazquez-Manrique, Rafael P et al. (2014) The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 12:e1001895
Kim, Jinho; Bordiuk, Olivia L; Ferrante, Robert J (2011) Experimental models of HD and reflection on therapeutic strategies. Int Rev Neurobiol 98:419-81
Fox, Jonathan H; Connor, Teal; Stiles, Megan et al. (2011) Cysteine oxidation within N-terminal mutant huntingtin promotes oligomerization and delays clearance of soluble protein. J Biol Chem 286:18320-30
Faideau, Mathilde; Kim, Jinho; Cormier, Kerry et al. (2010) In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects. Hum Mol Genet 19:3053-67
Kim, Jinho; Moody, Jennifer P; Edgerly, Christina K et al. (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet 19:3919-35
Kim, Jinho; Amante, Daniel J; Moody, Jennifer P et al. (2010) Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease. Biochim Biophys Acta 1802:673-81
Ferrante, Robert J (2009) Mouse models of Huntington's disease and methodological considerations for therapeutic trials. Biochim Biophys Acta 1792:506-20
Yang, Lichuan; Calingasan, Noel Y; Wille, Elizabeth J et al. (2009) Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases. J Neurochem 109:1427-39
Lee, Junghee; Kannagi, Mari; Ferrante, Robert J et al. (2009) Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB J 23:1739-49
Lee, Junghee; Hagerty, Sean; Cormier, Kerry A et al. (2008) Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation. Hum Mol Genet 17:1774-82

Showing the most recent 10 out of 35 publications