Huntington's disease clinical research

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Main article: Huntington's disease
Predicted crystal structure of the N-terminus of huntingtin
Predicted structure of part of the huntingtin protein. Mutant huntingtin is responsible for damaging neurons in Huntington's disease.

Huntington's disease is a genetic neurological disorder characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities for which there is no present cure or effective treatments.

Research into the mechanism of Huntington's disease (HD) has focused on identifying the functioning of the huntingtin protein (Htt), how mutant huntingtin (mHtt) differs or interferes with it, and the brain pathology that the disease produces. Research is conducted using in vitro methods, animal models and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.[1] The identification of the causative gene has enabled the development of many transgenic animal models including nematode worms, Drosophila fruit flies, mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive neurodegeneration and HD-like symptoms.[1]

Three broad approaches are under study to attempt to slow the progression of Huntington's disease: reducing production of the mutant protein, improving cells' ability to survive its diverse harmful effects, and replacing lost neurons.[2]

Reducing huntingtin production[edit]

Simplified diagram of RNA interference
RNA interference is one form of gene silencing that is under investigation as a possible treatment for HD.

Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHtt is reduced, symptoms improve.[2] Safety of non-allele specific RNAi and ASO gene silencing has now been demonstrated in mice and the large, human-like brains of primates.[3][4] but clinical delivery of RNAi therapy remains problematic. Allele-specific silencing attempts to silence mutant Htt while leaving wild-type Htt untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.[5]

Improving cell survival[edit]

Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring dysfunction of synapses.[2]

Neuronal replacement[edit]

Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials.[6] Whatever their future therapeutic potential, stem cells are already a valuable tool for studying HD in the laboratory.[7]

Clinical trials[edit]

Numerous drugs have been reported to produce benefits in animals, such as creatine, and coenzyme Q10. Some of these have then been tested by humans in clinical trials, with more underway, but as yet none has proven effective.[8] Large observational studies involving human volunteers have revealed insights into the pathobiology of HD and supplied outcome measures for future clinical trials.[9]


folding@home client running on a user's computer

There have been different candidate therapies investigated for Huntington's disease which have not borne out. These are noted below for historic context.

Intrabody therapy (history)[edit]

Genetically-engineered intracellular antibody fragments called intrabodies have shown therapeutic results in fruit fly models, by inhibiting mHtt aggregation using an intrabody which binds to the end of mHtt within a cell.[10][11] Though they have some laboratory applications, intrabodies have largely been superseded by gene silencing techniques for lowering Htt levels, which are easier to deliver and more direct.[2]

Pharmacological (history)[edit]

Several randomized placebo-controlled clinical trials of possible treatments have been tested in humans, and more are underway.

Compounds that have failed to prevent or slow HD in human trials include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon.[12]

Bioinformatic approaches (history)[edit]

One (non-clinical) avenue of research was understanding the physical mechanics of protein folding using distributed computing. HD has been one of several targets of the folding@home project.[13] In 2009 this led to publication of a predicted structure for the Huntingtin protein headpiece.[14]


  1. ^ a b Ross, CA; Tabrizi, SJ (Jan 2011). "Huntington's disease: from molecular pathogenesis to clinical treatment". Lancet neurology 10 (1): 83–98. doi:10.1016/S1474-4422(10)70245-3. PMID 21163446. 
  2. ^ a b c d Munoz-Sanjuan, Ignacio; Bates, Gillian P. (2011). "The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease". Journal of Clinical Investigation 121 (2): 476–483. doi:10.1172/JCI45364. PMC 3026740. PMID 21285520. 
  3. ^ McBride, Jodi L; Pitzer, Mark R; Boudreau, Ryan L; Dufour, Brett; Hobbs, Theodore; Ojeda, Sergio R; Davidson, Beverly L (25 October 2011). "Preclinical Safety of RNAi-Mediated HTT Suppression in the Rhesus Macaque as a Potential Therapy for Huntington's Disease". Molecular Therapy 19 (12): 2152–2162. doi:10.1038/mt.2011.219. PMC 3242667. PMID 22031240. 
  4. ^ Kordasiewicz, Holly B.; Lisa M. Stanek, Edward V. Wancewicz, Curt Mazur, Melissa M. McAlonis, Kimberly A. Pytel, Jonathan W. Artates, Andreas Weiss, Seng H. Cheng, Lamya S. Shihabuddin, Gene Hung, C. Frank Bennett, Don W. Cleveland (21 June 2012). "Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis". Neuron 74 (6): 1031–1044. doi:10.1016/j.neuron.2012.05.009. 
  5. ^ Barnes, DW; Whitley, RJ (Feb 1987). "Antiviral therapy and pulmonary disease.". Chest 91 (2): 246–51. doi:10.1172/JCI45130. PMC 3026739. PMID 21285523. 
  6. ^ Clelland CD, Barker RA, Watts C (2008). "Cell therapy in Huntington disease". Neurosurg Focus 24 (3–4): E9. doi:10.3171/FOC/2008/24/3-4/E8. PMID 18341412. 
  7. ^ Cundiff, Paige E; Anderson, Stewart A (31 May 2011). "Impact of induced pluripotent stem cells on the study of central nervous system disease". Current Opinion in Genetics & Development 21 (3): 354–361. doi:10.1016/j.gde.2011.01.008. PMID 21277194. 
  8. ^ Walker FO (2007). "Huntington's disease". Lancet 369 (9557): 218–28 [225]. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289. 
  9. ^ Tabrizi, Sarah J; Reilmann, Ralf, Roos, Raymund AC, Durr, Alexandra, Leavitt, Blair, Owen, Gail, Jones, Rebecca, Johnson, Hans, Craufurd, David, Hicks, Stephen L, Kennard, Christopher, Landwehrmeyer, Bernhard, Stout, Julie C, Borowsky, Beth, Scahill, Rachael I, Frost, Chris, Langbehn, Douglas R (1 December 2011). "Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data". The Lancet Neurology 11 (1): 42–53. doi:10.1016/S1474-4422(11)70263-0. PMID 22137354. 
  10. ^ Lecerf JM, Shirley TL, Zhu Q, et al. (2001). "Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4764–9. doi:10.1073/pnas.071058398. PMC 31908. PMID 11296304. 
  11. ^ Miller TW, Zhou C, Gines S, et al. (2005). "A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease". Neurobiol. Dis. 19 (1-2): 47–56. doi:10.1016/j.nbd.2004.11.003. PMID 15837560. 
  12. ^ "Completed Clinical Trials". Huntington Study Group. Retrieved 4 February 2012. 
  13. ^ Vijay Pande (2011). "Folding@home Diseases Studied FAQ". Stanford University. Retrieved 2012-01-27. 
  14. ^ Kelley NW, Huang X, Tam S, Spiess C, Frydman J, Pande VS (May 2009). "The predicted structure of the headpiece of the Huntingtin protein and its implications on Huntingtin aggregation". J. Mol. Biol. 388 (5): 919–27. doi:10.1016/j.jmb.2009.01.032. PMC 2677131. PMID 19361448. 

External links[edit]

Scientific resources for lay readers[edit]

Major research organizations[edit]