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HD INSIGHTS The Use of Antisense Oligonucleotides, cont... The optimal timing and treatment regimen for HD patients is also not known. Studies suggest that relatively early treatments are more beneficial; however, tracking the benefits of a treatment administered before the appearance of symptoms remains difficult. Groups worldwide are working to establish more quantifiable indicators of early symptoms of HD. Further, even though ASO treatment in animal models reduced symptoms for longer than expected, human patients must deal with the disease for decades, and it is not known how often a "booster" might be needed for continued benefit. 1 Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis. Neuron2012 Jun 21;74(6): 1031-44. 2 Nasir J, Floresco SB, O'Kusky JR, et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995 Jun;81(5):811-23. 3 Zeitlin S, Liu JP, Chapman DL, et al. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Gen. 1995 Oct; 11(2):155-63. 4 Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nature Gen. 2000 Nov;26(3):300-6. 5 Boudreau RL, McBride JL, Martins I, et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Molecula therapy. 2009 Jun;17(6):1053-63. A number of clinical trials utilizing ASOs have been completed, and more are currently underway. Previous trials have used ASOs for the treatment of various cancers, asthma, arthritis, Duchenne muscular dystrophy, Crohn's disease, heart disease and familial amyotrophic lateral sclerosis (ALS). The ALS clinical trial is of particular interest because it uses spinal infusion for the delivery of ASOs. Phase I of this clinical trial was completed in early 2012, and its results may provide information on the safety of ASO spinal infusion. Many different gene silencing techniques are being used to lower 6 Grondin R, Kaytor MD, Ai Y,et al. Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain. 2012 April;135(4):1197-209. 7 McBride JL, Pitzer MR, Boudreau RL, et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. Molecular therapy. 2011 Dec;19(12):2152-62. 8 Gagnon KT, Pendergraff HM, Deleavey GF, et al. Allele- selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry. 2010 Nov 30;49(47):10166-78. 9 Carroll JB, Warby SC, Southwell AL, et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. Mol Ther 2011 Dec;19(12): 2178-85. mHtt expression in animal models of HD. RNA-based strategies, including short-hairpin RNAs (shRNA)11; small interfering RNAs (siRNA)2; and microRNAs (miRNA)3, also show promise in alleviating mHtt-mediated phenotypes. Some of these strategies are moving toward human clinical trials. Despite the challenges of gene silencing, ASO therapy and other mHtt knockdown approaches for HD remain exciting avenues of treatment. Each new development brings us closer to the discovery of disease- modifying therapy for HD. discovery of disease-modifying therapy for HD. 10Stiles DK, Zhang Z, Ge P, Nelson B, et al. Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exper Neurol 2012; 233(1):463-71. 11 Harper SQ, Staber PD, He X, et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc Nat Acad Sc USA. 2005 Apr;102(16): 5820-5. 12 DiFiglia M, Sena-Esteves M, Chase K, et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Nat Acad Sc USA. 2007 Oct;104(43):17204-9. 13 McBride JL, Boudreau RL, Harper SQ, et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Nat Acad Sc USA. 2008 Apr;105(15):5868-73. Upcoming HD Events DATE October 7-10, 2012 October 13-17, 2012 November 8-10, 2012 EVENT American Neurological Association Meeting Society for Neuroscience Annual Meeting Huntington Study Group Annual Meeting and Huntington Disease Clinical Research Symposium February 17-19, 2013 Clinical Neurology and Neurophysiology Update Symposium April 8-11, 2013 CHDI HD Therapeutics Conference ABSTRACT DEADLINE Closed Closed Closed LOCATION Boston, MA New Orleans, LA Seattle, WA November 20, 2012 Jerusalem, Israel Not yet posted To have your conference added for future publications, please e-mail HD Insights at editor@hdinsights.org. Copyright © Huntington Study Group 2012. All rights reserved. HD Insights, Vol. 3 Venice, Italy 7