Huntington's disease is an autosomal dominant neurodegenerative disease caused by a toxic gain of function mutation in the huntingtin gene (Htt). Silencing of Htt with RNA interference using direct ...CNS delivery in rodent models of Huntington's disease has been shown to reduce pathology and promote neuronal recovery. A key translational step for this approach is extension to the larger non-human primate brain, achieving sufficient distribution of small interfering RNA targeting Htt (siHtt) and levels of Htt suppression that may have therapeutic benefit. We evaluated the potential for convection enhanced delivery (CED) of siHtt to provide widespread and robust suppression of Htt in nonhuman primates. siHtt was infused continuously for 7 or 28days into the nonhuman primate putamen to analyze effects of infusion rate and drug concentration on the volume of effective suppression. Distribution of radiolabeled siHtt and Htt suppression were quantified by autoradiography and PCR, respectively, in tissue punches. Histopathology was evaluated and Htt suppression was also visualized in animals treated for 28days. Seven days of CED led to widespread distribution of siHtt and significant Htt silencing throughout the nonhuman primate striatum in an infusion rate and dose dependent manner. Htt suppression at therapeutic dose levels was well tolerated by the brain. A model developed from these results predicts that continuous CED of siHtt can achieve significant coverage of the striatum of Huntington's disease patients. These findings suggest that this approach may provide an important therapeutic strategy for treating Huntington's disease.
► Chronic convection enhanced delivery of siRNA targeting Huntingtin in primate brain. ► Widespread drug distribution results in Huntingtin lowering throughout striatum. ► Empirical model of data enables scaling of siRNA delivery. ► Potential as key disease-modifying therapeutic approach for Huntington's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A 64-run, 2-level partial factorial experimental analysis was conducted on a 2D axisymmetric finite-element model of the convection-enhanced drug delivery to the parenchyma of the brain. The purpose ...of this ANOVA analysis was to determine the relative importance of eight factors and their interaction in the volume of distribution for the drug. The analysis revealed that the infusion flowrate and concentration, the overall half-life of the drug and the in vivo effective concentration played an overwhelmingly dominant role in the drug distribution. The results of this analysis will guide the design of an appropriate drug delivery device by focusing research resources on the determined factors of most importance
