Abstract:
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 28 days 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 28 days. 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.
Summary:
The new pre-clinical studies employed direct delivery of the huntingtin-specific siRNA to the striatum using an implantable infusion system and convection-enhanced delivery (CED) . Direct delivery to the central nervous system (CNS) by intrastriatal CED for seven days resulted in broad distribution of the siRNA across the striatum and surrounding brain regions. This level of distribution of the siRNA resulted in the silencing of the huntingtin gene throughout the putamen by an average of approximately 45 percent, as well as reductions in the levels of huntingtin protein when evaluated by immunohistochemistry. This silencing of huntingtin occurred in a manner dependent on infusion rate and siRNA concentration.
A new pre-clinical model developed from these findings suggests that continuous CED of an siRNA targeting huntingtin has the potential to achieve physiologically significant coverage of the striatum of Huntington’s disease patients with therapeutically relevant drug levels.
The authors of the paper include researchers from Alnylam, Medtronic, and the University of Kentucky where the work was conducted.
