Affiliations: [a] Department of Medicine, RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA | [b] Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA | [c] Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA | [d] Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
Correspondence to: Neil Aronin, MD, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655, USA. Tel.: +1 508 856 3239; Fax: +1 508 856 6950; [email protected]
Note:  Contributed equally.
Background: The immune system In Huntington’s disease (HD) is activated and may overreact to some therapies. RNA interference using siRNA lowers mutant huntingtin (mHTT) protein but could increase immune responses.
Objective: To examine the innate immune response following siRNA infusion into the striatum of wild-type (WT) and HD transgenic (YAC128) mice.
Methods: siRNAs (2′-O-methyl phosphorothioated) were infused unilaterally into striatum of four month-old WT and YAC128 mice for 28 days. Microglia number and morphology (resting (normal), activated, dystrophic), cytokine levels, and DARPP32-positive neurons were measured in striatum immediately or 14 days post-infusion. Controls included contralateral untreated striatum, and PBS and sham treated striata.
Results: The striata of untreated YAC128 mice had significantly fewer resting microglia and more dystrophic microglia than WT mice, but no difference from WT in the proportion of activated microglia or total number of microglia. siRNA infusion increased the total number of microglia in YAC128 mice compared to PBS treated and untreated striata and increased the proportion of activated microglia in WT and YAC128 mice compared to untreated striata and sham treated groups. Cytokine levels were low and siRNA infusion resulted in only modest changes in those levels. siRNA infusion did not change the number of DARPP32-positive neurons.
Conclusion: Findings suggest that siRNA infusion may be a safe method for lowering mHTT levels in the striatum in young animals, since treatment does not produce a robust cytokine response or cause neurotoxicity. The potential long-term effects of a sustained increase in total and activated microglia after siRNA infusion in HD mice need to be explored.