Antisense oligonucleotides extend survival of prion-infected mice
Gregory J. Raymond, … , Byron Caughey, Sonia M. Vallabh
Gregory J. Raymond, … , Byron Caughey, Sonia M. Vallabh
Published July 30, 2019
Citation Information: JCI Insight. 2019;4(16):e131175. https://doi.org/10.1172/jci.insight.131175.
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Research Article Neuroscience Therapeutics

Antisense oligonucleotides extend survival of prion-infected mice

Abstract

Prion disease is a fatal, incurable neurodegenerative disease of humans and other mammals caused by conversion of cellular prion protein (PrPC) into a self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs of concept support lowering PrP expression as a therapeutic strategy. Antisense oligonucleotides (ASOs) can provide a practical route to lowering 1 target mRNA in the brain, but their development for prion disease has been hindered by 3 unresolved issues from prior work: uncertainty about mechanism of action, unclear potential for efficacy against established prion infection, and poor tolerability of drug delivery by osmotic pumps. Here, we test ASOs delivered by bolus intracerebroventricular injection to intracerebrally prion-infected WT mice. Prophylactic treatments given every 2–3 months extended survival times 61%–98%, and a single injection at 120 days after infection, near the onset of clinical signs, extended survival 55% (87 days). In contrast, a nontargeting control ASO was ineffective. Thus, PrP lowering is the mechanism of action of ASOs effective against prion disease in vivo, and infrequent — or even single — bolus injections of ASOs can slow prion neuropathogenesis and markedly extend survival, even when initiated near clinical signs. These findings should empower development of PrP-lowering therapy for prion disease.

Authors

Gregory J. Raymond, Hien Tran Zhao, Brent Race, Lynne D. Raymond, Katie Williams, Eric E. Swayze, Samantha Graffam, Jason Le, Tyler Caron, Jacquelyn Stathopoulos, Rhonda O’Keefe, Lori L. Lubke, Andrew G. Reidenbach, Allison Kraus, Stuart L. Schreiber, Curt Mazur, Deborah E. Cabin, Jeffrey B. Carroll, Eric Vallabh Minikel, Holly Kordasiewicz, Byron Caughey, Sonia M. Vallabh

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Figure 1

Potency and persistence of anti-PrP ASOs in the mouse brain.

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Potency and persistence of anti-PrP ASOs in the mouse brain. (A) ASOs we...
(A) ASOs were administered i.c.v. at 500 or 700 μg to groups of n = 3 mice, and ipsilateral hemispheres were collected 8 weeks later and microdissected for regional PrP RNA quantification by RT-PCR (Supplemental Table 1). Data were normalized to the mean value for saline-treated animals. Error bars indicate 95%CI of the mean. (B) Western blots from whole contralateral hemispheres of SWR/R mice 8 weeks after treatment with 700 μg ASO. (C) RT-PCR quantification of PrP RNA in the ipsilateral cortex of n = 4 mice at 4, 12, and 16 weeks after a single 500 μg ASO dose. Data were normalized to the mean value for saline-treated animals. Error bars indicate 95%CI of the mean. (D) IHC images of sagittal midline cortical sections stained using antibodies to PrP (D13) or the ASO backbone at the indicated number of days after a single 300 μg i.c.v. injection of ASO. Representative images of a total of 3 mice per treatment group per time point, except saline 62–63 days, for which 5 mice were analyzed. Scale bar: 50 μm.