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 2

Benefit of prophylactic ASO treatment in prion-infected mice.

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Benefit of prophylactic ASO treatment in prion-infected mice. (A) Delay ...
(A) Delay of onset of clinical signs characteristic of prion disease in animals treated at NIH. Arrows indicate timing of 300 μg i.c.v. doses. One ASO 1–treated mouse at NIH showed no clinical signs prior to euthanasia at 527 dpi (Figure 2C); its brain was negative for prion pathology by IHC and for prion seeding activity by RT-QuIC (75), suggesting that either the infection was cleared or the original inoculum had failed to deliver an infectious dose. (B) Disease duration (onset to end stage) in animals treated at NIH. Bars indicate mean and 95%CI of the mean. (C) All-cause mortality in animals treated at NIH. (D) Body weights of animals treated at the Broad Institute. Lines indicate means, and shaded areas indicate 95%CI of the means. Only time points with ≥ 2 animals are included. (E) All-cause mortality in animals treated at the Broad Institute. One control ASO-treated mouse at Broad Institute showed no symptoms prior to euthanasia at 315 dpi; its brain was positive by RT-QuIC, with endpoint at a 1 × 10–7 dilution, suggesting it had eventually reached a prion titer similar to or slightly below that in terminal mice, but its survival > 15 SDs longer than the mean endpoint for its cohort suggests that the original inoculation had delivered an incomplete dose of prion infectivity. Arrows indicate timing of 500 μg i.c.v. doses. Treatment groups were n = 9 animals at NIH and n = 12 animals at Broad Institute, with some animals censored; see Supplemental Table 2 for details.