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.
Highlights
Human prion disease is an incurable, uniformly fatal neurodegenerative disease that typically presents as a rapidly progressive dementia
Substantial Prnp mRNA reduction was observed in the ipsilateral entorhinal cortex, hippocampus, and thoracic spinal cord in prion protein (PrP) Antisense oligonucleotides (ASOs)-treated mice compared with saline-treated mice (Figure 1A)
We demonstrate the efficacy of PrP-lowering ASOs against prion disease in mice, addressing 3 questions that hindered the development of ASOs for prion disease
Summary
Human prion disease is an incurable, uniformly fatal neurodegenerative disease that typically presents as a rapidly progressive dementia. Regardless of etiology — sporadic, genetic, or acquired — and regardless of clinical name — Creutzfeldt-Jakob disease, fatal familial insomnia, or Gerstmann-Sträussler-Scheinker disease — all prion disease shares a single molecular mechanism. Lowering PrP levels should be an effective treatment for prion disease because PrP KO and postnatal suppression are known to confer protection from prion disease [2,3,4], and Prnp gene dosage is correlated with the pace of disease across a wide range of models and expression levels [5,6,7]. PrP lowering should be well tolerated, as PrP-KO mice, goats, and cattle are viable, fertile, have normal lifespans, and exhibit normal behavior [8,9,10], and humans with heterozygous loss-of-function variants in PRNP are healthy [11, 12]. The 1 phenotype that appears reliably attributable to PrP KO, a mild sensorimotor defect caused by lack of stimulation of myelin maintenance in peripheral nerves by a PrP-derived signaling peptide, is not seen in heterozygous animals, nor in the CNS [13, 14]
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